Clinical trial NCT04163718
Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2019-11-12; Completion date: 2022-10-19
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see how safe and effective the investigational drug umbralisib (TGR-1202) is in individuals with Chronic Lymphocytic Leukemia (CLL)

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Umbralisib
Intervention descriptions: intervention 1: 800 mg Umbralisib will be self-administered on an outpatient basis. Umbralisib will be taken orally once daily within 30 minutes of a meal until removal from study. This treatment will be administered in 4 week (28-day) cycles.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Phase 2 Study to Assess the Efficacy, Safety, Pharmacokinetic and 
Pharmacodynamic Parameters of Umbralisib in Treatment Naïve Patients with 
Chronic Lymphocytic Leukemia (CLL) 
 
NCT04163718 
 
Version 4.0 
March 1, 2021 


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Protocol version/Date: 
1.0/ 05 March 2018 
 
2.0/ 27 April 2018 
 
                                                              3.0/ 26 November 2018 
 
3.1 / 18 January 2019 
 
3.2 / 28 May 2019 
 
3.3 / 20 Jun 2019 
                                                            4.0/  01 March 2021 
 
Local Protocol #: 
MCC 19585 
 
TITLE: A Phase 2 Study to Assess the Efficacy, Safety, Pharmacokinetic and 
Pharmacodynamic Parameters of Umbralisib in Treatment Naïve Patients with Chronic 
Lymphocytic Leukemia (CLL) 
 
Sponsor: 
H. Lee Moffitt Cancer Center 
 
IND Number: 
Umbralisib 
142308 
 
Principal Investigator: 
Javier Pinilla-Ibarz, MD, PhD 
Department of Malignant Hematology 
H. Lee Moffitt Cancer Center 
12902 Magnolia Drive, Tampa, FL 33612 
 
Statistician: 
Qianxing Mo, PhD 
 
This trial is supported by TG Therapeutics, Inc. (Tracking Number:  TGR-NTG-006) 
 
 


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TABLE OF CONTENTS 
Study Sypnosis……………………………………………………………………………………………………….. 5-10 
LIST OF ABBREVIATION AND DEFINITIONS OF TERMS ………………………………………    11-12 
 
1.1 
CHRONIC LYMPHOCYTIC LEUKEMIA…………………………………………………………………. .13 
1.2 
UMBRALISIB…………………………………………………………………………………………………… …. 13 
1.1.2 NOVEL MECHANISM OF ACTION………………………………………………………………………………15 
1.2.2 
CLINICAL DEVELOPMENT OF UMBRALISIB…………………………………………………………..16 
1.2.2.1 SINGLE AGENT IN PATIENTS WITH RELAPSED OR REFRACTORY HEMATOLOGIC 
MALIGNANCIES………………………………………………………………………………………………………….16-17 
1.3 RATIONALE FOR THE PHASE 2 TRIAL…………………………………………………………………… ..   19 
 
2       OBJECTIVES AND ENDPOINTS 
…………………………………………………………………………………..19 
 
    2.1 
STUDY OBJECTIVES………………………………………………………………………………… ……………19 
              PRIMARY OBJECTIVE …………………………………………………………………………… …………... 19 
              SECONDARY OBJECTIVES………………………………………………………………………………………19 
              EXPLORATORY OBJECTIVES…………………………………………………………………………………..20 
   2.2 
EFFICACY ENDPOINTS……………………………………………………………………………………..20-21 
               Overall response rate (ORR)……………………………………………………………………………….....21 
               Progression-free survival (PFS)……………………………………………………………………………..21 
              Complete Response (CR) Rate…………………………………………………………................................21 
               Minimal Residual Disease (MRD) Negativity Rate…………………………………………………...21 
               Duration of response (DOR)…………………………………………………………………………………..21 
 
3 
ELIGIBILITY CRITERIA……………………………………………………………………………………………………21 
 
              3.1 INCLUSION CRITERIA…………………………………………………………………………………………………21 
              3.2 EXCLUSION CRITERIA…………………………………………………………………………………………………22 
 
4 
STUDY DESIGN……………………………………………………………………………………………………………23 
 
              4.1 OVERVIEW OF STUDY DESIGN……………………………………………………………………………………23 
              4.2 REGISTRATION/ENROLLMENT………………………………………………………………………………….. 23 
              4.3 STUDY SITES…………………………………………………………………………………………………………….. 23 
              4.4 DISCONTINUATION FROM STUDY TREATMENT……………………………………………………….. 24 
        
5          STUDY ASSESSMENTS AND TREATMENT SCHEDULE……………………………………………………   25 
 
            5.1.1 LOCAL LABORATORY ASSESSMENTS……………………………………………………………………. ….26 
            5.1.2 CENTRAL LABORATORY ASSESSMENTS………………………………………………………………….   27 
         5.1.3 PHARMACODYNAMICS………………………………………………………………………………………………….28 
         5.1.4 CORRELATIVE STUDIES (EXPLORATORY OBJECTIVE)………………………………………………………28 
         5.1.5 IMMUNE-PROFILING STUDIES ……………………………………………………………………………………..29 
 
5       TREATMENT PLAN………………………………………………………………………………………………… 
30 
         5.1 TREATMENT SUMMARY………………………………………………………………………………………. 
30 


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         5.2 AGENT ADMINISTRATION………………………………………………………………………………………………..30 
         6.2.1 GUIDELINES FOR ADMINISTRATION OF UMBRALISIB…………………………………………………… 30 
         6.2.11 DISPENSING OF UMBRALISIB………………………………………………………………………………………31 
         6.2.2 CRITERIA FOR ONGOING TREATMENT………………………………………………………………………… 31 
         6.3 DOSING DELAYS AND MODIFICATIONS…………………………………………………………………………….31 
        6.3.1 DOSE DELAY/MODIFICATIONS: UMBRALISIB…………………………………………………………….31-34 
        6.4 ORDERING UMBRALISIB…………………………………………………………………………………………………… 34 
        6.5 DURATION OF THERAPY………………………………………………………………………………………………….. 34 
        6.6 STOPPING RULES…………………………………………………………………………………………………………34-35 
 
 7     STUDY MEDICATION OVERVIEW AND SAFETY……………………………………………………….. 
35 
         7.1 UMBRALISIB…………………………………………………………………………………………………………………….35 
         7.1.1 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS)…….. 
36 
         7.1.1.2 GENERAL   DISORDERS   AND   ADMINISTRATION   SITE   CONDITIONS:   FATIGUE…… 36 
8     MEASUREMENT OF EFFECT………………………………………………………………………………………………. 36 
        8.1 METHOD OF ASSESSMENT………………………………………………………………………………………………..37 
        8.2 RESPONSE REVIEW……………………………………………………………………………………………………………37 
        8.3 IDENTIFICATION AND MEASUREMENT OF TUMOR LESIONS AND ORGANOMEGALY……….. 37 
        8.3.1 TARGET LESIONS…………………………………………………………………………………………………………… 37 
        8.3.2 SPLEEN AND LIVER……………………………………………………………………………………………………….. 38 
        8.3.3 NON-TARGET LESIONS………………………………………………………………………………………………….. 38 
        8.4 DEFINITIONS OF TUMOR RESPONSE AND PROGRESSION………………………………………………… 39 
        8.5 LYMPHOCYTOSIS DURING THERAPY………………………………………………………………………………… 39 
 
