Clinical trial NCT02301156
Conditions: Chronic Lymphocytic Leukemia
Sponsor: TG Therapeutics, Inc.
Start date: 2015-01-27; Completion date: 2020-04-01
Enrollment: 126 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the effect of the addition of ublituximab, a novel monoclonal antibody, to ibrutinib compared to ibrutinib alone on antitumor activity, as measured by the overall response rate (ORR = CR \[complete response\] + PR \[partial response\]) in previously treated Chronic Lymphocytic Leukemia (CLL) participants with high-risk cytogenetic features. Half of the participants will receive ublituximab in combination with ibrutinib, while the other half will receive ibrutinib alone.

Detailed description:

Arms: arm 1: Participants will receive ublituximab intravenous (IV) infusion, up to 150 milligrams (mg) once on Day 1, 750 mg on Day 2, 900 mg on Days 8 and 15 of Cycle 1 (Cycle duration=28 days) followed by 900 mg on Day 1 of Cycles 2 to 6 and 900 mg on Day 1 of every 3rd cycle thereafter for up to 62 months along with ibrutinib 420 mg capsules, orally, once daily (QD) in each 28-day cycle for up to 62 months. arm 2: Participants will receive ibrutinib 420 mg capsules, orally, QD in each 28-day cycle up to 62 months.
Interventions: intervention 1: Ublituximab intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Administered as an IV infusion intervention 2: Administered orally

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Phase 3 Randomized Study to Assess the Efficacy and Safety 
of Ublituximab in Combination with Ibrutinib Compared to Ibrutinib Alone, 
in Patients with Previously Treated High-Risk Chronic Lymphocytic 
Leukemia (CLL)
NCT Number: 
NCT02301156 
Document Date: 
Protocol Version 2.5: 31 July 2017 


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Protocol version/Date:  
 
Version 2.5 / July 31, 2017 
Local Protocol #: 
 
 
Protocol UTX-IB-301 
TITLE: 
A Phase 3, Randomized, Study to Assess the Efficacy and Safety of Ublituximab in Combination 
with Ibrutinib Compared to Ibrutinib Alone, in Patients with Previously Treated High-Risk 
Chronic Lymphocytic Leukemia (CLL). 
 
Sponsor: 
 
 
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort Street, 9th Floor 
 
 
 
 
New York, NY 10014 
 
 
 
 
Tel: (212) 554-4484 
 
IND Number:  
 
Ublituximab: 114,779 
 
Study Chair:   
 
Study Chair 
 
 
 
 
, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tel: 
 (Office) 
 
 
 
 
 
 
 
 
 
 
Medical Monitor: 
 
, MD 
 
 
 
 
Tel: (212) 554-4484 
 
 
Study Coordination:  
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort Street, 9th Floor 
 
 
 
 
New York, NY 10014 
 
 
 
 
Tel: (212) 554-4484 
 
Version: 1.0 
 
 
 
 
 
 
Date:  9 September 2014 
 
 
Version: 1.1 
 
 
 
 
 
 
Date:  30 September 2014 
Version: 2.0 
 
 
 
 
 
 
Date:  8 October 2016 
Version: 2.1 
 
 
 
 
 
 
Date:  21 October 2016 
Version: 2.2 
 
 
 
 
 
 
Date:  27 January 2017 
 
    
Version: 2.5 
 
 
 
 
 
 
Date:  31 July 2017 
 
 
 
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: 
A Phase 3 Randomized Study to Assess the Efficacy and 
Safety of Ublituximab in Combination with Ibrutinib 
Compared to Ibrutinib Alone, in Patients with Previously 
Treated High-Risk Chronic Lymphocytic Leukemia (CLL). 
Protocol Number: 
UTX-IB-301 
Study Drug: 
Ublituximab (TG-1101) + Ibrutinib Versus Ibrutinib 
IND Number: 
Ublituximab 
 
114,779 
 
Date FINAL: 
31 July 2017 
 
I have read the attached protocol and agree that it contains all the necessary details for performing 
UTX-IB-301. 
I will provide copies of the protocol and of the ublituximab Investigators’ Brochure, which was 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 ublituximab and Ibrutinib, and the conduct of the study. 
Once the protocol has been approved by the 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) including all amendments up to and 
including the Washington Clarification (2002). 
 
 
 
 
 
 
Print Name 
 
Signature 
 
Date 
 
 


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TABLE OF CONTENTS 
1 STUDY SYNOPSIS .............................................................................................................................. 10 
2 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................... 18 
3 INTRODUCTION ................................................................................................................................ 20 
3.1 CLL ................................................................................................................................................................................... 20 
3.2 Ublituximab ................................................................................................................................................................. 20 
3.2.1 Pre-Clinical Evaluations of Ublituximab .................................................................................................................................................. 21 
3.2.2 Clinical Development of Ublituximab - CLL ............................................................................................................................................ 21 
3.3 Ibrutinib ........................................................................................................................................................................ 23 
3.4 Ublituximab in Combination with Ibrutinib ................................................................................................... 24 
4 OBJECTIVES AND ENDPOINTS ..................................................................................................... 25 
4.1 Efficacy Endpoints .................................................................................................................................................... 25 
5 ELIGIBILITY CRITERIA ................................................................................................................... 27 
5.1 Inclusion Criteria ....................................................................................................................................................... 27 
5.2 Exclusion Criteria ...................................................................................................................................................... 28 
6 STUDY DESIGN .................................................................................................................................. 30 
6.1 Overview of Study Design ...................................................................................................................................... 30 
6.2 Registration and Randomization ........................................................................................................................ 30 
6.3 Study Sites .................................................................................................................................................................... 31 
6.4 Discontinuation from Study Treatment ........................................................................................................... 31 
7 STUDY ASSESSMENTS AND TREATMENT SCHEDULE .......................................................... 33 
7.1 Laboratory Assessments ........................................................................................................................................ 34 
7.1.1 Local Laboratory Assessments ..................................................................................................................................................................... 34 
7.1.2 Central Laboratory Assessments ................................................................................................................................................................. 34 
 35 
 36 
8 TREATMENT PLAN .......................................................................................................................... 37 
8.1 Treatment Summary ................................................................................................................................................ 37 
8.2 Agent Administration .............................................................................................................................................. 37 
8.2.1 Guidelines for Administration of Ublituximab ...................................................................................................................................... 37 
8.2.2 Guidelines for Administration of Ibrutinib ............................................................................................................................................. 40 
8.3 Criteria for Ongoing Treatment ........................................................................................................................... 41 
8.4 Dose Delays/Dose Modifications ........................................................................................................................ 41 
8.4.1 Dose Delay: Ublituximab ................................................................................................................................................................................. 41 
8.4.2 Dose Delays/Modifications: Ibrutinib ....................................................................................................................................................... 42 


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8.5 Ordering Ublituximab and Ibrutinib ................................................................................................................. 42 
8.6 Duration of Therapy ................................................................................................................................................. 43 
9 STUDY MEDICATIONS ..................................................................................................................... 44 
9.1 Ublituximab ................................................................................................................................................................. 44 
9.1.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ....................................................................................... 45 
9.2 Ibrutinib ........................................................................................................................................................................ 46 
9.2.1 Adverse Reactions - Ibrutinib ....................................................................................................................................................................... 46 
9.2.2 Adverse Reactions – Ublituximab in Combination with Ibrutinib .............................................................................................. 48 
10 MEASUREMENT OF EFFECT ....................................................................................................... 49 
10.1 Method of Assessment .......................................................................................................................................... 49 
10.2 Response Review .................................................................................................................................................... 49 
10.3 Identification and Measurement of Tumor Lesions and Organomegaly ......................................... 50 
10.3.1 Target Lesions .................................................................................................................................................................................................... 50 
10.3.2 Spleen and Liver................................................................................................................................................................................................ 50 
10.3.3 Non-Target Lesions ......................................................................................................................................................................................... 51 
10.4 Definitions of Tumor Response and Progression ...................................................................................... 51 
10.5 Complete Response ................................................................................................................................................ 52 
10.6 Partial Response ..................................................................................................................................................... 52 
10.7 Stable Disease........................................................................................................................................................... 53 
10.8 Definitive Disease Progression ......................................................................................................................... 53 
10.9 Non-Evaluable .......................................................................................................................................................... 54 
10.10 Lymphocytosis During Therapy .................................................................................................................... 54 
10.11 Minimum Residual Disease .............................................................................................................................. 54 
11 STATISTICAL CONSIDERATIONS .............................................................................................. 55 
11.1 Sample Size and Power ........................................................................................................................................ 55 
11.2 General Analysis Conventions ........................................................................................................................... 55 
11.3 Analysis Populations ............................................................................................................................................. 55 
11.4 Patient Disposition ................................................................................................................................................. 55 
11.5 Patient Demographics and Baseline Characteristics ............................................................................... 55 
11.6 Medical History........................................................................................................................................................ 56 
11.7 Extent of Exposure ................................................................................................................................................. 56 
11.8 Efficacy Analyses ..................................................................................................................................................... 56 
11.9 Missing Value Handling Procedures ............................................................................................................... 56 
11.10 Statistical Analyses .............................................................................................................................................. 56 
11.10.1 Primary Efficacy Variables ........................................................................................................................................................................ 56 
11.10.2 Secondary Efficacy Variables ................................................................................................................................................................... 57 
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12 SAFETY REPORTING AND ANALYSIS ....................................................................................... 59 
12.1 Safety Analyses ........................................................................................................................................................ 59 
12.2 Adverse Event Characteristics .......................................................................................................................... 59 
12.3 Definitions of Adverse Events ........................................................................................................................... 59 
12.4 Adverse Events (AE’s) and Treatment Emergent Adverse Events (TEAE’s) ................................. 60 
12.5 Adverse Events/Serious Adverse Event Causality Assessment .......................................................... 60 
12.5.1 Recording of Adverse Events ...................................................................................................................................................................... 61 
12.5.2 Abnormal Laboratory Values and Vital Signs ..................................................................................................................................... 61 
12.5.3 Handling of Adverse Events ........................................................................................................................................................................ 61 
12.6 Serious Adverse Events ........................................................................................................................................ 62 
12.6.1 Definitions of Serious Adverse Events ................................................................................................................................................... 62 
12.6.2 Serious Adverse Event Reporting by Investigators ......................................................................................................................... 63 
12.7 Sponsor SAE Reporting Requirements .......................................................................................................... 63 
12.8 Recording of Adverse Events and Serious Adverse Events ................................................................... 64 
12.9 Diagnosis vs. Signs and Symptoms .................................................................................................................. 64 
12.9.1 Persistent or Recurrent Adverse Events ............................................................................................................................................... 64 
12.9.2 Abnormal Laboratory Values ..................................................................................................................................................................... 64 
12.9.3 Deaths .................................................................................................................................................................................................................... 65 
12.9.4 Hospitalization, Prolonged Hospitalization, or Surgery ................................................................................................................ 65 
12.9.5 Pre-Existing Medical Conditions ............................................................................................................................................................... 65 
12.9.6 Protocol-Defined Events of Special Interest ........................................................................................................................................ 65 
13 Data Safety Monitoring Board (DSMB) .................................................................................. 67 
14 CLINICAL DATA COLLECTION AND MONITORING .............................................................. 68 
14.1 Site Monitoring Plan .............................................................................................................................................. 68 
14.2 Amendments to the Protocol ............................................................................................................................. 68 
14.3 Curricula Vitae and Financial Disclosures .................................................................................................... 69 
14.4 Data Ownership and Publication ..................................................................................................................... 69 
15 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ....................................... 70 
15.1 IRB Approval ............................................................................................................................................................ 70 
15.2 Regulatory Approval ............................................................................................................................................. 70 
15.3 Insurance and Indemnity .................................................................................................................................... 70 
15.4 Informed Consent ................................................................................................................................................... 70 
15.5 Confidentiality.......................................................................................................................................................... 71 
15.6 Investigator and Staff Information .................................................................................................................. 72 
15.7 Financial Information ........................................................................................................................................... 72 
16 RECORD RETENTION AND DOCUMENTATION OF THE STUDY ...................................... 73 
16.1 Documentation Required to Initiate Study .................................................................................................. 73 


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16.2 Study Documentation and Storage .................................................................................................................. 73 
16.3 Amendments to the Protocol ............................................................................................................................. 75 
16.4 Data Collection ......................................................................................................................................................... 75 
16.5 Study Monitoring, Auditing, and Inspecting ................................................................................................ 76 
16.6 Quality Assurance and Quality Control ......................................................................................................... 76 
16.7 Disclosure and Publication Policy.................................................................................................................... 76 
17 REFERENCES ................................................................................................................................... 77 
18 Appendix A – CLL Response Definition .................................................................................. 78 
19 Appendix B- Contraceptive Guidelines and Pregnancy ................................................... 81 
20 Appendix C – NYHA Classifications ......................................................................................... 83 
21 Appendix D – HEPATITIS B SEROLOGIC TEST RESULTS .................................................. 84 
22 Appendix E – Inhibitors of CYP3A ........................................................................................... 85 
 
 
 


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Version 2.0 (Dated 8 October 2016) of this Protocol is the first amendment to this clinical trial and 
contains the following modifications: 
• 
Sponsor and Study Coordination address updated;  
 
 
 
• 
Further clarification was provided for inclusion criteria #1b, central FISH analysis can be 
performed on study UTX-IB-301 or on a separate TGTX-LAB-001 screening protocol; 
• 
Further clarification was provided for exclusion criteria #3, now requiring evaluation for 
the presence of HBV, HCV or CMV by DNA (PCR) if HBc antibody, HCV antibody or CMV are 
positive during serum virology; 
• 
The phrasing of response assessment intervals has been revised for clarity from “after cycles 
2, 4, and 6 then at weeks 8, 16, 24, 36, 48 and every 12 weeks thereafter,” to “after the 
completion of cycles 2, 4, 6 then after the completion of every 3 cycles thereafter” and it was 
further clarified that patients being followed for PFS off treatment should have evaluations 
done every 3 months; 
• 
MRD will be evaluated in all patients achieving a PR or CR following the Cycle 6 response 
assessment as opposed to previously only in patients achieving a CR;   
• 
Schedule of assessments and treatment schedule (Section 7) was updated, including 
o Revised wording for Tumor Evaluation (as listed above); 
• 
Ublituximab packaging has been updated from “one 15 mL vial containing 10 mg/mL 
solution of ublituximab” to “six 15 mL vials containing 10 mg/mL solution of ublituximab or 
one 15 mL vial containing 10 mg/mL solution of ublituximab (for replacement if needed)”; 
• 
Sections 9.1.1 and 9.2.2 have been updated to include the latest CAEPRS information; 
• 
Clarification was provided in Section 10.3.1 to better describe appropriate selection of 
target lesions; and  
• 
Appendix D has changed from “Inhibitors of CYP3A” to “Hepatitis B Serologic Test Results”. 
“Inhibitors of CYP3A” is now Appendix E. 
Version 2.1 (Dated 21 October 2016) of this Protocol is the second amendment to this clinical trial 
and contains the following modification: 
• 
The Intent-to-Treat population has been updated to now include all patients who received 
at least one dose of study medication, instead of all randomized patients.  All ORR and safety 
analysis will now be based on the ITT population 
Version 2.2 (Dated 27 January 2017) of this Protocol is the third amendment to this clinical trial 
and contains the following modification: 
• 
The primary analysis population has been updated    
Version 2.5 (Dated 31 July 2017) of this Protocol is the fourth amendment to this clinical trial and 
contains the following modifications: 
• 
Sections 8.2.1.3.1 and 9.1 were updated to include information regarding the new 
concentration and vial size of ublituximab 
• 
Sections 9.1 and 9.2 have been updated to include the latest CAEPRS information for 
ublituximab, ibrutinib, and the combination of ublituximab and ibrutinib. 
• 
Section 10.3.1 has been updated to remove the following statement: “At follow-up time 
points, the LDs for individual lesions and the SPD of all nodal target lesions will be 


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considered.  Because nodal target lesions that have one or both diameters >0 cm and < 1.0 
cm cannot be reliably measured, a default value of 1.0 cm will be assigned for each diameter 
that meets these criteria and the resulting PPD will be used in SPD calculations. Based on this 
convention, a CR may be achieved even if an SPD value is >0 cm2 (i.e., if all lymph nodes 
measure < 1.0 cm2).” 
 
 






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f. 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. 
3. Adequate organ system function, defined as follows: 
a. Absolute neutrophil count (ANC) > 750 / platelet count > 40,000 
(patients with bone marrow infiltration due to CLL are eligible if their 
ANC is > 500) 
b. Total bilirubin ≤1.5 times the upper limit of normal (ULN) 
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) 
4. Presence of measurable lymphadenopathy, defined as the presence of > 
1 nodal lesion that measures > 2.0 cm in the longest diameter (LD) and 
> 1.0 cm in the longest perpendicular diameter (LPD) as assessed by 
computed tomography (CT) or magnetic resonance imaging (MRI) 
5. ECOG performance status ≤ 2 
6. Male or female ≥ 18 years of age 
7. Ability to swallow and retain oral medication 
8. Female patients who are not of child-bearing potential (see Appendix B- 
Contraceptive Guidelines and Pregnancy), and female patients of child-
bearing potential who have a negative serum pregnancy test within 3 
days prior to Cycle 1, Day 1.  Female patients of child-bearing potential, 
and male partners must consent to use a medically acceptable method 
of contraception throughout the study period and for 30 days after the 
last dose of either study drug. 
9. Willingness and ability to comply with study and follow-up procedures, 
 
and give written informed consent. 










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performed on the ITT and Treated Population.  The secondary efficacy 
analysis and safety analysis will be performed on the Treated Population 
according to the actual treatment regimen received. 
 
 
Efficacy Analyses: 
Demographic (e.g., gender, age, race, ethnicity) and baseline characteristics 
(e.g., performance status, height, weight, and prior therapy) will be 
summarized with descriptive statistics. 
 
