Conditions: Chronic Lymphocytic Leukemia CLL Progression CLL/SLL
Keywords: CLL progression
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
This study evaluates the efficacy and safety of umbralisib and ublituximab (U2) as salvage therapy in patients with chronic lymphocytic leukemia (CLL) who have progressed either on a BTK inhibitor (BTKi) or BCL-2 inhibitor. The study will evaluate this combination in two parallel cohorts and subjects will be assigned based on which class of novel agent-containing regimen was used prior. Cohort A will consist of patients who progress after BTKi containing regimens and Cohort B will consist of patients who progress after a BCL-2 containing regimen. Subjects who progress on a regimen containing both a BTKi and a BCL-2 inhibitor, will be enrolled in cohort B. Each cohort will be evaluated independently of each other.

Detailed description:
This is a single-center, two cohort Phase 2 clinical trial investigating the effectiveness of umbralisib and ublituximab in patients with progressive CLL. Cohort A will consist of patients who who have progressed after receiving either a BTK inhibitor (BTKi) or BCL-2 inhibitor.

Arms:
arm 1: Patients who progress after a BTKi containing regimen arm 2: * Patients who progress after BCL-2 containing regimens
* Patients who progress on a regimen containing both a BTKi and a BCL-2 inhibitor

Interventions: intervention 1: Umbralisib intervention 2: Ublituximab
Intervention descriptions: intervention 1: * Lead-in cycle of 28 days (Cycle -1) of umbralisib monotherapy, 800mg oral daily
* Continued 800mg oral daily dosing in all subsequent cycles (combination therapy cycles 1-6, then continued monotherapy cycle 7 and beyond) intervention 2: -Co-administered on days 1 and 2 (dose split over days 1 and 2), 8, 15 of cycle 1 then on day 1 for subsequent cycles 2-6

Protocol document:
Prot_SAP_000.pdf: 
 
 
  
i 
 
 
 
 
COVER LETTER 
 
Protocol Title: Phase II study of umbralisib plus ublituximab (U2) after CLL progression on 
targeted therapy  
 
IRB Protocol #: 19-06020316 
IND#: 144076 
NCT#: NCT04149821 
Version Date: May 24, 2021 
Sponsor:  Weill Cornell Medicine 
Sponsor Investigator:  John Allan, M.D. 
 
Principal Investigator: 
 
John Allan, M.D. 
1305 York Avenue, 7Pth
P Floor, NY, NY 10021 
646-962-2064 
646-962-1617 
Joa9069@med.cornell.edu 
 
 
 
Participating Sites: Weill Cornell Medicine  
 
 
This trial is supported by TG Therapeutics, Inc. (Tracking Number:  U2-NTG-004) 
 
  
 


Phase II study of umbralisib plus ublituximab (U2) after CLL progression on targeted therapy 
IRB Protocol #: 19-06020316 
IND#: 144076 
Version Date: May 24, 2021 
Sponsor:  Weill Cornell Medicine 
Sponsor Investigator:  John Allan, M.D. 
Principal Investigator: 
John Allan, M.D. 
1305 York Avenue, 7Pth
P Floor, NY, NY 10021 
646-962-2064
646-962-1617
Joa9069@med.cornell.edu
Co-Investigators: 
Richard R. Furman M.D. 
Peter Martin M.D. 
Sarah Rutherford M.D. 
John P. Leonard M.D. 
Jia Ruan M.D. Ph.D 
Lisa Roth M.D. 
Gail Roboz M.D. 
 Sangmin Lee M.D. 
Pinkal Desai M.D. 
Ellen Ritchie M.D. 
Dan Landau M.D. Ph.D. 
Statistician: 
Paul Christos Dr.Ph, M.S. 
Participating Sites: Weill Cornell Medicine 
This trial is supported by TG Therapeutics, Inc. (Tracking Number:  U2-NTG-004) 


IRB Protocol #: 19-06020316 
Version Date: May 24, 2021 
 
ii 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM


 
 
  
1 
 
Protocol Summary 
 
Title: Phase II Study of umbralisib plus ublituximab (U2) after CLL progression on targeted therapy  
Study Drugs: 
Umbralisib 
Ublituximab 
Indication: 
BTK or BCL-2 inhibitor Resistant CLL 
Study Phase: 
Phase II 
Subjects to be enrolled: 
24 subjects 
Cohort A Post BTKi Therapy: 12 Subjects  
Cohort B Post BCL-2 Therapy: 12 Subjects 
Background and Rationale: 
Novel agents have permanently altered therapeutic strategies in patients with chronic lymphocytic 
lymphoma (CLL).  In relapsed settings, Bruton’s tyrosine kinase (BTK), B cell lymphoma-2 (Bcl-2) and 
Phosphatidylinositol 3 kinase delta (PI3Kδ) inhibitors have proven efficacy and garnered FDA approval 
in multiple therapeutic settings. Each drug demonstrates unique toxicities, efficacy, drug-drug 
interactions and monitoring schedules, making patient and disease specific characteristics important to 
consider when prescribing a particular therapy. For CLL, ibrutinib, a BTK inhibitor (BTKi), has become 
a standard of care for frontline therapy and is commonly the first line novel agent in patients with relapsed 
or refractory disease, owing to its ease of administration, safety profile, and durable efficacy[1-3]. 
Venetoclax, a Bcl-2 inhibitor, has also been shown to be safe and effective in salvaging BTKi resistant 
disease and is now approved as a frontline therapy in combination with obinutuzumab and for patients 
with relapsed CLL after 1 prior line of treatment in combination with rituximab [4-6]. Its use is 
complicated by a potential for life threatening tumor lysis which requires an intensive monitoring 
program during initiation and dose escalation, which can be burdensome to patients and physician 
practices, and may limit its widespread use outside of academic centers. Lastly, the use of PI3Kδ 
inhibitors such as idelalisib or duvelisib, have been relegated to third or fourth line treatment options 
largely due to historically inferior efficacy and toxicity secondary to increased infectious risks and 
autoimmune complications such as colitis, pneumonitis and hepatitis [7, 8]. 
Despite the increasing numbers of therapeutic options, the optimal sequencing of therapies remains 
unknown with only limited retrospective data available estimating therapeutic benefit of each class of 
drug after progression on a BTKi.   
Umbralisib, a PI3Kδ inhibitor, has proven safe and effective in relapsed disease when combined with 
ibrutinib and or ublituximab [9, 10].  Umbralisib is built on a different chemical backbone than previous 
PI3Kδ inhibitors such as idelalisib and duvelisib, and to date has demonstrated a significantly improved 
safety profile making it an attractive option as a salvage regimen in patients with BTK or BCL2 resistant 
disease.  
Methodology: 
 
We propose a single center Phase II study to evaluate the efficacy and safety of umbralisib and 
ublituximab (U2) as salvage in patients with CLL who have progressed either on a BTK inhibitor or 
BCL-2 inhibitor. The study will enroll in two parallel cohorts and subjects will be assigned based on 
which class of novel agent containing regimen was used prior. Cohort A will consist of patients who 
progress after BTKi containing regimens and Cohort B will consist of patients who progress after a 
BCL-2 containing regimens. Subjects who progress on a regimen containing both a BTKi and a BCL-2 
inhibitor, will be enrolled in cohort B. Each cohort will be evaluated independently of each other.  
Objectives: 
 
Primary Objective: The primary objective of this study will be to evaluate the overall response rate 
(ORR) of umbralisib in combination with ublituximab in patients with CLL who have progressed on a 
BTK or BCL-2 inhibitor.  
Secondary Objectives: Secondary objectives will be to evaluate complete remission rate, duration of 
response and safety.  


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Exploratory Objectives: Progression free survival (PFS) and overall survival (OS) will be assessed as 
exploratory objectives. We will also be collecting samples for future use in research as yet undetermined 
subject to review and approval by TG Therapeutics, Inc. Potential correlative studies may evaluate 
molecular predictors of response or resistance, changes in immune profile, and clonal evolution patterns 
in patients exposed to U2.  
Drug Administration and Study Schedule:  
 
Subjects that meet eligibility criteria will be enrolled and initiate therapy with umbralisib monotherapy 
for a one cycle lead in Cycle -1. During this lead in cycle of 28 days subjects will initiate umbralisib 
monotherapy at 800mg orally daily. Starting at C1D1 subjects will initiate combination therapy with U2, 
on 28 day cycles. During combination therapy, starting cycle 1 subjects will be treated with umbralisib 
800mg orally daily and continue daily dosing through all subsequent cycles. Ublituximab will be co-
administered on days 1 and 2 (split over days 1 and 2), 8, 15 of Cycle 1 then on D1 for subsequent cycles 
2-6. After cycle 6, combination therapy will be completed and subjects will continue with monotherapy 
umbralisib daily. Subjects will be eligible for response assessment if they complete two cycles of therapy 
or are noted to have documented clinical progression of disease prior to first study mandated radiographic 
assessments. Radiographic evaluation for response will occur prior to C3, then occur prior to C7D1 and 
then every 6 months for up 2 years. Subjects who remain on study after two years will be radiographically 
evaluated annually thereafter until complete remission or upon evidence of clinical progression. Subjects 
that have achieved a CR will be followed clinically with physical exam and labwork but will not be 
required to undergo routine scanning. Study visits will occur monthly on D1 for Cycles 1-7 then every 3 
months thereafter as long as patient continues to have clinical benefit.  
Subject Selection: 
 
Inclusion Criteria: 
A subject will be eligible for participation in the study if he/she meets the following criteria: 
1. Subject must have confirmed diagnosis of CLL/SLL and a treatment indication based upon 2018 
International Workshop on CLL (IWCLL) criteria. 
2. Subject must have documented disease progression on a BTK and or BCL-2 containing 
regimen as the most recent prior line of therapy. Subjects who were treated with a regimen 
containing both classes of novel agents will be allowed to enroll and will be enrolled into 
Cohort B. Subjects who receive a temporizing non-experimental treatment such as 
monotherapy with an anti-CD20 monoclonal antibody or corticosteroids including high dose 
methylprednisolone for up to 2 cycles immediately after progression on a BTK or BCL-2 
inhibitor will be considered for enrollment after discussion with the study sponsor.   
3. Subject must be ≥18 years of age. 
4. Subject must have an Eastern Cooperative Oncology Group performance status of ≤2. 
5. Subject must have adequate bone marrow function to meet the below thresholds. 
a. Absolute neutrophil count of >750 cell/μL in absence of G-CSF for 7 days prior to 
screening. 
b. Platelet count of ≥ 30,000 cells/μL independent of transfusion for 21 days prior to 
enrollment 
6. Subject must have adequate organ function and meet the thresholds below: 
a. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Subjects with bilirubin 
exceeding this limit due to Gilbert’s disease are eligible.   
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if 
no liver involvement or ≤5 x the ULN if known liver involvement. 
c. Creatinine clearance >30 ml/min/1.73mP2
P as calculated by the MDRD equation. 
7. Ability to swallow and retain oral medication. 
8. Female subjects who are not of child-bearing potential (see Appendix: CONTRACEPTION 
GUIDELINES AND PREGNANCY), and female subjects of child-bearing potential who have 


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a negative serum pregnancy test within 3 days prior to initial trial treatment.  Male subjects of 
reproductive potential may not participate unless they agree to use medically acceptable 
contraception.  Female subjects of child-bearing potential and all male partners, and male 
subjects must consent to use a medically acceptable method of contraception throughout the 
study period and for 4 months after the last dose of study drug.  
9. Willingness and ability to comply with trial and follow-up procedures, and give written informed 
consent.  
Exclusion Criteria: 
A subject will be ineligible for the study if he/she meets any of the following criteria: 
10. Subject has had prior exposure to a PI3K inhibitor at any point in treatment history. 
11. Subject has discontinued the BTKi or BCL2 due to intolerance. Intolerance will be defined as 
discontinuing prior BTKi or BCL2 therapy for any reason without evidence of progression. 
Subjects who were re-challenged after discontinuation for therapeutic reasons will be allowed if 
the toxicity did not recur or was managed without indication for discontinuation.  Subjects who 
progress on BTKi or BCL2 therapy who were on a reduced dose due to an AE/intolerance are 
eligible as long as progression has been documented on that reduced dose.   
12. Subject has history of or clinical or radiographic evidence of, or has biopsy proven Richter’s 
transformation or prolymphocytic leukemia. 
13. Subject has undergone an allogeneic stem cell transplant. 
14. Subject has received an autologous hematologic stem cell transplant within 6 months of study 
entry.  
15. 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. 
16. Subject is known to be positive for HIV. 
17. Subject has history of hepatitis C infection, active infection with hepatitis B or active 
cytomegalovirus (CMV) as determined by positive PCR.  
18. Previous exposure to BTK or Bcl-2 inhibitor therapy within 14 days of initiating study treatment 
on Cycle - 1 Day 1, or previous exposure to anti-cancer therapy including chemotherapy, 
radiotherapy, or investigational therapy, including other investigational targeted small molecule 
agents within 21 days of initiating study treatment on Cycle 1 Day 1.  
19. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal 
infections of skin or nails. 
20. History of anaphylaxis (excluding infusion related reactions) in association with previous anti-
CD20 administration. 
21. A known history or active autoimmue disease even if not requiring systemic 
immunosuppression. Subjects with known history of immune thrombocytopenic purpura 
or autoimmune hemolytic anemia secondary to CLL are allowed to enroll.Malabsorption 
syndromes 
22. Irritable bowel syndrome with greater than 3 loose stools per day as a baseline.  
23. Any severe and/or uncontrolled medical conditions or other conditions that could affect 
participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (New York Heart 
Association functional classification III-IV [see Appendix:  NYHA Classifications]) 
b. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
CHF, or myocardial infarction within 6 months of enrollment.  
c. Concomitant use of medication known to cause QT prolongation or torsades de pointes 
should be used with caution and at investigator discretion. 


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d. Poorly controlled or clinically significant atherosclerotic vascular disease including 
cerebrovascular accident (CVA), transient ischemic attack (TIA), symptomatic 
peripheral arterial disease, angioplasty, cardiac or vascular stenting within 6 months of 
enrollment. 
24. Females who are pregnant or lactating. 
Statistical Analysis Plan: 
 
Currently available retrospective evidence demonstrates an ORR of ~35-40% when idelalisib is used as 
first salvage after ibrutinib failure [11]. Given umbralisib’s unique molecular properties and combination 
therapy with ublituximab, we hypothesize a response rate of 55% using U2 as first salvage. Salvage rates 
with novel agents after venetoclax failure in subjects considered double refractory are unknown. We 
anticipate close to 90% of patients enrolled in cohort B will have double refractory disease and represent 
a high risk group. Given these limitations, we anticipate a response rate of 40% in this group based off 
the efficacy seen with idelalisib after ibrutinib failure.  
 
Because this is a pilot study, no formal sample size/power calculation is required. Given the anticipated 
different patient populations in each cohort, no cross cohort comparisons will be performed. However, 
with 12 patients enrolled in cohort A, an exact binomial (Clopper-Pearson) 95% confidence interval for 
the overall response rate can be constructed to have a width of approximately 57.6% (25.0%, 82.5%). 
This calculation assumes that the overall response rate will approach 55% in cohort A. 
 