9     STATISTICAL CONSIDERATIONS………………………………………………………………………………………… 39 
 
       9.1 SAMPLE SIZE………………………………………………………………………………………………………… 
39       
9.2 
GENERAL ANALYSIS CONVENTION……………………………………………………………………………. 
40 
       9.3 STUDY POPULATIONS…………………………………………………………………………………………… 
40 
       9.4 PATIENT DEMOGRAPHICS AND BASELINE CHARACTERISTICS…………………………………… 
40 
       9.5 MEDICAL HISTORY……………………………………………………………………………………………….. 
40 
       9.6 EXTENT OF EXPOSURE……………………………………………………………………………………………….. 
40 
       9.7 EFFICACY ANALYSES…………………………………………………………………………………………….. 
40 
       9.8 MISSING VALUE HANDLING PROCEDURES…………………………………………………………………….. 41 
       9.9 STATISTICAL ANALYSES…………………………………………………………………………………………………. 41 
       9.9.1 PRIMARY EFFICACY VARIABLE – PFS…………………………………………………………………………….. 41 
 
10  SAFETY REPORTING AND ANALYSIS…………………………………………………………………………….. 
42 
 
      10.1 SAFETY ANALYSES………………………………………………………………………………………………………. 
42 
      10.2 ADVERSE EVENT CHARACTERISTICS………………………………………………………………………………… 42 
      10.3 ADVERSE  EVENTS  (AES)  AND  TREATMENT  EMERGENT  ADVERSE  EVENTS (TEAES)…….. 43 
      10.4 ADVERSE EVENTS/SERIOUS ADVERSE EVENT CAUSALITY ASSESSMENT………………………….. 43 
      10.4.1 RECORDING OF ADVERSE EVENTS………………………………………………………………………………. 44 
      10.4.2 ABNORMAL LABORATORY VALUES AND VITAL SIGNS………………………………………………. 
44 
      10.4.3 HANDLING OF ADVERSE EVENTS…………………………………………………………………………….. 
44 
      10.5 SERIOUS ADVERSE EVENTS………………………………………………………………………………………. 
45 
      10.5.1 DEFINITIONS OF SERIOUS ADVERSE EVENTS………………………………………………………….. 
45 


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      10.6 SAE REPORTING REQUIREMENTS BY INVESTIGATOR TO FDA AND IRB………………….. 
46 
      10.7 RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS…………………………… 
46 
      10.8 DIAGNOSIS VS. SIGNS AND SYMPTOMS………………………………………………………………………… 47 
      10.8.1 PERSISTENT OR RECURRENT ADVERSE EVENTS…………………………………………………………….. 47 
      10.8.2 ABNORMAL LABORATORY VALUES…………………………………………………………………………. 
47 
      10.8.3 DEATHS………………………………………………………………………………………………………………. 
47 
      10.8.4 HOSPITALIZATION, PROLONGED HOSPITALIZATION, OR SURGERY…………………….. 
48 
      10.8.5  PRE-EXISTING MEDICAL CONDITIONS ………………………………………………………………………….48 
      10.8.6 PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST………………………………………….. 
48 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies…………………………………………………….. 
48 
Study Drug Overdose……………………………………………………………………………………………………………….. 
49 
Secondary / Second Primary Malignancy…………………………………………………………………………………. 
49 
 
11 CLINICAL DATA COLLECTION AND MONITORING………………………………………………………. 
49 
 
      11.1 AMENDMENTS TO THE PROTOCOL………………………………………………………………………… 
49 
      11.2 DATA OWNERSHIP AND PUBLICATION………………………………………………………………… 
49 
      11.3 STUDY RECORDS RETENTION…………………………………………………………………………………….. 
49 
      11.4 CLINICAL MONITORING………………………………………………………………………………………………… 49 
      11.5 QUALITY ASSURANCE AND QUALITY CONTROL……………………………………………………………. 
50 
      11.6 PROTOCOL DEVIATIONS…………………………………………………………………………………………….. 
50 
 
12 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS………………………………………… 
51 
 
      12.1 IRB APPROVAL…………………………………………………………………………………………………………… 
51 
      12.2 INFORMED CONSENT………………………………………………………………………………………………….. 
51 
      12.3 CONFIDENTIALITY……………………………………………………………………………………………………… 
51 
      Patient Confidentiality…………………………………………………………………………………………………………51-52 
 
13 REFERENCES………………………………………………………………………………………………………………. 
53 
 
14 APPENDIX A- CONTRACEPTIVE GUIDELINES AND PREGNANCY…………………………………………… 54 
 
      Women Not of Childbearing Potential are Defined as Follows:……………………………………. 
54 
      Contraceptive Guidelines for Women of Child-Bearing Potential:……………………………………….. 
54 
      Fertile Males:………………………………………………………………………………………………………………………. 
55 
      Pregnancies………………………………………………………………………………………………………………………. 
55 
 
15 APPENDIX B – NYHA CLASSIFICATIONS…………………………………………………………………………….. 56 
 
16 APPENDIX C – HEPATITIS B SEROLOGIC TEST RESULTS……………………………………………………….. 57 
17 APPENDIX D – IWCLL RESPONSE CRITERIA VERSION 2018……………………………………………….. 
58 
     STUDY SYNOPSIS 
 
 
 
 
 