For each part of the study, ORR, as determined by the IRC, will be compared 
between treatment groups by a Cochran-Mantel-Haenzel test with 
adjustment for the randomization stratification factors. 
 
The CR and MRD negativity rates will be compared between treatment 
groups using the same methodology as in the analysis of ORR. 
 
Safety Analyses: 
Treatment-emergent AEs through 30 days after last dose of study treatment 
will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA™), Version 13.1 (or higher), System Organ Class and preferred 
term.  The incidences and percentages of patients experiencing each AE 
preferred term will be summarized with descriptive statistics.  The severity 
of AEs will also be summarized by National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0 (or 
higher) grade and by causality (relationship to study treatment).  Grade 3 
and 4 AEs, SAEs, and AEs leading to withdrawal, dose modification, or 
treatment discontinuation will also be summarized by preferred term.  
Laboratory results will be classified according to NCI-CTCAE, Version 4.0 (or 
higher).  Laboratory results not corresponding to an NCI-CTCAE term will 
not be graded.  Incidences of laboratory abnormalities will be summarized 
with descriptive statistics.  Vital signs and physical examination results will 
be summarized with descriptive statistics. 






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3 INTRODUCTION 
3.1 CLL 
In the US, an estimated 15,720 new cases of Chronic Lymphocytic Leukemia (CLL) will be reported 
in 2014, with deaths totaling 4,600 due to the disease according to American Cancer Society 
estimates (American Cancer Society, 2014). CLL affects mainly older adults, accounts for one third of 
all diagnosed cases of leukemia, and is characterized by the accumulation of clonal mature B 
lymphocytes in the blood, bone marrow, and secondary lymphoid tissues (Lin K, 2002).  CLL is a 
heterogeneous disease, with several higher risk cytogenetic abnormalities which are generally more 
difficult to treat including, 17p deletion, P53 gene mutation and 11q deletion (Hallek M, 2008) (Lin 
K, 2002).  Patients with 17p deletion show higher resistance to conventional chemotherapies as well 
as shorter duration of survival than non 17p deletion patients.   Patients with 11q deletion have been 
associated with marked lymphadenopathy (Hallek M, 2008).  Patients with P53 gene mutations are 
associated with an adverse clinical outcome (Lin 2002).  
Chemotherapy regimens in combination with monoclonal antibody therapy comprise the current 
standard of care for patients with CLL, with novel targeted agents now entering the market.  Frontline 
therapy for patients with CLL generally consists of the anti-CD20 monoclonal antibody rituximab, in 
combination with either fludarabine and cyclophosphamide, or bendamustine.  Depending on the age 
and comorbidities of the patient, chlorambucil is also considered, though its use within the US has 
been limited.  Other anti-CD20 antibodies have also been approved for the treatment of CLL, 
including ofatumumab and obinutuzumab.  Recently the BTK inhibitor, ibrutinib was approved by 
the FDA for the treatment of patients with CLL in the relapsed or refractory setting after 
demonstrating superiority to ofatumumab as measured by progression free survival (Byrd et al, 
2014).  Despite these advancements in available therapies, CLL remains an incurable disease, and 
many patients will progress and eventually die from their disease.  Furthermore, patients with higher 
risk cytogenetic abnormalities still present with a less than optimal response to approved therapies 
and shorter duration of response and progression free survival.  As such, there is a pressing need for 
new, innovative, targeted therapies for the treatment of patients with relapsed/refractory CLL, 
especially those with cytogenetic abnormalities. 
3.2 UBLITUXIMAB 
Ublituximab is a novel third generation chimeric anti-CD20 monoclonal antibody bioengineered for 
potent activity, exhibiting a unique glycosylation profile with a low fucose content, designed to induce 
superior antibody-dependent cytotoxicity (ADCC).  Ublituximab exhibits competitive complement-
dependent cytotoxicity (CDC), on par with rituximab, and has also been demonstrated to induce 
programmed cell death (PCD) upon binding to the CD20 antigen on B-lymphocytes.  Ublituximab has 
a unique protein sequence, and targets epitopes on CD20 not targeted by rituximab or ofatumumab, 
both currently approved anti-CD20 antibodies (Esteves IT, 2011). 
 
 
 


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3.2.1 PRE-CLINICAL EVALUATIONS OF UBLITUXIMAB 
3.2.1.1 IN VITRO ACTIVITY  
In an in-vitro assay using B-CLL cells from patient donors, ublituximab demonstrated an enhanced 
ability to kill CLL 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 cells, and a higher FcγRIIIA 
mediated interleukin-2 (IL2) production by FcγRIIIA+ Jurkat cells (de Romeuf C, 2008).  Ublituximab 
demonstrated high ADCC against both patient-derived CLL cells and NHL cell lines.  Ublituximab’s 
engagement to FcγRIIIA triggers a stronger NK cell cytotoxicity against CLL as compared to rituxan 
(in vitro) despite CD20 density, likely related to the glycosylation pattern. (de Romeuf C, 2008).  
3.2.1.2 IN VIVO ACTIVITY 
The antitumor effect of ublituximab was compared to that of rituximab with chemotherapy in 
follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft murine models.  Single agent 
ublituximab demonstrated dose-related anti-tumor activity with 100% tumor growth inhibition in 
the FL xenograft at a dose of 100mg/kg, and a superior tumor growth delay (21 days) compared to 
rituximab. Ublituximab also demonstrated superior anti-tumor activity compared to rituximab 
against MCL xenografts at all dose levels (4).  
3.2.1.3 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 Ublituximab Investigator Brochure). 
3.2.2 CLINICAL DEVELOPMENT OF UBLITUXIMAB - CLL 
Ublituximab has been studied in a variety of patient populations, both as a single agent, and in 
combination with other agents, with over 100 patients having received ublituximab therapy to date 
across all studies.  Two Single-Agent Phase I/Ib trials have been conducted with ublituximab treating 
both NHL and CLL patients, with a total of 41 patients with relapsed or refractory CLL having been 
treated with single-agent ublituximab (TG-1101).  Further, 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 patients who have received ublituximab in early-phase 
trials, the safety and side effect profile of the agent is well characterized.  Summaries of the single-
agent experience are provided below as well as data with use of ublituximab in combination with 
ibrutinib.   
In a two part, first-in human dose escalation study (protocol CD20-0703), patients with relapsed or 
refractory CLL received one 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 clinical summary will focus on the Part II part of the study as the dose is more relevant to the 
clinical application used in current clinical studies.  In Part II, 12 patients were enrolled at 9 centers 


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in France and followed for 12 months.  Demographic data for the 12 patients 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 [1–8].  Seven patients (58%) received at 
least one prior rituximab-containing regimen.  The median lymphocyte bone marrow infiltration was 
85% [40–94]. 
Most frequent drug-related adverse events (AE’s) reported were infusion related reactions (IRR) 
(75% of the patients, including 33% of patients with Grade 3 IRR).  Other Grade 3/4 AE’s > 10% 
included: neutropenia (67%) and increase ALT/AST (17%).  All AEs were reversible spontaneously 
or with supportive care intervention.  None of the reported adverse events were considered as a 
dose-limiting toxicity according the judgment of the study Safety Committee.  Therefore, the 
maximum tolerated dose was not reached in this study.  Significant blood lymphocyte depletion was 
observed in all patients:  median lymphocyte count at baseline was 46.6 (x109/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 (Cazin B, 2013).  
Clinical response was based on the criteria established by the National Cancer Institute (NCI)-
Working Group updated in 2008 (Hallek M, 2008).  All patients but one received the planned 8 
infusions without any dose reduction--one patient was prematurely withdrawn due to a concomitant 
secondary leukemia unrelated to ublituximab therapy.  Response was evaluated at month 4 for the 
11 evaluable patients, with an initial response rate of 64% (7/11) with a confirmed response at 
month 6 in 5/11 patients (45%) patients (all PRs).  Four of the 11 patients achieved stable disease.  
At the 1 year follow-up, no responders had progressed, demonstrating all confirmed responses were 
durable despite no ublituximab maintenance therapy.  The median progression-free survival (PFS) 
was not reached at the 12 month follow-up (Cazin B, 2013). 
A Phase I trial of ublituximab (NCT01647971) was subsequently undertaken in patients with B-cell 
lymphoma who were relapsed or refractory to a prior rituximab containing regimen, which included 
8 patients with CLL.  This trial utilized a 3+3 design, assessing dose levels of 450, 600, 900, and 1200 
mg.  No DLTs were observed amongst the 12 patients enrolled into the dose-escalation component, 
and expansion cohorts were subsequently undertaken at 600, 900, and 1200 mg.  Patients with CLL 
were eligible to enroll into the expansion cohorts at 600 and 900 mg, receiving ublituximab on days 
1, 8 & 15 of Cycles 1 & 2, with monthly maintenance infusions starting in Cycle 3, followed by every 
3 months starting in Cycle 6.   
Of the 8 CLL patients enrolled, 4 had infusion related reactions that were manageable with infusion 
interruptions only and all patients received all schedule doses.  Other observed adverse events which 
were considered at least possibly related to study drug included neutropenia Grade 1/2 (n=1) and 
Grade 3/4 (n=3), as well as thrombocytopenia Grade 1/2 (n=1) and Grade 3/4 (n=1).  Six patients 
were evaluable for efficacy as of data cutoff for ASCO 2014, with 4 out of 6 patients achieving a partial 
response.  Rapid and profound circulating lymphocyte depletion (> 50% reduction) was noted with 
median time to peripheral response of 1 day (O'Connor OA, 2014). 
3.2.2.1 PHARMACOKINETICS 
After infusion of ublituximab (previously known as LFB-R603) at 150 mg dose followed by seven 
weekly injection infusions at 450 mg, results suggested non-linear pharmacokinetics with respect to 
dose (450 mg vs. 150 mg) and time (week 4 vs. week 8); and more than proportional increase of 
Cmax and AUC∞ due to a clearance decrease.  The volume of distribution at steady state was small 
(~5 L), approximately equal to blood volume.   These non-linear pharmacokinetics may be explained 






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4 OBJECTIVES AND ENDPOINTS 
PRIMARY OBJECTIVE 
• 
To evaluate the effect of the addition of ublituximab to ibrutinib on antitumor activity, as 
measured by the overall response rate (ORR = CR + PR) in patients with previously treated 
CLL with high-risk cytogenetics.   
 
SECONDARY OBJECTIVES 
• 
To evaluate the effect of the addition of ublituximab to ibrutinib on complete response (CR) 
rate. 
• 
To evaluate the effect of the addition of ublituximab to ibrutinib on the rate of patients 
achieving minimum residual disease (MRD) negativity. 
• 
To evaluate the effect of the addition of ublituximab to ibrutinib on progression-free survival 
(PFS), duration of response (DOR), and time to response (TTR). 
• 
To describe the safety profile observed with the addition of ublituximab to ibrutinib. 
 
 
 
4.1 EFFICACY ENDPOINTS 
Progression-free survival (PFS) 
PFS is defined as the interval from randomization to the earlier of the first documentation of 
definitive disease progression or death from any cause. 
 
Definitive disease progression based on standard criteria (Hallek et al. 2008) and occurring for any 
reason (i.e., increasing lymphadenopathy, organomegaly or bone marrow involvement; decreasing 
platelet count, hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other 
than lymphocytosis. 
Overall response rate (ORR) 
ORR is defined as sum of CR and PR rates. 
 
Duration of Response (DOR) 
Defined as the interval from the first documentation of CR or PR to the earlier of the first 
documentation of disease progression or death from any cause. 
 
Complete Response (CR) Rate 
CR rate is defined as the proportion of patients who achieve a CR. 
 
Minimal Residual Disease (MRD) Negativity Rate 
MRD negativity rate is defined as the proportion of patients who are MRD negative, excluding any 
patients who remain on study treatment at the time of the analysis and have a Cycle 1/Day 1 start 
date less than 6 months from the time of the analyses.  For the sake of clarity, the MRD negative 
analysis will exclude those patients that are too early to evaluate because MRD negativity is only 
tested for patients on study > 6 months.  Patients who drop off study for any reason prior to their 6- 
month visit will be included in the analysis. 
 


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Time to Response (TTR) 
TTR is defined as the interval from randomization to the first documentation of CR or PR 
 


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5 ELIGIBILITY CRITERIA 
Patients must meet all of the following inclusion criteria and none of the exclusion criteria to be 
eligible for participation in this study. 
5.1 INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for participation in this study: 
1. Diagnosis of B-cell CLL, with diagnosis established according to IWCLL criteria [Hallek 2008] 
and documented within medical records.  Patients must have: 
a. Received at least 2 cycles of one prior standard treatment regimen (NOTE:  Prior anti-
CD20 antibody or cytotoxic drugs, including investigational or commercially available 
therapies, may have been administered as single agents or as components of 
combination therapies) 
b. High-risk cytogenetics confirmed by FISH analysis (presence of at least one of the 
following: 17p deletion, 11q deletion and/or P53 gene mutation).  Central FISH 
analysis can be performed on UTX-IB-301 study or the TGTX-LAB-001 screening 
protocol.    
2. CLL that warrants treatment consistent with accepted IWCLL criteria for initiation of therapy.  
Any of the following conditions constitute CLL that warrants treatment: 
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), 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 (as long as initial ALC was ≥30,000/L), or 
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy, or 
f. 
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. 
3. Adequate organ system function, defined as follows: 
a. Absolute neutrophil count (ANC) > 750 / platelet count > 40,000 
(patients with bone marrow infiltration due to CLL are eligible if their ANC is > 500) 
b. Total bilirubin ≤1.5 times the upper limit of normal (ULN) 
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 


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d. Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault 
formula) 
4. Presence of measurable lymphadenopathy, defined as the presence of > 1 nodal lesion that 
measures > 2.0 cm in the longest diameter (LD) and > 1.0 cm in the longest perpendicular 
diameter (LPD) as assessed by computed tomography (CT) or magnetic resonance imaging 
(MRI) 
5. ECOG performance status ≤ 2 
6. Male or female ≥ 18 years of age 
7. Ability to swallow and retain oral medication. 
8. Female patients not of child-bearing potential (see Appendix B- Contraceptive Guidelines and 
Pregnancy), and female patients of child-bearing potential who have a negative serum 
pregnancy test within 3 days prior Cycle 1, Day 1.  Female patients of child-bearing potential, 
and male partners must consent to use a medically acceptable method of contraception 
during the study period and for 30 days after the last dose of either study drug. 
9. Willingness and ability to comply with study and follow-up procedures, 
 
 and give written 
informed consent. 
5.2 EXCLUSION CRITERIA 
Patients who meet any of the following exclusion criteria are not to be enrolled to this study: 
1. Patients 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 randomization (contact sponsor for < 21- day washout 
period requests) 
a. Corticosteroid therapy started at least 7 days prior to study entry (prednisone ≤10 
mg daily or equivalent) is allowed as clinically warranted.  Topical or inhaled 
corticosteroids are permitted. 
2. Autologous hematologic stem cell transplant within 3 months of study entry.  Prior Allogeneic 
hematologic stem cell transplant is excluded.  
3. Evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B 
vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C infection 
(HCV), cytomegalovirus (CMV), or known history of HIV.  If HBc antibody, HCV antibody or 
CMV is positive, the subject must be evaluated for the presence of HBV, HCV, or CMV by DNA 
(PCR) - See Appendix D. 
4. Known histological transformation from CLL to an Aggressive lymphoma (i.e. Richter’s 
transformation) 
5. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal 
infections of skin or nails.  NOTE:  Patients may be receiving prophylactic antiviral or 
antibacterial therapies at investigator discretion.   
6. Patients requiring treatment with moderate or strong CYP3A inhibitors/inducers. 
7. Any severe and/or uncontrolled medical conditions or other conditions that could affect their 
participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (NY Heart 
Association functional classification III-IV [see Appendix C – NYHA Classifications]) 
b. Myocardial infarction within 6 months of randomization 
c. QTcF >470 msec 


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d. Angina not well-controlled by medication 
e. 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. 
8. Malignancy within 3 years of study enrollment except for adequately treated basal, squamous 
cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the cervix, superficial 
bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, localized 
prostate cancer and 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. 
9. Patients in which ibrutinib therapy is medically contraindicated. 
10. Women who are pregnant or lactating. 
11. Current participation in another therapeutic clinical study. 
12. Previous therapy with ibrutinib, CC-292, or any drug that specifically inhibits Bruton’s 
tyrosine kinase (BTK). 


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6 STUDY DESIGN 
6.1 OVERVIEW OF STUDY DESIGN 
This study is a fixed-dose, randomized, two-arm Phase 3 trial to assess the efficacy and safety of 
ublituximab in combination with ibrutinib compared to ibrutinib alone in patients with CLL who have 
received at least one prior standard treatment regimen and who have at least one high-risk 
cytogenetic abnormality (17p deletion, 11q deletion, and/or P53 gene mutation).   
Following screening, patients meeting the inclusion/exclusion criteria will be randomized in a 1:1 
ratio, to either: 
• 
Arm A: Ublituximab + ibrutinib; or 
• 
Arm B: Ibrutinib 
Randomized patients will be stratified according to prior lines of therapy (1 prior vs 2 or more prior 
lines of therapy). 
All study patients will be evaluated for response after cycles 2, 4, and 6, then every 3 cycles thereafter 
if patient is on active treatment, or approximately every 3 months thereafter if patient is in follow up.  
The best clinical response as well as disease progression will be determined by an Independent 
Review Committee (IRC).   
Patients will continue treatment until the occurrence of definitive disease progression, unacceptable 
toxicity, or withdrawal from the study due to investigator decision or other reasons.  Patients who 
discontinue study treatment for reasons other than disease progression will continue to be followed 
for progression and/or survival approximately every 3 months.   
Upon first assessment scan, or confirmation scan (if necessary), of the last randomized patient, and 
site submission of all required efficacy and safety data, the independent DSMB will review the 
primary and secondary efficacy analyses, and safety data. 
 