Similarly, with 12 patients enrolled in cohort B, an exact binomial (Clopper-Pearson) 95% confidence 
interval for the overall response rate can be constructed to have a width of approximately 56.9% (14.1%, 
70.9%). This calculation assumes that the overall response rate will approach 40% in cohort B.  
 
Given this is a pilot study with low subject enrollment with lack of power, analysis of outcomes will 
remain descriptive. Assuming adequate follow-up time, Kaplan-Meier survival analysis will be used to 
assess, progression-free survival (PFS), and overall survival (OS), in the entire cohort.  All p-values will 
be two-sided with statistical significance evaluated at the 0.05 alpha level.  Ninety-five percent 
confidence intervals for 1) the overall response rate, 2) median PFS/OS-time, and 3) PFS/OS proportions, 
will be calculated to assess the precision of the obtained estimates.  All analyses will be performed in 
SAS Version 9.4 (SAS Institute, Inc., Cary, NC) and Stata Version 15.0 (StataCorp, College Station, 
TX). 
 
 
 
 


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Table of Contents 
1. 
STUDY OBJECTIVES ......................................................................................................... 8 
1.1. 
Primary Objectives ......................................................................................................... 8 
1.2. 
Secondary Objectives ..................................................................................................... 8 
1.3 
Exploratory Objectives ................................................................................................... 8 
2. 
BACKGROUND ................................................................................................................... 8 
2.1 
Disease ............................................................................................................................ 8 
2.2 
Rationale ......................................................................................................................... 9 
2.3 
Investigational Agents - Umbralisib ............................................................................. 10 
2.3.1 
Umbralisib .................................................................................................................... 10 
2.3.2  Umbralisib Non-Clinical Studies ................................................................................. 10 
2.3.3 
Non-Clinical Pharmacokinetics .................................................................................... 11 
2.3.4  Non-Clinical Toxicity ................................................................................................... 11 
2.3.5  Umbralisib Clinical Pharmacokinetics/Pharmacodynamics ........................................ 12 
2.3.6 
Umbralisib Clinical Studies .......................................................................................... 12 
2.4 
Investigational Agents – Ublituximab .......................................................................... 13 
2.4.1 
Ublituximab .................................................................................................................. 13 
2.4.2 
Ublituximab Non-Clinical Studies ............................................................................... 13 
2.4.3 
Ublituximab Non-Clinical Pharmacokinetics .............................................................. 14 
2.4.4 
Ublituximab Clinical Pharmacokinetics/Pharmacodynamics ...................................... 14 
2.4.5 
Ublituximab Clinical Studies Safety/Efficacy ............................................................. 15 
2.5 
Risk/Benefit Assessment .............................................................................................. 16 
3. 
SUBJECT SELECTION .................................................................................................... 17 
3.1 
Study Population .......................................................................................................... 17 
3.2  
Inclusion Criteria .......................................................................................................... 17 
3.3  
Exclusion Criteria ......................................................................................................... 18 
4. 
REGISTRATION PROCEDURES ................................................................................... 20 
4.1 Patient Registration ............................................................................................................. 20 
5. 
STUDY PROCEDURES .................................................................................................... 20 
5.1  
Schedule of Evaluations ............................................................................................... 20 
5.1.1 
Screening Visit ............................................................................................................. 24 
5.1.2 
Treatment Phase ........................................................................................................... 24 
5.2. 
Treatment Administration ............................................................................................ 27 
5.2.1  Ublituximab .................................................................................................................. 28 
5.2.2  Management of Infusion Related Reactions ................................................................ 29 
5.2.3  Umbralisib .................................................................................................................... 30 
5.3  
General Concomitant Medication and Supportive Care Guidelines ............................ 31 
5.4  
Duration of Therapy and Criteria for Removal from Study ......................................... 31 
5.4.1  Procedures for Subject Removal if Less Than PR at Completion of Combination 
Therapy ......................................................................................................................... 32 
5.5  
Duration of Follow Up ................................................................................................. 32 


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6. DOSING DELAYS/DOSE MODIFICATIONS ................................................................... 33 
6.1 
Ublituximab .................................................................................................................. 33 
6.2 
Umbralisib .................................................................................................................... 33 
7. 
PHARMACEUTICAL INFORMATION ......................................................................... 38 
7.1 
Investigational Agent – Ublituximab ........................................................................... 38 
7.2  
Investigational Agent – Umbralisib ............................................................................. 39 
7.3 
Availability ................................................................................................................... 39 
7.4 
Investigational Agent Ordering .................................................................................... 39 
7.5 
Investigational Agent Accountability ........................................................................... 40 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................ 40 
9. 
MEASUREMENT OF EFFECT ....................................................................................... 40 
9.1. 
Response Criteria ......................................................................................................... 40 
9.1.1 
Complete Response ...................................................................................................... 40 
9.1.2 
Partial Response ........................................................................................................... 41 
9.1.3 
Progressive Disease ...................................................................................................... 41 
9.1.4 
Stable Disease ............................................................................................................... 42 
9.2. 
Duration of response .................................................................................................... 42 
9.3. 
Progression-Free Survival ............................................................................................ 42 
9.4. 
Overall Survival ........................................................................................................... 42 
10. DATA REPORTING / REGULATORY CONSIDERATIONS ..................................... 42 
10.1  
Data Collection ............................................................................................................. 42 
10.2  
Regulatory Considerations ........................................................................................... 43 
11. STATISTICAL CONSIDERATIONS .............................................................................. 43 
11.1  
Study Design/Endpoints ............................................................................................... 43 
11.2  
Analysis of Endpoints .................................................................................................. 43 
11.3  
Interim Analysis ........................................................................................................... 44 
11.4  
Reporting and Exclusions ............................................................................................. 44 
12. ADVERSE EVENT REPORTING REQUIREMENTS ................................................... 44 
12.1 
Adverse Event Definition ............................................................................................. 45 
12.1.1  Ublituximab Risks ........................................................................................................ 45 
12.1.2  Umbralisib Risks .......................................................................................................... 45 
12.1.3  Ublituximab + Umbralisib Combination Risks ............................................................ 46 
12.2  
Adverse Event Characteristics and Related Attributions ............................................. 47 
12.3  
Recording of Adverse Events ....................................................................................... 48 
12.4 
Reporting of AE to WCM IRB ..................................................................................... 48 
12.5  
Definition of SAE ......................................................................................................... 48 
12.6  
Reporting of SAE to IRB ............................................................................................. 48 
12.7   Reporting of SAE to FDA ............................................................................................ 48 
12.8  
Reporting of SAE to TG Therapeutics ......................................................................... 49 
12.9  
AE/SAE Follow Up ...................................................................................................... 50 


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13. DATA AND SAFETY MONITORING PLAN (DSMP) ................................................. 50 
REFERENCES ............................................................................................................................ 51 
APPENDIX A:  CONTRACEPTION GUIDELINES AND PREGNANCY .......... 54 
APPENDIX B:  NEW YORK HEART ASSOCIATION CLASSIFICATION ..................... 56 
 
 
 


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1. Study Objectives 
 
The objective of this study is to assess the efficacy and safety of umbralisib in combination with 
ublituximab (U2) in patients after progression on Bruton’s tyrosine kinase (BTK) or B-cell 
lymphoma-2 (Bcl-2) inhibitors.  
 
1.1. Primary Objectives 
 
Primary Objective: The primary objective of this study will be to evaluate the overall response rate 
(ORR) of umbralisib plus ublituximab in patients with CLL who have progressed on a BTKi or BCL-2 
inhibitor. 
 
1.2. Secondary Objectives 
 
 
Secondary Objectives: Secondary objectives to be evaluated in the study will be complete remission rate, 
duration of response, and safety. 
 
1.3 Exploratory Objectives 
 
Exploratory Objectives: Progression free survival (PFS) and overall survival will be exploratory 
objectives. We will also be collecting samples for future use in research as yet undetermined subject to 
review and approval by TG Therapeutics, Inc.  Potential correlative studies may evaluate molecular 
predictors of response or resistance, changes in immune profile, and clonal evolution patterns in patients 
exposed to U2.  
 
 
 
2. Background 
 
2.1 Disease 
 
Chronic lymphocytic leukemia (CLL) is one of the most common leukemias diagnosed in the 
United States with approximately 20,000 new cases each year [12]. The median age at diagnosis 
is 71 and follows an indolent and prolonged asymptomatic interval for the majority of patients. 
Symptomatic disease is characterized by the increased accumulation of leukemic cells in the 
peripheral blood, spleen, lymph nodes and bone marrow which lead to B symptoms, bulky 
adenopathy, splenomegaly and the onset of cytopenias. Early studies have shown that early 
intervention with treatment at diagnosis could not meaningfully impact patient survival and thus 
upon diagnosis patients are actively monitored until symptoms of the disease manifest [13].   
 
Over past the 20 years there has been numerous prognostic factors that impact outcomes to 
standard CIT regimens. Specifically IGHV mutational status and cytogenetic abnormalities have 
the ability to identify patients at risk of early progression or who will have inferior outcomes 
with chemo immunotherapy [14-16]. Increasingly mutational data has identified patients at high 
risk of failure to CIT regimens with mutations in SF3B1, NOTCH1, TP53, BIRC3 and EGR2 
independently predicting early progression and or poor outcomes to standard chemo 
immunotherapy (CIT) regimens [17-21]. 
 


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Given the early and long term toxicities associated with CIT and the significant proportion of 
patients that have poor outcomes when used in salvage settings highlights an important unmet 
need in the treatment of patients with CLL. The advent of novel therapies such as BTK, PI3 
kinase δ and Bcl-2 inhibitors have provided durable and effective therapies for patients with high 
risk disease that have failed standard CIT regimens [2, 22, 23]. Importantly the BTK inhibitor 
ibrutinib is approved for frontline treatment by the Federal Drug Administration for patients with 
CLL providing the first upfront small molecule therapy for all patients with CLL [1].   
 
Current management trends for CLL are moving away from CIT based therapy to upfront 
therapy with novel agents such as ibrutinib. Combination BTK and BCL-2 inhibitors that may 
provide prolong treatment free intervals and deep remissions and are currently being tested in 
frontline and relapsed settings. Upon relapse it remains unknown how patients will respond to 
repeated courses of these agents and or whether prolong durable disease control can be achieved 
with repeated courses of novel therapies. In relapsed previously treated settings, despite the use 
of these agents, patients with high risk disease still remain at risk for progression and thus 
represent a shifting unmet need [24]. There remains an ongoing need for additional agents and 
combinations of treatments with non-overlapping toxicities and unique mechanisms of action. 
 
2.2 Rationale 
 
In relapsed settings, BTK, BCL-2 and PI3Kδ inhibitors have proven efficacy and are FDA 
approved in multiple therapeutic settings. Each class of drug demonstrates unique toxicities, 
efficacy, drug- drug interactions and monitoring schedules, making patient and disease specific 
characteristics important to consider when prescribing a particular therapy. Ibrutinib, BTKi, has 
become a standard of care for frontline therapy and is commonly the first line novel agent 
administered in patients with relapsed or refractory disease, owing to its ease of administration, 
safety profile, and durable efficacy [1, 2, 25]. Venetoclax, a Bcl2 inhibitor, has also been shown 
to be safe and effective in salvaging BTK resistant disease but currently is only approved for use 
in 17p deleted relapsed/refractory settings with likely broader approval for use after 1 prior therapy 
in 2018 based on the Murano study [4, 5]. Its use is complicated by a potential for life threatening 
tumor lysis which requires an intensive monitoring program upon drug initiation and escalation, 
which can be burdensome to patient and physician practices and may limit its widespread use 
outside of academic centers. Lastly, the use of PI3Kδ inhibitors such as idelalisib, have been 
relegated to third or fourth line treatment options largely due to efficacy and toxicity secondary to 
increased infectious risks and autoimmune complications such as colitis, pneumonitis and 
hepatitis. Despite multiple therapeutic options the optimal sequencing of therapies remains 
unknown with only limited retrospective data available estimating therapeutic benefit of each class 
of drug after progression on a BTKi [26].   
 
 
Umbralisib, a PI3Kδ inhibitor, has proven safe and effective in relapsed disease as a monotherapy 
and when combined with ibrutinib and or ublituximab [9, 10, 27].  Umbralisib has well 
documented safety profile which differs from previous PI3Kδ inhibitors making it an attractive 
option as a salvage regimen in patients with BTK resistant disease in that it does not require an 
intensive monitoring program upon drug initiation or inpatient hospitalization. Ublituximab is a 
novel anti-CD20 antibody that has proven safe and effective in rituximab treated patients as 
monotherapy and also in combination with novel agents [28-30]. Additionally, for patients that 


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have progressed on venetoclax and ibrutinib, idelalisib remains an option for salvage though this 
is complicated by toxicities and the effectiveness of PI3Kδ inhibitors in this setting is unknown. 
We propose a multi-center Phase II study to evaluate the efficacy and safety of umbralisib and 
ublituximab (U2) as salvage in patients with CLL who have progressed either on a BTK or BCL-
2 inhibitor. 
 
2.3 Investigational Agents - Umbralisib 
 
2.3.1 Umbralisib 
 
Umbralisib is a highly specific and orally available PI3Kδ inhibitor with nanomolar inhibitor 
potency and high selectivity for delta compared to alpha, beta, and gamma isoforms with a delta 
IC50 of 22.23 nM compared to >10,000, 1,116, and 1065nM respectively for alpha, beta and 
gamma isoforms. The PI3Ks are a family of enzymes involved in various cellular functions, 
including cell proliferation and survival, cell differentiation, intracellular trafficking and 
immunity. The delta isoform of PI3K is highly expressed in cells of hematopoietic origin and are 
strongly implicated in various hematologic malignancies.  
 
2.3.2  Umbralisib Non-Clinical Studies 
 
The potency and specificity for PI3kδ has been evaluated in both in vitro and in vivo models. 
Data from a homogenous time resolved fluorescence (HTRF) based enzyme assay demonstrated 
the specificity of umbralisib to PI3kδ with >1000, 50 and 48 fold selectivity for δ over α, β, and γ 
isoforms respectively indicating the primary mode of action is via inhibition of the δ isoform.  
 
To confirm potency and selectivity for the PI3Kδ isoform, inhibition of CD63 activation whole 
blood was determined. Samples were collected from healthy volunteers and treated with vehicle 
or increasing concentrations of compound prior to activation of fMLP and FcεR1 signaling, 
which is mediated through PI3K γ and δ isoforms respectively. By measuring CD63 surface 
expression the EC 50 was 3274nM and 66.22nM after activation via fMLP and FcεR1 
respectively, demonstrating selectivity of umbralisib for the δ isoform.  
 
Umbralisib has been tested in an LPS induced human whole blood proliferation assay with data 
suggesting that 100-1000nM concentration is sufficient to cause inhibition of B cell proliferation 
by 50-80%. Additionally, this finding was confirmed using a similar proliferation assay in the 
mouse demonstrating a slightly lower potency with only 50% reduction in proliferation at 
1000nM. This was confirmed with in vivo experiments in mice pretreated with increasing 
concentrations of umbralisib which indicated that a circulating plasma concentration of ~3μM 
was necessary to cause arrest of B cell proliferation by 50% in normal mice.  
 