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Protocol no. 
MCC 19585 
Study Title 
A Phase 2 Study to Assess the Efficacy, Safety, Pharmacokinetic and 
Pharmacodynamic Parameters of Umbralisib in Treatment Naïve Patients with 
Chronic Lymphocytic Leukemia (CLL) 
Sponsor 
H. Lee Moffitt Cancer Center 
IND # 
Umbralisib: 142308 
Principal 
Investigator 
Javier Pinilla-Ibarz, MD, PhD 
Department of Malignant Hematology 
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 
Study 
Sites & 
Enrollment 
• 
This study will be a single-center trial conducted at H. Lee Moffitt Cancer 
Center 
• 
Enrollment is expected to take approximately 18 months 
Study Rationale 
The purpose of this study is to evaluate the efficacy, safety, pharmacokinetic 
properties, and pharmacodynamic properties of umbralisib in treatment naïve 
chronic lymphocytic leukemia (CLL) patients. 
Umbralisib is a highly-specific and orally available phosphoinositide-3-kinase 
(PI3K) delta (δ) inhibitor with nanomolar inhibitory potency, and  high selectivity 
over the alpha, beta, and gamma Class I isoforms of PI3K. Umbralisib has 
completed a Phase I dose escalation trial and has been administered safely at 
daily doses up through 1200 mg QD. 
In the Phase I study, 90 subjects with relapsed and refractory hematologic 
malignancies were treated with umbralisib, including 24 with CLL. The most 
commonly reported AEs (all grades, all causality) were diarrhea, nausea, and 
fatigue, the majority of which were Gr1/2. The only Gr≥3 AE in >10% of patients 
was neutropenia (13%). In the modified intention-to-treat population, which 
included subjects who received at least 800 mg per day of the original 
formulation or any dose of the micronized formulation and had at least one 
response assessment, 17 (85%) of 20 subjects with relapsed or refractory CLL 
achieved an objective response, with ten (50%) achieving an objective response 
per 2008 IWCLL criteria, seven (35%) achieving a partial response with 
lymphocytosis, and the remaining three (15%) achieving stable disease. 
Due to the differentiated safety profile, once-daily dosing and clinical activity in 
CLL with umbralisib, the primary aim of this study is to evaluate the overall 
response rate and progression-free survival of umbralisib, while better 
understanding the PK/PD profile of umbralisib. 
 
 
 
 
 


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Study 
Objectives 
PRIMARY OBJECTIVE 
• 
To evaluate the overall response rate (CR + PR) 
 
SECONDARY OBJECTIVES 
• 
To determine the progression free survival of umbralisib in patients with 
CLL 
• 
To assess safety of umbralisib, tolerability and other efficacy outcomes 
• 
To determine the pharmacokinetics and pharmacodynamics of umbralisib 
EXPLORATORY OBJECTIVES 
• 
Alterations in T lymphocyte function 
• 
Alterations in B lymphocyte function 
• 
Alterations in global systemic cytokine patterns 
• 
Alteration in the myeloid cells, function 


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Inclusion 
Criteria 
Patients  must  meet  all  of  the  following  inclusion  criteria  to  be  eligible  for 
participation in this study: 
1) Have a diagnosis of B-cell CLL that has not been previously treated and now 
warrants treatment consistent with accepted iwCLL criteria (Hallek2018) 
for initiation of therapy. Any one of the following conditions constitute CLL 
that warrants treatment: 
a) Evidence of progressive marrow failure as manifested by the onset or 
worsening of anemia and/or thrombocytopenia, or 
b) Massive (i.e., lower edge of spleen ≥ 6 cm below the left costal margin), 
progressive, or symptomatic splenomegaly, or 
c) Massive (i.e., ≥ 10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy, or 
d) Progressive lymphocytosis in the absence of infection, with an increase 
in blood absolute lymphocyte count (ALC) > 50% over a 2-month period 
or lymphocyte doubling time of < 6 months (as long as initial ALC was ≥ 
30,000/µL), or 
e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive 
to corticosteroids or other standard therapy, or 
f) Symptomatic or functional extranodal involvement (e.g. skin, kidney, 
lung, or spine), or 
g) Constitutional symptoms, defined as any one or more of the following 
disease-related symptoms or signs occurring in the absence of evidence 
of infection: 
i) Unintentional weight loss of ≥ 10% within the previous 6 months, or 
ii) Significant fatigue (≥ Grade 2), or 
iii) Fevers ≥100.5°F or 38.0°C for ≥ 2 weeks, or 
iv) Night sweats for ≥ 1 month. 
2) Adequate organ system function, defined as follows: 
a) Absolute neutrophil count (ANC) ≥ 1,000/mm3 platelet count ≥ 
30,000/mm3, (ANC ≥ 500/mm3 and platelet count ≥ 20,000/mm3 
permitted if known marrow involvement). Growth factors are permitted 
at any time during the study, but not to meet eligibility criteria. 
b) Total  bilirubin  ≤  1.5  times  the  upper  limit  of  normal  (ULN)  (unless 
diagnosed with Gilbert’s syndrome). 
c) c)   Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5  x  ULN  if  no  liver  involvement  or  ≤  5  x  the  ULN  if  known  liver 
involvement 
d) d) Calculated creatinine clearance > 30 mL/min (as calculated by the 
Cockcroft-Gault or MDRD formula, 24 hour urine Cr clearance also 
acceptable)  
 
 
 
 


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3) ECOG performance status ≤ 2 
4) Male or female ≥ 18 years of age 
5) Ability to swallow and retain oral medication 
6) Female patients who are not of child-bearing potential and female patients 
of child-bearing potential who have a negative serum pregnancy test within 
3 days prior to Cycle 1, Day 1. Female patients of child-bearing potential and 
all male partners, and male patients must consent to use a medically 
acceptable method of contraception throughout the study period and for 30 
days after the last dose of study drug. 
7) Willingness and ability to comply with trial and follow-up procedures, and 
give written informed consent 
  
Exclusion  
  Criteria 
Patients who meet any of the following exclusion criteria are not to be enrolled 
to this study: 
1) Has ever received any form of treatment for CLL. 
2) Corticosteroid therapy of > 10 mg daily or equivalent started less than 7 
days prior to Cycle 1, Day 1 is prohibited. Prednisone ≤ 10 mg daily or 
equivalent is allowed as clinically warranted. Topical or inhaled 
corticosteroids are permitted. 
3) Prior treatment with umbralisib. 
4) Prior treatment with autologous hematologic stem cell transplant or 
allogeneic hematologic stem cell transplant. 
5) Evidence of chronic active Hepatitis B (HBV, not including patients  with prior 
hepatitis B vaccination; or positive serum Hepatitis B antibody) or chronic 
active Hepatitis C infection (HCV), active cytomegalovirus (CMV), or known 
history of HIV. If HBc antibody is positive, the subject must be evaluated for 
the presence of HBV DNA by PCR. If HCV antibody is positive, the subject 
must be evaluated for the presence of HCV RNA by PCR.  See Appendix C. If 
the subject is CMV IgM positive, the subject must be evaluated for the 
presence of CMV DNA by PCR. Subjects with positive HBc antibody and 
negative HBV DNA by PCR are eligible. Subjects with positive HCV antibody 
and negative HCV RNA by PCR are eligible. Subjects who are  CMV IgM 
positive but who are CMV DNA negative by PCR are eligible. Antiviral 
prophylaxis should be considered per institutional protocol. 
6) Known histological transformation from CLL to an aggressive lymphoma (i.e. 
Richter’s transformation / Hodgkin Lymphoma). 
7) Evidence of ongoing systemic bacterial, fungal, or viral infection, except 
localized fungal infection of skin/nails. N O T E :   Subjects may be receiving 
prophylactic antiviral or antibacterial therapies at investigator discretion. Use 
of anti-pneumocystis and antiviral prophylaxis is required. 
8) Inflammatory bowel disease (such as Crohn’s disease or ulcerative colitis) 
9) Malabsorption syndromes 
10) Irritable bowel syndrome with greater than 3 loose stools per day as a 
baseline. 
11) Any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 
 