 
6.2 REGISTRATION AND RANDOMIZATION 
The patient must sign consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks and 


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discomforts.  Patients who have signed informed consent and who are eligible will be randomized in 
a 1:1 ratio to Arm A (ublituximab plus ibrutinib) or Arm B (ibrutinib alone).   
Investigators will use an interactive web response system (IWRS) which will assign patients to either 
treatment Arm A (ublituximab plus ibrutinib) or treatment Arm B (ibrutinib alone). 
Patients should begin study treatment within 4 days of randomization.  In case of 
administrative or other delays, every attempt should be made to initiate study drug as soon 
as possible but no more than 7 days from randomization.  Please see the IWRS Manual for 
additional information on randomization. 
Upon entering patient information into the IWRS, investigators will receive an enrollment approval 
and a unique patient identifier that will include the randomization assignment.  This confirmation 
must be received by the site prior to dispensing study drug to the participant.  Further details about 
the patient registration process using the IWRS system will be outlined in the IWRS Manual. 
6.3 STUDY SITES 
Up to 200 study sites may be asked to participate in this study.  Enrollment is expected to be 
completed approximately 18-24 months after the first patient is randomized.       
6.4 DISCONTINUATION FROM STUDY TREATMENT 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
Disease progression 
• 
Intolerable toxicity related to study drug 
• 
Patient requests to withdraw consent or discontinue treatment 
• 
Pregnancy 
• 
Inability of the patient to comply with study requirements 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Non-compliance/lost to follow-up 
• 
Investigator discretion 
• 
Discontinuation of the study by the Sponsor 
Patients who discontinue from study treatment (for reasons other than progressive disease) will 
continue to be followed for progression.  Every attempt to continue to follow the patient for 
progression should be made. 
After withdrawal from protocol treatment, patients should be followed for AEs for 30 calendar days 
after their last dose of either study drug.  All new AEs occurring during this period must be reported 
and followed until resolution, unless, in the opinion of the investigator, these values are not likely to 
improve because of the underlying disease.  In this case the investigators must record his or her 
reasoning for this decision in the patient’s medical records and as a comment on the electronic Case 
Report Form (eCRF). 
All patients 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 


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case, the investigator must record his or her reasoning for making this decision in the patient’s 
medical records and as a comment on the eCRF. 
 






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• 
Hypersensitivity and Infusion Reaction Precautions: Medication and resuscitation equipment 
must be available per institutional guidelines prior to ublituximab administration for the 
emergency management of potential anaphylactic reactions.   
• 
Patient Care Implications:   
o Ublituximab should not be administered as an IV push or bolus. 
o Ublituximab should only be diluted in 0.9% NaCl. 
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 adverse event). 
o Concurrent glucocorticoid therapy as long as started for at least 7 days prior to study 
entry (< 10 mg per day of prednisone or equivalent) is allowed as clinically warranted.  
o Since infusion-related hypotension may occur, antihypertensive medications should 
be withheld 24 hours prior to and throughout infusion of ublituximab 
o For patients at risk for tumor lysis syndrome in the opinion of the treating investigator, 
prophylaxis with allopurinol or per recommended institutional standards should be 
considered. 
 
8.2.1.1 INFUSION RELATED REACTIONS AND INFUSION RATE GUIDANCE - UBLITUXIMAB 
Infusion related reactions, including severe reactions, have been reported with ublituximab 
administration in patients with CLL.  Guidelines are provided below for patients 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/delay guidelines for patients who 
experience severe Infusion Related Reactions (IRR’s) in which treatment should be interrupted. Final 
decision for infusion rate reduction/delay or discontinuation resides with the treating investigator. 
1st or 2nd Infusion Interruption: 
• 
Hold infusion and closely monitored patient, institute symptomatic medical management 
until resolution of IRR symptoms. 
• 
Following the judgment of the Investigator, and provided the patient is stable, the infusion 
may be resumed at no more than half the previous rate. 
• 
If the patient does not experience any further IRR symptoms, infusion rate escalation may 
resume at the increments and intervals as appropriate at the treatment cycle dose (see 
Section 8.2.1.2). 
 






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Ibrutinib should be obtained via standard commercial channels.  Ibrutinib should be self-
administered (by the patient).  Starting on Cycle 1 Day 1 the patient should maintain a daily diary 
recording the time and date of the administration of ibrutinib.  Tablets should be taken at 
approximately the same time each day, except for days when the patient has a scheduled visit to the 
site.   Patients should be instructed to swallow the tablets as a whole and should not chew or crush 
them.  If a dose of ibrutinib is missed, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should not be replaced.  If vomiting occurs, no attempt should be made 
to replace the vomited dose. 
Study drug compliance (i.e. the patient’s daily diary) should be reviewed with the patient at the 
beginning of each new treatment cycle.  Missed doses should be documented in the appropriate eCRF.  
Patients should record the dose of ibrutinib taken for each dose in a drug diary. 
For patients having surgery, hold ibrutinib for at least 7 days prior to planned surgery and for 7 days 
following surgery. 
8.3 CRITERIA FOR ONGOING TREATMENT 
Continue treatment as per protocol provided that patient has: 
• 
No intolerable toxicities related to study drug. 
o Treatment may be delayed to recover from toxicity for a maximum of four weeks. 
• 
No clinical or radiographic evidence of disease progression. 
• 
Not withdrawn from the study for other reasons. 
8.4 DOSE DELAYS/DOSE MODIFICATIONS 
Patients should be assessed clinically for toxicity at each visit using the NCI CTCAE v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) grading scale.  Dose delay and/or modification 
guidance is for adverse events considered at least possibly related to either ublituximab or ibrutinib.  
If cytopenias are deemed related to the underlying disease rather than study drug, dose modifications 
are not required, or are per investigator discretion. 
A maximum four (4) week delay of treatment for recovery from toxicity is allowed to recover from 
hematologic toxicities to ≤ Grade 3 or non-hematologic toxicities to ≤ Grade 2 or to baseline level.  If 
greater than a four (4) week delay is necessary, then the patient should discontinue treatment and 
continue to be followed for progression.  If a patient withdraws consent or has documented 
progression, an end of study visit should be completed. 
8.4.1 DOSE DELAY: UBLITUXIMAB 
No reduction in the dose of ublituximab is permitted.  Please refer to Section 8.2.1.1 and 8.2.1.2 for 
detailed information on infusion rate guidance for infusion related reactions related to ublituximab.  
Supportive care should be considered for any patient who experiences Grade ≥ 2 cytopenias, or Grade 
≥ 1 non-hematologic toxicities.  A maximum four (4) week delay for recovery from toxicity is allowed 
for both study drugs (individually or together) to allow recovery of hematologic toxicities to ≤ Grade 
3 or non-hematologic toxicities to ≤ Grade 2 or to baseline level.  If greater than a four (4) week delay 
is necessary for both study drugs, then the patient should discontinue treatment and continue to be 
followed for progression.  If the patient withdraws consent or has documented progression, an end 
of study visit should be completed. 




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Upon receipt of treatment supplies, the Pharmacist or the appropriate person of the site should 
update the accountability forms for ublituximab.  If any abnormality on the supplied boxes is 
observed, the Pharmacist or the appropriate person should document that on the acknowledgement 
of receipt and contact that Sponsor and/or Sponsor designee. 
Ibrutinib should be prescribed via commercial supply by the treating investigator. 
8.6 DURATION OF THERAPY 
In the absence of treatment delays due to adverse event(s), treatment should continue through Cycle 
1 and beyond unless one of the following criteria applies: 
• 
Disease progression or inter-current illness that prevents further treatment, 
• 
Patient decides to withdraw from the study, or changes in the patient's condition render the 
patient unacceptable for further treatment in the judgment of the investigator. 
 
During the study period, patients will be evaluated for response by CT and/or MRI after the 
completion of cycles 2, 4, and 6, then after the completion of every 3 cycles thereafter if under 
treatment or every 3 months if in follow up.  The best clinical response as well as disease progression 
will be determined by an independent review committee (IRC).  Patients 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. Patients who discontinue 
from study treatment (either for toxicity or physician choice) and have not progressed will continue 
to be followed for progression. 
 


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9 STUDY MEDICATIONS 
9.1 UBLITUXIMAB 
Chemical Name: 
ublituximab 
 
Other Names:    
TG-1101 
Classification:    
Recombinant chimeric anti-CD20 monoclonal antibody 
Mode of Action: 
Targets CD20 antigen on B-cells 
Description: 
Ublituximab is a genetically engineered chimeric murine/human mAb 
directed against the CD20 antigen found on the surface of B lymphocytes.  
Ublituximab displays the typical structure of immunoglobulins, consisting of 
two gamma (γ) heavy chains and two kappa (κ) light chains linked by disulfide 
bridges. It is composed of a murine variable region (37.2% of total amino 
acids) fused onto human constant regions. 
How Supplied: 
Concentration of 10 mg/mL in 15 mL (150 mg) OR 25 mg/mL in 6 mL (150 
mg) single-use glass vials 
Storage: 
Ublituximab must be stored in a secured limited-access area at a temperature 
ranging +2°C / + 8°C.  Ublituximab must not be frozen. 
Stability: 
Once a vial of ublituximab has been opened it must be diluted immediately.  
After dilution, ublituximab is stable in static conditions for 24 hours at 25°C, 
and in dynamic conditions, stable for 8 hours at 25°C. 
Ublituximab has a shelf-life of 36 months if stored between +2°C / + 8°C, 
based on stability data. 
Route of  
Administration: 
Intravenous 
Packaging: 
 
Ublituximab is packed in unit boxes.  Each unit box contains:  
• 
Six vials containing 150 mg solution of ublituximab each 
or 
• 
One vial containing 150 mg solution of ublituximab (for replacement 
if needed) 
 
The container closure system for the vials containing 6 mL is a type I glass vial 
closed by a siliconized chlorobutyl rubber stopper sealed with an aqua plastic 
and aluminum cap. 
The container closure system for the vials containing 15 mL is a Type I plus 
borosilicate vial closed by a siliconized bromobutyl rubber stopper sealed 
with a white plastic and aluminum cap 
Availability: 
 
Ublituximab is available from TG Therapeutics. 


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9.1.1 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) 
The following adverse events were observed in patients treated with single agent ublituximab and 
were considered at least possibly related to study medication.  See the ublituximab investigator 
brochure for a complete list of all adverse events. 
9.1.1.1 COMMON (>20%) 
• 
Blood and lymphatic system disorders:  Neutropenia, Thrombocytopenia 
• 
General disorders and administration site conditions: Infusion-related reaction, Pyrexia, 
Chills 
• 
Nervous system disorders: Headache 
 
9.1.1.2 LESS COMMON (10%-20%) 
• 
Blood and lymphatic system disorders:  Anemia 
• 
Gastrointestinal disorders: Diarrhea, Nausea, Abdominal Pain Upper  
• 
General disorders and administration site conditions:  Fatigue, Asthenia  
 
9.1.1.3 UNCOMMON (≥5% - <10%) 
• 
Blood and lymphatic system disorders:  Febrile neutropenia, Pancytopenia 
• 
General disorders and administration conditions:  Pain 
• 
Infections and infestation:  Bronchitis 
• 
Investigations: Blood bilirubin increased, Alanine aminotransferase increased, Aspartate 
aminotransferase increased, Gamma-glutamyltransferase increased, Elevated liver enzymes 
• 
Musculoskeletal and connective tissue disorders:  Muscular weakness 
• 
Nervous system disorder: Dysguesia 
• 
Respiratory, thoracic and mediastinal disorders: Throat irritation/tightness, Dyspnea 
• 
Skin and subcutaneous tissue disorders: Pruritus  
• 
Vascular disorders: Hypertension 
 
9.1.1.4  EVENTS REPORTED IN AT LEAST ONE SUBJECT 
• 
Blood and lymphatic system disorders: Lymph Node Pain 
• 
Cardiac disorders: Supraventricular Arrhythmias 
• 
Gastrointestinal disorders: Constipation, Gastroesophageal Reflux Disease, Oral Pruritus 
• 
General disorders and administration conditions: Edema 
• 
Immune system disorders: Serum Sickness, Hypocomplementemia 
• 
Infections and infestations: Herpes Zoster, Paronychia, Pneumonia, Urinary Tract Infection, 
Pyuria 
• 
Investigations: Blood Creatinine Increase, Blood Potassium Increase, Blood Urea Increase, 
Heart Rate Irregular, Urine Output Decrease, Weight Increase 
• 
Metabolism and nutrition disorders: Hypoalbuminemia 
• 
Musculoskeletal and connective tissue disorders: Arthralgia, Groin Pain, Muscle Spasms 
• 
Nervous system disorders: Ageusia, Dizziness, Sciatica, Cognitive Disorder 
• 
Renal and urinary disorders: Hematuria, Proteinuria, Acute Kidney Failure, 
Tubulointerstitial Nephritis 
• 
Respiratory, thoracic and mediastinal disorders: Cough, Lung Infiltration, Pneumonitis, 
Wheezing 
• 
Skin and subcutaneous tissue disorders: Cold Sweat, Hyperhidrosis, Rash 


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• 
Vascular Disorders: Flushing 
 
9.2 IBRUTINIB 
Classification:    
Covalent inhibitor of the enzyme Bruton’s tyrosine kinase (Btk) 
Formulation: 
 
See Prescribing Information 
 
How Supplied:  
140 mg strength capsules 
 
Storage: 
See ibrutinib prescribing information 
Route of  
Administration: 
Oral 
Potential Drug 
Interactions: 
Avoid 
co-administration 
with 
strong 
and/or 
moderate 
CYP3A 
inhibitors/inducers. If a moderate CYP3A inhibitor/inducers must be used, 
see ibrutinib prescribing information for dosingguidelines and further 
information.  Also, avoid grapefruit and Seville oranges during treatment, as 
these contain strong or moderate inhibitors of CYP3A and can alter ibrutinib 
pharmacokinetics. 
Availability: 
 
Ibrutinib is available commercially from Pharmacyclics and Janssen. 
9.2.1 ADVERSE REACTIONS - IBRUTINIB 
The data described below reflect adverse reactions in ≥ 20% of patients who received ibrutinib  in 
three clinical trials; an open-label, single-arm clinical trial (Study 1102) that included 51 patients 
with previously treated CLL, a randomized clinical trial (RESONATE) that included 391 (195 on 
ibrutinib) patients with previously treated CLL or SLL, and a randomized clinical trial (RESONATE-
2) that included 267 (135 on ibrutinib) patients ≥ 65 years old with previously treated CLL or SLL 
(Janssen Biotech, Inc. & Pharmacyclics LLC, 2017). 
To ensure reference to the most up to date adverse reaction profile, please refer to the full 
IMBRUVICA® (ibrutinib) full prescribing information.  The prescribing information can be found at 
www.imbruvica.com. 
9.2.1.1 COMMON (≥ 20%) 
• 
Blood and lymphatic system disorders:  Anemia, Neutropenia, Thrombocytopenia 
• 
Gastrointestinal disorders: Diarrhea, Constipation, Nausea, Stomatitis 
• 
General disorders and administrative site conditions: Fatigue, Pyrexia, Peripheral edema 
• 
Infections and infestations:  Upper respiratory tract infection, Sinusitis 
• 
Skin and subcutaneous tissue disorders:  Rash, Bruising 
• 
Musculoskeletal disorders:  Musculoskeletal pain, Arthralgia 
• 
Nervous system disorders: Dizziness 
• 
Respiratory, thoracic and mediastinal disorders: Cough 


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9.2.1.2 IBRUTINIB – WARNINGS AND PRECAUTIONS (JANSSEN BIOTECH INC. & 
PHARMACYCLICS LLC, 2017) 
Hemorrhage  
Fatal bleeding events have occurred in patients treated with ibrutinib.  Grade 3 or higher bleeding 
events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, 
hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events 
of any grade, including bruising and petechiae, occurred in approximately half of patients treated 
with ibrutinib.  
Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant 
therapies and patients should be monitored for signs of bleeding.  
 
Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery 
depending upon the type of surgery and the risk of bleeding.  
Infections  
Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with ibrutinib 
therapy.  Grade 3 or greater infections occurred in 14% to 29% of patients.  Cases of progressive 
multifocal leukoencephalopathy (PML) and pneumocystis jirovecii pneumonia (PJP) have occurred 
in patients treated with ibrutinib.  Monitor patients for fever and infections and treat appropriately.  
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), 
thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) occurred in patients with B-cell 
malignancies treated with ibrutinib.  
Atrial Fibrillation  
Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with ibrutinib, 
particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous 
history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients 
who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea 
should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of 
ibrutinib treatment and dose modification in the prescribing information.  
Hypertension 
Hypertension (range, 6 to 17%) has occurred in patients treated with ibrutinib with a median time 
to onset of 4.6 months (range, 0.03 to 22 months).  Monitor patients for new onset hypertension or 
hypertension that is not adequately controlled after starting ibrutinib.  Adjust existing anti-
hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. 
Second Primary Malignancies  
Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred 
in patients treated with ibrutinib. The most frequent second primary malignancy was non-melanoma 
skin cancer (range, 2 to 13%). 
Tumor Lysis Syndrome 


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Tumor lysis syndrome has been infrequently reported with ibrutinib therapy. Assess the baseline 
risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat 
as appropriate. 
9.2.2 ADVERSE REACTIONS – UBLITUXIMAB IN COMBINATION WITH IBRUTINIB 
The following adverse events were observed in at least 1 of the 62 patients treated with ublituximab 
in combination with ibrutinib in an ongoing Phase II clinical trial, and were considered at least 
possibly related to ublituximab.  See the ublituximab investigator brochure for a complete list of all 
adverse events. 
9.2.2.1 COMMON >20% 
• 
General disorders and administration site conditions: Infusion related reaction 
 
9.2.2.2 LESS COMMON ≥10% - ≤20% 
• 
Blood and lymphatic system disorders: Neutropenia, Thrombocytopenia 
• 
Gastrointestinal disorders: Nausea, Diarrhea 
• 
General disorders and administration site conditions:  Fatigue 
• 
Musculoskeletal and connective tissue disorders: Muscle spasms 
9.2.2.3 UNCOMMON ≥1% - <10% 
• 
Blood and lymphatic system disorders: Anemia, Lymph node pain 
• 
Ear and labyrinth disorders: Tinnitus 
• 
Gastrointestinal disorders:  Stomatitis, Abdominal pain, Dyspepsia, Gastroesophageal 
reflux disease, Abdominal distension, Constipation,  Oral pain 
• 
General disorders and administration conditions: Malaise, Pyrexia, Chills, Non-cardiac 
chest pain 
• 
Hepatobiliary disorders: Hyperuricemia 
• 
Infections and infestations: Wound infection 
• 
Injury, poisoning, and procedural complications:  Contusion 
• 
Investigations: Aspartate aminotransferase increased, Blood creatinine increased, Alanine 
aminotransferase increase 
• 
Metabolism 
and 
nutrition 
disorders: 
Hypomagnesaemia, 
Decreased 
appetite, 
Hypercalcemia, Hyperglycemia,  
• 
Musculoskeletal and connective tissue disorders: Back pain, Pain in extremity, Myalgia, 
Arthralgia, Joint swelling 
• 
Nervous system disorders: Dysgeusia, Headache, Neuropathy peripheral, Memory 
impairment, Tremor, Dizziness, Dementia Alzheimer’s type 
• 
Psychiatric disorders: Insomnia 
• 
Renal and urinary disorders: Hematuria 
• 
Respiratory, thoracic and mediastinal disorders: Cough, Dysphonia, Epistaxis, Nasal 
congestion, Sinus congestion, Upper-airway cough syndrome, Hiccups 
• 
Skin and subcutaneous tissue disorders: Onychoclasis, Alopecia, Rash, Rosacea 
• 
Vascular disorders: Hypotension 


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10 MEASUREMENT OF EFFECT 
During the study period, all patients will be evaluated for response by CT and/or MRI after the 
completion of cycles 2, 4, and 6 then after the completion of every 3 cycles thereafter while under 
protocol treatment.  If a patient is off study in follow up, assess for response every 3 months. All 
efficacy assessments have a +/- 7 day window.  The determination of response and progression will 
be based on IWCLL criteria (Hallek M, 2008).  Radiographic and clinical tumor assessments will be 
subject to independent confirmation by the Independent Review Committee (IRC) which will be 
blinded to treatment assignment.  The findings of the IRC will be considered primary for analyses of 
ORR, PFS, and other tumor control endpoints. 
CT scan is the preferred method of tumor assessment but MRI may be used at the investigator’s 
discretion.  The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and throughout the study.  Please see study manual 
for detailed instructions for tumor assessment, and submission of scans for independent review. 
All baseline assessments to characterize disease will be performed within 30 days of Cycle 1 Day 1, 
prior to initiation of therapy. 
 Patients 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. 
Patients 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. 
10.1 METHOD OF ASSESSMENT 
In addition to clinical examination, imaging-based evaluation will be used in this study in all patients 
enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI scanning may be 
used at the investigator’s discretion in patients 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 patients 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, 
scanner, patient 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 patient is imaged without contrast at baseline, subsequent assessments should be performed with 
contrast, unless the patient cannot tolerate the contrast. 
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC. 
10.2 RESPONSE REVIEW 
An Independent Review Committee (IRC) will provide a blinded review of radiographic data and 
pertinent clinical data in order to provide expert interpretation of changes in tumor status.  CLL 
response and progression data collected from the study will be subjected to review by the IRC.  The 


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patient should continue study treatment pending confirmation of progression status by the IRC.  
CT/MRI should be attempted in order to document definitive disease progression by the IRC.   
The review of radiographic and clinical data by the IRC will be performed on an ongoing basis.  The 
specifics of the IRC’s processes and reading methods will be described in an independent review 
charter developed by the contracted imaging facility in conjunction with the Sponsor.  The findings 
of the IRC will be considered primary for analyses of ORR, PFS, and other tumor control endpoints. 
See IRC manual for instructions on process for submission of scans. 
10.3 IDENTIFICATION 
AND 
MEASUREMENT 
OF 
TUMOR 
LESIONS 
AND 
ORGANOMEGALY 
10.3.1 TARGET LESIONS 
At baseline, up to 6 lymph nodes should be selected as target lesions that will be used to quantitate 
the status of the disease during study treatment. Ideally, the target lesions should be located in 
disparate regions of the body. Only peripheral nodes need be selected as target lesions. However, it 
is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever these sites are 
involved. 
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 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. 
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered progressive 
disease. 
In cases in which a large lymph node mass has split into multiple components, all subcomponents 
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 


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Both the spleen and liver will be assessed by CT/MRI scan and/or 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 further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters. 
By imaging, the spleen will be considered enlarged if it is >12 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 patients 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. 
A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the spleen in its LVD 
or decrease to ≤ 12 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. 
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 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 at the stipulated 
intervals during treatment. 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 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 by the IRC as CR, 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. 


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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). Where imaging 
data are available, these data will supersede physical examination data in determining tumor status. 
10.5 COMPLETE RESPONSE 
To satisfy criteria for a CR, all of the following criteria must be met: 
• 
No evidence of new disease 
• 
ALC in peripheral blood of <4 x 109/L 
• 
Regression of all target nodal masses to normal size ≤1.5 cm in the LD 
• 
Normal spleen and liver size 
• 
Regression to normal of all nodal non-target disease and disappearance of all detectable 
• 
non-nodal, non-target disease 
• 
Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age 
• 
Peripheral blood counts meeting all of 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) 
Patients who fulfill all the criteria for a CR (including bone marrow criteria) but who have a persistent 
anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow that is related to prior or 
ongoing drug toxicity (and not to CLL) will be considered as a CR with incomplete marrow recovery 
(CRi). 
10.6 PARTIAL RESPONSE 
To satisfy criteria for a PR, all of the following criteria must be met: 
• 
No evidence of new disease 
• 
A change in disease status meeting ≥2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: 1) only lymphadenopathy is present at baseline; 2) only 
lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:   
o In a patient 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 
o In a patient with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Section 10.3.2 
o In a patient 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 marrow infiltrate or in B-lymphoid 
nodules 
• 
No target, splenic, liver, or non-target disease with worsening that meets the criteria for 
definitive PD 


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• 
Peripheral blood counts meeting 1 of the following criteria: 
o ANC >1.5 x 109/L or >50% increase over baseline without need for exogenous growth 
factors (e.g., G-CSF) 
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) 
10.7 STABLE DISEASE 
To satisfy criteria for SD, the following criteria must be met: 
• 
No evidence of new disease 
• 
There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD 
10.8 DEFINITIVE DISEASE PROGRESSION 
The occurrence of any of the following events indicates definitive PD: 
• 
Evidence of any new disease: 
o A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD 
o New or recurrent splenomegaly, with a minimum LVD of 14 cm 
o New or recurrent hepatomegaly, with a minimum LVD of 20 cm 
o 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) 
*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. 
• 
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 and an LPD of > 1.0 cm 
o Splenic progression, defined as an increase in splenic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm) 
o Hepatic progression, defined as an increase in hepatic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm) 
o Unequivocal increase in the size of non-target disease (e.g., effusions, ascites, or other 
organ abnormalities related to CLL) 
o Transformation to a more aggressive histology (e.g., Richter’s syndrome) as established 
by biopsy (with the date of the biopsy being considered the date of CLL progression if the 
patient has no earlier objective documentation of CLL progression). 
• 
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
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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 
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 
If there is uncertainty regarding whether there is true progression, the patient should continue study 
treatment and remain under close observation pending confirmation of progression status by the 
IRC. In particular, worsening of constitutional symptoms in the absence of objective evidence of 
worsening CLL will not be considered definitive disease progression; in such patients, both CLL-
related and non-CLL-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. If subsequent evaluations suggest that the patient has experienced 
persistent definitive CLL progression, then the date of progression should be the time point at which 
progression was first objectively documented. 
10.9 NON-EVALUABLE 
In a patient who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 
• 
There are no images or inadequate or missing images 
• 
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 patient known to have undergone 
splenectomy). 
Note: 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. 
10.10 LYMPHOCYTOSIS DURING THERAPY 
Upon initiation of ibrutinib, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from 
baseline and above absolute lymphocyte count of 5,000/mcL) may occur. The onset of isolated 
lymphocytosis usually occurs during the first few weeks of ibrutinib therapy and usually resolves by 
a median of 8 weeks.  Patients with lymphocytosis should be continued on study drug until the 
occurrence of definitive disease progression (i.e., disease progression that is manifest by worsening 
CLL-related signs other than lymphocytosis alone), or the occurrence of another reason to 
discontinue study therapy.  New or increasing lymphocytosis after 6 months of starting treatment 
may be considered disease progression and should be confirmed as per the response criteria. 
10.11 MINIMUM RESIDUAL DISEASE 
In patients who achieve a PR or CR, minimum residual disease will also be assessed first by peripheral 
blood.  If a patient is determined to be MRD negative by peripheral blood, a bone marrow aspirate 
will be obtained to assess MRD in the bone marrow.  Patients will be defined as having a clinical 
remission in the absence of MRD (i.e. “MRD negative”) when they have blood or marrow with less 
than one CLL cell per 10,000 leukocytes. 


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11 STATISTICAL CONSIDERATIONS 
11.1 SAMPLE SIZE AND POWER 
 
 
 
 
 
 
 
 
 
 
11.2 GENERAL ANALYSIS CONVENTIONS 
Statistical analyses will be conducted by TG Therapeutics or its designee.  Statistical analysis will be 
performed on the intent-to-treat (ITT) population for primary efficacy endpoints and the Treated 
Population for primary and secondary efficacy endpoints and for safety endpoints. 
Baseline is defined as the last measurement for a variable prior to the initial dose of study treatment.  
Hypotheses will be tested at the 5%, two-sided statistical significance level, unless otherwise 
specified. Efficacy and safety analyses will be performed using SAS® version 9.2 or higher (SAS 
Institute, Cary, NC), or comparable software. 
All data collected on the eCRF will be listed. Routine data listing or tabulation review during the study 
conduct will be performed to identify missing data, anomalies, outliers, etc. A complete description 
of data handling rules and planned statistical analyses is detailed in a separate statistical analysis 
plan (SAP) prior to conducting any planned analysis. 
11.3 ANALYSIS POPULATIONS 
The intent-to-treat (ITT) population will include all randomized patients.  The Treated Population 
will include all randomized patients who received at least one dose of study medication. 
11.4 PATIENT DISPOSITION 
The disposition of patients includes the number and percentage of patients for the following 
categories: patients enrolled, patients in the ITT and Treated Population, and patients discontinued 
from the study.  The reasons for study discontinuation will also be summarized in this table.  Only 
one primary reason for study discontinuation will be reported in the summary.  However, all reasons 
will be presented in the listing. 
A listing will present data concerning patient disposition. 
11.5 PATIENT DEMOGRAPHICS AND BASELINE CHARACTERISTICS 


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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 and Treated 
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 ITT and Treated 
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 patients whose dose is modified at any time will be summarized by each 
type of modification by cycle and overall.  The proportion of patients completing each cycle of 
treatment will be summarized. 
11.8 EFFICACY ANALYSES   
All patients included in the study should have a baseline tumor assessment within 30 days of Cycle 
1/Day 1.  Each patient will be assigned one of the following categories:  1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) 
early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). 
The primary analyses of efficacy variables that include measures of tumor response (e.g., ORR, CR 
rate) will involve response as determined by the IRC.  Supportive analyses of these variables will 
involve response as determined by the investigators. 
11.9 MISSING VALUE HANDLING PROCEDURES 
Missing data will not be imputed, except for missing dates concerning major efficacy or safety 
parameters.  The algorithms for imputation of partial dates vary depending upon the parameter and 
are presented in the Statistical Analysis Plan. 
11.10 STATISTICAL ANALYSES 
11.10.1 PRIMARY EFFICACY VARIABLES 
The ORR is defined as the proportion of patients with a best overall response of partial response (PR) 
or complete response (CR).  Patients who do not have a tumor response assessment for any reason 
will be considered non-responders and will be included in the denominator when calculating the 
ORR.  For the ITT analysis, for each treatment group, the number of patients achieving a response 
will be divided by the total of patients in the ITT population to yield the proportion responding. 


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The primary efficacy variable (i.e. ORR) will be analyzed in the ITT population first and then will also 
be analyzed for the Treated Population.   
The ORR will be compared between treatment groups by a Fisher’s Exact Test.  Testing of ORR will 
be at the 5%, 2-sided statistical significance level. 
ORR will also be analyzed based on Per Protocol patients.  Additional sensitivity analyses will also be 
performed as appropriate. 
11.10.2 SECONDARY EFFICACY VARIABLES  
11.10.2.1.1 COMPLETE RESPONSE RATE 
The CR rate is defined as the proportion of patients with a best overall response of complete response 
(CR).  Patients who do not have a tumor response assessment for any reason will be considered non-
responders and will be included in the denominator when calculating the CR rate.  For each treatment 
group, the number of patients achieving a CR will be divided by the total of patients in the Treated  
Population to yield the proportion responding.      
The CR rate will be compared between treatment groups at the 5%, two-sided statistical significance 
level using the same methodology as that described in Section 11.10.1 found for ORR. 
11.10.2.1.2 DURATION OF RESPONSE 
The Duration of Response (DOR) is defined as the interval from the first documentation of CR or PR 
to the earlier of the first documentation of disease progression or death from any cause.  The DOR 
rate will be compared between treatment groups at the 5%, two-sided statistical significance level 
using an ANOVA model with treatment effect. 
11.10.2.1.3 TIME TO RESPONSE 
The Time to Response (TTR) is defined as the interval from the start of study drug to the first 
documentation of CR or PR. The TTR rate will be analyzed via Kaplan-Meier methodology using a 
stratified Cox regression model with treatment effect and stratification effect to compare the 
treatment groups to generate the treatment group HR and 95% CI. 
11.10.2.1.4 MINIMAL RESIDUAL DISEASE NEGATIVITY RATE 
The MRD negativity rate is defined as the proportion of patients who are MRD negative post-baseline.  
MRD negativity rate is defined as the proportion of the patients in the Treated Population who are 
MRD negative, excluding any patients who remain on study treatment at the time of the analysis and 
have a Cycle 1/Day 1 start date less than 6 months from the time of the analyses.  For the sake of 
clarity, the MRD negative analysis will exclude those patients that are too early to evaluate because 
MRD negativity is only tested for patients on study > 6 months.  Patients who drop off study for any 
reason prior to their 6 month visit will be included in the analysis. 
The MRD negativity rate will be compared between treatment groups at the 5%, two-sided statistical 
significance level using the same methodology as that described in Section 11.10.1 for ORR. 
11.10.2.1.5 SAFETY 


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Safety analyses will be performed on the Treated  Population.  Safety evaluations will be based on the 
incidence, intensity, and type of adverse events, as well as on clinically significant changes in the 
patient’s physical examination, vital signs, and clinical laboratory results.  Safety variables will be 
tabulated and presented by study drug actually received. 
Because there is no pre-specified safety outcome defined in terms of AEs, clinically relevant 
laboratory parameters, or vital signs, any formal comparisons between the treatment arms with 
respect to specific safety parameters will be post-hoc. 
11.10.2.1.6 PROGRESSION-FREE SURVIVAL 
Progression-free survival is defined as the time from the date of randomization until the date of first 
documentation of definitive disease progression or date of death from any cause, whichever occurs 
first.  Patients who die without a reported prior progression will be considered to have progressed 
on the day of their death.  Patients who did not progress or are lost to follow-up will be censored at 
the day of their last tumor response assessment.  If no baseline or post-baseline assessment is 
available, the patient will be censored at the date of randomization.  If death or PD occurs after 2 or 
more consecutive missing tumor response assessments, censoring will occur at the date of the last 
response 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 tumor response assessment prior to 
initiation of new therapy. 
This variable will be analyzed via Kaplan-Meier methodology.  The median PFS will be estimated for 
each arm, however no formal hypothesis testing will be conducted.  
 
 
 
  
 
 
 
 
 


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12 SAFETY REPORTING AND ANALYSIS 
12.1 SAFETY ANALYSES 
Safety evaluations will be based on the incidence, intensity, and type of adverse events, as well as on 
clinically significant changes in the patient’s physical examination, vital signs, and clinical laboratory 
results.  Safety analyses will be performed using the Treated Population.  Safety variables will be 
tabulated and presented by the dose of ublituximab and/or ibrutinib actually received.  Exposure to 
study treatment and reasons for discontinuation of study treatment will also be tabulated. 
The number of dose reductions of ibrutinib due to toxicity (adverse events) in each treatment arm 
will be compared.  
12.2 ADVERSE EVENT CHARACTERISTICS  
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy 
of 
the 
CTCAE 
version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.     
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only. 
Expected AEs are defined as those described in the ublituximab Investigator Brochure.  Please refer 
to the ibrutinib prescribing information for a listing of expected AEs. 
12.3 DEFINITIONS OF ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product. An AE does not necessarily have to have a causal 
relationship with this treatment.   An adverse event (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. 
In clinical studies, an AE can include an undesirable medical condition occurring at any time, 
including run-in or washout periods, even if no study treatment has been administered.  The NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0 is to be used for the grading of 
severity of symptoms and abnormal findings.  For adverse events not covered by the NCI-CTCAE 
Version 4.0 grading system, the following definitions will be used: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 


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• 
Grade 5: Death related to AE. 
12.4 ADVERSE EVENTS (AE’S) AND TREATMENT EMERGENT ADVERSE EVENTS 
(TEAE’S) 
All AEs and SAEs occurring on study will be listed by patient.  The frequency and percentages of 
patients with treatment-emergent adverse events (TEAEs) will be tabulated by system organ class 
(SOC) and preferred term (PT), where treatment-emergent is defined as any AE that: 
• 
Occurs after first dosing of study medication and through the end of the study or up through 
30 days after the last dose of study treatment, or 
• 
Is considered treatment-related regardless of the start date of the event, or  
• 
Is present before first dosing of study medication but worsens in intensity or the investigator 
subsequently considers treatment-related.  
TEAEs that are considered at least possibly related to study treatment will be tabulated as well as 
deaths, SAEs, and events resulting in treatment discontinuation. 
AEs that occur after informed consent but before first dosing of study medication will not be 
summarized but will be listed.   
At each level of summarization, a patient will be counted only once for each AE, SOC, or PT 
experienced within that level.  In the summation for AE severity, within each level of AE, SOC, or PT 
experienced, the one with the highest severity will be included.  In the summation for AE’s 
relationship to the study drug, within each level of AE, SOC, or PT experienced, the one with the 
closest relationship to the study drug will be included. 
12.5 ADVERSE EVENTS/SERIOUS ADVERSE EVENT CAUSALITY ASSESSMENT 
The Investigator must also assess the relationship of any adverse event to the use of study drugs 
(whether none, one, or both), based on available information, using the following guidelines: 
• 
Not Related: Clear-cut temporal and/or mechanistic relation to a cause other than the study 
drug(s). 
• 
Doubtful: There is no reasonable possibility that the event is related to the study drug(s) but 
a definite cause cannot be ascertained. 
• 
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. 
• 
Probable: The most likely cause of the event is the study drug(s) but other causes cannot be 
completely excluded. 
• 
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. 
 