Similarly, inhibition of LPS-induced AKT phosphorylation was determined ex vivo using 
isolated mouse splenocytes. In these studies umbralisib caused a dose dependent reduction in 
phosphorylation of AKT.     
 
Next proliferation of immortalized leukemic cells representative different hematologic 
malignancies were treated with umbralisib demonstrating different potencies (Study No. IVT-5264-


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11 
 
LCA-01). Overall 50% growth inhibition for the majority of B, T, and monocytic cell lines was 
achieved at concentrations of 0.5-7.5 μM of umbralisib.  
 
Lastly the activity of umbralisib was tested in vivo within an adoptive transfer eu-TCL1 mouse 
model of CLL (Maharaj et al IWCLL 2017). In these studies umbralisib was compared to 
duvelisib and idelalisib. Anti-tumor activity was similar between all three molecules. Umbralisib 
was found to have less effect on Treg numbers comparatively to the two other drugs. Umbralisib 
mice experienced significantly lower incidence of severe adverse events compared to duvelisib 
mice. Additionally duvelisib combined with a CK1e-inhibitor was able to partially restore Treg 
numbers suggesting CK1ε inhibition by umbralisib may influence Treg survival.  
 
2.3.3 Non-Clinical Pharmacokinetics 
 
Pharmacokinetic studies following single dose and repeat dose administration were performed in 
mice, rats, dogs and cynomolgus monkeys. Except for a P-gp inhibitory potential, the results 
demonstrated no DDI effects against major CYPs, conjugating enzymes, and transporters evaluated.  
 
Absorption of umbralisib was rapid with peak concentrations (Tmax) achieved within 2 hours 
after oral dosing in all species with moderate clearance. Oral bioavailability was approximately 
30-50% in all species except in rats where oral bioavailability was >90%. Elimination half-life 
(T1/2) was 5.26 hours in mice, 1.59 hours in rats, 3.21 hours in monkeys and 20.63 hours in 
dogs. 
 
The primary elimination route after oral administration was found to be fecal with no detectable 
levels found in urine upon single dose administration in rats.  
 
2.3.4  Non-Clinical Toxicity 
 
In acute single dose oral toxicity studies, umbralisib was well tolerated at a dose of 2000 mg/kg 
in male and female rats. The animals tolerated 2000mg/kg with no adverse findings with no 
mortality observed after 14 days of observation. In mice umbralisib was well tolerated at a dose 
of 1000mg/kg though mortality was observed in the confirmatory single dose study of 
1000mg/kg and 2000mg/kg. Less than 500mg/kg was found to be tolerated in the study.  
 
In a 28 day repeated dose study performed in CD1 mice, no umbralisib-related mortality 
occurred during the study. Umbralisib treatment related effects found in clinical pathology were 
slight decreases in leukocytes and lymphocytes at 750mg/kg/day, increases in cholesterol at 150 
and 750mg/kg/day and increases in AST, ALT and GGT at 750mg/kg/day in female mice only. 
After a 14 day recovery period there was complete recovery of organ weight changes and 
microscopic findings of liver abnormalities noted in female mice. Based on these studies the no-
observed-adverse-effect-level (NOAEL) was considered to be 150mg/kg/day.  
 
A similar study with repeated dosing was performed in dogs. Umbralisib treatment related 
clinical effects were observed in dogs dosed at 655 and 196.5 mg/kg/day consisting of 
dehydration, diarrhea, vomiting, and ocular discharge. Based on severity, 3 animals were 
euthanized and the remaining animals had doses reduced. After reduction of dosing, treatment 
related clinical effects were seen primarily at 400mg/kg/day including diarrhea, vomiting, ocular 


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12 
 
discharge and partial palpebral closure. Once daily oral administration in dogs was well tolerated 
in dogs at levels of 50 and 150mg/kg/day with the GI tract being the target organ system based 
on clinical signs and symptoms. The NOAEL was determined to be 150mg/kg/day. 
 
2.3.5  Umbralisib Clinical Pharmacokinetics/Pharmacodynamics 
 
Two healthy subject bioequivalence studies have been completed. The first study, TGR-1202-PK 
101, was performed to assess the mean plasma concentration of umbralisib over time. In general, 
administration of umbralisib under fed conditions results in a higher rate of exposure relative to 
when the drug was administered in fasting conditions. Food increased both the extent and rate of 
exposure of umbralisib. The peak plasma levels of umbralisib increased by over 173% when 
administered with food. Using this data, a 334mg dose of umbralisib in fasting conditions can be 
extrapolated to an oral dose of 200mg of umbralisib under fed conditions.  
 
The second bioequivalence study was performed to assess different formulations of product. The 
mean rate and extent of exposure to umbralisib were higher following administration of 
micronized drug product compared to the original drug product formulation. The peak plasma 
levels of umbralisib increased by over 124% following administration of the micronized drug 
product formulation in fasting conditions.  
 
Pharmacokinetic sampling was performed on TGR-1202 101 in patients with relapse and 
refractory heme malignancies with 24 hour sampling conducted on day 1 of cycle 1 and cycle 2. 
Umbralisib was rapidly absorbed Tmax ~2 hours with steady state concentrations achieved by 
Day 15 of dosing with a half-life of ~100 hours. The improved exposure with the micronized 
formulation of umbralisib in the healthy volunteer study was confirmed during the Phase 1 dose 
escalation study with the 800mg dose demonstrating a mean Cmax of ~4500 ng/Ml with a mean 
steady state concentration of ~3500 ng/Ml measured 24 hours after dosing which is well above 
the IC90 of PI3Kδ of ~400ng/mL.  
 
2.3.6 Umbralisib Clinical Studies 
 
TGR-1202-101 
 
Umbralisib has been evaluated in a single agent Phase I dose escalation study TGR-1202-101 in 
patients with relapsed and refractory hematologic malignancies which is published [27]. Patients 
were enrolled in 3+3 dose escalation design starting at 50mg daily with subsequent cohorts 
evaluating doses up to 1800mg daily. The primary objective was to determine the maximal 
tolerated dose (MTD). At the end of the study, 90 patients were enrolled with low rates of grade 
3 or 4 adverse events. No significant safety concerns have been recognized or reported in the 
trial up through 1200mg daily of the micronized formulation. The most common treatment-
emergent adverse events were diarrhea (43%), nausea (42%), and fatigue (31%) The most 
common grade 3 or 4 adverse events were neutropenia (13%), anemia (9%) and 
thrombocytopenia (7%). Serious adverse events considered at least possibly related to umbralisib 
occurred in seven patients: pneumonia (3%), lung infection (1%), febrile neutropenia (1%) and 
colitis (2%). The MTD was found to be 1200mg. A dose dependent response has been observed 


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13 
 
with umbralisib with a dose of 800mg or higher producing significant nodal reductions among 
CLL patients with response rates approaching 60%.  
 
UTX-TGR-103 
 
Ublituximab plus umbralisib has also been studied in subjects with previously treated CLL/SLL 
or NHL in a Phase I/Ib study. Additionally, cohorts evaluating ublituximab in combination with 
umbralisib as a doublet and with ibrutinib as a triplet or in combination with ublituximab, 
umbralisib and bendamustine have been performed and are accruing. These studies have been 
presented in abstract form demonstrating durable responses and low rates of Grade 3 or 4 
toxicities. Common toxicities of all grades in >20% of patients treated across all studies with the 
U2 combination were confined to neutropenia, nausea, diarrhea, and fatigue.  
 
2.4 Investigational Agents – Ublituximab 
 
2.4.1 Ublituximab 
 
Ublituximab is a monoclonal recombinant anti-CD20 immunoglobulin, produced by a stable 
expression in a clone of the rat myeloma cell line YB2/0. Ublituximab displays the classic 
structure of IgG1 immunoglobulins. It is a chimeric antibody composed of a murine variable 
region fused onto a human constant region. Due to a specific glycosylation pattern of its FC 
region, ublituximab displays an increased affinity for the FCγRIIIa and induces a higher in vitro 
antibody dependent cellular cytotoxicity (ADCC) against B cells compared to rituximab and 
ofatumumab.  
 
2.4.2 Ublituximab Non-Clinical Studies 
 
Ublituximab specifically targets human CD20 antigens expressed on Raji cells with a high 
affinity (equilibrium dissociation constant KD= 1x10P-8
P and dissociates from CD20 faster than 
rituximab (RTX).  
 
Exploratory investigations suggested both ADCC and complement dependent cytotoxicity 
(CDC) play a role in killing of B cells since ublituximab mediated lysis was inhibited by the 
depletion of NK cells and by complement inactivation at high antibody concentrations.  
 
NK cells from CLL patients displayed the same cytotoxic activity against tumor cell lines 
suggesting the patient derived NK cells have normal capacity to be activated. In the presence of 
NK cells from CLL patients, ublituximab mediates more than 80% ADCC of Raji cells at the 
highest antibody concentration tested, 10ng/mL.  
 
Complement dependent cytotoxicity was measured with ublituximab in Raji cells demonstrating 
an EC50 of 1.5 to 2 fold higher CDC activity for RTX compared with ublituximab. Similar 
results were seen in WIL2-S lymphoma cells.  
 
No apoptosis was seen in ublituximab exposed cells without effector cells or complement present 
and direct killing from binding CD20 is not the mechanism of action of cell kill for the molecule.  


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In vivo CLL clearance studies have been performed and have shown complete clearance of 
human CLL cells injected into SCID mice at 1mg/kg at 30 minutes of administration. The 
clearance was complement independent as the same effect was seen in SCID-NOD mice. 
Additionally, its cell clearance was specific for CD20 as controls did not demonstrate CLL death.  
 
Ublituximab efficacy versus RTX has been investigated in a xenograft follicular lymphoma 
model. An ublituximab dose of 100mg/kg demonstrated superior antitumor activity with a 21 
delay in tumor growth compared to the same dose of RTX treated mice.  
 
Cross reactivity studies were performed on normal adult human tissues. The study confirmed 
binding was restricted to CD20 expressing cells and restricted to lymphoid tissues.  
 
2.4.3 Ublituximab Non-Clinical Pharmacokinetics 
 
Pharmacokinetic studies following single dose administration were performed in rabbits and 
cynomolgus monkeys.  
 
A single-dose pharmacokinetic study at doses of 0.3, 10, 100 mg/kg given intravenously. The 
mean terminal half-life was 7 days at 10 or 100mg/kg of ublituximab with Cmax of 211 and 
2086 μg/mL respectively.  
 
In single dose toxicology studies with doses up to 100mg/kg no treatment-related effects on 
mortality, clinical signs, body weight, food consumption, and gross necropsy. No clinically 
significant changes in blood chemistry values were noted on day of sacrifice.  
 
Repeated dose toxicology studies have been performed. At 10mg/kg no clinical signs were 
observed. No treatment related effects on mortality, body weight, food consumption, hematology 
parameters, clinical chemistry or coagulation parameters were observed. At the 50mg/kg dose, 
two animals had shown signs of distress. Body weight loss was noted and slight reduction of 
food consumption were observed in males. Under the experimental conditions of the repeat dose 
study, the NOAEL was established at 10mg/kg 
 
No reproductive or developmental studies have been conducted. In humans, cross reactivity 
studies demonstrated that no staining was observed in genital systems and it did not cross react 
with human placenta.  
 
2.4.4 Ublituximab Clinical Pharmacokinetics/Pharmacodynamics 
 
Ublituximab has been investigated in 10 sponsored clinical trials in patients with relapsed and 
refractory hematologic malignancies. Pharmacokinetics (PK) of ublituximab has been 
determined in subjects with relapsed or refractory CLL in a dose escalation Phase I study. Main 
PK findings demonstrated intrasubject variability for ublituximab serum concentrations over 
different time points and at all dose levels ranging from 10%-220%. Exposure appeared to 
increase more than dose proportionally with increasing dose over the tested ranges. Clearance 
after single and repeated infusion decreased with increasing dose thereby increasing terminal 


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15 
 
half-life. Lastly upon additional dosing of 4 weekly doses of 450mg resulted in higher serum 
concentrations at Day 50 indicating accumulation of free ublituximab in serum is maintained 
after seven successive infusions.  
 
Significant lymphocyte depletion was observed in all subjects reflecting the intended biological 
activity ublituximab. Lymphocyte depletion was maximal after the 4Pth
P dose with median 
depletion of 97% relative change persisting for one month. After 8 weekly doses lymphocyte 
depletion was unchanged but persisted for over 6 months after the last dose.  
 
2.4.5 Ublituximab Clinical Studies Safety/Efficacy 
 
CD20-0703 
 
The first in human trial was initiated in November 2008 CD20-0703. Thirty-three subjects were 
treated which established the safety and schedule of the drug. Of the 33 subjects 45% completed 
all infusions. Of the 18 subjects who discontinued 13 did due to lack of efficacy, 2 due to AEs 
and 1 withdrew consent. A total of 332 adverse events (AEs) were experienced with 170 of them 
attributable to ublituximab. Of those 170 AEs, 146 occurred during the study infusion period. 
Drug related grade 3 and 4 events were reported in 63.6% and 27.3%, respectively most 
commonly related to neutropenia, infusion reactions, and elevated liver enzymes. The most 
frequent drug-related AEs were infusion related reactions (60.6%), pyrexia (54.5%), neutropenia 
(45.5%), thrombocytopenia (30.3%), headache (24.2%), chills (21.2%), elevated liver enzymes 
(18.2%), nausea and asthenia (12.1%). 
 
Twenty three infusion related reactions (IRR) were reported in 20 subjects. Sixteen of the IRRs 
were Grade 2, and 7 were Grade 3. Sixteen of the 23 IRRs occurred after the first infusion of 
ublituximab, 3 after the second infusion, and 4 after subsequent infusions. Fifteen drug-related 
infections were reported in 9 subjects. Ten of the 15 were mild to moderate upper respiratory 
infections, herpes outbreaks, or anal abscesses. Grade 3 or greater infections were noted in 5 
patients in heavily pretreated patients with listeriosis, pulmonary aspergillosis, varicella and 
staph aureus sepsis.  
 
Regarding efficacy, no complete remissions (CR) were reported. Out of 18 evaluable patients 5 
(27.5%) were in partial remission (PR) in Part I at month 4 and 7 (63.6%) were in PR in part II at 
month 4. Rapid and profound lymphocyte depletion was observed and sustained in most 
subjects. No dose limiting toxicity was reported.  
 
UTX-TGR-103 
 
The doublet U2 which will be utilized in this protocol has been evaluated in a Phase I/Ib trial in 
CLL/SLL and NHL, initially reported by (Lunning et al ASH 2015). In the doublet cohort one 
dose limiting toxicity (DLT) of Grade 4 neutropenia occurred in CLL cohort which later resolved 
in later cycles. In this study the most common AEs of Grade 3 or higher occurring in more than 
3% of patients were neutropenia (28%), diarrhea (8%), abdominal pain (8%), pneumonia (8%), 
thrombocytopenia (4%), asthenia (4%), febrile neutropenia (4%), sepsis (4%). Grade 3 or greater 
IRRs were experienced in only 1% of subjects.  