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a) Symptomatic, or history of documented congestive heart failure (NY 
Heart Association functional classification III-IV) – See Appendix B 
b) 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. 
d) Angina not well-controlled by medication 
e) Poorly controlled or clinically significant atherosclerotic vascular disease 
including cerebrovascular accident (CVA), transient ischemic attack 
(TIA), 
symptomatic 
peripheral 
arterial 
disease, 
angioplasty, 
cardiac/vascular stenting within 6 months of enrollment. 
12) Malignancy (including myelodysplastic syndromes) within 3 years of study 
enrollment except for  basal, squamous cell carcinoma or  melanoma in  situ , 
carcinoma in situ of the cervix, superficial bladder cancer not treated with 
intravesical chemotherapy or BCG within 6 months, localized prostate 
cancer following curative treatment and with a normal PSA..  
13) Women who are pregnant or lactating. 
14) Subjects requiring immediate cytoreductive therapy. 
Study Design 
This study is designed as a Phase 2, single-center, single-arm trial to evaluate the 
efficacy and safety of umbralisib, in patients with CLL. The primary objective will 
be measured by overall response rate (ORR). 
Enrollment 
Following Screening, qualified patients will be enrolled and receive  the following: 
• 
Umbralisib 800 mg once daily within 30 minutes of a meal. 
During the study period, all patients will be evaluated for response by CT or MRI 
within 14 days prior to Cycle 4, Day 1 for Cycle 3 assessment, and within 14 days 
prior to Cycle 13, Day 1 for Cycle 12 assessment, and at any other time point to 
confirm progression. Patients who fail to achieve a partial or complete response 
to umbralisib at the Cycle 3 assessment will discontinue study treatment. At that 
time, patients- will be provided appropriate options to receive established 
frontline therapy. Patients who demonstrate a partial or complete 
response will be treated until disease progression, unacceptable toxicity, or 
the end of the study. 
 
The primary efficacy variable will be ORR. 
 
 
 
 
 


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Statistics 
The study will plan to enroll up to 40 subjects, and assuming 10% 
attrition, there will be approximately 35 subjects remaining for analysis. 
Enrollment is expected to be completed in approximately 18 months with 
24 months follow- up. The ORR for the standard of care is about 60%.  We 
expect that Umbralisib treatment could lead to 80% ORR.  A Simon 2-stage 
minimax design that differentiates ORRs of 0.60 (null hypothesis) and 0.80 
(alternative hypothesis) will be used to assess treatment efficacy, with the 
probabilities of a type I error (falsely accepting a non-promising therapy) 
and type II error (falsely rejecting a promising therapy) both set at 0.10.  
Twenty seven patients will be accrued in the first stage of the study.  If 18 or 
fewer patients have a response, then the study will be terminated and declared 
negative.  If 19 or more patients have a response, then an additional 8 patients 
will be accrued to the second stage.  At the conclusion of the study, if 25 or more 
patients have a response out of a total of 35 patients enrolled, the regimen will 
be considered worthy of further investigation.    
Safety will be examined on an ongoing basis while the study is being conducted. 
Adverse events will be recorded as per CTCAE v5.0. 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviations and Definitions of Terms 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BM 
Bone Marrow 
BTK 
Bruton’s Tyrosine Kinase 
Ca 
Calcium 
CBC 
Complete Blood Cell Count 
Cl 
Clearance 
CLL 
Chronic Lymphocytic Leukemia 
cm 
Centimeter 
Cmax 
Maximum Concentration 
CR 
Complete Response 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebro-Vascular Accident 
D, d 
Day 
DSMB 
Data Safety Monitoring Board 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
DRG 
Data Review Group 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FCR 
Fludarabine, Cyclophosphamide, Rituximab 
FISH 
Fluorescence In-Situ Hybridization 
GCP 
Good Clinical Practice 
IEC/IRB 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
Ig 
Immunoglobulin 
ICH 
International Conference on Harmonisation 
IRC 
Independent Review Committee 
ITT 
Intent-To-Treat 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
Intravenous 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
LPD 
Longest Perpendicular Diameter 
LTFU 
Long-Term Follow Up 
MRD 
Minimum Residual Disease 


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Abbreviations and Definitions of Terms 
MRI 
Magnetic Resonance Imaging 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHL 
Non-Hodgkin’s Lymphoma 
OS 
Overall Survival 
ORR 
Overall Response Rate 
PCR 
Polymerase Chain Reaction 
PE 
Physical Examination 
PFS 
Progression-Free Survival 
PD 
Pharmacodynamic or Progressive Disease 
PK 
Pharmacokinetic 
PPD 
Perpendicular Diameters 
PPS 
Per Protocol Set 
PR 
Partial Response 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SLL 
Small Lymphocytic Lymphoma 
SOC 
System Organ Class 
SPD 
Sum of the Products 
SUV 
Standardized Uptake Value 
t1/2 
Half-Life of Elimination 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
V 
Visit 
Vd 
Volume of Distribution 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 


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1. INTRODUCTION 
 
 
 
1.1 CHRONIC LYMPHOCYTIC LEUKEMIA 
 
 
 
In the US, an estimated 14,620 new cases of Chronic Lymphocytic Leukemia (CLL) will be 
reported in 2015 with deaths totaling 4,650 due to the disease according to American Cancer 
Society estimates (American Cancer Society, 2015). CLL affects mainly older adults, accounts for 
one third of all diagnosed cases of leukemia, and is characterized by the accumulation of 
clonal mature B lymphocytes in the blood, bone marrow, and secondary lymphoid tissues (Lin 
K, 2002). CLL is a heterogeneous disease, with several higher risk cytogenetic abnormalities 
which are  generally more difficult to treat, including 17p deletion, P53 gene mutation, and 
11q deletion (Hallek M, 2008) (Lin K, 2002). Patients with 17p deletion show higher 
resistance to conventional chemotherapies as well as shorter duration of survival than non 
17p deletion patients. Patients 
with 11q deletion have been associated with marked 
lymphadenopathy (Hallek M, 2008). Patients  with P53 gene mutations are associated with an 
adverse clinical outcome (Lin 2002). 
 