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12.5.1 RECORDING OF ADVERSE EVENTS 
All adverse events of any patient during the course of the study will be reported on the case report 
form, and the investigator will give his or her opinion as to the relationship of the adverse event to 
study drug treatment (i.e., whether the event is related or unrelated to study drug administration – 
either ublituximab and/or ibrutinib).  If the adverse event is serious, it should be reported as soon as 
possible and no greater than 24 hours to the sponsor or designee.  Other untoward events occurring 
in the framework of a clinical study are also to be recorded as AEs (i.e., AEs that occur prior to 
assignment of study treatment that are related to a protocol-mandated intervention, including 
invasive procedures such as biopsies, medication washout, or no treatment run-in). 
All AEs regardless of seriousness or relationship to ublituximab or ibrutinib treatment spanning from 
Cycle 1/Day 1 until 30 calendar days after discontinuation or completion of either protocol-specific 
treatment as defined by the protocol for that patient, are to be recorded on the eCRF. 
12.5.2 ABNORMAL LABORATORY VALUES AND VITAL SIGNS 
The reporting of abnormalities of vital signs as adverse events should be avoided.  Abnormalities of 
vital signs should not be reported unless any criterion for an SAE is fulfilled, the vital signs 
abnormalities cause the patient to discontinue study treatment, or the investigator insists that the 
abnormality should be reported as an AE.  Abnormal laboratory results should be noted in the eCRF 
as an adverse event if they are associated with an overdose, require or prolong inpatient 
hospitalization, or are otherwise considered clinically significant by the investigator. If an abnormal 
laboratory value or vital sign is associated with clinical signs and/or symptoms, 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. 
Clinical Laboratory Results will be summarized.  Summary statistics for actual values and for changes 
from baseline will be tabulated for laboratory results by scheduled visit.  Patients with laboratory 
values outside of the normal reference range at any post-baseline assessment will be summarized, 
and graded per NCI CTCAE Version 4.0 when applicable.  Patient incidence of abnormal laboratory 
results will be summarized by treatment group and maximum grade for each abnormal laboratory 
finding. 
12.5.3 HANDLING OF ADVERSE EVENTS 
All adverse events resulting in discontinuation from the study should be followed until resolution or 
stabilization.  Patients should be followed for AEs for 30 calendar days after discontinuation or 
completion of protocol-specific treatment (either ublituximab or ibrutinib).  All new AEs occurring 
during this period must be reported and followed until resolution unless, in the opinion of the 
investigator, these values are not likely to improve because of the underlying disease.  In this case, 
the investigators must record his or her reasoning for this decision in the patient’s medical record 
and as a comment on the eCRF.  After 30 days, only AEs, SAEs, or deaths assessed by the investigator 
as treatment related are to be reported. 
 


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12.6 SERIOUS ADVERSE EVENTS 
12.6.1 DEFINITIONS OF SERIOUS ADVERSE EVENTS 
The definitions of serious adverse events (SAEs) are given 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:  
• 
results in death, is immediately life-threatening,  
• 
requires at least a 24-hour in-patient hospitalization or prolongation of existing 
hospitalization, 
• 
results in persistent or significant disability/incapacity, and/or 
• 
causes a congenital anomaly/birth defect. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the previous definition.  These should also 
usually be considered serious.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate method 
(for example, as per IWCLL Hallek et al. 2008, should not be reported as a serious adverse event.   
A suspected unexpected serious adverse reaction (SUSAR) is defined as an SAE that is suspected to 
be at least possibly related to study medication(s) and is an unexpected event. SUSAR reporting is 
encompassed within SAE reporting guidelines as defined in this section. 
Treatment within or admission to the following facilities is not considered to meet the criteria of “in-
patient hospitalization” (although if any other SAE criteria are met, the event must still be treated as 
an SAE and immediately reported): 
• 
Emergency Department or Emergency Room 
• 
Outpatient or same-day surgery units 
• 
Observation or short-stay unit 
• 
Rehabilitation facility 
• 
Hospice or skilled nursing facility 
• 
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 a serious adverse event to the 
Sponsor. 
 


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12.6.2 SERIOUS ADVERSE EVENT REPORTING BY INVESTIGATORS 
It is important to distinguish between “serious” and “severe” adverse events, 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. 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to the Sponsor in order to comply with regulatory requirements.  Serious adverse events 
may occur at any time from the signing of the informed consent form through the 30-day follow-up 
period after the last study treatment.  Sponsor or designee should be notified of all SAEs, regardless 
of causality, within 24 hours of the first knowledge of the event by the treating physician or research 
personnel.   
To report an SAE, see the appropriate form. 
All SAEs (regardless of causality assessment) occurring on study or within 30 days of last study 
treatment should be immediately reported to the sponsor as SAEs within the eCRF and followed until 
resolution (with autopsy report if applicable). 
CLL progression or death due to CLL progression should be reported by the investigator as a serious 
adverse event only if it is assessed that the study drugs caused or contributed to the CLL progression 
(i.e. by a means other than lack of effect).  Unrelated events of CLL progression should be captured 
on the appropriate eCRF. 
The investigator must review and sign off on the SAE data on the SAE report.  The SAE should be 
reported to the Sponsor (or Sponsor designee) as outlined in the Safety Monitoring Plan.   
When an SAE is reported to the sponsor or designee, the same information should be entered on the 
eCRF within 24 hours (1 business day).  Transmission of the SAE report should be confirmed by the 
site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should also 
be reported to the sponsor or designee as soon as it is available; these reports should be submitted 
using the appropriate SAE form.  The detailed SAE reporting process will be provided to the sites in 
the Safety Monitoring Plan. 
Investigators must report SAEs and follow-up information to their responsible Institutional Review 
Board (IRBs)/Independent Ethics Committee according to the policies of the responsible IRB 
(Research Ethics Committee). 
12.7  SPONSOR SAE REPORTING REQUIREMENTS 
Sponsor is responsible for reporting relevant SAEs to the competent authority, other applicable 
regulatory authorities, and participating investigators, in accordance with ICH guidelines, FDA 
regulations, and/or local regulatory requirements. 


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Sponsor is responsible for reporting unexpected fatal or life-threatening events associated with the 
use of the study drugs to the regulatory agencies and competent authorities within 7 calendar days 
after being notified of the event.  The Sponsor will report all related but unexpected SAEs including 
non-death/non-life-threatening related but unexpected SAEs (SUSAR) associated with the use of the 
study medications to the regulatory agencies and competent authorities by a written safety report 
within 15 calendar days of notification.  Following the submission to the regulatory agencies and 
competent authorities, Investigators and trial sites will be notified of the SUSAR.  Investigators must 
report SUSARs and follow-up information to their responsible Institutional Review Board 
(IRBs)/Independent Ethics Committee according to the policies of the responsible IRB (Research 
Ethics Committee). 
12.8 RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on the 
SAE Report Forms and AE eCRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE eCRF; AEs 
that meet the definition of an SAE should additionally be reported. 
12.9 DIAGNOSIS VS. SIGNS AND SYMPTOMS 
All AEs should be recorded individually in the patient’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. 
12.9.1 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between patient evaluation time 
points.  Such events should only be recorded once on the SAE Report Form and/or the AE 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 AE eCRF.   
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE eCRF 
for each recurrence. 
12.9.2 ABNORMAL LABORATORY VALUES 
Abnormal laboratory results should be noted in the eCRF as an adverse event if they are associated 
with an overdose, require or prolong inpatient hospitalization, or are otherwise considered clinically 
significant by the investigator. If an abnormal laboratory value or vital sign is associated with clinical 


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signs and/or symptoms, 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. 
12.9.3 DEATHS 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of the patient’s CLL for up to 30 days post the last dose of study 
drug will be recorded on the appropriate study eCRF and reported on the Adverse Event page of the 
eCRF, i.e. are exempted from expedited reporting. All other on-study deaths, regardless of attribution, 
will be recorded on an SAE Report Form and expeditiously reported to the Sponsor. 
When recording a serious adverse event with an outcome of death, the event or condition that caused 
or contributed to the fatal outcome should be recorded as the single medical concept on the Adverse 
Event 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 Adverse Event page. 
12.9.4 HOSPITALIZATION, PROLONGED HOSPITALIZATION, OR SURGERY 
Any AE that results in hospital admission of >24 hours or prolongs hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this protocol.  There 
are some hospitalization scenarios that do not require reporting as an SAE when there is no 
occurrence of an AE.  See Section 12.6.1.   
12.9.5 PRE-EXISTING MEDICAL CONDITIONS 
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 AE eCRF, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
12.9.6 PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST 
The following are events of special interest, and will need to be reported expeditiously: 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies: 
During the course of the study, all female patients of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix B- Contraceptive Guidelines and Pregnancy) 
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 patient 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 patient must not receive any study drug(s), and must be discontinued from the 
study.   


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If an investigator suspects that a patient may be pregnant after the patient 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 patient must be discontinued from the study, and the investigator must notify the Study 
Chair or Medical Monitor as soon as possible.   
If a patient becomes pregnant while enrolled in the study, an SAE form should be completed and 
submitted to the Sponsor.  Abortions (spontaneous, accidental, or therapeutic) must also be reported 
to the Sponsor. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be expeditiously 
reported as an SAE, using the previously described process for SAE reporting. 
Study Drug Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment (either ublituximab and/or ibrutinib) that is 
symptomatic, even if not fulfilling a seriousness criterion, is to be reported to the Sponsor 
immediately (within 24 hours) using the corresponding SAE form, and following the same process 
described for SAEs.  If a study drug overdose occurs, patients should stop study drug dosing and be 
clinically monitored as appropriate, managing symptoms/side effects that may occur. 
Secondary Malignancy 
Any secondary malignancy event must be reported via the SAE form (in addition to the routine AE 
reporting mechanisms).  Any malignancy possibly related to cancer treatment should also be 
reported via the routine reporting mechanisms outlined in the protocol. 


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13 DATA SAFETY MONITORING BOARD (DSMB) 
Upon first assessment scan or confirmation scan if necessary, of the last randomized study patient, 
and following site submission of all required efficacy and safety data, the independent DSMB will 
review the primary and secondary efficacy analyses and safety data. 
 


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14 CLINICAL DATA COLLECTION AND MONITORING 
14.1 SITE MONITORING PLAN 
A Sponsor representative or designee will have made a site visit to each trial site within 12 months 
prior to initiating the protocol to inspect the drug storage area, and fully inform the Investigator of 
his/her responsibilities for studies and the procedures for assuring adequate and correct 
documentation.  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 
initiation, the electronic case report forms (eCRFs) and other pertinent study materials will be 
reviewed with the investigator’s research staff.  During the course of the study, the Sponsor will make 
visits to the sites as necessary in order to review protocol compliance, examine eCRFs, and individual 
patient medical records, and ensure that the study is being conducted according to the protocol and 
pertinent regulatory requirements.  Selected eCRF entries will be verified with source 
documentation.  The review of medical records will be done in a manner to assure that patient 
confidentiality is maintained. 
Site monitoring shall be conducted to ensure the human patient 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. 
14.2 AMENDMENTS TO THE PROTOCOL 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation.   
If an amendment to the protocol is required, the amendment will be originated and documented by 
the Sponsor.  All amendments require review and approval of the Sponsor and the Principal 
Investigator supporting the study.  The written amendment must be reviewed and approved by the 
Sponsor, and submitted to the IRB at the investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be reviewed 
and approved by the IRB at the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the Sponsor 
as applicable, and specifically when an increase to dosing or patient exposure and/or patient number 
has been proposed; or, when the addition or removal of an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and Ethics Committee and/or FDA and Competent 
Authority approval may include the following: 
• 
Change to study design  
• 
Risk to patient 
• 
Increase to dose or patient exposure to drug  
• 
Patient number increase of more than 20% 


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• 
Addition or removal of tests and/or procedures  
• 
Addition/removal of a new Investigator  
It should be further noted that, if an amendment to the protocol substantially alters the study design 
or the potential risks to the patients, their consent to continue participation in the study should be 
obtained. 
14.3 CURRICULA VITAE AND FINANCIAL DISCLOSURES 
All Principal Investigators will be required to submit to the Sponsor or its designee a signed 
up-to-date curriculum vitae (CV), current within two years, a current copy of their medical license, 
and a completed FDA form 1572 and financial disclosure statement.  In addition, all sub-investigators 
will be required to submit to the Sponsor or its designee a signed up-to-date CV, current within two 
years, a current copy of their medical license, and a completed financial disclosure statement. 
14.4 DATA OWNERSHIP AND PUBLICATION 
By conducting this study, the Investigator affirms to Sponsor that he or she will maintain, in strict 
confidence, information furnished by the Sponsor including data generated from this study and 
preliminary laboratory results, except as exempted for regulatory purposes.  
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. 


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15 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This study will be conducted according to the standards of Good Clinical Practice outlined in the ICH 
E6 Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, institutional 
research policies and procedures and any other local applicable regulatory requirement(s).  
15.1 IRB APPROVAL 
The study protocol, ICF, IB, available safety information, patient documents (e.g., study diary), patient 
recruitment procedures (e.g., advertisements), information about payments (i.e., PI payments) and 
compensation available to the patients and documentation evidencing the PI’s qualifications must be 
submitted to the IRB 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.  Investigators will be advised by the sponsor or designee whether an amendment is 
considered substantial or non-substantial and whether it requires submission for approval or 
notification only to an IRB. 
If applicable, the PI will notify the IRB within 90 days of the end of the study, or if the study 
terminates early, the PI must notify the IRB within 15 days of the termination.  A reason for the early 
termination must be provided (as defined in Directive 2001/20/EC). The Sponsor will either prepare 
or review all submission documents prior to submission to the IRB. 
15.2 REGULATORY APPROVAL 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and approval 
of the appropriate regulatory bodies 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 will be prepared by the Sponsor or its representative as required, for 
submission to the relevant regulatory authority.   
15.3 INSURANCE AND INDEMNITY 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI or site and the Sponsor. 
15.4 INFORMED CONSENT 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form. 


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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 patient’s medical record.  A copy of the informed consent form, to include the patient’s 
signature, will be provided by the investigator to the patient.   
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study must be obtained. 
15.5 CONFIDENTIALITY 
Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), and national data protection laws. HIPAA 
regulations require that, in order to participate in the study, a patient must sign an authorization 
from the study that he or she has been informed of following: 
• 
What protected health information (PHI) will be collected from patients in this study; 
• 
Who will have access to that information and why; 
• 
Who will use or disclose that information;  
• 
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;  
• 
The information collected about the research study will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the 
conclusion of the study; 
• 
Whether the authorization contains an expiration date; and 
• 
The rights of a research patient to revoke his or her authorization.  
In the event that a patient 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 patient 
authorization.  For patients 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 patient 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 patient’s original medical records at the site for 
verification of study-related procedures and data.  


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Measures to protect confidentiality include: only a unique study number and initials will identify 
patients on the eCRF or other documents submitted to the Sponsor. This information, together with 
the patient’s date of birth, will be used in the database for patient identification. Patient names or 
addresses will not be entered in the eCRF or database. No material bearing a patient’s name will be 
kept on file by the Sponsor. Patients will be informed of their rights within the ICF. 
15.6 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. 
15.7 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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16 RECORD RETENTION AND DOCUMENTATION OF THE STUDY 
16.1 DOCUMENTATION REQUIRED TO INITIATE STUDY 
Before the study may begin, certain documentation required by FDA regulations must be provided 
by the Investigator.  The required documentation should be submitted to the Sponsor. 
Documents at a minimum required to begin the study include, but are not limited to, the following: 
• 
A signature-authorized protocol and contract; 
• 
A copy of the official IRB approval of the study and the IRB members list; 
• 
Current Curricula Vita for the principal investigator and any associate investigator(s) who 
will be involved in the study; 
• 
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; 
• 
Original Form FDA 1572 (Statement of Investigator), appropriately completed and signed; 
• 
A copy of the IRB-approved consent form containing permission for audit by representatives 
of the Sponsor, the IRB, and the FDA;  
• 
Financial disclosure forms for all investigators listed on Form FDA 1572; 
• 
GCP Certificate for study training; 
• 
Site qualification reports, where applicable; 
• 
Verification of Principal Investigator acceptability from local and/or national debarment 
list(s). 
The Sponsor/Sponsor designee will ensure that all documentation that is required to be in place 
before the study may start, in accordance with ICH E6 and Sponsor SOPs, will be available before any 
study sites are initiated. 
16.2 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 patient’s eCRF are to be supported by source 
documentation where appropriate. 
Source documents are the original documents, data, records and certified copies of original records 
of clinical findings, observations and activities from which the patient’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. 