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16 
 
 
In the doublet cohort the combination was found to be effective with an overall response rate 
(ORR) of 80% in CLL/SLL patients with a 10% CR rate. 
 
Currently a Phase III study UTX-TGR-304 Unity CLL study was initiated Feb 2016. This study 
is a 4 arm study evaluating the combination doublet U2 versus monotherapy umbralisib, 
monotherapy ublituximab, and combination obinutuzumab and chlorambucil. No results are 
currently available but 3 INDSRs have been reported during the trial. Anaphylactic shock, 
multiple organ failure and tumor lysis syndrome all of which have been closed.  
 
Clinical data summary 
 
Over 400 subjects have been exposed to ublituximab. Exposure has ranged in dose from 450mg 
to 1200mg both as induction and maintenance. The maximal tolerated dose has not been 
established but in oncology setting the 900mg dose has been chosen for additional studies. In all 
studies, infusion-related reactions were the most frequent drug-related AE, typically occurring 
during the first ublituximab infusion. Infusion related reaction symptoms may include, but are 
not limited to: chills, fever, weakness and flushing. Grade 3-4 neutropenia, rarely associated with 
a febrile episode, has been reported and usually resolved either spontaneously or in a few days 
with G-CSF support. Drug-related Grade 3 thrombocytopenia and Grade 3-4 pancytopenia has 
also been reported. Asymptomatic, isolated, and transient Grade 2-3 drug-related elevated liver 
enzymes have been observed as well. Most subjects who experience ublituximab related adverse 
events may have a dose interruption or delay, and usually resume at the original dose. 
 
Seventy-five patients have been exposed to combination therapy (U2) through the ongoing Phase 
I/Ib clinical trials in patients with relapsed or refractory NHL or CLL as of July 2017. Twenty-
eight (28%) percent of patients experienced Grade 3/4 neutropenia. No other Grade 3/4 events 
occurred in ≥ 10% of patients in the doublet cohort of UTX-TGR-103. 
 
2.5 Risk/Benefit Assessment 
 
Overall, the data from non-clinical studies in non-human species have not revealed any 
potentially serious toxicities that would preclude the use of umbralisib in patients with 
hematologic malignancies. Further, data from the ongoing studies of umbralisib has not revealed 
any unexpected safety trends, and umbralisib has been well tolerated up through 1200 mg QD of 
the micronized formulation, with patients now on umbralisib for durations in excess of four-
years; however long term safety data is only available from a limited number of patients, and 
should therefore be cautiously extrapolated to other target populations. Considering the clinical 
activity demonstrated by the class of PI3Kδ inhibitors to date, along with the preliminary activity 
demonstrated by umbralisib thus far, in conjunction with manageable safety profile, the potential 
benefit-risk ratio of umbralisib is anticipated to be positive in patients with hematologic 
malignancies. Upon the administration of ublituximab to subjects with CD20-positive 
lymphoproliferative disorders, one should be aware of the AEs reported in the safety data from 
the completed and ongoing Phase I studies with ublituximab and the known side-effects reported 
thus far with other anti-CD20 monoclonal antibodies. 
 


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17 
 
Preliminary safety profile of ublituximab has been inferred from two Phase I studies in advanced 
stage subjects with CLL and lymphoma exposed to 4 to 8 weekly infusions of the product, and 
from a limited number of B-Cell Lymphoma subjects exposed to ublituximab in combination 
with other anti-cancer agents for longer durations. It should therefore be cautiously extrapolated 
to other target populations and other schedules of ublituximab infusions and or combinations. 
Taking into account the above mentioned risks, special attention has to be focused on 
management of acute infusion-related reactions and monitoring of complete blood cell count in 
order to detect and treat if necessary early or late episodes of neutropenia. In conclusion, 
considering the more active pre-clinical profile of ublituximab compared with rituximab in B-
cell lymphoproliferative disorders, the rapid, profound and sustained blood lymphocyte 
depletion, the interim assessment of response and the manageable toxicity observed in the Phase 
I and II studies, the potential benefit-risk ratio of ublituximab is anticipated to be positive in 
subjects with B-cell malignancies. 
 
 
3. Subject Selection 
 
3.1 Study Population 
 
Subjects with a diagnosis of CLL/SLL and who have had progressive disease on either a BTK 
inhibitor, BCL-2 inhibitor, or combination regimen containing one or both of those two classes 
of drugs will be eligible for participation in this study.  Subjects who have received each class of 
drug in any sequence will be eligible to enroll.  
    
3.2 Inclusion Criteria 
 
A subject will be eligible for participation in the study if he/she meets the following criteria: 
 
1. Subject must have confirmed diagnosis of CLL/SLL and a treatment indication based 
upon 2018 InternationalWorkshop on CLL (IWCLL) criteria. 
 
2. Subject must have documented disease progression on a BTK and or BCL-2 
containing regimen as the most recent prior line of therapy. Subjects who were treated 
with a regimen containing both classes of novel agents will be allowed to enroll and 
will be enrolled into Cohort B. 
Subjects who receive a temporizing non-experimental treatment for up to 2 cycles 
such as monotherapy with an anti-CD20 monoclonal antibody or corticosteroids 
including high dose methylprednisolone immediately after progression on a BTK 
or BCL-2 inhibitor will be considered for enrollment after discussion with the 
study sponsor.   
 
3. Subject must be ≥18 years of age. 
 
4. Subject must have an Eastern Cooperative Oncology Group performance status of ≤2. 
 
5. Subject must have adequate bone marrow function and meet the below thresholds. 


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18 
 
 
a. Absolute neutrophil count of ≥ 750 cell/μL in absence of G-CSF for 7              
days prior to enrollment. 
b. Platelet count of ≥ 30,000 cells/μL independent of transfusion for 21 days 
prior to enrollment 
 
6. Subject must have adequate organ function and meet the thresholds below: 
a. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Subjects with 
bilirubin exceeding this limit due to Gilbert’s disease are eligible. 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
ULN if no liver involvement or ≤5 x the ULN if known liver involvement  
c. Creatinine clearance >30 ml/min/1.73m2 as calculated by the MDRD               
equation. 
 
7. Ability to swallow and retain oral medication. 
 
8. Female subjects who are not of child-bearing potential (see Appendix: 
CONTRACEPTION GUIDELINES AND PREGNANCY), and female subjects of 
child-bearing potential who have a negative serum pregnancy test within 3 days prior 
to initial trial treatment.  Male subjects of reproductive potential may not participate 
unless they agree to use medically acceptable contraception.  Female subjects of 
child-bearing potential and all male partners, and male subjects must consent to use a 
medically acceptable method of contraception throughout the study period and for 4 
months after the last dose of study drug.  
 
9. Willingness and ability to comply with trial and follow-up procedures, and give 
written informed consent. 
 
3.3 Exclusion Criteria 
 
A subject will be ineligible for the study if he/she meets any of the following criteria: 
 
1. Subject has had prior exposure to a PI3K inhibitor at any point in treatment                 
history. 
 
2. Subject has discontinued the BTK or BCL2 inhibitor due to intolerance.  Intolerance 
will be defined as discontinuing prior BTKi or BCL-2 therapy for any reason without 
evidence of progression.  Subjects who were re-challenged after discontinuation for 
therapeutic reasons will be allowed if the toxicity did not recur or was managed 
without indication for discontinuation.  Subjects who progress on BTKi or BCL-2 
therapy who were on a reduced dose due to an AE/intolerance are eligible as long as 
progression has been documented on that reduced dose. 
 
3. Subject has clinical or radiographic evidence of, or has biopsy proven                          
Richter’s transformation or prolymphocytic leukemia. 
 


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19 
 
4. Subject has undergone an allogeneic stem cell transplant.  
 
5. Subject has received an autologous hematologic stem cell transplant within 6 months 
of study entry.  
 
6. 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. 
 
7. Subject is known to be positive for HIV.  
 
8. Subject has history of hepatitis C infection, active infection with hepatitis B or active 
cytomegalovirus (CMV) as determined by PCR. 
 
9. Previous exposure to a BTK or Bcl-2 inhibitor therapy within 14 days of initiating 
study treatment on Cycle -1 Day 1, or previous exposure to anti-cancer therapy 
including chemotherapy, radiotherapy, or investigational therapy, including other 
investigational targeted small molecule agents within 21 days of initiating study 
treatment on Cycle 1 Day 1. 
 
10. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized 
fungal infections of skin or nails. 
 
11. History of anaphylaxis (excluding infusion related reactions) in association with 
previous anti-CD20 administration. 
 
12. A known history or active autoimmue disease even if not requiring systemic 
immunosuppression. Subjects with known history of immune thrombocytopenic 
purpura or autoimmune hemolytic anemia secondary to CLL are allowed to enroll. 
 
13. Malabsorption syndromes. 
 
14. Irritable bowel syndrome with greater than 3 loose stools per day as a baseline. 
 
15. Any severe and/or uncontrolled medical conditions or other conditions that could 
affect participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (New York 
Heart Association functional classification III-IV)[see Appendix:  NYHA 
Classifications] 
b. Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, CHF, or myocardial infarction within 6 months of enrollment.  
c. Concomitant use of medication known to cause QT prolongation or torsades 
de pointes should be used with caution and at investigator discretion. 


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20 
 
d. Poorly controlled or clinically significant atherosclerotic vascular disease 
including cerebrovascular accident (CVA), transient ischemic attack (TIA), 
angioplasty, cardiac or vascular stenting within 6 months of enrollment. 
 
16. Females who are pregnant or lactating. 
 
 
4. Registration Procedures 
 
4.1 Patient Registration 
 
Patients will be centrally registered with the Weill Cornell Medicine (WCM), Division of 
Hematology and Medical Oncology, Joint Clinical Trials Office.  To register a patient, email the 
following documents to your assigned registration contact:   
 
• WCM Patient registration form 
• First and last page of the fully executed informed consent form, plus additional 
pages if checkboxes for correlative studies are required. 
• Fully executed HIPAA research authorization form (if separate from the consent 
document) 
• Eligibility checklist signed and dated by investigator and research nurse 
• Documentation of any eligibility waivers granted  
• Redacted source documentation to verify eligibility 
 
Central registration documents should be scanned/emailed Monday to Friday from 9:00 AM to 
4:00 PM EST to study investigators and 
24Tjctoiit@med.cornell.edu24T24T24T, along with all other assigned 
registration contacts for this study. Central registration information is reviewed and entered into 
the REDCap database by the Coordinating Center.  Patients will be assigned a sequence number 
for the protocol.  The registering institution will then be emailed a copy of the sequence number 
as confirmation of a completed registration.  Subjects should NOT receive any study medication 
prior to receipt of registration confirmation.  Note that attachments larger than 4.5 MB are not 
accepted, so larger attachments should be split into more than one email. 
 
Registration of patients cannot occur until the Coordinating Center has received proper 
documentation from the registering institution of IRB approval, including a copy of the current 
approval letter, stamped consent and signed FDA Form 1572, along with other required 
regulatory documents.  These documents will be requested at site activation and may be 
scanned/emailed to the Coordinating Center. 
 
 
5. Study Procedures 
 
5.1 Schedule of Evaluations 
 
 
 


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21 
 
Table 1. Schedule of trial events 
 
 
Schedule of Assessments 
  
Year 1 
Study Procedure 
Screening 
C-1 
D1 
C-1 
D15 
Cycle 1 
C2 
D1 
C3 
D1 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C10 
D1 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
ECOG 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
  
  
  
Weight 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone Marrow Biopsy 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone Marrow Aspirate 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry 
(CMP)Pa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Rapid Screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Hepatitis Antibody 
ScreenPb 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Cytomegalovirus 
(CMV) PCR 
X 
  
  
  
  
  
  
  
  
X 
  
  
X 
X 
B-HCGPc
P (FCBP only) 
X 
  
  
 
  
  
  
 
 
 
 
 
 
 
Circulating DNA 
(research) 
  
X 
 
X 
  
  
  
X 
  
  
  
  
X 
  
Clonal Evolution 
Analysis (research) 
  
X 
 
X 
  
  
  
X 
  
  
  
  
X 
  
Ublituximab Infusion 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Umbralisib 
Dispensation 
  
X 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
MonitoringPd 
At each timepoint AEs will be collected 
Radiologic EvaluationPe 
X 
  
  
  
  
  
  
X 
  
  
  
  
X 
  
 


IRB Protocol #: 19-06020316 
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22 
 
 
Schedule of 
Assessments 
Year 2 
Year 3+ 
EOT 
Follow-up* 
Study Procedure 
C13 D1 
C16 D1 
C19 D1 
C22 D1 
C25 D1 then  
Every 3 
months 
 30 days 
post last 
dose 
Every 3 months 
Informed Consent 
  
  
  
  
  
  
 
Inclusion/Exclusion 
  
  
  
  
  
  
 
ECOG 
X 
X 
X 
X 
X 
X 
X 
Demographics 
  
  
  
  
  
  
 
Medical History 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Height 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
EKG 
  
  
  
  
  
  
 
Bone Marrow Biopsy 
  
  
  
  
  
  
 
Bone Marrow Aspirate 
  
  
  
  
  
  
 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry 
(CMP)Pa 
X 
X 
X 
X 
X 
X 
X 
HIV Rapid Screen 
  
  
  
  
  
  
 
Hepatitis Antibody 
ScreenPb 
  
  
  
  
  
  
 
Cytomegalovirus 
(CMV) PCR 
X 
X 
X 
X 
X 
  
 
B-HCGPc
P (FCBP only) 
 
 
 
 
 
 
 
Circulating DNA 
(research) 
X 
  
X 
  
X 
X 
 
Clonal Evolution 
Analysis (research) 
X 
  
X 
  
X 
X 
 
Ublituximab Infusion 
  
  
  
  
  
 
 
Umbralisib 
Dispensation 
X 
X 
X 
X 
X 
  
 
Adverse Event 
MonitoringPd 
At each timepoint AEs will be collected 
Radiologic EvaluationPe 
X 
  
X 
  
  
  
X 
(q12mo) 


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23 
 
 
Footnotes: 
*  Subjects who discontinue treatment due to toxicity, but have not progressed will continue in study follow-
up. Visits should occur q3months after EOT visit or until subsequent non-study drug administration. 
Patients who discontinue treatment due to progression of disease will enter survival follow-up. Survival 
follow-up will be documented by phone call every 6 months up to 5 years. 
a. CMP includes a Basic Metabolic panel (Sodium, potassium, chloride, bicarb, blood urea nitrogen, 
creatinine, calcium, glucose) and a Hepatic function panel (protein total, albumin, globulin, alanine 
aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase), Uric acid required 
only at screening, C-1 D1, C-1 D15, C1 D1, and C1 D2. 
b.  Hepatitis antibody screening will consist of Hepatitis A ab, HBsAg, HBcAb, Hepatitis C Ab. If HBcAb is 
positive, an HBV DNA PCR should be performed. 
c. B-HCG pregnancy testing required only for females of child bearing potential (FCBP). At screening should 
be tested by serum within 3 days prior to C-1 D1.  
d. Adverse events should be assessed up to 30 days post last dose. For all serious adverse events (SAE), 
concomitant medications should be assessed and appropriately captured/reported. 
e. CT neck, chest, abdomen, pelvis with contrast. Radiologic evaluation during follow-up should occur every 
12 months or as clinically warranted to document disease progression. 
 