1.2 UMBRALISIB 
 
 
 
Umbralisib is a highly-specific and orally available phosphoinositide-3-kinase (PI3K) delta (δ) 
inhibitor with nanomolar inhibitory potency, and high selectivity over the alpha, beta, and 
gamma Class I isoforms of PI3K.3 
Umbralisib also targets casein kinase-1 epsilon (CK-1Ɛ) a protein which may inhibit regulatory 
T- cell function. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.1.1NOVEL MECHANISM OF ACTION 
 
 
A study was done to compare the effects of umbralisib, duvelisib, and idelalisib on T cells in a 
CLL mouse model and analyze immune-mediated adverse events following oral  administration 


14 | P a g e  
 
(Maharaj et al, ASH 2017). Peripheral Treg count was negatively correlated with incidence  of 
toxicity in mice treated with PI3K inhibitors. Umbralisib showed decreased anti-Treg effects in 
a dose-dependent manner compared to other PI3K inhibitors in CLL T cells. Furthermore, 
umbralisib was shown to uniquely inhibit CK1e in euTCL1 T cells dose-dependently. In this way, 
CK1e inhibition by umbralisib may offer an explanation for less anti-Treg effects. The goal of this 
phase 2 study is to further analyze the relationship between PI3K delta inhibition and T cell 
subsets. 
 
 
 
 
 
 
1.2.2 CLINICAL DEVELOPMENT OF UMBRALISIB 
 
 
 
1.2.2.1 SINGLE-AGENT  IN  PATIENTS  WITH  RELAPSED  OR  REFRACTORY  
HEMATOLOGIC MALIGNANCIES 
 
Umbralisib was evaluated in a single-agent Phase I dose-escalation study (Study TGR-1202-
101; NCT01767766) in subjects with relapsed and refractory hematologic malignancies (Burris 
et al, Lancet Oncology 2018). There were 90 subjects enrolled and eligible for safety evaluation, 
and 73 subjects evaluable for efficacy in the modified intention to treat population. The median 
age was 64 years (range 51-72), 63% male, median number of prior therapies was 3, and 49% of 
subjects were refractory to their most recent prior therapy. Histological diagnoses included; 
CLL (n=24), FL (n=22), DLBCL (n=16), HL (n=11), MCL (n=6), MZL (n=5), WM (n=2), HCL and 
TCL (n=1 each).  The 
majority of subjects (58%) had received 3 or more prior therapies. 
 
Patients were enrolled in a 3+3 dose-escalation design starting at 50 mg QD with subsequent 
cohorts evaluating doses as high as 1800 mg QD. In an effort to further improve the oral 
bioavailability of umbralisib, the particle size of the drug product was reduced through a 
micronization process, resulting in greater absorption when tested in a bioequivalence crossover 
study in healthy subjects (see Section 1.3.2.2 Healthy Subject Pharmacokinetic Studies below). This 
micronized formulation was introduced into dose escalation at 200 mg QD and dosed as high 
as 1800 mg QD. The maximum tolerated dose (MTD) was 1200 mg QD of the micronized 
formulation, with 800 mg of this formulation selected as the recommended phase 2 dose based 
on changes in tumor burden correlated with dose-proportional plasma exposure. Intra-subject 
dose escalation rules allowed subjects enrolled into the study in early cohorts to increase their 
dose of umbralisib as subsequent higher cohorts cleared safety evaluation. The most common 
treatment-emergent adverse events irrespective of causality were diarrhea (in 39 [43%] of 
90 subjects), nausea (38 [42%]), and fatigue (28 [31%]).  The most common grade 3 or 4 adverse 
events were neutropenia 
(in 12 [13%] subjects), anemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse 
events considered at least possibly related to umbralisib occurred in seven subjects: pneumonia 
in three (3%) subjects, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in 
two (2%), one of whom also had febrile neutropenia. Both cases of colitis occurred above the 
recommended phase 2 dose. No time-related trends in toxicity were noted. See the umbralisib 
investigator’s brochure for a complete overview of the umbralisib side effect profile. 


15 | P a g e  
 
Dosing of umbralisib initially occurred in the fasting state, but was transitioned mid-study to 
fed state dosing, with subjects instructed to take umbralisib with food. All dosing of umbralisib 
is now conducted using the micronized formulation and in the fed state. 
 
Among 73 subjects in the modified intention-to-treat population, which included subjects who 
received at least 800 mg per day of the original formulation or any dose of the micronized 
formulation and had at least one response assessment, 53 (73%) had reductions in disease burden, 
including 33 (45%) subjects with reductions of 50% or more, of which three (4%) were a complete 
response and 30 (41%) were a partial response. In subjects with relapsed or refractory CLL, 
17 (85%) of 20 achieved an objective response, with ten (50%) achieving an objective response 
per 2008 IWCLL criteria, seven (35%) achieving a partial response with lymphocytosis, and the 
remaining three (15%) achieving stable disease. Of eight assessable subjects with CLL who had 
high-risk cytogenetic features, six (75%) had a response, of whom two (25%) had a partial 
response with lymphocytosis, and the remainder had stable disease.  In subjects with follicular 
lymphoma, nine (53%) of 17 subjects achieved an objective response, including two (12%) 
who achieved a complete response; the remainder had a partial response. In subjects with diffuse 
large B-cell lymphoma, four (31%) of 13 achieved an objective response and two (15%) further 
subjects achieved stable disease. Responses for the other subject subgroups were Hodgkin 
lymphoma: one complete response, four stable disease, four progressive disease; marginal zone 
lymphoma: one partial response, four stable disease; Waldenström’s macroglobulinemia: two 
stable disease; and mantle cell lymphoma: one partial response, four stable disease, and one 
progressive disease. In a post-hoc exploratory analysis, tumor reductions in most subjects with 
indolent lymphoma and CLL treated with umbralisib tended to improve over time. The mean 
duration of response was 13.4 months (95% CI 7.7–19.1) in 16 subjects in the CLL cohort, 6.4 
months (4.5–17.3) in four subjects in the DLBCL cohort, and 9.3 months (3.6–15.1) in nine 
subjects in  the  follicular  lymphoma cohort. In a post-hoc exploratory analysis of progression-
free survival, median progression-free survival was 24.0 months (95% CI 7.4 months–not 
reached) in 20 subjects with CLL, and 16 months (9.2 months–not reached) in 24 subjects with 
indolent non-Hodgkin lymphoma (follicular lymphoma, Waldenström’s macroglobulinemia, and 
marginal zone lymphoma). Overall, umbralisib was well tolerated and displayed promising signs 
of clinical activity at the higher dosing cohorts. Umbralisib monotherapy is being studied in a 
registration directed trial in various NHL subtypes 
(Study UTX-TGR-205 [UNITY-NHL]; 
NCT02793583). The combination of ublituximab and umbralisib is also being studied in Study 
UTX-TGR-205 [UNITY-NHL]; NCT02793583) and in another registration directed trial in CLL 
(Study UTX-TGR-304 [UNITY-CLL]; NCT02612311). See the latest Investigator’s Brochure for 
updated information regarding the clinical development of umbralisib. 
 