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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 
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 Section 13 and 21 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, patient identification lists, enrollment logs, 
delegation of authority log, staff qualification documents, laboratory normal ranges, records relating 
to the study drug including accountability records.  Drug accountability records should, at a 
minimum, contain information regarding receipt, shipment, and disposition.  Each form of drug 
accountability record, at a minimum, should contain PI name, date drug shipped/received, date, 
quantity and batch/code, or lot number for identity of each shipment.  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 21 CFR 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 21 CFR 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 patients (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. 
 


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16.3 AMENDMENTS TO THE PROTOCOL 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented by 
the Sponsor.  All amendments require review and approval of the Sponsor and the Principal 
Investigator supporting the study.  The written amendment must be reviewed and approved by the 
Sponsor, and submitted to the IRB at the investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be reviewed 
and approved by the IRB at the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the Sponsor 
as applicable, and specifically when an increase to dosing or patient exposure and/or patient number 
has been proposed; or, when the addition or removal of an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and REC and/or FDA and Competent Authority 
approval include, but are not limited to, the following: 
• 
Change to study design  
• 
Risk to patient 
• 
Increase to dose or patient exposure to drug  
• 
Patient number increase of more than 20% 
• 
Addition or removal of tests and / or procedures  
• 
Addition/removal of a new Investigator  
It should be further noted that, if an amendment to the protocol substantially alters the study design 
or the potential risks to the patients, their consent to continue participation in the study should be 
obtained. 
16.4 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 patients’ status throughout 
the course of the study. 
In order to maintain confidentiality, only study number, patient number, initials and date of birth will 
identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g. laboratory 
report), it must be obliterated on the copy of the document to be supplied to the investigator site and 
replaced instead with the patient number and patient’s initials.  The investigator will maintain a 
personal patient identification list (patient numbers with corresponding patient identifiers) to 
enable records to be identified and verified as authentic. Patient data/information will be kept 
confidential, and will be managed according to applicable local, state, and federal regulations. 


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16.5 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.   
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities and the sponsor or its representative(s). At the Sponsor’s 
discretion, Source Document Verification (SDV) may be performed on all data items or a percentage 
thereof. 
16.6 QUALITY ASSURANCE AND QUALITY CONTROL 
In addition to the Clinical Monitoring component of this protocol, the Sponsor’s Quality Assurance 
(QA) department shall establish an Auditing Plan document separate from the protocol to establish 
the criteria by which independent auditing shall 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 applicable regulations. 
Each study site shall be required to have Standard Operating Procedures (SOP’s) to define and ensure 
quality assurance/control processes for study conduct, data generation & collection, recording of 
data/documentation and reporting according to the protocol, GCP and any applicable local, national 
or international regulations. 
16.7 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.  The Sponsor reserves the right to 
release literature publications based on the results of the study. 
A clinical study report will be prepared upon completion of the study.  The Sponsor will disclose the 
study results, in the form of a clinical study report synopsis, to the IEC and the applicable regulatory 
authorities within one year of the end of the study.  The format of this synopsis and that of the clinical 
study report and its addendum will comply with ICH E3 guidelines for structure and content of a 
clinical study report. 
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.  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 data generated from this study and 
preliminary laboratory results, except as exempted for regulatory purposes.  
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. 


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17 REFERENCES 
Altekruse SF, K. C. (2010, November). SEER Cancer Statistics Review. Retrieved from seer.cancer.gov: 
http://seer.cancer.gov/csr/1975.2007 
American Cancer Society. (2014). Cancer Facts and Figures. Retrieved June 2014, from 
www.cancer.org: 
http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-
042151.pdf 
Cazin B, L. S. (2013). Final results of a multicenter phase Ib single agent study with the novel anti-
CD20 monoclonal antibody ublituximab (TG-1101) in patients with relapsed chronic 
lymphocytic leukemia (CLL). European Hematology Assocation, (p. abstractP111). Stockholm. 
de Romeuf C, D. C.-T.-B. (2008). Chronic lymphocytic leukaemia cells are effeciently killed by an anti-
CD20 monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16. 
British Journal of Haematology, 6(140), 635-643. 
Esteves IT, D. C. (2011). LFB-R603 (ublituximab), a third-generation monoclonal anti-CD20 antibody, 
displays additive antitumor activity with antileukemic chemotherpeutic agents in mouse 
xenograft models. American Society of Hematology, abstract 1660. 
Hallek M, C. B.-C. (2008). Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: 
a report from the International Wrokshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institue - Wroking Group 1996 Guidelines. blood, 12(111), 5446-5456. 
Lin K, S. P. (2002). Relationship between p53 dysfunction, CD38 expression and IgVH mutatin in 
chronic lymphcytic leukemia. blood, 1404. 
O'Connor OA, D. C. (2014). A phase I trial of ublituximab (TG-1101), a novel anti-CD20 monoclonal 
antibody (MAB) in B-cell lymphoma patients with prior exposure to rituximab. American 
Society of Clinical Oncology, (p. abstract 8524). Chicago. 
 


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18 APPENDIX A – CLL RESPONSE DEFINITION 
Assessment of response will follow the guidelines published by Hallek et al. (2008). 
Assessment of response should include a careful physical examination and evaluation of the blood and 
marrow. 
Complete 
Response: 
(CR) 
CR requires all of the following criteria as assessed at least 2 months after completion of 
therapy: 
a. Peripheral blood lymphocytes (evaluated by blood and differential count) below 4 
x 109/L (4000/µL). 
b. Absence of significant lymphadenopathy (e.g., lymph nodes >1.5 cm in diameter) 
by physical examination. 
c. No hepatomegaly or splenomegaly by physical examination and CT. 
d. Absence of constitutional symptoms. 
e. Blood counts above the following values: 
a. Neutrophils >1.5 x 109/L (1500/µL) without need for exogenous growth 
factors. 
b. Platelets >100 x 109/L (100 000/µL) without need for exogenous growth 
factors. 
c. Hemoglobin >110 g/L (11.0 g/dL) without red blood cell transfusion or 
need for exogenous erythropoietin. 
 
For patients in clinical studies, a marrow aspirate and biopsy should be performed at least 2 
months after the last treatment and if clinical and laboratory results listed above a-e 
demonstrate that a CR has been achieved.  To define a CR, the marrow sample must be at least 
normocellular for age, with less than 30% of nucleated cells being lymphocytes.  Lymphoid nodules 
should be absent.  In some cases, lymphoid nodules can be found, which often reflect residual disease.  
These nodules should be recorded as "nodular PR."  Moreover, immunohistochemistry should be 
performed to define whether these nodules are composed primarily of T cells or lymphocytes other 
than CLL cells or of CLL cells.  If the marrow is hypocellular, a repeat determination should be 
performed after 4 weeks, or until peripheral blood counts have recovered.  However, this time interval 
should not exceed 6 months after the last treatment.  A marrow biopsy should be compared with that 
of pretreatment marrow. In general practice, the use of a marrow biopsy for evaluating a CR is at the 
discretion of the physician.  
In clinical studies aiming at maximizing the CR rate, the quality of the CR should be assessed for 
MRD by flow cytometry or by immunohistochemistry. 
A controversial issue is how best to categorize the response of patients who fulfill all the criteria 
for a CR (including the marrow examinations described above) but who have a persistent 
anemia or thrombocytopenia or neutropenia apparently unrelated to CLL but related to drug 
toxicity.  We recommend that these patients be considered as a different category of remission:  CR 
with incomplete marrow recovery (CRi).  For the definition of this category, CRi, the marrow 
evaluation (described above) should be performed with scrutiny and not show any clonal infiltrate.  
In clinical studies, CRi patients should be monitored prospectively to determine whether their 
outcome differs from that of patients with detectable residual or with noncytopenic CR. 
 
 
 
 


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Chronic Lymphocytic Leukemia Response Definition (Hallek et al. 2008) (continued) 
Partial 
Response: 
(PR) 
To define a PR (partial remission): at least two of the criteria of Group A plus one of 
the criteria of Group B have to be met. The parameters below should be documented 
for no less than 2 months.  Constitutional symptoms persisting for >1 month should be 
recorded. 
Group A 
a. Decrease in the number of blood lymphocytes by 50% or more from the value 
before therapy. 
b. Reduction in lymphadenopathy (by PE and CT scans) as defined by the 
following: 
• 
A decrease in lymph node size by 50% or more either in the sum 
products of up to 6 lymph nodes, or in the largest diameter of the 
enlarged lymph node(s) detected prior to therapy. 
• 
No increase in any lymph node, and no new enlarged lymph node. In 
small lymph nodes (<2 cm), an increase of less than 25% is not 
considered to be significant. 
c. Reduction in the noted pretreatment enlargement of the spleen or liver by 50% 
or more, as detected by CT scan. 
Group B 
d. Blood count should show one of the following: 
• 
Neutrophils >1.5 x 109/L (1500/µL) without need for exogenous growth 
factors. 
• 
Platelet count >100 x 109/L (100 000/µL) or 50% improvement over 
baseline without need for exogenous growth factors. 
• 
Hemoglobin >110 g/L (11.0 g/dL), or 50% improvement over baseline 
without requiring red blood cell transfusions or exogenous 
erythropoietin. 
 


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Chronic Lymphocytic Leukemia Response Definition (Hallek et al. 2008) (continued) 
Progressive 
Disease: 
(PD) 
Progressive disease during or after therapy is characterized by at least one of the 
following: 
a. Lymphadenopathy:  Progression of lymphadenopathy is often 
discovered by physical examination and should be recorded. In CLL, the 
use of CT scans usually does not add much information for the detection 
of progression or relapse.  Therefore, the use of imaging methods to 
follow CLL progression is at the discretion of the treating physician. 
Disease progression occurs if one of the following events is observed: 
• 
Appearance of any new lesion, such as enlarged lymph nodes 
(>1.5 cm), splenomegaly, hepatomegaly, or other organ 
infiltrates. 
• 
An increase by 50% or more in greatest determined diameter of 
any previous site. 
b. An increase in the previously noted enlargement of the liver or spleen 
by 50% or more, or the de novo appearance of hepatomegaly or 
splenomegaly. 
c. An increase in the number of blood lymphocytes by 50% or more, with 
at least 5000 B-lymphocytes per µL. 
d. Transformation to a more aggressive histology (e.g., Richter syndrome).  
Whenever possible, this diagnosis should be established by lymph node 
biopsy. 
e. Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) 
attributable to CLL  
• 
During therapy:  Cytopenias may occur as a side effect of many 
therapies.  During therapy, cytopenias cannot be used to define 
disease progression. 
• 
After treatment:  The progression of any cytopenia (unrelated to 
autoimmune cytopenia), as documented by a decrease of Hb 
levels by >20 g/L (2 g/dL) or to <100 g/L (10 g/dL), or by a 
decrease of platelet counts by >50% or to <100 x 109/L 
(100,000/µL), which occurs at least 3 months after treatment, 
defines disease progression, if the marrow biopsy demonstrates 
an infiltrate of clonal CLL cells. 
 
Stable 
Disease:  
(SD) 
Patients who have not achieved a CR or a PR, and who have not exhibited progressive 
disease, will be considered to have stable disease (which is equivalent to a non-response). 
Source:  Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111:5446-56. 


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19 APPENDIX B- CONTRACEPTIVE GUIDELINES AND PREGNANCY 
Women Not of Childbearing 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 six 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 six 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. 
Contraceptive Guidelines for Women of Child-Bearing Potential: 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 30 days after stopping 
treatment. The highly effective contraception is defined as either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
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 six 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 patients on the study, the vasectomised male 
partner should be the sole partner for that patient. 
4. Use of a combination of any two 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 women of childbearing potential:  
• 
Oral contraception, injected or implanted hormonal methods are not allowed as IBRUTINIB 
potentially decreases the effectiveness of hormonal contraceptives. 
• 
IUD progesterone T  
• 
Female condom  
• 
Natural family planning (rhythm method) or breastfeeding  
• 
Fertility awareness  
• 
Withdrawal  
• 
Cervical shield 


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Women of child-bearing potential must have a negative serum or urine 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, for 30 days after discontinuation of study treatment, and should for an additional 
12 weeks (3 months in total after study drug discontinuation), and should not father a child in this 
period.   
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to TG 
Therapeutics Inc. within 24 hours of learning of its occurrence. The pregnancy should be followed up 
for 3 months after the termination of the pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the investigator 
to TG Therapeutics Inc.  Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study drug and reported by the investigator 
to TG Therapeutics Inc.  Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 


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20 APPENDIX C – 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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21 APPENDIX D – HEPATITIS B SEROLOGIC TEST RESULTS 
 


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22 APPENDIX E – INHIBITORS OF CYP3A 
Examples 
of 
inhibitors 
of 
CYP3A4/5 
can 
be 
found 
at 
the 
following 
website: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
and 
http://www.pharmacologyweekly.com/content/pages/online-drug-therapy-tables.   
The list below reflects information obtained from the website on May 6, 2014.  Please refer to the 
ibrutinib prescribing information for all updates at www.imbruvica.com. 
Inhibitors of CYP3A4/5 
Strong inhibitors: 
Moderate inhibitors: 
Indinavir 
Aprepitant 
Nelfinavir 
Erythromycin 
Ritonavir 
Fluconazole 
Clarithromycin 
Grapefruit juice 
Itraconazole 
Verapamil 
Ketoconazole 
Diltiazem 
Nefazodone 
 
Saquinavir 
 
Suboxone 
 
Telithromycin 
 
 
 
 
 
 

SAP_001.pdf: 
Official Title: 
NCT Number: 
Document Date: 
A Phase 3 Randomized Study to Assess the Efficacy and Safety 
of Ublituximab in Combination with Ibrutinib Compared to Ibrutinib Alone, 
in Patients with Previously Treated High-Risk Chronic Lymphocytic 
Leukemia (CLL)
NCT02301156 
SAP Version 2.2: 10 December 2020 


TG Therapeutics, Inc. 
 
Version 2.2 December 10, 2020 
UTX-IB-301 SAP 
Page 1 of 27 
 
Protocol UTX-IB-301 
Phase 3 
 
A Phase 3 Randomized Study to Assess the Efficacy and Safety of Ublituximab in 
Combination with Ibrutinib Compared to Ibrutinib Alone, in Patients with 
Previously Treated High-Risk Chronic Lymphocytic Leukemia (CLL) 
 
Statistical Analysis Plan 
 
Sponsor 
TG Therapeutics, Inc. 
2 Gansevoort Street, 9th Floor 
New York, NY 10014 
Tel: (212) 554-4484 
 
 
Study Coordination 
TG Therapeutics, Inc. 
2 Gansevoort Street, 9th Floor 
New York, NY 10014 
Tel: (212) 554-4484 
 
Medical Monitor 
, MD 
Tel: (212) 554-4484 
 
Study Chair 
, MD 
 
 
 
Tel: 
 (Office) 
Version 1.0 
Version 2.0 
Version 2.1 
Version 2.2 
September 9, 2014 
October 21, 2016 
January 27, 2017 
December 10, 2020 
 
 


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SPONSOR APPROVAL 
The undersigned have reviewed the format and content of this prospective statistical analysis plan 
(SAP) and have approved it for use to analyze the UTX-IB-301 study data. 
Reviewers: 
Signatures/Date: 
 / 
 
 
 / 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10-DEC-2020
10-DEC-2020
          


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DOCUMENT HISTORY 
Version Date  
Changes made since previous version 
 
1.0 
September 9, 2014 
Final SAP Version 1.0 Protocol 
2.0 
October 21, 2016 
Amended SAP per Version 2.0 Protocol Dated October 21, 2016 
2.1 
January 27, 2017 
Amended SAP per Version 2.2 Protocol Dated January 27, 2017 
2.2 
December 10, 2020 
Clarify analysis methods for efficacy endpoints 
 
 


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TABLE OF CONTENTS 
1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................... 6 
2 INTRODUCTION .................................................................................................................................. 7 
3 STUDY DESCRIPTION ........................................................................................................................ 8 
3.1 Study Design .................................................................................................................................................................. 8 
3.2 Study Treatment .......................................................................................................................................................... 9 
3.3 Schedule of Events .................................................................................................................................................... 10 
3.4 Study Objectives ........................................................................................................................................................ 11 
3.4.1 Primary Objective ............................................................................................................................................................................................... 11 
3.4.2 Secondary Objectives ........................................................................................................................................................................................ 11 
 11 
3.5 Power and Sample Size Considerations ........................................................................................................... 11 
3.5.1 Overall Response Rate ...................................................................................................................................................................................... 11 
3.6 Randomization ........................................................................................................................................................... 12 
3.7 Analysis PopulationS ............................................................................................................................................... 12 
4 GENERAL CONVENTIONS ............................................................................................................... 12 
4.1 Definition of Baseline............................................................................................................................................... 12 
4.2 Definition of Time ..................................................................................................................................................... 12 
4.3 Missing and Partial Data ......................................................................................................................................... 13 
4.4 Software ........................................................................................................................................................................ 13 
4.5 Changes to Planned Analyses ............................................................................................................................... 13 
5 STUDY POPULATION SUMMARIES ............................................................................................. 13 
5.1 Disposition ................................................................................................................................................................... 13 
5.2 Demographic and Baseline Characteristics .................................................................................................... 13 
5.3 Medical History .......................................................................................................................................................... 14 
5.4 History of Chronic Lymphocytic Leukemia .................................................................................................... 14 
5.5 Prior Treatment for Chronic Lymphocytic Leukemia ................................................................................ 14 
5.6 Prior and Concomitant Medications .................................................................................................................. 14 
5.7 Study Treatment Exposure ................................................................................................................................... 14 
6 EFFICACY ANALYSES ....................................................................................................................... 15 
6.1 Primary Efficacy Outcome ..................................................................................................................................... 15 
6.1.1 Primary Objective:  Overall Response Rate ............................................................................................................................................ 15 
6.1.2 Secondary Objectives ........................................................................................................................................................................................ 15 
6.2 Analysis Methods:  DOR and PFS ........................................................................................................................ 18 