 
 
 


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24 
 
5.1.1 Screening Visit 
 
• Informed consent 
• Inclusion/exclusion checklist 
• ECOG 
• Medical history 
• Physical exam 
• Vital Signs 
• Height  
• Weight 
• EKG 
• Bone marrow biopsy 
• Bone marrow aspirate 
• CBC with differential 
• CMP (with uric acid) 
• HIV 
• Hepatitis antibody screen 
• CMV testing by PCR  
• For women of childbearing age serum B-HCG within 3 days prior to 
Cycle -1 Day 1  
• CT neck, chest, abdomen and pelvis with contrast 
 
 
 
 
5.1.2 Treatment Phase 
 
5.1.2.1      Cycle -1 Day 1 
• ECOG 
• Medical history 
• Physical exam 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP (with uric acid) 
• Research tubes (2 purple top tubes for banking) 
• Umbralisib pill dispensation 
• Adverse event assessment 
 
5.1.2.2      Cycle -1 Day 15 
• ECOG 
• Medical history 
• Physical exam 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP (with uric acid) 


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25 
 
• Umbralisib pill dispensation 
• Adverse event assessment 
 
5.1.2.3      Cycle 1 Day 1 
 
• ECOG 
• Medical history 
• Physical exam 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP (with uric acid) 
• Research tubes (2 purple top tubes for banking) 
• Ublituximab infusion 
• Umbralisib pill dispensation 
• Adverse event assessment 
 
5.1.2.4     Cycle 1 Day 2 
 
• Medical history 
• Physical exam 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP (with uric acid) 
• Ublituximab infusion 
• Adverse event assessment 
 
5.1.2.5      Cycle 1 Day 8 and 15 (+/- 2 days) 
 
• ECOG 
• Medical history 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP 
• Ublituximab infusion 
• Adverse event assessment 
 
5.1.2.6      Cycle 2-6, Day 1 (+/- 2 days) 
 
• ECOG 
• Medical history 
• Physical exam 


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26 
 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP 
• Research tubes (2 purple top tubes for banking) (Cycle 2 only) 
• Ublituximab infusion (+/- 3 days) 
• Umbralisib pill dispensation 
• CT neck, chest, abdomen and pelvis with contrast (Prior to C2D1 only 
+/- 7 days) 
• CMV testing by PCR 
• Adverse event assessment 
 
5.1.2.7     Cycle 7, Day 1 and Beyond, Study visits occur every 3 cycles with a Day 
1 visit (+/- 5 days) 
 
• ECOG 
• Medical history 
• Physical exam 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP 
• Research tubes (2 purple top tubes for banking) (Cycle 7, 13, 19, 25 
only) 
• Umbralisib pill dispensation 
• CT neck, chest, abdomen and pelvis with contrast (Prior to C7D1, 
C13D1, C19D1, C25D1only +/- 7 days) 
• CT neck, chest, abdomen and pelvis C37D1, C49D1, C61D1 +/- 7 
days for subjects on study beyond 2 years.  
• CMV testing by PCR 
• Adverse event assessment 
• After Cycle 7D1 study visit and response assessments subjects must be 
evaluated for objective response by treating investigator. See Section 
5.4.1 for further details in subject management. 
 
5.1.2.8      End of Treatment Visit (30 days post last dose) 
 
• ECOG 
• Medical history 
• Physical exam 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP 


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27 
 
• Research tubes (2 purple top tubes for banking) 
• Return all study drug in subject possession.  
• Adverse event assessment 
 
5.2. Treatment Administration 
 
All treatment will be administered on an outpatient basis. See section 5.2.1 and 5.2.2 for special 
precautions relevant for each specific study agent administration. All therapy will be 
administered in cycles with each cycle consisting of 28 days. 
 
Enrolled subjects will initiate umbralisib monotherapy for a one cycle lead-in defined by Cycle -
1. This cycle is designed to allow for correlative assay sample collection to assess early clonal 
shifts after umbralisib therapy. Without the lead-in these shifts may otherwise be masked by 
peripheral elimination of circulating tumor cells by anti-CD20 therapy. Subjects will be 
monitored closely upon initiation with a C-1D15 visit to assess tolerability of umbralisib 
monotherapy. Upon completion of Cycle -1 subjects will then continue on daily umbralisib and 
initiate combination therapy with ublituximab (U2). Ublituximab administration and 
induction/continuation is defined in Section 5.2.1. Ublituximab will only be administered 
through Cycle 6 (i.e no maintenance administration). Starting at C7D1 enrolled subjects will 
continue on umbralisib monotherapy.  Umbralisib will be given on a continuous once daily basis 
starting at Cycle -1 for each 28 cycle until disease progression, discontinuation due toxicity, 
subject death, subject withdrawal of consent, or investigator withdrawal. Administration 
schedule and timing of umbralisib administration in relation to ublituximab are further defined in 
Section 5.2.3.  The overall treatment administration is depicted in the schema below Figure 1. 
 
Subjects will be evaluated for objective response after completion of 6 cycles of combination 
therapy. Subjects with a response ≥ PR will be allowed to continue on study (umbralisib 
monotherapy maintenance). A subject that does not meet objective response criteria by IwCLL 
2018 guidelines outlined in Section 9.1 at C7D1 must be taken off study. See section 5.4.1 for 
further details in management of these subjects not meeting strict response criteria after 
completion of combination therapy.  
 
Figure 1. Study Drug Administration Schema 
 
 
 


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28 
 
5.2.1 Ublituximab 
 
Ublituximab infusions will be administered as an outpatient and consistent with previous Phase 
II and Phase III dosing schemes. During Cycle 1, infusions will occur on Day 1, Day 2, Day 8, 
and Day 15. On days 1 and 2 the 900mg will be split, with each subject receiving 150mg on day 
1 and the remaining 750mg on day 2. All subsequent infusions starting from Cycle 1 Day 8 will 
consist of a single 900mg infusion of ublituximab. After completion of Cycle 1, dosing of 
ublituximab will occur on a monthly basis (q28 days) on day 1 of Cycles 2-6 (+/- 3 days). 
Starting at Cycle 1 Day 1 through Cycle 6 Day 1 ublituximab infusions will be in combination 
with oral administration of umbralisib. After 6 cycles of combination treatment, ublituximab 
infusions will be stopped and subjects will continue on umbralisib monotherapy. Titration 
schedules should follow the schema depicted in the Table 2. Upon completing Cycle 6 
ublituximab infusions will be completed and subjects will not receive maintenance ublituximab. 
Subjects will continue with umbralisib monotherapy as described in Section 5.2.3.   
 
Subjects will be eligible to start a new cycle of combination therapy with ublituximab unless 
they are experiencing toxicity requiring treatment delay as outlined in Section 6.2 Table 4. 
 
Ublituximab should not be administered as an IV push or bolus. All subjects must be 
premedicated before ublituximab infusion with an antihistamine (diphenhydramine 50mg or 
equivalent), and a corticosteroid (dexamethasone 20 mg or equivalent dose) as follows:  
 
o If pre-medications are administered IV:  start the ublituximab infusion 30 minutes 
after conclusion of the last pre-medication infusion. If IV premedications are 
given over longer than a 30 minute timeframe per institutional standards, begin 
ublituximab within 10 minutes of stop time of last pre-medicaiton. 
o If pre-medications are administered orally:  start the ublituximab infusion 45-60 
minutes after ingestion of the oral pre-medications 
o Adjusting antihistamine and corticosteroid doses, adjusting the timing of 
administration and/or additional pre-medications may be used at investigator 
discretion for additional prophylaxis against infusion related reactions  
 
Corticosteroid premedication should be given on day 1, 8 and 15 of cycle 1. Subsequent use of 
steroid premedication starting with cycle 2, will be left to investigator discretion and is not 
mandatory with these subsequent infusions in the absence of infusion related reactions with 
previous doses. Use of oral acetaminophen 650 mg (or equivalent) should be restricted to 
patients who experience fever or pyrexia after week 1 dose, or as clinically warranted.  During 
infusion the following monitoring schema should be followed by nursing: 
 
a) Nurse should remain with the patient during the first 15 minutes of the infusion 
b) Nurses should monitor vital signs (temperature, BP, and HR) and assess for signs of 
infusion reaction every 15 minutes for the first hour, then every 30 minutes for the 
remainder of the infusion, and upon infusion completion 
 
 
 


IRB Protocol #: 19-06020316 
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29 
 
Table 2. 
Ublituximab Titration Schedules 
 
Cycle 1 Day 1 & 2 infusion of 4 hours 
Cycle 1 
Ublituximab 
Dose 
Total volume to 
be infused 
Infusion rate 
T0 to 
T30min 
T30min to 
T1H 
T1H to T2H 
T2H to T4H 
Day 1 
150 mg 
250 mL 
10 mL/H 
20 mL/H 
35 mL/H 
100 mL/H 
Day 2 
750 mg 
500 mL 
10 mL/H 
20 mL/H 
85 mL/H 
200 mL/H 
Cycle 1 Day 8 & 15 infusion of 3 hours 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T1H 
T1H to T2H 
T2H to T3H 
900 mg 
500 mL 
50 mL/H 
150 mL/H 
300 mL/H 
Cycle 2 and remaining infusions over 90 minutes 
Ublituximab Dose 
Total volume to be infused 
Infusion rate 
T0 to T30min 
T30min to T90min 
900 mg 
500 mL 
200 mL/H 
400 mL/H 
 
 
5.2.2 Management of Infusion Related Reactions 
 
Since infusion-related hypotension may occur, antihypertensive medications should be held 12-
24 hours prior to and throughout ublituximab infusion. 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. 
 
If an infusion related reaction is observed at any time during the ublituximab treatment, the 
treating investigator may reduce the infusion flow rate at their discretion. 
 
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 monitor patient, institute symptomatic medical management 
until resolution of IRR symptoms. Treating investigator must be notified by research 
team and documentation should occur in the patient chart.   
o Symptomatic medical management should include administration of 
acetaminophen, antihistamines, and/or corticosteroids for fever (temperature 
>38°C) and/or chills 
o Physician may order meperidine for persistent rigors, caution to be exercised if 


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30 
 
patient is hypotensive and meperidine may contribute to ongoing hypotension.  
o Administer antihistamines and/or corticosteroids for flushing, urticarial, pruritus, 
or angioedema 
o Administer IV fluid boluses for hypotension 
o Administer epinephrine, corticosteroids and antihistamines in the event of an 
anaphylactic reaction 
• Following the judgment of the Investigator, and provided the patient is stable, the 
infusion may be resumed at 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 5.2.1  
• For any Grade 4 infusion related reaction, ublituximab should be stopped indefinitely.  
Subjects that experience a Grade 4 infusion reaction will not be allowed to be 
rechallenged.  
 
3rd Infusion Interruption (same day):  
• Discontinue infusion for that day – monitor patient for resolution of all symptoms. Patient 
should have all vital signs completed as well as any other standard of care procedures 
completed as warranted by the Investigator prior to release of patient from study site. 
• Administer symptomatic medical management as above.   
• Any remaining diluted investigational product should be discarded. 
• If the infusion discontinued is the Cycle 1 Day 1 infusion, administer the scheduled Cycle 
1 Day 2 dose according to the protocol dosing schedule. 
• For any Grade 4 infusion related reaction ublituximab should be stopped indefinitely. 
Subjects that experience a Grade 4 infusion reaction will not be allowed to be 
rechallenged. 
 
5.2.3 Umbralisib 
 
Umbralisib will be administered orally as four 200mg capsules taken once daily for a total daily 
dose of 800mg. Umbralisib should be taken within 30 minutes of starting a meal. All subjects 
will initiate a one cycle lead in prior to starting combination therapy with ublituximab, subjects 
will initiate taking umbralisib on Cycle -1 day 1 through Cycle -1 day 28. Starting on Cycle 1 
day 1, subjects may take the dose of umbralisib before or after infusion with ublituximab but 
umbralisib must be taken within 30 minutes of starting a meal. Subjects will continue daily oral 
dosing of 800mg umbralisib for 28 days which will constitute a cycle. Subjects should try to take 
the drug at the same time each day throughout the trial.  Subjects should be instructed to swallow 
the tablets whole and should not chew or crush them.  If a dose of umbralisib is missed, it should 
be taken as soon as possible on the same day.  If it is missed for a period of greater than 12 
hours, it should be skipped for that day.  If vomiting occurs, no attempt should be made to 
replace the vomited dose.  Subjects will continue daily dosing of umbralisib until disease 
progression, toxicities, or study completion whichever comes first.   
 
Subjects will be eligible to start a new cycle of either combination or monotherapy of umbralisib 
unless they are experiencing toxicity requiring treatment delay as outlined in Section 6.2 Table 4.   
 


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31 
 
Umbralisib will be dispensed at the sites by the research coordinator or designee under the 
direction of the PI or by a pharmacist at the site.  Before dispensing, the site pharmacist or 
authorized designee must check that the umbralisib is in accordance with the product 
specifications and the validity is within the re-test date.  Immediately inform TG Therapeutics, 
Inc. at productquality@tgtxinc.com with any product quality concerns or questions. 
 
Subjects must be provided drug in its original container.  Subjects will be dispensed sufficient 
umbralisib for roughly 1 cycle of treatment.  If the interval between visits is greater than 1 cycle, 
subjects may be given more than 1 cycle of umbralisib so that they do not have to return between 
scheduled visits.  Subjects should be instructed to return all empty and partially filled bottles 
including any unused tablets when they return to the site.  Study drug compliance should be 
reviewed with the subject at the beginning of each new treatment cycle and as needed. 
 
5.3 General Concomitant Medication and Supportive Care Guidelines 
 
No clinical drug drug interactions with ublituximab or umbralisib have been reported to date and 
thus there are no specific prohibited concomitant medications based on potential for drug drug 
interactions. Supportive medications in accordance with standard practice (such as for emesis, 
diarrhea, etc.) are permitted and patient should receive full supportive care during study 
participation (including fluids and electrolyte replacement, and antibiotics when appropriate). 
Use of myeloid growth factors or red blood cell growth factors (erythropoietin) is permitted per 
institutional policy. Transfusions may be given in accordance with institutional policy. After 
consultation with the Sponsor the following may be considered; localized hormonal or bone 
sparing treatment for non-B-cell malignancies. Short courses (≤14 days) of steroid treatment for 
non-cancer related medical reasons (i.e., joint inflammation, asthma exacerbation, rash, 
antiemetic use and infusion reactions) at doses that do not exceed 60 mg per day of prednisone or 
equivalent are permitted. Treatment for autoimmune cytopenias are permitted for <14 days at 
doses that do not exceed 60 mg per day of prednisone or equivalent, IVIG will be allowed for 
immune mediated platelet or red cell destruction or for hypogammaglobulinemia and infection 
risk. IVIG may not be given on the same day as ublituximab. 
 