. 
 
 
 
 
 
 
 
 


16 | P a g e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                
 
1.3 RATIONALE FOR THE PHASE 2 TRIAL 
 
 
 
Previously, umbralisib has been demonstrated to be safe and efficacious in the treatment of CLL 
as part of a broad Phase 1 study enrolling a variety of hematologic malignancies (Burris et al, 
Lancet Oncology 2018). While clinically active, the mechanism of action for umbralisib and the 
mechanism underlying its unique safety profile remain unclear. Previous studies in mice 
demonstrated inhibition of pAKT suggesting activity through inhibition of the PI3K pathway, 
however recently the CK1e targeting properties of umbralisib which may have a T-cell 
supportive role have also been described in pre-clinical models. The goal of this study is to further 
describe the safety and efficacy profile, while characterizing the pharmacodynamic properties 
of umbralisib in relation with pharmacokinetics. 
 
2. TRIAL OBJECTIVES AND ENDPOINTS 
 
 
2.1 STUDY OBJECTIVES 
 
PRIMARY OBJECTIVE 
• 
To evaluate the overall response rate (CR + PR) 
SECONDARY OBJECTIVES 
• 
To determine the progression free survival of umbralisib in patients with CLL  
• 
To assess safety of umbralisib, tolerability and other efficacy outcomes 
• 
To determine the pharmacokinetics and pharmacodynamics of umbralisib 
EXPLORATORY OBJECTIVES 
• 
Alterations in T lymphocyte function, including changes in: 
a. TH1:TH2 polarization, and Treg:TH17 distributions 
 
b. Markers of T cell exhaustion and/or inhibition 
 
c. Alterations in distribution of naïve vs. memory 
 
d. Cellular activation and cell-mediated cytotoxic capacity 
 
• 
Alterations in B lymphocyte function, including changes in: 


17 | P a g e  
 
a. Change in the B cell receptor repertoire, perhaps clonal evolution 
 
b. Quantitative serum immunoglobulin levels and subtyping 
 
c. Fc-receptor (FcR) expression patterns 
 
• 
Alterations in global systemic cytokine patterns: Includes IFN-γ, TNF-α, IL-2, IL-4, IL-10, 
IL-6, IL-17A, allowing discrimination between TH1, TH2, TH17 and Treg profiles 
• 
Alteration in the Myeloid cells, function, including changes in: 
-Antigen presentation capacity (Functional assay) 
 
-Alterations in the distribution of M1 vs M2 & N1 vs N2 
 
• 
Pharmacodynamics analysis, including pAKT changes in: 
-T cell compartment 
 
-B cell compartment 
 
Samples (blood, bone marrow, etc.) may not be taken from subjects and stored for future research 
that is not defined within this protocol without a contractual agreement between the institution 
and TG Therapeutics, Inc. to govern the ensuing research prior to its conduct. 
 
1.3 EFFICACY ENDPOINTS 
 
 
 
Overall response rate (ORR) 
ORR is defined as sum of CR and PR rates. 
Progression-free survival (PFS) 
PFS is defined as the interval from  registration to the earlier of the first documentation of 
definitive disease progression or death from any cause. 
Definitive disease progression based on standard criteria (Hallek et al. 2018) and occurring for 
any reason (i.e., increasing lymphadenopathy, organomegaly or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of disease-related 
symptoms) other than lymphocytosis. 
 
 
Complete Response (CR) Rate 
CR rate is defined as the proportion of patients who achieve a CR. 
 
Minimal Residual Disease (MRD) Negativity Rate 
MRD negativity rate is defined as the proportion of patients who are MRD negative. 
 
Duration of response (DOR) 
DOR is defined as the interval from the first documentation of CR or PR to the earlier of the 
first documentation of definitive disease progression or death from any cause. 
 
3. ELIGIBILITY CRITERIA 
 


18 | P a g e  
 
 
 
Patients must meet all of the following inclusion criteria and none of the exclusion criteria to be 
eligible for participation in this study. 
 
3.1 INCLUSION CRITERIA 
 
 
 
Patients must meet all of the following inclusion criteria to be eligible for participation in this 
study: 
1) Have a diagnosis of B-cell CLL that has not been previously treated and now warrants 
treatment consistent with accepted iwCLL criteria (Hallek 2018) for initiation of therapy. 
Any one of the following conditions constitute CLL that warrants treatment: 
a) Evidence of progressive marrow failure as manifested by the onset or worsening of 
anemia and/or thrombocytopenia, or 
b) Massive (i.e., lower edge of spleen ≥ 6 cm below the left costal margin), progressive, 
or symptomatic splenomegaly, or 
c) Massive (i.e., ≥ 10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy, or 
d) Progressive lymphocytosis in the absence of infection, with an increase in blood 
absolute lymphocyte count (ALC) >50% over a 2-month period or lymphocyte 
doubling time of <6 months (as long as initial ALC was ≥30,000/µL), or 
e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy, or 
f) Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, or spine), or 
g) Constitutional symptoms, defined as any one or more of the following disease-
related symptoms or signs occurring in the absence of evidence of infection: 
i) Unintentional weight loss of ≥10% within the previous 6 months, or 
ii) Significant fatigue (≥ Grade 2), or 
iii) Fevers >100.5°F or 38.0°C for ≥2 weeks, or 
iv) Night sweats for >1 month. 
2) Adequate organ system function, defined as follows: 
a) Absolute neutrophil count (ANC) > 1,000/mm3 platelet count > 30,000/mm3, (ANC ≥ 
500/mm3 and platelet count ≥ 20,000/mm3 permitted if known marrow involvement). 
Growth factors are permitted at any time during the study, but not to meet  eligibility 
criteria. 
b) Total bilirubin ≤1.5 times the upper limit of normal (ULN) (unless diagnosed with 
Gilbert’s syndrome). 
c) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if 
no liver involvement or ≤5 x the ULN if known liver involvement 
d) Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault or 
MDRD formula, 24 hour urine Cr clearance also acceptable) 
3) ECOG performance status ≤ 2 
4) Male or female ≥ 18 years of age 
5) Ability to swallow and retain oral medication 
6) Female patients who are not of child-bearing potential and female patients of child-
bearing potential who have a negative serum pregnancy test within 3 days prior to 
Cycle 1, Day 1. Female patients of child-bearing potential and all male partners, and 
male patients must consent to use a medically acceptable method of contraception 


19 | P a g e  
 
throughout the study period and for 30 days after the last dose of study drug. 
7) Willingness and ability to comply with trial and follow-up procedures, and give written 
informed consent 
 