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 18 
6.5 Multiplicity ................................................................................................................................................................... 18 
6.5.1 Primary Objective: Overall Response Rate ............................................................................................................................................. 18 
7 SAFETY ANALYSES ........................................................................................................................... 19 
8 ADVERSE EVENTS ............................................................................................................................ 20 
8.1 Laboratory Assessments ........................................................................................................................................ 20 
8.1.1 Variables .................................................................................................................................................................................................................. 21 
8.1.2 Statistical Analysis .............................................................................................................................................................................................. 22 
8.2 Vital Signs ..................................................................................................................................................................... 22 
8.2.1 Variables .................................................................................................................................................................................................................. 22 
8.2.2 Statistical Analysis .............................................................................................................................................................................................. 22 
8.2.3 Physical Exam ....................................................................................................................................................................................................... 22 
8.2.4 ECOG Performance Status ............................................................................................................................................................................... 22 
9 IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS ....................................... 23 
10 DATA QUALITY ASSURANCE ...................................................................................................... 24 
11 REFERENCES ................................................................................................................................... 25 
12 Appendix A – Imputation Rules for Missing Data .............................................................. 26 
 
 


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1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ANC  
absolute neutrophil count 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
CLL 
Chronic Lymphocytic Leukemia 
CMH 
Cochran–Mantel–Haenszel 
CR  
complete response 
CT 
Computerized Axial Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
°C  
degrees Celsius 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
ICH  
International Conference on Harmonization 
IRC 
Independent Review Committee 
ITT 
intent-to-treat 
IWRS  
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MRI  
magnetic resonance imaging 
NCI  
National Cancer Institute 
ORR 
overall response rate 
OS  
overall survival 
PD  
progressive disease 
PFS  
progression-free survival 
PR  
partial response 
PT 
MedDRA Preferred Term 
SAE  
serious adverse event 
SOC 
MedDRA System Organ Class 
TEAE 
treatment-emergent adverse event 
 


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2 INTRODUCTION 
The original statistical analysis plan (SAP) was based on TG Therapeutics Protocol UTX-IB-301, dated 
September 9, 2014.  This SAP, dated December 10, 2020 is based on the revised Protocol UTX-IB-301, 
dated July 31, 2017.  The SAP summarizes key aspects of the study to provide context for statistical 
methods and presents details of the statistical methods that the sponsor plans to use to address the 
study aims. The statistical principles applied in the design and planned analyses of this study are 
consistent with ICH guidelines E9 (Statistical Principles for Clinical Trials). 
 
The SAP may evolve over time, for example, to reflect the requirements of protocol amendments or 
regulatory requests.  However, the final SAP must be finalized, approved by the Sponsor, and placed 
on file before database is locked.  Deviations from the approved plan will be noted in the clinical study 
report. 


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3 STUDY DESCRIPTION 
3.1 STUDY DESIGN 
This study is a fixed-dose, randomized, two-arm Phase 3 trial to assess the efficacy and safety of 
ublituximab in combination with ibrutinib compared to ibrutinib alone in patients with CLL who have 
received at least one prior standard treatment regimen and who have at least one high-risk 
cytogenetic abnormality (17p deletion, 11q deletion, and/or P53 gene mutation). 
 
Following screening, patients meeting the inclusion/exclusion criteria will be randomized in a 1:1 
ratio to one of the following treatment regimens: 
• 
Arm A: Ublituximab + ibrutinib 
• 
Arm B: Ibrutinib 
 
Randomization will be stratified according to prior lines of therapy (1 prior vs. 2 or more prior lines 
of therapy) 
All study patients will be evaluated for response after cycles 2, 4, and 6, then every 3 cycles thereafter 
if patient is on active treatment, or approximately every 3 months thereafter if patient is in follow up.  
The best clinical response as well as disease progression will be determined by an Independent 
Review Committee (IRC).   
Patients will continue treatment until the occurrence of definitive disease progression, unacceptable 
toxicity, or withdrawal from the study due to investigator decision or other reasons.  Patients who 
discontinue study treatment for reasons other than disease progression will continue to be followed 
for progression and/or survival approximately every 3 months.   
Upon first assessment scan of the last randomized patient, and site submission of all required efficacy 
and safety data, the independent DSMB will review the primary and secondary efficacy analyses, and 
safety data.   
 
 
 
 


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3.2 STUDY TREATMENT 
Treatment will be administered on an outpatient basis in 4-week (28 day) cycles.  Patients 
randomized to Arm A will receive ublituximab and ibrutinib, while patients randomized to Arm B 
will receive ibrutinib alone.  Treatment cycle of study treatment is summarized in Table 1. 
TABLE 1: TREATMENT OVERVIEW BY CYCLE OF STUDY TREATMENT 
Cycle 1: 
Arm A 
Arm B 
Ublituximab 
Ibrutinib 
Ibrutinib 
Day 1 
Day 2 
Day 8 & 15 
Daily 
Daily 
≤150mg 
750 mg 
900 mg 
420 mg 
420 mg 
 
Cycles 2 through 6: 
Arm A 
Arm B 
Ublituximab 
Ibrutinib 
Ibrutinib 
Day 1 Cycles 2, 3, 4, 5, 6 
Daily 
Daily 
900 mg 
420 mg 
420 mg 
 
Beyond Cycle 6: 
Arm A 
Arm B 
Ublituximab 
Ibrutinib 
Ibrutinib 
Day 1 every 3 months thereafter 
(e.g. cycles 9, 12, etc.) 
Daily 
Daily 
900 mg 
420 mg 
420 mg 
 
Patients will continue treatment until the occurrence of definitive disease progression, unacceptable 
toxicity, or withdrawal from the study due to investigator decision or other reasons. 
 
 
 
 
 
 
 
 
 
 


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3.3 SCHEDULE OF EVENTS 
The Schedule of Events is presented in Table 2. 
TABLE 2: STUDY ASSESSMENTS AND TREATMENT SCHEDULE 
Cycle = 28 days 
Screen
* 
Cycle  11 
Cycles 2-62 
After Cycle 63 
End of  
study 
C2 
C3 
C4 
C5 
C6 
q3 Cycles (C9, 12, etc.) 
Procedure\Days 
-21-0 
D1 
D24 
D8 
D15 
Day 1 
Day 1 
Informed consent 
Х 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
Х 
 
 
 
 
 
 
 
 
 
 
 
Rai Staging 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
Х 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
Х 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs (pulse, BP, 
temp) 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BM aspirate/biopsy5 
Х 
 
 
 
 
 
 
 
 
 
 
 
12-lead EKG 
Х 
 
 
 
 
 
 
 
 
 
 
 
Tumor evaluation6 
X 
After the completion of cycles 2, 4 and 6 then after the completion of every 3 cycles  
if under treatment or every 3 months if in follow up 
 
Serology: HCV, HBV, CMV7 
Х 
 
 
 
 
 
 
 
 
 
 
 
MRD8 
 
 
 
 
 
For patients in PR or CR at response assessment 
intervals beginning at the Cycle 6 response assessment 
 
Hematology9 
X 
X 
X 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry8 
X 
X 
 
Х 
X 
X 
Х 
Х 
Х 
X 
X 
X 
PT/INR 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Serum Pregnancy Test10 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
Quantitative 
Immunoglobulin11 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
β2-microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
FISH Analysis12 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Evaluation15 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment Schedule 
Ublituximab Dose 
 
Х16 
X 
Х 
Х 
X 
X 
X 
X 
X 
X 
 
 
1 Physical Exam, Vital Signs, ECOG PS, Hematology and Serum Chemistry visit days have +/- 3 day window  
2 Physical Exam, Vital Signs, ECOG PS, Hematology and Serum Chemistry visit days have +/- 7 day window 
3 Physical Exam, Vital Signs, ECOG PS, Hematology and Serum Chemistry visit days have +/- 14 day window 
4 Day 2 visit only required for patients randomized into Arm A. 
5 Unilateral bone marrow aspirate and/or biopsy performed at investigator discretion in patients for whom assessment of extent of CLL involvement and 
bone marrow cellularity is important in determining eligibility.  In addition, a post-baseline bone marrow biopsy should be completed to confirm potential 
CR by radiological assessment. 
6 Scans for screening should be completed within 30 days prior to Day 1 of Cycle 1. Response tumor evaluations have a +/- 7 day window. Radiology 
assessment should include CT or MRI imaging of neck, chest, abdomen, and pelvis.     
7 Serum virology to include HBsAg, HBc antibody and CMV.  If HBcAg, HBc antibody, HCV or CMV is positive, patients must be evaluated for the presence of 
DNA/PCR 
8 Peripheral Blood sample draw (See study manual for all central lab instructions. +/- 7 day window for MRD sample).  For patients MRD negative by 
peripheral blood, a bone marrow sample should be completed to confirm MRD negativity. 
9 Must be obtained prior to ublituximab administration if on a day of infusion. 
10 For women of child bearing potential, completed within 3 days prior to Day 1 of Cycle 1 
11 IgA, IgE, IgG, IgM 
12 For del(13q), del(11q), del(17p), and (12)trisomy, IgHV and P53 gene mutation status in peripheral blood.  Central FISH analysis can be performed on 
UTX-IB-301 study or the TGTX-LAB-001 screening protocol.  
 
   
15 If clinically significant adverse event or abnormal result is observed that is not resolved by the end-of treatment visit, continue to monitor and record until 
stabilization or resolution of event 
16 Patients should receive up to 150 mg on Day 1 and 750 mg on Day 2.  Collect a hematology panel prior to Day 2/Cycle 1 infusion. 


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Ibrutinib Dose 
 
Days 1 – 28 (Daily) 
 
*Randomize Days -7 to 0 
 
 
3.4 STUDY OBJECTIVES 
3.4.1 PRIMARY OBJECTIVE 
The primary objective is to evaluate the effect of the addition of ublituximab to ibrutinib on antitumor 
activity, as measured by the overall response rate (ORR = CR + PR) in patients with previously treated 
CLL with documented high-risk cytogenetics. 
3.4.2 SECONDARY OBJECTIVES 
The secondary objectives are to evaluate the effect of the addition of ublituximab to ibrutinib with 
respect to: 
• 
Complete response (CR) rate 
• 
Duration of response (DOR) 
• 
Time to Treatment Response (TTR) 
• 
Achievement of minimum residual disease (MRD) negativity 
• 
Progression-free Survival (PFS) 
• 
Safety profile 
 
 
 
3.5 POWER AND SAMPLE SIZE CONSIDERATIONS 
3.5.1 OVERALL RESPONSE RATE 
 
 
 
 
 
 
 
 
 
 
 
 
The ORR study analysis will be performed when all ITT patients have the opportunity to complete 
efficacy, safety, and other assessments through at least 16 weeks of evaluation (first planned efficacy 
evaluation, allowing for a second evaluation to confirm a potential response at first assessment). 


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3.6 RANDOMIZATION 
In this open label study, approximately 120 patients will be centrally randomized in a 1:1 fashion to 
one of the two treatment regimens.  Investigators will use an interactive web response system 
(IWRS) which will assign patients to either treatment Arm A (ublituximab plus ibrutinib) or 
treatment Arm B (ibrutinib alone).  Randomization will be stratified by prior lines of therapy (1 prior 
vs. 2 or more prior lines of therapy). 
3.7 ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) population will include all randomized patients.  The Treated Population 
will include all patients who received at least one dose of study medication.  The Treated Population 
will be the same as the Safety Population.     
Any ITT patient who meets any of the following criteria below will not be included in the Per Protocol 
analysis: 
• 
Patients who do not meet the following required eligibility criteria: 
o Diagnosis of CLL which is confirmed as high-risk per the protocol requirement 
o Does not have measurable nodal disease 
o Has been previously treated with ibrutinib or a BTK inhibitor 
o Does not have a baseline or have at least one on-study post baseline efficacy 
evaluation by the independent radiology committee 
4 GENERAL CONVENTIONS 
Descriptive and inferential statistics will be used to summarize results of the study.  Standard 
descriptive statistics, such as mean, standard deviation, quartiles, minimum, and maximum, will be 
calculated for continuous variables. For discrete variables, descriptive analyses will be based on 
numbers of patients and related percentages.  
All tabular presentations will display two columns of results, one for each of the two treatment 
regimens.  Throughout this analysis plan, the phrase “by treatment regimen” will be understood to 
mean the two groups described in the previous sentence. 
In addition to tabular summaries, all relevant eCRF data will be summarized by patient listings. 
4.1 DEFINITION OF BASELINE 
In general, the last observed measurement prior to or on the first administration of study treatment 
will be considered the baseline measurement. 
4.2 DEFINITION OF TIME 
For the purpose of summarizing/analyzing efficacy data, time will be defined relative to the date of 
randomization.  Unless otherwise stated, for visits (or events) that occur on or after the date of 
randomization, time is calculated as: 
• 
time (days) = visit date (event date) – randomization + 1 
For visits (or events) that occur prior to randomization, time is calculated as: 


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• 
time (days) = visit date (event date) – randomization date 
 
For listings (such as for adverse events) of the quantity ‘days since first/last dose’ is defined as: 
• 
days since first/last dose = event date – date of first/last dose 
 
Events that occur on the same day as the first/last dose will therefore be described as occurring zero 
days from the first/last dose.  In most cases, listings will include the number of days since first/last 
dose of ublituximab/ibrutinib or ibrutinib; however, some listings may present the number of days 
since first/last dose of study treatment, which is a combination of two agents, or the dose of ibrutinib 
alone.  Labels and footnotes in the data presentations will specify clearly which reference date and 
therapeutic agent are used. 
4.3 MISSING AND PARTIAL DATA 
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 Appendix A – Imputation Rules for Missing Data. 
4.4 SOFTWARE 
Unless otherwise stated, all analyses will be conducted using SAS Version 9.2 or higher or other 
validated software.  
4.5 CHANGES TO PLANNED ANALYSES 
The Clinical Study Report will document any changes to the SAP made after data base is locked. 
5 STUDY POPULATION SUMMARIES 
5.1 DISPOSITION 
The number and percentage of patients who are included in ITT, Treated Population, Per Protocol 
populations and the number and percentage of patients withdraw from the study early will be 
presented by treatment regimen. For randomized patients who withdraw early, the number and 
percentage withdrawing by withdrawal reason will be presented.  
5.2 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
A summary of demographics and baseline characteristics will be presented by treatment arm for the 
ITT and Treated Population. 
The demographic characteristics consist of age, age category (defined below), sex, ethnicity, race, and 
Eastern Cooperative Oncology Group (ECOG) performance status.  Baseline height and weight will 
also be presented using standard descriptive statistics. 
Age (years) will be calculated as (date of informed consent – date of birth) / 365.25. 
Age categories, < 65 years and 65 years or older, will be presented using frequencies and percentages. 


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The number and percentage of patients’ ethnicity, race category, cytogenetics category will also be 
summarized. 
5.3 MEDICAL HISTORY 
A data listing will present medical history.  If useful for interpretation of the results of the study, a 
table will summarize the data. 
5.4 HISTORY OF CHRONIC LYMPHOCYTIC LEUKEMIA 
Tables will present information regarding the patients’ history of Chronic Lymphocytic Leukemia, 
including time since initial diagnosis to randomization, primary diagnosis, patient status (relapsed 
only, or relapsed and refractory), as well as the screening results of the disease assessments and prior 
lines of therapy. 
5.5 PRIOR TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA 
Use of prior treatment for CLL will be presented as frequency counts and percentages. 
Prior chemotherapy will be coded using the World Health Organization (WHO) and MedDRA 
dictionary and summarized by treatment arms for the safety population. 
By WHO Drug base substance preferred name using frequency counts and percentages. 
By regimen number using frequency counts and percentages on unique combinations of WHO Drug 
base substance preferred names. 
5.6 PRIOR AND CONCOMITANT MEDICATIONS 
All medications recorded on the CRFs will be coded using the WHO or MedDRA dictionary.  Prior and 
concomitant medications will be summarized by treatment arm in the ITT and Treated Population 
by anatomical therapeutic chemical (ATC) Class Level 4 and WHO Drug base substance preferred 
name. 
Prior medications are defined as medications with stop dates occurring before the date of first 
administration of any study treatment component.  Concomitant medications are defined as 
medications with start dates occurring on or after the date of first administration of any study 
treatment component and no more than 30 days after the last administration of any study treatment 
component.  Medications with start and stop dates that bracket the date of first administration of any 
study treatment component will be summarized as both prior and concomitant medications. 
For the purpose of summarizing prior and concomitant medications, incomplete medication start 
and stop dates will be imputed as detailed in Appendix A.  Based on imputed start and stop dates, 
medications that clearly stopped prior to date of first administration of any study treatment 
component will be included in the prior medications table, and medications that clearly started on or 
after date of first administration of any study treatment component will be included in the 
concomitant medications table.  All other medications will be included in both the prior and 
concomitant medications tables. 
5.7 STUDY TREATMENT EXPOSURE 


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The following will be summarized by treatment arm for each of the two study treatment components 
using descriptive statistics: 
• 
Number and percentage of patients who received at least one dose (Treated Population 
analysis) 
• 
Duration of exposure, calculated as (date of last dose – date of first dose + 1) (for subjects 
who are continuing on treatment at the time of data cutoff, the duration will be data cutoff 
date – date of first dose +1)  
• 
Number of doses received 
• 
Cumulative dose received 
 
A data listing of reasons for early treatment discontinuation will be summarized (including sites 
number, patient number, dates of first and last dose administered and last date of contact or visit) 
6 EFFICACY ANALYSES 
All efficacy analyses will be performed on the ITT population and Treated Population.  Measures of 
tumor response (i.e., ORR, CR rate, DOR, TTR and PFS) will be determined by an Independent Review 
Committee (IRC).   
6.1 PRIMARY EFFICACY OUTCOME 
6.1.1 PRIMARY OBJECTIVE:  OVERALL RESPONSE RATE 
ORR is defined as the proportion of patients with a best overall response of partial response (PR) or 
complete response (CR).  Patients who do not have a tumor response assessment for any reason will 
be considered non-responders and will be included in the denominator when calculating the ORR.  
For the ITT analysis, for each treatment group, the number of patients achieving a response will be 
divided by the total of patients in the ITT population to yield the proportion responding. 
The primary efficacy variable (i.e. ORR) will be analyzed in the ITT population first and then will also 
be analyzed for the Treated Population.     
The ORR will be compared between treatment groups by the CMH Test controlling for the 
randomization strata.  Testing of ORR will be at the 5%, 2-sided statistical significance level.   
ORR will also be analyzed based on Per Protocol patients.  Additional sensitivity analyses will also be 
performed as appropriate. 
6.1.2 SECONDARY OBJECTIVES 
6.1.2.1 COMPLETE RESPONSE RATE 
The CR rate is defined as the proportion of patients with a best overall response of complete response 
(CR).  Patients who do not have a tumor response assessment for any reason will be considered non-
responders and will be included in the denominator when calculating the CR rate.  For each treatment 
group, the number of patients achieving a CR will be divided by the total of patients in the Treated 
Population to yield the proportion responding. 