Prophylactic antibiotics against Pneumocystis jiroveci pneumonia (PJP) should start prior to 
starting umbralisib. All subjects should also be prophylaxed against herpes zoster virus with 
famciclovir, valacyclovir or acyclovir. Dapsone 100mg daily is recommended for PJP 
prophylaxis, but the agents of choice for antibiotic prophylaxis is left to investigator discretion. 
Standard dosing for prophylactic purposes should be followed for each respective required 
antibiotic.  
 
Any non-study protocol related chemotherapy, anti-cancer immunotherapy, experimental 
therapy, or radiotherapy are prohibited while the subject is on protocol except as outlined above. 
 
 
5.4 Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse event(s) greater than 8 weeks from scheduled 
dose, combination treatment may continue for 6 months followed by at least 18 months of 


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32 
 
umbralisib monotherapy. Patients deriving benefit at 2 years will be allowed to continue on study 
drug. If a subject meets the following criteria, they will be removed from study treatment: 
 
o Disease progression 
o Failure to achieve ≥ PR to combination therapy (See section 5.4.1) 
o Intercurrent illness that prevents further administration of both study drugs 
o Unacceptable adverse event(s) 
o Patient decides to withdraw from the study, or 
o General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
5.4.1 Procedures for Subject Removal if Less Than PR at Completion of 
Combination Therapy 
 
Subjects will be evaluated for objective response after completion of 6 cycles of combination 
therapy ublituximab and umbralisib (i.e. C7D1 radiographic evaluation and clinical and 
laboratory assessment). Subjects with a response ≥ PR will be allowed to continue onto the 
umbralisib monotherapy maintenance portion of the study. Subjects not meeting at least the PR 
response definition outlined in Section 9.1.2 at the C7D1 study visit will be removed from study 
with the following exception; 
 
If a subject has stable disease, is deriving clinical benefit per investigator assessment, and for 
whom an approved therapy with known efficacy is not available (i.e. double refractory to 
BTKi or Bcl2 inhibitor) those subjects will be allowed to continue on study and proceed with 
umbralisib monotherapy. 
 
All subjects will be allowed to start C7D1 and continue on study for up to 3 cycles as complete 
response assessment data may not be readily available to make clinical decisions and 
arrangement of subsequent therapy may take additional time to ensure safe transition of subjects 
to alternative treatments. This is to prevent abrupt removal of subjects from therapy and to allow 
sufficient time for data to be evaluated in an objective manner. All subjects must be assessed by 
the investigator for suitability to continue on umbralisib monotherapy prior to C10D1. Effort 
must be made by investigator to expeditiously make response assessment and arrange for 
alternative management at the earliest timepoint prior to C10D1. No subject meeting criteria 
outlined in this Section 5.4.1 will be allowed to continue on study beyond C10D1.  
 
5.5 Duration of Follow Up 
 
The anticipated duration of patients on study therapy will be 2 years though patients deriving 
benefit will be allowed to continue on study beyond two years. Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse event 
even if that period is longer than 30 days after removal.  
 
After withdrawal from protocol treatment, all 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 


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33 
 
must be recorded and followed until resolution, unless, in the opinion of the investigator, these 
values are not likely to improve because of the underlying disease. 
 
Subjects who discontinue study treatment for reasons other than disease progression or 
withdrawal of consent will be followed for progression free survival and survival every 3 months 
until documentation of disease progression, death or initiation of CLL directed non study 
treatment. 
 
Visits for subjects with early treatment discontinuation other than disease progression, death or 
withdrawal of consent, will continue for 3 months after study drug discontinuation. Subjects and 
study team should collect the following data during this follow-up period: 
 
• ECOG 
• Medical history 
• Physical exam 
• Vital Signs 
• Weight 
• CBC with differential 
• CMP 
• CT neck, chest, abdomen and pelvis with contrast every 12 months or 
as clinically warranted to document disease progression 
 
Subjects who discontinue therapy for any reason except withdrawal of consent will be followed 
for overall survival for up to 5 years. Survival follow-up will be documented by either chart 
review if the subject remains an active patient in the investigators clinic or by phone call every 6 
months up to 5 years. If subject is not in active follow-up then a chart note should be placed 
within the patient chart to confirm survival status.  
 
When the first subject enters year five of treatment or follow-up the study may be amended to 
address continuation of study therapy or follow-up beyond year 5.  
 
 
6. Dosing Delays/Dose Modifications 
 
6.1 Ublituximab 
 
Dose modification of ublituximab is not permitted. Dose delays will be the primary method for 
managing ublituximab-related toxicities (see Table 3 below:  Dose delay and modification 
schema for umbralisib and ublituximab). During infusion dose delays should follow the 
guidelines outlined in Section 5.2.2.  
 
Supportive care should be provided and growth factor support should be applied as outlined in 
Section 5.3. 
 
6.2 Umbralisib 
 


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34 
 
Dose delays and modifications will be the primary method for managing umbralisib related 
toxicities. Ublituximab and umbralisib therapy should be held upon onset of any of the following 
toxicities until recovery as outlined in Table 3 below.  Upon recovery of toxicities as outlined in 
Table 3 below, umbralisib dosing should be the initial drug restarted.  Ublituximab infusions 
should restart at least 7 days after umbralisib dosing has resumed and there has been no 
recurrence of the toxicity.  One exception to this rule, are any toxicities related to infusion 
reactions.  Upon recovery of any Grade 3 or greater infusion related toxicities back to baseline of 
less than or equal to Grade 1, the requirement of 7 days of umbralisib dosing before ublituximab 
dosing can be waived in order to keep patients on schedule during the first cycle induction.  
During the first cycle, if there is a toxicity observed that requires holding of therapy that would 
cause the dosing of ublituximab to fall out of window or schedule, then that dose should be 
skipped, the patient should reinitiate umbralisib upon recovery and be dosed with ublituximab at 
the next scheduled infusion per protocol.  If there is a recurrence of toxicity felt attributable to 
ublituximab then further ublituximab infusions may be stopped at investigator discretion. 
 
Table 3. Hematologic Grading Scheme for subjects entering with abnormal platelets or 
hemoglobin. 
Hematologic Grading Scheme 
Grade 
Decrease in plateletsP1
P or hemoglobinP2
P from pretreatment value 
0 
0-10% 
1 
10.01-24% 
2 
24.01-49% 
3 
49.01-74% 
4 
≥74.01% 
1. Platelet counts must be below normal levels for Grades 1 to 4. If, at any level of decrease, 
the platelet count is < 20 x 109/L (20,000/μL), this will be considered Grade 4 toxicity. 
2. Hemoglobin levels must be below normal levels for Grades 1 to 4. Baseline and 
subsequent hemoglobin determinations must be performed before any given transfusions. 
The use of erythropoietin will not affect grading of toxicity and use should be documented 
 
 
 Table 4. Dose delay and modification schema for umbralisib and ublituximab.  
NCI-CTCAE Grade 
Dose Delay and/or Modification 
Hematologic Adverse Event 
Neutropenia 
Grade ≤ 2 neutropenia 
Maintain current dose and schedule of umbralisib and ublituximab 
(if applicable). Consider supportive care as warranted. 
Grade 3 neutropenia 
Maintain current dose and schedule of umbralisib and ublituximab 
(if applicable). Consider supportive care.  If recurrence or persistent 
Grade 3, consider reducing umbralisib to next lower dose level at 
discretion of the investigator. 


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35 
 
Grade 4 neutropenia or 
occurrence of neutropenic 
fever or infection 
Delay umbralisib and ublituximab (if applicable) until Grade ≤3 
and/or neutropenic fever or infection is resolved; thereafter, resume 
umbralisib at current dose and schedule.  Consider supportive 
care.  If delay is > 56 days despite the use of G-CSF, discontinue 
umbralisib and, if applicable, ublituximab.   
 
When/if restarting, restart ublituximab (if applicable) after 7 days of 
umbralisib dosing. 
  
If recurrence after rechallenge, repeat these steps with allowance for 
reducing umbralisib to next lower dose level at discretion of the 
investigator. 
 
If the absolute neutrophil count was <1 x 10P9
P/L before therapy, the 
patient will not be evaluable for toxicity referable to ANC. The use 
of growth factors such as granulocyte colony-stimulating factor (G-
CSF) is not relevant to the grading of toxicity, but should be 
documented. If a subject enters with a decreased ANC then any 
count <500 should be considered as Grade 4 and managed as 
outlined above. 
Thrombocytopenia 
Grade ≤3 
thrombocytopenia 
Maintain current dose level and schedule of umbralisib and 
ublituximab (if applicable).  Provide supportive care as clinically 
warranted. 
Grade ≥3 
thrombocytopenia with 
bleeding or Grade 4 
thrombocytopenia without 
bleeding 
Delay umbralisib and ublituximab (if applicable) until Grade ≤3 
without bleeding; thereafter, resume umbralisib at current dose and 
schedule.  Consider supportive care intervention as warranted.  If 
delay is > 56 days, discontinue umbralisib and, if applicable, 
ublituximab.   
 
Restart ublituximab (if applicable) after 7 days of umbralisib 
dosing.   
  
If recurrence after rechallenge, repeat these steps with allowance for 
reducing umbralisib to next lower dose level at discretion of the 
investigator. 
 
Immune Related Pneumonitis* 
Grade 1 & 2 
Stop all therapy and hold until complete resolution.  Restart 
umbralisib at one lower dose level.  Restart ublituximab (if 
applicable after 7 days of umbralisib dosing).  If delay is > 56 days, 
discontinue umbralisib and, if applicable, ublituximab. 
If recurrence after re-challenge, discontinue all treatment therapy. 
Grade ≥3 
Discontinue all therapy 
* For sinopulmonary infections clearly not related to immune-mediated pneumonitis, 
umbralisib may be continued at investigator’s discretion.  While pneumonitis has been 


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minimal with umbralisib, it is a reported adverse event associated with other PI3K delta 
inhibitors.  Use of anti-pneumocystis and anti-herpetic viral prophylaxis is required. 
Diarrhea and/or Colitis 
Diarrhea Grade ≤2 
Maintain current dose and schedule if tolerable or hold umbralisib 
and ublituximab (if applicable); thereafter, resume umbralisib at 
current dose and schedule, and resume ublituximab (if applicable) 
after 7 days of umbralisib dosing. 
NOTE: If persistent grade 2 diarrhea, despite supportive care, delay 
umbralisib and ublituximab (if applicable) until ≤ grade 1; 
thereafter, resume umbralisib at current dose and schedule, and 
resume ublituximab (if applicable) after 7 days of umbralisib 
dosing.  If recurrence after rechallenge, repeat these steps with 
allowance for resuming umbralisib at current dose or next lower 
dose level at discretion of the investigator. 
 
If delay is > 56 days, discontinue umbralisib and, if applicable, 
ublituximab.  Restart ublituximab (if applicable) after 7 days of 
umbralisib dosing. 
Diarrhea Grade 3 
Withhold umbralisib and ublituximab (if applicable) until Grade 
≤2.  Resume umbralisib at next lower dose level.  If delay is > 56 
days, discontinue umbralisib and, if applicable, ublituximab.   
Restart ublituximab (if applicable) at full dose after 7 days of 
umbralisib dosing.   
If recurrence after rechallenge, repeat these steps with allowance for 
resuming umbralisib at next lower dose level at discretion of the 
investigator.  
A diagnostic workup for Grade 3 diarrhea should be performed 
including a colonoscopy to evaluate for underlying colitis. 
Monitoring of the patient should occur at least weekly until 
improvement and or resolution.  
Diarrhea Grade 4 
Discontinue all treatment, rechallenge prohibited. 
Colitis Grade ≤ 3 
Hold umbralisib and ublituximab (if applicable). Treat with 
supportive care and after resolution of colitis, resume umbralisib at 
next lower dose level. 
 
If delay is > 56 days, discontinue umbralisib and, if applicable, 
ublituximab.  
 
Restart ublituximab (if applicable) after 7 days of umbralisib 
dosing. 
Colitis Grade 4 
Discontinue all treatment, rechallenge prohibited. 
Liver Toxicity (ALT/SGPT, AST/SGOT, Bilirubin, Alkaline Phosphatase) 
Grade 1 
Maintain current umbralisib dose. 


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Assess concomitant medications and risk factors*. 
Monitor labs every 1-2 weeks. 
 
Maintain full dose and schedule of ublituximab, if applicable. 
 
Grade 2 
Maintain current umbralisib dose. 
Assess concomitant medications and risk factors*.   
Begin supportive care (prednisone 0.5-1.0 mg/kg/day or equivalent 
per investigator discretion) **.   
Monitor labs at least weekly until Grade 1.   
Once resolved to Grade ≤1, taper prednisone by 10 mg per week 
until off. 
 
Maintain full dose and schedule of ublituximab, if applicable. 
 
If liver toxicity recurs to Grade 2: 
o Re-initiate steroids. 
o Monitor labs at least weekly until Grade 1.   
o Consider delaying umbralisib.   
o If applicable, consider delaying ublituximab.  
o Once resolved to Grade ≤1 
o If umbralisib was delayed, restart umbralisib at 
current dose. 
o If applicable:  if ublituximab was delayed, restart 
ublituximab after 7 days of umbralisib dosing. 
o Taper prednisone by 10 mg per week until off. 
 
If umbralisib is delayed for > 56 days, discontinue umbralisib. 
 
If ublituximab is delayed for > 56 days, discontinue ublituximab. 
Restart ublituximab (if applicable) after 7 days of umbralisib dosing. 
 
Grade 3 
Delay umbralisib. 
Assess concomitant medications and risk factors*.   
Begin/continue supportive care (prednisone 0.5-1.0 mg/kg/day or 
equivalent per investigator discretion) **.   
Monitor labs at least weekly until Grade 1.   
Once resolved to Grade ≤1: 
o Restart umbralisib at one lower dose level. 
o Taper prednisone by 10 mg per week until off. 
 
If applicable, delay ublituximab until ≤ grade 1; thereafter, resume 
ublituximab after 7 days of umbralisib dosing. 
 
If umbralisib is delayed for > 56 days, discontinue umbralisib. 
 


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If ublituximab is delayed for > 56 days, discontinue ublituximab.  
Restart ublituximab (if applicable) after 7 days of umbralisib 
dosing. 
 
Grade 4 
Discontinue all treatment, rechallenge prohibited. 
* Assess for disorders of lipids and glucose, thyroid disorders, alcohol use, viral infections, etc. 
 
**Supportive Care – Aggressive management of lipid, glucose, other metabolic disorders, viral 
infections, etc. 
 
Important: Before initiating steroids, check for viral hepatitis or CMV infection. 
 
All Other Non-Hematological Adverse Events 
Grade ≤2 
Maintain current dose level. 
Grade ≥3 
Withhold umbralisib and ublituximab (if applicable) until Grade ≤2; 
thereafter, resume umbralisib at current dose.  If delay is > 56 days, 
discontinue umbralisib and, if applicable, ublituximab.   
 
Restart ublituximab (if applicable) at full dose after 7 days of 
umbralisib dosing. 
  
If recurrence after re-challenge, repeat these steps with allowance 
for resuming umbralisib at current dose or next lower dose level at 
discretion of the investigator. 
   