 
3.2 EXCLUSION CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients who meet any of the following exclusion criteria are not to be enrolled to this study: 
1) Has ever received any form of treatment for CLL. 
2) Corticosteroid therapy of prednisone > 10 mg or equivalent started at least 7 days prior to Cycle 
1, Day 1 is prohibited. Prednisone ≤ 10 mg daily or equivalent is allowed as clinically warranted. 
Topical or inhaled corticosteroids are permitted. 
3) Prior treatment with umbralisib. 
4) Prior treatment with autologous hematologic stem cell transplant or prior 
Allogeneic hematologic stem cell transplant is excluded. 
5) Evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B 
vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C infection 
(HCV), active cytomegalovirus (CMV), or known history of HIV. If HBc antibody is positive 
the subject must be evaluated for the presence of HBV DNA by PCR.  If HCV antibody is 
positive, the subject must be evaluated for the presence of HCV RNA by PCR.  See Appendix 
C. If the subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the 
presence of CMV DNA by PCR. Subjects with positive HBc antibody and negative HBV DNA 
by PCR are eligible. Subjects with positive HCV antibody and negative HCV RNA by PCR are 
eligible.  Subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by 
PCR are eligible. Antiviral prophylaxis should be considered per institutional protocol. 
6) Known histological transformation from CLL to an aggressive lymphoma (i.e. 
Richter’s transformation / Hodgkin Lymphoma). 
7) Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal 
infection of skin/nails. NOTE: Subjects may be receiving prophylactic antiviral or 
antibacterial therapies at investigator discretion. Use of anti-pneumocystis and antiviral 
prophylaxis is required. 
8) Inflammatory bowel disease (such as Crohn’s disease or ulcerative colitis) 
9) Malabsorption syndromes 
10) Irritable bowel syndrome with greater than 3 loose stools per day as a baseline. 
11) Any severe and/or uncontrolled medical conditions or other conditions that could affect 
their participation in the study such as: 
a) Symptomatic, or history of documented congestive heart failure (NY Heart 
Association functional classification III-IV) – See Appendix B 
b) 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. 
d) Angina not well-controlled by medication 
e) Poorly controlled or clinically significant atherosclerotic vascular disease including 
cerebrovascular accident (CVA), transient ischemic attack (TIA), symptomatic 
peripheral arterial disease, angioplasty, cardiac/vascular stenting within 6 months of 
enrollment. 
12) Malignancy, including myelodysplastic syndromes, within 3 years of study enrollment 


20 | P a g e  
 
except for basal, squamous cell carcinoma or  melanoma in situ, carcinoma in situ of the 
cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG 
within 6 months, localized prostate cancer following curative treatment and with a 
normalPSA level  
. 
13) Women who are pregnant or lactating. 
 
14) Subjects requiring immediate cytoreductive therapy. 
 
 
 
4. STUDY DESIGN 
 
 
 
 
4.1 OVERVIEW OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
This study is designed as a Phase 2, single-center, single-arm trial to evaluate the ORR and PFS 
of umbralisib in treatment naïve CLL patients requiring therapy. Daily doses of oral umbralisib 
will be administered in the absence of disease progression, unacceptable toxicity, or 
withdrawal from treatment. Treatment cycles are 4 weeks, with the efficacy evaluations within 
14 days prior to Cycle 4, Day 1 for Cycle 3 assessment, and within 14 days prior to Cycle 13, 
Day 1 for Cycle 12 assessment, and at any other time point to confirm progression. Patients who 
fail to achieve a partial or complete response to umbralisib at the Cycle 3 assessment will 
discontinue study treatment. At that time, patients- will be provided appropriate options to receive 
established frontline therapy. Patients who demonstrate a partial or complete response will be 
treated until disease progression, unacceptable toxicity, or the end of the study. Enrollment will be 
up to 35 patients. 
4.2 REGISTRATION/ENROLLMENT 
 
 
 
 
 
 
Following Screening, qualified patients will receive the following: 
• 
Umbralisib 800 mg once daily 
During the study period, all patients will be evaluated for response by CT or MRI within 14 days 
prior to Cycle 4, Day 1 for Cycle 3 assessment, and within 14 days prior to Cycle 13, Day 1 for Cycle 
12 assessment, and at any other time point to confirm progression.  Patients who fail to achieve a 
partial or complete response to umbralisib at the Cycle 3 assessment will discontinue study 
treatment. At that time, patients- will be provided appropriate options to receive established 
frontline therapy. Patients who demonstrate a partial or complete response will be 
treated until disease progression, unacceptable toxicity, or the end of the study. 
 
4.3 STUDY SITES 
 
 
 
 
 
 
 
 
 
This is a single-center study.  Enrollment is expected to be completed in approximately 18 months. 
 
4.4 DISCONTINUATION FROM STUDY TREATMENT 
 
 
 
 
 
 
 
 
 
 
 


21 | P a g e  
 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
Disease progression 
• 
Failure to achieve a partial or complete response to umbralisib at the Cycle 3 assessment 
• 
Intolerable toxicity related to study drug 
• 
Patient requests to withdraw consent or discontinue treatment 
• 
Pregnancy 
• 
Inability of the patient to comply with study requirements 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Non-compliance/lost to follow-up 
• 
Investigator discretion 
• 
Discontinuation of the study 
 
 
 
 
 
 
 
 
Patients who discontinue from study treatment prior to Cycle 12 (for reasons other than 
progressive disease) should continue to be followed for progression approximately every 3 
months up until the time Cycle 12 would have occurred, then approximately every 6 months. 
Patients who discontinue from study treatment after Cycle 12 for reasons other than disease 
progression should be followed for progression approximately every 6 months. 
 
After withdrawal from protocol treatment, patients should be followed for AEs for 30 calendar days 
after their last dose of study drug. All new AEs occurring during this period must be reported and 
followed until resolution, unless, in the opinion of the investigator, these values are not likely 
to improve because of the underlying disease. In this case the investigators must record his or 
her reasoning for this decision in the patient’s medical records. 
All patients who have CTCAE Grade 3 or 4 laboratory abnormalities at the time of withdrawal 
should be followed until the laboratory values have returned to Grade 1 or 2, unless in the opinion 
of the investigator, it is not likely that these values are to improve because of the underlying disease. 
In this case, the investigator must record his or her reasoning for making this decision in the 
patient’s medical records. 
All patients that begin therapy outside of the scope of this protocol within 30 days of discontinuing 
umbralisib do not need to be followed for AEs, unless umbralisib is determined to be the direct 
cause of the AE in the opinion of the treating investigator. After 30 days from discontinuation 
of umbralisib, these AEs no longer need to be followed. 
 
 5. STUDY ASSESSMENTS AND TREATMENT SCHEDULE 
 
  The table below lists all required assessments that should be performed at each study visit. 
 