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The CR rate will be compared between treatment groups at the 5%, two-sided statistical significance 
level using the same methodology described in Section 6.1.1. 
6.1.2.2 DURATION OF RESPONSE 
The Duration of Response (DOR) is defined as the interval from the first documentation of CR or PR 
to the earlier of the first documentation of disease progression or death from any cause. 
The DOR rate will be compared between treatment groups at the 5%, two-sided statistical 
significance level using stratified log-rank test. The median DOR will be estimated by Kaplan-Meier 
method, The hazard ratio (HR) with 2-sided 95% confidence interval will be estimated using 
stratified Cox regression model.   The DOR analysis will be performed for responders only (CR/PR) 
in the ITT population. 
6.1.2.3 TIME TO TREATMENT RESPONSE 
The Time to Treatment Response (TTR) is defined as the interval from the date of randomization to 
the first documentation of CR or PR.  In this analysis, subjects who never reached response will be 
censored at the time of last assessment. 
This variable will be analyzed using stratified log-rank test and median TTR will be estimated via 
Kaplan-Meier methodology.  The HR with 95% CI will be analyzed using a stratified Cox regression 
model. 
6.1.2.4 MINIMAL RESIDUAL DISEASE NEGATIVITY RATE 
MRD negativity rate is defined as the proportion of patients in the Treated Population who are MRD 
negative, excluding any patients who remain on study treatment at the time of the analysis and have 
a Cycle 1/Day 1 start date less than 6 months from the time of the analyses.  For the sake of clarity, 
the MRD negative analysis will exclude those patients that are too early to evaluate because MRD 
negativity is only tested for patients on study > 6 months.  Patients who drop off study for any reason 
prior to their 6 month visit and do not have an MRD assessment will be included in the analysis and 
considered non-responders. 
For each treatment group, the number of patients achieving MRD negativity will be divided by the 
total number of eligible patients (see above paragraph) to yield the proportion responding.  The MRD 
negativity rate will be compared between treatment groups at the 5%, two-sided statistical 
significance level using the same methodology described in Section 6.1.1. 
6.1.2.5 PROGRESSION-FREE SURVIVAL 
Progression-free survival is defined as the time from the date of randomization until the date of first 
documentation of definitive disease progression or date of death from any cause, whichever occurs 
first.  Patients who die without a reported prior progression will be considered to have progressed 
on the day of their death.  Patients who did not progress or are lost to follow-up will be censored at 
the day of their last tumor response assessment.  If no baseline or post-baseline assessment is 
available, the patient will be censored at the date of randomization.  If death or PD occurs after 2 or 
more consecutive missing tumor response assessments, censoring will occur at the date of the last 
response assessment prior to the missed assessments.  The use of a new anticancer therapy prior to 


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the occurrence of PD will result in censoring at the date of last tumor response assessment prior to 
initiation of new therapy. 
This variable will be analyzed using stratified log-rank test, and median PFS will be estimated via 
Kaplan-Meier methodology.  PFS may not be formally analyzed at the time when the planned formal 
ORR analysis is conducted with approximately 120 patients who have had the opportunity to provide 
two efficacy assessments as it is expected that the majority of the patients from both treatment arms 
will not have progressed by the time of the primary ORR analysis (PFS may not be reliably estimated 
due to high censoring).  Following the primary analysis of ORR, PFS may be analyzed at a later date. 
PFS will be analyzed using a stratified Cox regression model with treatment effect and stratification 
effect to estimate HR and 95% CI. 
Censoring rules for PFS are summarized in Table 3. 
TABLE 3:  CENSORING RULES FOR PFS 
Situation 
Date of Progression or Censor 
Censored/ 
Progressed 
No baseline radiological tumor assessments 
Randomization date  
Censored 
No post-baseline tumor assessments and no 
death reported before data cut-off 
Randomization date 
Censored 
Disease progression 
Date of progression 
Progressed 
No disease progression 
Date of last tumor assessment 
Censored 
Treatment discontinuation for toxicity or 
other reasons with no disease progression 
per IRC 
Date of last tumor assessment  
Censored 
Patient lost to follow-up without disease 
progression 
Date of last tumor assessment 
Censored 
Death before first tumor assessment 
Date of death  
Progressed 
Death between adequate tumor assessments 
Date of death 
Progressed 
Death or disease progression after ≥ 2 
missed tumor assessments  
Date of last tumor assessment before 
missed assessments or randomization 
date if no other tumor assessment in 
between 
Censored 
Withdrawal due to symptomatic 
deterioration without further tumor 
assessments 
Date of last tumor assessment before 
discontinuation 
Censored 
Patient use of any anti-cancer therapy 
and/or surgery for curative intent. 
Date of last tumor assessment prior to 
therapy or surgery, whichever occurs first 
Censored 
Note: Progression-free survival = date of event / censor – randomization date + 1 
 
Once the progression and survival dates are derived, PFS will be calculated as follows for patients 
with a PFS event: 
PFS (days) = date of PD or death due to any case – randomization date + 1 
(with censoring indicator = event) 
For those patients who are censored for a PFS event: 
PFS (days) = date of censoring – randomization date + 1 
(with censoring indicator = censored) 


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6.2 ANALYSIS METHODS:  DOR AND PFS 
The date of definitive progression will be the timepoint at which progression is first identified and 
confirmed by the independent radiographic committee. Death following the discontinuation of study 
drug will be considered as an event for the DOR and PFS calculation. Data will be censored on the 
date of the last tumor assessment (including assessments with a Not Evaluable (NE) outcome) for 
patients who: 
• 
Start alternative anti-tumor therapy prior to disease progression 
• 
Do not have disease progression within 30 days after discontinuation of study drug(s) 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
6.5 MULTIPLICITY 
6.5.1 PRIMARY OBJECTIVE: OVERALL RESPONSE RATE 
 
If the primary efficacy analysis of ORR is statistically significant for the ITT population, the following 
secondary outcomes will be tested: 


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• 
Complete response rate 
• 
Duration of response 
• 
Time to response 
 
For each of these outcomes, ublituximab + ibrutinib will be compared to ibrutinib.  The Hochberg 
approach will be used to control the type I error rate.  The null hypotheses state that the secondary 
outcomes do not differ between ublituximab + ibrutinib and ibrutinib.  The three p-values associated 
with these three secondary outcomes are denoted p1, p2, and p3.  The ordered p-values, from largest 
to smallest, are denoted p(1) ≥ p(2) ≥ p(3).  Specifically: 
• 
If p(1) is less than 0.05, all three null hypotheses will be rejected. 
• 
Otherwise, if p(2) is less than 0.025, the null hypotheses associated with p(2) and p(3) will be 
rejected. 
• 
Otherwise, if p(3) is less than 0.0167, the null hypothesis associated with p(3) will be rejected. 
 
If the primary efficacy analysis of ORR is not statistically significant, the secondary efficacy variable 
defined above will not be formally conducted.   
7 SAFETY ANALYSES 
Safety analyses will be performed on the Treated Population.  Safety evaluations will be based on the 
incidence, intensity, and type of adverse events, as well as on clinically significant changes in the 
patient’s physical examination, vital signs, and clinical laboratory results.  Safety variables will be 
tabulated and presented by study drug actually received. 
Because there is no pre-specified safety outcome defined in terms of AEs, clinically relevant 
laboratory parameters, or vital signs, any formal comparisons between the treatment arms with 
respect to specific safety parameters will be post-hoc. 


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8 ADVERSE EVENTS 
Each AE and SAE term recorded on the case report forms (CRFs) will be mapped to a preferred term 
(PT) using the MedDRA dictionary.  The investigator will classify the severity of AEs and SAEs using 
the NCI CTCAE v4.0 and will assess the relationship of each event to study treatment. 
All AEs and SAEs occurring on study will be listed by treatment drug, center, and patient.  The 
frequency and percentages of patients with treatment-emergent adverse events (TEAEs) will be 
tabulated by system organ class (SOC) and PT, where treatment-emergent is defined as any AE that; 
• 
occurs on or after Cycle 1/Day 1 and through the end of the study or, if serious, up through 
30 days after the last dose of study treatment; 
• 
is present before Cycle 1/Day 1 but worsens in intensity or the investigator subsequently 
considers treatment-related. 
 
For the purpose of calculating treatment emergence and inclusion in summary tables, incomplete 
onset dates will be imputed as detailed in Appendix A – Imputation Rules for Missing Data.  
Summaries will display incidence by study drug received and total incidence, and PTs within each 
SOC will appear in decreasing order of total incidence as well as in alphabetical order.  At each level 
of summarization, a patient will be counted only once for each AE, SOC, or PT experienced within that 
level. 
Related TEAEs, serious TEAEs, Grade 3 or higher TEAEs, related serious TEAEs, related Grade 3 or 
higher TEAEs, and TEAEs resulting in discontinuation of study treatment will be similarly 
summarized.  Summaries of TEAEs by relationship to the study treatment will also be prepared. 
At each level of summarization, a patient will be counted only once for each AE, SOC, or PT 
experienced within that level.  In the summation for AE severity, within each level of AE, SOC, or PT 
experienced, the one with the highest severity will be included.  In the summation for AE’s 
relationship to the study drug, within each level of AE, SOC, or PT experienced, the one with the 
closest relationship to the study drug will be included. 
AEs will be summarized for the treatment that the patient last receives prior to the occurrence of the 
AEs. 
8.1 LABORATORY ASSESSMENTS 
Laboratory data for hematology and serum chemistry tests will be reported in International Units. 
Individual values outside the central laboratory reference ranges will be identified (by “H” for high 
and “L” for low) in the data listings displaying the absolute values for each patient. 
 
 
 
 


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8.1.1 VARIABLES 
8.1.1.1 LOCAL LABORATORY ANALYSES 
The following laboratory evaluations will be performed at a laboratory affiliated with the site: 
• 
Hematologic profile will be performed at baseline and on Days 1, 2 (Arm A only for 
ublituximab), 8 & 15 of Cycle 1, Day 1 of Cycles 2-6, and every 3 cycles thereafter. 
 
Hematologic Profile 
Hematocrit 
Neutrophils 
Platelet count 
Hemoglobin 
Lymphocytes 
 
Erythrocyte count 
Monocytes 
 
Absolute neutrophil count 
Eosinophils 
 
Absolute leukocyte count 
Basophils 
 
 
• 
Serum chemistry will be obtained at baseline and on Days 1, 8 & 15 of Cycle 1, Day 1 of Cycles 
2-6, and every 3 cycles thereafter  
 
Serum Chemistry 
Albumin 
Creatinine 
SGOT [AST] 
Alkaline phosphatase 
Glucose 
SGPT [ALT] 
Bicarbonate 
LDH 
Sodium 
BUN 
Magnesium 
Total bilirubin 
Calcium 
Phosphorus 
Total Protein 
Chloride 
Potassium 
Uric acid 
 
• 
Serum β-HCG test will be obtained within 3 days prior to the initiation of therapy for women 
of childbearing potential. 
• 
Coagulation lab tests to include, PT, aPTT, and INR will be drawn at screening. 
• 
Quantitative immunoglobulin (IgG, IgM, IgA, IgE) test will be obtained at pre-dose on Day 1 
and Day 15 of Cycle 1, on Day 1 of Cycle 3 and Cycle 6. 
• 
Urinalysis to be obtained at screening (dipstick for pH, protein, glucose, blood, nitrite, 
leukocytes. 
• 
Beta2-microglobulin to be obtained at screening. 
• 
Serum Virology at screening to include HBsAG, HBc antibody, HCV antibody, and  CMV 
8.1.1.2 CENTRAL LABORATORY ANALYSES 
The following laboratory evaluations will be performed at a central laboratory contracted by the 
Sponsor: 
• 
FISH analyses at screening for del(13q), del(11q), del(17p), and (12)trisomy, t(11:14), IgHV 
and p53 mutation 
• 
Minimal Residual Disease negativity analyses in patients with documented PR or CR at 
response assessment intervals beginning at the Cycle 6 response assessment. 
 


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8.1.2 STATISTICAL ANALYSIS 
Continuous laboratory test results will be summarized descriptively by study drug received for actual 
values and for changes from Cycle 1 Day 1.  Visits to be summarized include all scheduled post-Cycle 
1 Day 1 visits. 
Shift from baseline tables for laboratory parameters will be presented. Categories will be based on 
CTCAE grade (where applicable) or by high/low flags (where CTCAE grades are not defined).  Data 
will be analyzed at all post-Cycle 1 Day 1 visits, by worst grade post-Cycle 1 Day 1.  Laboratory tests 
that have high and low abnormalities will be summarized separately for each direction (e.g., 
hypocalcemia and hypercalcemia). 
Abnormalities in laboratory tests that the investigator considers clinically significant will be 
recorded and summarized as AEs. 
8.2 VITAL SIGNS 
8.2.1 VARIABLES 
The following vital signs will be summarized: 
• 
Blood pressure (systolic and diastolic, mmHg) 
• 
Oral temperature (Celsius) 
• 
Pulse rate (beats/min) 
• 
Respiration rate (breaths/min) 
• 
Body weight (kg) 
8.2.2 STATISTICAL ANALYSIS 
Summary tables of vital signs and change from baseline will be presented for all scheduled visits 
where vital signs were assessed.  All recorded vital sign data will be listed. 
8.2.3 PHYSICAL EXAM 
Physical examination data will be presented in a data listing. 
8.2.4 ECOG PERFORMANCE STATUS 
ECOG Performance Status will be summarized as shift from baseline tables by visit using frequencies 
and percentages at all scheduled visits where performance status was assessed. 


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9 IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS 
Major protocol deviations from entry criteria and treatment compliance will be summarized as far as 
they can be extracted from numeric or coded study data. 


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10 DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be ensured by verification and cross check of the CRFs 
against the investigator’s records by the study monitor (source document verification) and by the 
maintenance of a drug–dispensing log by the investigator.  Collected data will be entered into a 
computer database and subject to electronic and manual quality assurance procedures. 


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11 REFERENCES 
Hallek M., Cheson B.D., Catovsky D., Caligaris-Cappio F., Dighiero G., Dohner H., . . . Kipps R.J. (2008). 
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the 
International Wrokshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institue - Working Group 1996 Guidelines. blood, 12(111), 5446-5456. 


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12 APPENDIX A – IMPUTATION RULES FOR MISSING DATA 
Terminology in this appendix: first dose = first administration of any study treatment  
The date of event (death/progression) is the documented date of event. 
 
The missing date will be handled as follows: 
What is missing in event date 
Imputed value is 
Year 
 
• 
If month is missing or cannot be confirmed 
to be earlier than the month of last 
assessment 
the year of last assessment 
• 
If, without considering year, the date of the 
event is confirmed to be earlier than the date 
of the last assessment (e.g., January vs 
November or May 15 vs May 1) 
the year of last assessment+1 
Month 
 
• 
If year of the event is missing or is confirmed 
to be the same as the year of the last 
assessment 
Month of the last assessment unless the day of death 
is earlier than the day of the last assessment (5th vs. 
10th).  In this case the month will be imputed as the 
month after the month of the last assessment 
• 
If year of the event is confirmed to be after 
the year of the last assessment 
January  
Day 
1, unless the resulting imputed date is earlier than 
the last assessment date.  In this case the imputed 
day is the day of the last assessment 
 
Adverse Event  
• 
If onset date is completely missing, onset date is set to date of first dose. 
• 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
o If year = year of first dose, then set month and day to month and day of first dose. 
o If year < year of first dose, then set month and day to December 31st. 
o If year > year of first dose, then set month and day to January 1st. 
• 
If month and year are present and day is missing: 
o If year=year of first dose and 
❖ if month = month of first dose then set day to day of first dose date. 
❖ if month < month of first dose then set day to last day of month. 
❖ if month > month of first dose then set day to 1st day of month. 
o if year < year of first dose then set day to last day of month. 
o if year > year of first dose then set day to 1st day of month. 
• 
For all other cases, set onset date to date of first dose. 
 


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Concomitant Medications/Medical History 
• 
If start date is completely missing, start date will not be imputed. 
• 
If (year is present and month and day are missing) or (year and day are present and month 
is missing), set month and day to January 1. 
• 
If year and month are present and day is missing, set day to 1st day of month. 
• 
If end date is completely missing, end date will not be imputed. 
• 
If (year is present and month and day are missing) or (year and day are present and month 
is missing), set month and day to December 31. 
• 
If year and month are present and day is missing, set day to last day of the month.