  
STUDY DRUG DOSE REDUCTION RECOMMENDATIONS 
Study Drug Starting Dose 1Pst
P Dose Reduction 2Pnd
P Dose Reduction 
TGR-1202 
800 mg 
600 mg 
400 mg 
  
 
 
 
A maximum of two dose level reductions are allowed for umbralisib.  If a patient requires a dose 
reduction of umbralisib due to study drug related toxicity, the dose may not be re-escalated.  If 
further evaluation of the toxicity reveals the event was not related to umbralisib, this must be 
recorded in the medical record and dose re-escalation to the next higher dose level may be 
considered at the discretion of the investigator and after discussion with the monitor.     
 
7. Pharmaceutical Information  
 
7.1 Investigational Agent – Ublituximab  
 


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Ublituximab is available as a sterile, clear to opalescent, preservative-free concentrate for 
solution for intravenous (IV) by infusion administration. It will be supplied at a concentration of 
25 mg/mL in 6 mL (150 mg) single-use glass vials. The shelf life of ublituximab is 36 months if 
stored between +2°C / + 8°C based on stability data and should be stored in a secured, limited-
access, refrigerated area at a temperature ranging from +2°C / + 8°C.  Ublituximab must not be 
frozen.  Ublituximab must not be mixed with other medicinal products during preparation and 
should only be diluted with 0.9% NaCl before use.  
 
No incompatibility of ublituximab with PVC bags containing 0.9% NaCl or PVC tubing has 
been observed. Studies performed in both static and dynamic conditions, showed no significant 
loss of CD16 activity and no adsorption or degradation of the protein were noted. Ublituximab 
diluted in 0.9% NaCl is stable for 24 hours in static condition at 25°C and in dynamic conditions 
it is stable for 8 hours at 25°C.   
 
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 TG Therapeutics, Inc. at productquality@tgtxinc.com with any product quality concerns 
or questions. 
 
It is recommended that ublituximab be administered immediately after dilution.  It should NOT 
be mixed the day before and mixing should only occur once confirmed that patient is eligible for 
therapy on the day of treatment. 
 
No live vaccines can be administered within 4 weeks of the initial dose of ublituximab or while 
receiving ublituximab. 
 
7.2 Investigational Agent – Umbralisib 
 
Umbralisib is available as tablets with the following description: 200 mg: Light green, oval 
tablets with “L474” debossed on one side and plain on the other side.  
 
Umbralisib should be stored at temperatures between 20°C and 25°C (excursions permitted 
between 15°C and 30°C).  Do not freeze.  Based on the results available to date, a shelf life of 36 
months is proposed for the drug product in the current packaging.  Retest dates will be provided 
periodically by TG Therapeutics, Inc. 
 
7.3 Availability 
 
Ublituximab and umbralisib are investigational agents supplied to investigators by TG 
Therapeutics Incorporated (TGTX). 
 
7.4 Investigational Agent Ordering 
 
Ublituximab and umbralisib are available from TG Therapeutics.  Please allow 5 to 7 business 
days between drug ordering and drug arrival.  Order ublituximab Monday through Wednesday to 
ensure shipment does not arrive on a weekend day.  Ensure staff will be available to unpack 


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shipment immediately upon arrival.  Please direct drug orders to 
24TISTdrugorder@tgtxinc.com24T24T24T.  The email should include the following: 
• Requested quantity of TG Therapeutics study drug(s) 
• Date needed 
• Principal Investigator name 
• Study title   
• TG Therapeutics, Inc. tracking number (U2-NTG-004) 
• Investigational drug pharmacy shipping address 
 
7.5 Investigational Agent Accountability 
 
UUblituximab and Umbralisib Inventory RecordsU – The investigator, or a responsible party 
designated by the investigator, in this case the investigational pharmacy of Weill Cornell, will 
maintain a careful record of the inventory and disposition of all agents received from TGTX on a 
Drug Accountability Record Form (DARF).  If there is any abnormality in the supplied boxes 
(ublituximab) or bottles (umbralisib), this should be documented during the acknowledgement of 
receipt and TG Therapeutics should be contacted at productquality@tgtxinc.com. 
 
8. Correlative/Special Studies 
 
Specific correlative studies are not planned with this protocol. However, specimens from 
subjects will be collected at prespecified time points as outlined in Section 5.1. These specimens 
will be processed and banked for potential use in future assays. Specimens will be processed and 
isolated for plasma and mononuclear layer buffy coats for later B and or T cell selection. Genetic 
analyses may be performed on isolated components.  Any and all correlative analyses, including 
from specimens stored for future research, require written approval by TG Therapeutics, Inc. 
prior to initiation of the correlative analyses.  Investigators and institution may not provide 
samples taken from subjects to anyone outside of their institution for any purpose without written 
pre-approval by TG Therapeutics, Inc. 
  
9. Measurement of Effect 
 
9.1. Response Criteria  
 
All response criteria will be assessed using the International Workshop on CLL 2018 guidelines.   
 
9.1.1 Complete Response 
 
Requires all of the following: 
 
1) Absence of clonal lymphocytes in the peripheral blood. 
2) Absence of significant lymphadenopathy. (eg, lymph nodes > 1.5 cm in diameter)   
 
by physical examination. In clinical trials, a CT scan of the abdomen, pelvis, and     
 
thorax is desirable if previously abnormal. Lymph nodes should not be larger than   
 
1.5 cm in diameter. 
3) No hepatomegaly or splenomegaly by physical examination. In clinical trials, a       


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CT scan of the abdomen should be performed at response assessment if found to     
 
be abnormal before therapy or if physical examination is inconclusive at the time    
 
of evaluation. 
4) Absence of constitutional symptoms. 
5) Blood counts above the following values.  
i) Polymorphonuclear leukocytes 1.5 × 109/L (1500/μL) or more. 
ii) Platelets more than 100 × 109/L (100 000/μL). 
iii) Hemoglobin more than 110 g/L (11.0 g/dL; untransfused). 
 
 
9.1.2 Partial Response 
 
To define a partial remission, at least 2 parameters of group A and 1 parameter of group B need 
to improve, if previously abnormal (Table 4; sections 5.2.1 to 5.2.5). If only 1 parameter of both 
groups A and B was abnormal before therapy, only 1 needs to improve. 
 
Group A 
1) A decrease in the number of blood lymphocytes by less than 50% or more from        
 
the value before therapy.  
2) A reduction of lymphadenopathy assessed by CT scans and must be decreased by     
 
50% or more in the sum of products of up to 6 lymph nodes. 
i) There must be no increase in any lymph node and no new enlarged lymph     
 
nodes. In small lymph nodes <2cm an increase up to 25% is considered         
 
insignificant. 
3)  A decrease in the size of the liver and/or spleen by 50% or more as defined by CT   
 
scan 
 
Group B 
 
4) The blood count must demonstrate one of the following: 
i) Polymorphonuclear leukocytes 1.5 × 109/L (1500/μL) or more or show a     
 
50% or greater improvement over baseline without the aid of growth             
 
factors. 
ii) Platelets more than 100 × 109/L (100 000/μL) or 50% or greater                   
 
improvement over baseline 
iii) Hemoglobin more than 110 g/L (11.0 g/dL; untransfused) or 50% or             
 
greater improvement over baseline untransfused.  
 
9.1.3 Progressive Disease 
 
Progressive disease is characterized by at least one of the following: 
 
1) Appearance of any new lesion such as an enlarged lymph node >1.5cm,                   
 
splenomegaly, hepatomegaly, or other organ infiltrate.  
2) An increase by 50% or more in the greatest determined diameter of any previous    
 
site. 


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3) An increase of 50% or more in the sum of the product of diameters of multiple         
 
nodes. 
4) An increase in the liver or spleen by 50% or more de novo appearance of                  
 
hepatomegaly or splenomegaly.  
5) An increase in the number of blood lymphocytes by 50% or more with at least             
5000 B lymphocytes per microliter. 
i) During umbralisib therapy a lymphocytosis may be seen. any lymphocytosis 
that occurs in the setting without establishing a nadir or in during a concurrent 
illness will not be counted as a progression  
6) Transformation to a more aggressive histology 
7) Occurrence of cytopenia attributable to CLL. During therapy cytopenias cannot be    
 
used to define disease progression.  
 
9.1.4 Stable Disease 
 
Any subject who has not achieved a CR or a PR and do not demonstrate progressive disease, will 
be considered to have stable disease.  
 
9.2. Duration of response 
 
Duration of response is defined as the interval between the first objective response to the first of 
disease progression        
 
9.3. Progression-Free Survival 
 
Progression-free survival is defined as the interval between the first treatment day to the first 
sign of disease progression or death. 
 
9.4. Overall Survival 
 
Overall survival duration is defined as the interval between the first treatment day to death. 
 
 
 
10. Data Reporting / Regulatory Considerations 
 
10.1 Data Collection  
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, 
efficacy, and adverse event data for all enrolled patients.  REDCap (Research Electronic Data 
Capture) is a free data management software system that is fully supported by the Weill-Cornell 
Medical Center CTSC.  It is a tool for the creation of customized, secure data management 
systems that include Web-based data-entry forms, reporting tools, and a full array of security 
features including user and group based privileges, authentication using institution LDAP 
system, with a full audit trail of data manipulation and export procedures.  REDCap is 
maintained on CTSC-owned servers that are backed up nightly and support encrypted (SSL-


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based) connections.  Nationally, the software is developed, enhanced and supported through a 
multi-institutional consortium led by the Vanderbilt University CTSA. 
 
10.2 Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator.  TG Therapeutics will have the opportunity to review and approve the changes prior 
to submission of these changes to the local IRB and distribution to participating sites. 
 
 
11. Statistical Considerations 
11.1 Study Design/Endpoints 
 
In this single center Phase II study we will evaluate the efficacy and safety of umbralisib and 
ublituximab (U2) as salvage in patients with CLL who have progressed either on a BTK inhibitor 
or BCL-2 inhibitor. The study will enroll in two parallel cohorts and subjects will be assigned to 
cohorts based on the previous novel agent containing regimen regardless of how the novel agents 
were sequenced, Cohort A will consist of patients who progress on BTKi containing regimens 
and Cohort B will consist of patients who progress on BCL-2 containing regimens. Subjects who 
progress on a regimen containing both a BTKi and a BCL-2 inhibitor, will be enrolled in cohort 
B. Each cohort will be evaluated independently of each other. 
 
Currently available retrospective evidence demonstrates an ORR of ~35-40% when idelalisib is 
used as first salvage after ibrutinib failure [11]. Given umbralisib’s unique molecular properties 
and combination therapy with ublituximab, we hypothesize a response rate of 55% using U2 as 
first salvage. Salvage rates with novel agents after venetoclax failure in subjects considered double 
refractory are unknown. We anticipate close to 90% of patients enrolled in cohort B will have 
double refractory disease and represent a high risk group. Given these limitations, we anticipate a 
response rate of 40% in this group based off the efficacy seen with idelalisib after ibrutinib failure.  
 
Because this is a pilot study, no formal sample size/power calculation is required. Given the 
anticipated different patient populations in each cohort, no cross cohort comparisons will be 
performed. 
 
11.2 Analysis of Endpoints 
 
11.2.1 
Analysis of Primary Endpoints 
 
With 12 patients enrolled in cohort A, an exact binomial (Clopper-Pearson) 95% confidence 
interval for the overall response rate can be constructed to have a width of approximately 57.6% 
(25.0%, 82.5%). This calculation assumes that the overall response rate will approach 55% in 
cohort A. 
 
Similarly, with 12 patients enrolled in cohort B, an exact binomial (Clopper-Pearson) 95% 
confidence interval for the overall response rate can be constructed to have a width of 
approximately 56.9% (14.1%, 70.9%). This calculation assumes that the overall response rate will 


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approach 40% in cohort B.  
 
11.2.2 
Analysis of Secondary and Exploratory Endpoints 
 
Analysis of outcomes will remain descriptive. With 12 patients enrolled in Cohort A, an exact 
binomial (Clopper-Pearson) 95% confidence interval for the CR rate can be constructed to have a 
width of approximately 46.3% (2.1%, 48.4%). This calculation assumes that the CR rate will 
approach 16.7% in cohort A. Similarly with 12 patients enrolled in cohort B, and exact binomial 
(Clopper-Pearson) 95% confidence interval for the CR rate can be constructed to have a width of 
approximately 38.5% (0.2%, 38.5%) This calculation assumes the CR rate will approach 8% in 
cohort B.  Assuming adequate follow-up time, Kaplan-Meier survival analysis will be used to 
assess DoR.,PFS, and OS, in the entire cohort. All p-values will be two-sided with statistical 
significance evaluated at the 0.05 alpha level.  Ninety-five percent confidence intervals for 
median DoR/PFS/OS-time and DoR/PFS/OS proportions, will be calculated to assess the 
precision of the obtained estimates.  Safety will be collected and adverse events will be tabulated 
per incidence of specific AE terms will be reported for the entire cohort. All analyses will be 
performed in SAS Version 9.4 (SAS Institute, Inc., Cary, NC) and Stata Version 15.0 
(StataCorp, College Station, TX). 
 
11.3 Interim Analysis 
 
As this is a single center pilot study with low enrollment numbers no interim analysis will be 
performed. 
 
11.4 Reporting and Exclusions 
 
11.4.1 
Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with ublituximab 
or umbralisib. If a subject comes off study due to an adverse event, the subject will be followed 
for 30 days or until resolution of the toxicity to baseline grade, whichever is longer. 
 
11.4.2 
Evaluation of Response 
 
All subjects included in the study will be assessed for response to treatment if they have 
completed at least one cycle of ublituximab and umbralisib combination therapy. 
 
 
12. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by patients or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, radiographic imaging, and physical exam.  


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12.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, and does not imply any judgment about causality. An adverse 
event can arise with any use of the drug (e.g., off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose.  
 
12.1.1 Ublituximab Risks 
 
The following adverse events were observed in patients treated with single agent ublituximab 
and were considered at least possibly related to ublituximab.  The preliminary safety data as of 
May 1, 2018 is provided for a total of 117 subjects exposed to single agent ublituximab with a 
maximum follow up of 2+ years.  See the latest ublituximab investigator brochure for a complete 
list of all adverse events reported regardless of causality.  
 
Very Common (≥ 10%) 
• Blood and Lymphatic System Disorders: neutropenia, thrombocytopenia 
• General Disorders and Administration Site Conditions: pyrexia 
• Injury, Poisoning and Procedural Complications: infusion related reaction 
• Nervous System Disorders: headache 
 
Common (≥ 2 - < 10%) 
• Blood and Lymphatic System Disorders: anemia, pancytopenia 
• Gastrointestinal Disorders: diarrhea, abdominal pain, nausea, oral pruritus 
• General Disorders and Administration Site Conditions: fatigue, asthenia, chills, edema 
peripheral, pain 
• Hepatobiliary Disorders: cytolytic hepatitis 
• Infections and Infestations: herpes zoster 
• Investigations: aspartate aminotransferase increased, blood bilirubin increased, gamma-
glutamyltransferase increased 
• Musculoskeletal and Connective Tissue Disorders: muscular weakness 
• Nervous System Disorders: dysgeusia 
• Respiratory, Thoracic and Mediastinal Disorders: throat irritation, throat tightness 
• Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis 
• Vascular Disorders: hypertension 
 
 
12.1.2 Umbralisib Risks 
 
The following adverse events were observed in patients treated with single agent umbralisib and 
were considered at least possibly related to the study medication, umbralisib.  The preliminary 
safety data as of May 1, 2018 is provided for a total of 136 subjects exposed to single agent 


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umbralisib with a maximum follow up of 5+ years.   See the latest umbralisib investigator 
brochure for a complete list of all adverse events reported regardless of causality. 
 
Very Common (≥ 10%) 
•  Blood and Lymphatic System Disorders: neutropenia 
• Gastrointestinal Disorders: nausea, diarrhea, vomiting 
• General Disorders and Administration Site Conditions: fatigue  
 
Common (≥ 2% - < 10%) 
• Blood and Lymphatic System Disorders: anemia, thrombocytopenia, leukocytosis, 
lymphocytosis 
• Ear and Labyrinth Disorders: tinnitus 
• Eye Disorders: vision blurred 
• Gastrointestinal Disorders: constipation, abdominal pain, abdominal distension, 
dyspepsia, colitis, dry mouth 
• General Disorders and Administration Site Conditions: pyrexia, edema peripheral  
• Infections and Infestations: pneumonia, oral candidiasis 
• Injury, Poisoning and Procedural Complications: contusion 
• Investigations: weight decreased, alanine aminotransferase increased, aspartate 
aminotransferase increased, blood creatinine increased 
• Metabolism and Nutrition Disorders: decreased appetite, dehydration, hyperglycaemia, 
hypokalaemia, hypophosphataemia 
• Musculoskeletal and Connective Tissue Disorders: muscle spasms, pain in extremity 
• Nervous System Disorders: dizziness, headache, dysgeusia, tremor 
• Psychiatric Disorders: insomnia 
• Respiratory, Thoracic and Mediastinal Disorders: cough 
• Skin and Subcutaneous Tissue Disorders: rash maculo-papular, alopecia, night sweats, 
pruritus, rash 
 
 
 
12.1.3 Ublituximab + Umbralisib Combination Risks 
 
Adverse Events and Potential Risks 
The following adverse events were observed in patients treated with the combination of 
ublituximab + umbralisib and were considered at least possibly related to one or both of the 
study medications.  The preliminary safety data as of May 1, 2018 is provided for a total of 75 
subjects exposed to ublituximab + umbralisib with a maximum follow up of 3+ years.  See the 
latest ublituximab and umbralisib investigator brochures for a complete list of all adverse events 
reported regardless of causality. 
 
Very Common (≥ 10%) 
• Blood and Lymphatic System Disorders: anemia, neutropenia 
• Gastrointestinal Disorders: diarrhea, nausea, vomiting 
• General Disorders and Administration Site Conditions: fatigue 


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• Injury, Poisoning and Procedural Complications: infusion related reaction 
• Metabolism and Nutrition Disorders: decreased appetite 
 
Common (≥1% - < 10%) 
• Blood and Lymphatic System Disorders: thrombocytopenia 
• Cardiac Disorders: cardiac failure congestive 
• Ear and Labyrinth Disorders: ear congestion, ear discomfort 
• Eye Disorders: conjunctival pallor, conjunctivitis, corneal edema, vision blurred 
• Gastrointestinal Disorders: abdominal discomfort, abdominal distension, abdominal 
pain, constipation, dyspepsia, flatulence, gastroesophageal reflux disease, hematochezia, 
salivary hypersecretion, stomatitis 
• General Disorders and Administration Site Conditions: asthenia, chills, face edema, 
infusion site pain, local swelling, edema peripheral, pyrexia, systemic inflammatory 
response syndrome 
• Hepatobiliary Disorders: hyperbilirubinaemia 
• Immune System Disorders: hypogammaglobulinaemia 
• Infections and Infestations: bronchitis, cellulitis, clostridium difficile colitis, 
enterocolitis infectious, oral candidiasis, oral herpes, otitis media, pneumonia, pneumonia 
streptococcal, rhinovirus infection, sepsis, sepsis syndrome, sinusitis, skin infection, 
upper respiratory tract infection, urinary tract infection 
• Injury, Poisoning and Procedural Complications: wound 
• Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, 
blood alkaline phosphatase increased, blood creatinine increased, computerized 
tomogram thorax abnormal, immunoglobulins decreased, weight decreased 
• Metabolism and Nutrition Disorders: dehydration, failure to thrive, hyperglycaemia, 
hyperuricaemia, hypokalaemia, hypophosphataemia 
• Musculoskeletal and Connective Tissue Disorders: joint swelling, muscle spasms, 
muscular weakness, myalgia, pain in extremity 
• Nervous System Disorders: dizziness, dysgeusia, headache, lethargy, sinus headache, 
somnolence 
• Psychiatric Disorders: agitation, anxiety 
• Renal and Urinary Disorders: micturition urgency, renal failure, renal failure acute 
• Reproductive System and Breast Disorders: scrotal cyst, semen discoloration 
• Respiratory, Thoracic and Mediastinal Disorders: choking, cough, dysphonia, 
dyspnea, epistaxis, hypoxia, oropharyngeal pain, pneumonitis, productive cough, sinus 
congestion 
• Skin and Subcutaneous Tissue Disorders: alopecia, cold sweat, dermatitis acneiform, 
dermatitis bullous, dry skin, ecchymosis, pruritus, rash, maculo-papular, rosacea, urticaria 
• Vascular Disorders: hypertension 
 
12.2 Adverse Event Characteristics and Related Attributions 
 
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.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site (24Thttp://ctep.cancer.gov24T24T24T). 


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Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
12.3 Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log. The AE log will be maintained 
by the research staff and kept in the patient’s research chart.    
 
 
12.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can be accessed via the following link:   
https://research.weill.cornell.edu/sites/default/files/immediate_reporting_policy.pdf  
 
12.5 Definition of SAE 
 
SAE’s include death, life threatening adverse experiences, hospitalization or prolongation of 
hospitalization, disability or incapacitation, overdose, congenital anomalies and any other serious 
events that may jeopardize the subject or require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Planned hospitalizations are an exception and events due 
to progression that lead to hospitalization will not be considered SAEs. For all SAEs, 
concomitant medications should be assessed, captured, and appropriately reported with the SAE 
report. 
 
12.6 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can be accessed via the following link:   
https://research.weill.cornell.edu/sites/default/files/immediate_reporting_policy.pdf 
 
12.7  Reporting of SAE to FDA 
 
If an SAE occurs on this study, the event will be filed on a MedWatch form with the FDA. The 
investigator must notify the FDA of any SAE’s as soon as possible but no later than 7 calendar 
days after the initial receipt of the information 
 
35T35TCDER INDs35T35T:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Central Document Room 


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5901-B Ammendale Rd. 
Beltsville, Md. 20705-1266 
 
12.8 Reporting of SAE to TG Therapeutics 
 
Institution will send TG Therapeutics copies of any and all serious adverse event reports filed 
with the FDA or other applicable regulatory authorities, as well as copies of any correspondence 
with the FDA or other applicable regulatory authorities, regarding any and all serious adverse 
events, irrespective of association with the Study Drug(s) in the course of the Clinical Trial.   
SAEs require expeditious handling and reporting to TG Therapeutics in order to comply with 
regulatory requirements.  All SAEs (regardless of causality assessment) occurring on study or 
within 30 days of last study treatment should be immediately reported to TG Therapeutics at 
24Tsafety@tgtxinc.com24T24T24T within 24 hours of the first knowledge of the event by the treating physician 
or research personnel on an SAE Form (MedWatch FORM FDA 3500 or equivalent) and 
followed until resolution (with autopsy report if applicable). 
 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
During the course of the study, all female patients of childbearing potential 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).  The definition of “females 
NOT of childbearing potential” is in Appendix - Contraception Guidelines and Pregnancy. 
 
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.   
 
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 and the investigator must submit a Pregnancy Report Form to TG 
Therapeutics at 24Tsafety@tgtxinc.com24T24T24T within 24 hours of the first knowledge of the event by the 
treating physician or research personnel.   
 
Abortions (spontaneous, accidental, or therapeutic) must also be reported to TG Therapeutics at 
24Tsafety@tgtxinc.com24T24T24T using a Pregnancy Report Form within 24 hours of awareness.   
 
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. 
 
In the event a subject’s partner becomes pregnant, a Pregnancy Report Form should be 
completed and submitted to TG Therapeutics, Inc. at safety@tgtxinc.com, and the partner will be 
requested to consent to access to medical records.  After the subject’s partner provides consent, 
the pregnant partner and baby will be followed to see what effect the drug(s) under study may 
have on the outcome of the pregnancy or the health of the newborn. 


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Please see APPENDIX A:  CONTRACEPTION GUIDELINES AND PREGNANCY for 
additional information pertaining to following the pregnant female (and infant, if applicable). 
 
Study Drug Overdose 
Any accidental or intentional overdose with the study treatment (either umbralisib or 
ublituximab) that is symptomatic, even if not fulfilling a seriousness criterion, is to be reported to 
TG Therapeutics at 24Tsafety@tgtxinc.com24T 24T24Timmediately (within 24 hours of awareness) on an 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. 
   
12.9 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This 
requirement indicates that follow-up may be required for some events after the patient 
discontinues participation from the study.  
 
 
13. Data and Safety Monitoring Plan (DSMP) 
 
Monitoring activities will be commensurate with the nature, size and complexity of the trial in 
accordance with institutional policies and will be determined after IRB and Data Safety Monitoring 
Committee (DSMC) review of the protocol immediately prior to study activation. For this study 
we will utilize a Weill Cornell Medicine DSMC. 
 
 
 
 
 
 


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Seymour, J.F., et al., Venetoclax-Rituximab in Relapsed or Refractory Chronic 
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Flinn, I.W., et al., The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed 
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Nastoupil, L., et al., CHEMO-FREE TRIPLET COMBINATION OF TGR-1202, 
UBLITUXIMAB, AND IBRUTINIB IS WELL TOLERATED AND HIGHLY ACTIVE IN 
PATIENTS WITH ADVANCED CLL AND NHL. Hematological Oncology, 2017. 
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Mato, A.R., et al., Optimal sequencing of ibrutinib, idelalisib, and venetoclax 
in chronic lymphocytic leukemia: results from a multicenter study of 683 
patients. Ann Oncol, 2017. 28(5): p. 1050-1056. 
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Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA Cancer J 
Clin, 2018. 68(1): p. 7-30. 
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Dighiero, G., et al., Chlorambucil in indolent chronic lymphocytic leukemia. 
French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med, 
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Hamblin, T.J., et al., Unmutated Ig V(H) genes are associated with a more 


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aggressive form of chronic lymphocytic leukemia. Blood, 1999. 94(6): p. 
1848-54. 
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Damle, R.N., et al., Ig V gene mutation status and CD38 expression as novel 
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1840-7. 
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Dohner, H., et al., Genomic aberrations and survival in chronic lymphocytic 
leukemia. N Engl J Med, 2000. 343(26): p. 1910-6. 
17. 
Baliakas, P., et al., Recurrent mutations refine prognosis in chronic 
lymphocytic leukemia. Leukemia, 2015. 29(2): p. 329-36. 
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Chiaretti, S., et al., NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients 
with chronic lymphocytic leukemia undergoing first-line treatment: 
correlation with biological parameters and response to treatment. Leuk 
Lymphoma, 2014. 55(12): p. 2785-92. 
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Stilgenbauer, S., et al., Gene mutations and treatment outcome in chronic 
lymphocytic leukemia: results from the CLL8 trial. Blood, 2014. 123(21): p. 
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Oscier, D.G., et al., The clinical significance of NOTCH1 and SF3B1 mutations 
in the UK LRF CLL4 trial. Blood, 2013. 121(3): p. 468-75. 
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Young, E., et al., EGR2 mutations define a new clinically aggressive subgroup 
of chronic lymphocytic leukemia. Leukemia, 2017. 31(7): p. 1547-1554. 
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Roberts, A.W., et al., Targeting BCL2 with Venetoclax in Relapsed Chronic 
Lymphocytic Leukemia. N Engl J Med, 2016. 374(4): p. 311-22. 
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Furman, R.R., et al., Idelalisib and rituximab in relapsed chronic lymphocytic 
leukemia. N Engl J Med, 2014. 370(11): p. 997-1007. 
24. 
Woyach, J.A., et al., BTK(C481S)-Mediated Resistance to Ibrutinib in Chronic 
Lymphocytic Leukemia. J Clin Oncol, 2017. 35(13): p. 1437-1443. 
25. 
O'Brien, S., et al., Single-agent ibrutinib in treatment-naive and 
relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. 
Blood, 2018. 131(17): p. 1910-1919. 
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Mato, A.R., et al., Outcomes of CLL patients treated with sequential kinase 
inhibitor therapy: a real world experience. Blood, 2016. 128(18): p. 2199-
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Burris, H.A., 3rd, et al., Umbralisib, a novel PI3Kdelta and casein kinase-
1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia 
and lymphoma: an open-label, phase 1, dose-escalation, first-in-human 
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Babiker, H.M., et al., Ublituximab for the treatment of CD20 positive B-cell 


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malignancies. Expert Opin Investig Drugs, 2018. 27(4): p. 407-412. 
29. 
Sharman, J.P., et al., Ublituximab (TG-1101), a novel glycoengineered anti-
CD20 antibody, in combination with ibrutinib is safe and highly active in 
patients with relapsed and/or refractory chronic lymphocytic leukaemia: 
results of a phase 2 trial. Br J Haematol, 2017. 176(3): p. 412-420. 
30. 
Sawas, A., et al., A phase 1/2 trial of ublituximab, a novel anti-CD20 
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chronic lymphocytic leukaemia previously exposed to rituximab. Br J 
Haematol, 2017. 177(2): p. 243-253. 
 
 
 


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APPENDIX A:  CONTRACEPTION GUIDELINES AND PREGNANCY 
 
Females Not of Childbearing Potential are Defined as Follows: 
Females 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 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 Females of Child-Bearing Potential: 
Females of child-bearing potential, defined as all females physiologically capable of becoming 
pregnant, must use effective contraception during the study and for 4 months after the last 
dose of study treatment.  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 
vasectomized male partner should be the sole partner for that patient. 
4. Oral contraception, injected or implanted hormonal methods. 
5. 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 
Uunacceptable 
Uforms of contraception for females of childbearing 
potential: 
• 
Female condom 
• 
Natural family planning (rhythm method) or breastfeeding 
• 
Fertility awareness 
• 
Withdrawal 
• 
Cervical shield 


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Females of child-bearing potential must have a negative serum pregnancy test ≤ 3 days prior to 
initiating treatment. 
 
Fertile Males 
Fertile males, defined as all males physiologically capable of conceiving offspring must use 
condom during treatment and for 4 months after the last dose of either study treatment. They 
should also not father a child during this period. 
 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
TG Therapeutics within 24 hours of learning of its occurrence as outlined in the Safety Reporting 
section of this protocol.  The pregnancy, both pregnant female and infant (if applicable), should be 
followed up for 5 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 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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APPENDIX B:  NEW YORK HEART ASSOCIATION CLASSIFICATION 
 
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.