STUDY ASSESSMENTS AND TREATMENT SCHEDULE 
 
All cycles are 28 day cycles 
Screening 
Cycle 11 
Cycles 2 - 62 
> Cycle 63 
End of 
Treatment 
F/U 
End of 
Study 
D-28 to D0 
D1 
D2 
D8 
D15 
D1 
Every 3 cycles 
Medical History 
X 
ECOG Performance Status 
X 
X 
 
 
 
 
 
Physical Examination/Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (QTcF) 
X 
Serology HCV, HBV, CMV 
X4 


22 | P a g e  
 
CMV surveillance4 
X4 
X4 
X4 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/INR, PTT 
X 
β2 -Microglobulin 
X 
 
 
CT Imaging (neck, chest, 
abdomen, pelvis) 
X5 
Within 14 days prior to Cycle 4, Day 1 for Cycle 3 assessment, 
and within 14 days prior to Cycle 13, Day 1 for Cycle 12 
assessment, and at any other time point to confirm 
progression 
Response assessment5 
X5 
X5 
X5 
X5 
X5 
Serum Pregnancy Test 
X6 
 
 
 
 
 
 
FISH + IgHV 
X 
Correlative Labs (PBMC)7 
X 
X8 
C7 only X8 
Disease progression 
PKs8 
 
X 
X 
 
 
X 
 
Bone Marrow aspirate for 
correlative studies 9 
X 
X12 
PDs8 
X 
 
 
X 
 
Umbralisib 800 mg 
Daily Days 1 – 28 
Bone Marrow Biopsy9,10 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
 
1     Visit days and all related assessments and testing have +/- 1 day window in Cycle 1. 
2     Unless otherwise noted (i.e. CT scans), visit days and all related assessments and testing have +/- 3 day window in Cycles 2 - 6. 
3     Unless otherwise noted (i.e. CT scans), visit days and all related assessments and testing have +/- 7 day window for Cycles > 6. 
4 Serum virology to include HBsAg, HBc antibody, HCV antibody, CMV IgG and CMV IgM. If HBc antibody is positive, the 
subject must be evaluated for the presence of HBV DNA by PCR - See Appendix C. If HCV antibody is positive, 
the subject must be evaluated for the presence of HCV RNA by PCR.If the subject is CMV IgM positive, 
the subject must be evaluated for the presence of CMV DNA by PCR.  CMV surveillance by PCR every 3 cycles while 
receiving study treatment.  In addition, a final CMV test by PCR should be done upon treatment discontinuation. 
. 
5    Baseline CT scan within 30 days prior to Cycle 1, Day 1; then within 14 days prior to Cycle 4, Day 1 for Cycle 3 
assessment, and within 14 days prior to Cycle 13, Day 1 for Cycle 12 assessment. Additional scans may be requested 
at the discretion of the investigator at any other time point to confirm progression (all scans +/-14 days). CT 
imaging should be performed at EOT visit if it hasn’t been completed within past 30 days. 
6    Serum pregnancy test within 3 days prior to starting treatment on Cycle 1, Day 1 for women of childbearing potential. 
7 Peripheral Blood Mononuclear Cells (PBMC) – Peripheral blood sample to be obtained pre-dose on C1D1, C2D1, C4D1, 
C7D1, C13D1 and at the time of disease progression, which may occur at any time point including at the End of 
Treatment visit or the End of Study visit.. 
8 PK samples (plasma) will be collected according to the schedule in Section 5.1.2. Additional PK samples may be 
collected outside of this schedule upon the occurrence of toxicity in order to correlate to plasma concentrations. 
PD samples (fresh peripheral blood) will be collected according to the schedule in Section 5.1.2. PBMCs will be 
isolated by Ficol centrifugation and B and T cell will be analyzed (post ex vivo stimulation) for phosphorylation of 
AKT. 
9 An aspirate sample of 8-10 ml will be obtained at the time of each bone marrow biopsy- screening and the end of C12- 
for correlative studies. 
10Bone Marrow aspirate/biopsy performed at baseline and within 14 days following the last dose of Cycle 12 study 
drug.. (Research lab Cycle 13 
5.1.1 LABORATORY ASSESSMENTS 
 
 
 
 
 
  Laboratory assessments  will  be  collected  as  specified  in  the  study  assessments  and  
  treatment schema 
 
 
5.1.1 LOCAL LABORATORY ASSESSMENTS 
 
1. Hematologic profile and serum chemistry to include through Cycle 6: 
 
 
Hematologic Profile 
Hematocrit 
Neutrophils 
Platelet count 
Hemoglobin 
Lymphocytes 
Absolute lymphocyte count 


23 | P a g e  
 
Erythrocyte count 
Monocytes 
Leukocyte count 
Basophils 
Eosinophils 
Absolute neutrophil count 
Serum Chemistry 
Albumin 
Creatinine 
SGOT [AST] 
Alkaline phosphatase 
Glucose 
SGPT [ALT] 
Bicarbonate (total CO2) 
LDH 
Sodium 
BUN 
Magnesium 
Total bilirubin 
Calcium 
Phosphorus 
Total protein 
Chloride 
Potassium 
Uric acid 
 
Hematologic and Serum Chemistry windows as follows: 
• 
Cycle 1: -1 day window 
• 
Cycles 2 – 6: +/- 3 day window 
 
2. After Cycle 6, required labs will include a standard CBC/differential and chemistry as below: 
Hematologic Profile 
Hematocrit 
Neutrophils 
Platelet count 
Hemoglobin 
Lymphocytes 
Absolute lymphocyte count 
Erythrocyte count 
Monocytes 
Leukocyte count 
Basophils 
Eosinophils 
Absolute neutrophil count 
Serum Chemistry 
Albumin 
Creatinine 
SGOT [AST] 
Alkaline phosphatase 
Glucose 
SGPT [ALT] 
Bicarbonate (total CO2) 
LDH 
Total protein 
BUN 
Sodium 
Calcium 
Total bilirubin 
Chloride 
Potassium 
• 
Cycle 6: +/- 7 day window 
3. Serum β-HCG test during screening  for women of childbearing potential as outlined in 
Section 5, STUDY ASSESSMENTS AND TREATMENT SCHEDULE. 
4. Serum Virology to include HBsAg, HBc antibody, HCV antibody, and CMV IgG and CMV IgM. 
If HBc antibody is positive, the subject must be evaluated for the presence of HBV DNA by 
13   Patients who discontinue study drug should have a follow up visit or telephone call to assess for AEs. This should be done 30 
days (+/- 7 days) after the last dose of study drug. In addition, SAEs will be reported for 30 days after the last dose of study 
drug. (see section 10.4.3) 
PCR. If HCV antibody is positive, the subject must be evaluated for the presence of HCV RNA by PCR.  
See Appendix C. If the subject is CMV IgM positive, the subject must be evaluated for the presence 
of CMV DNA by PCR. CMV surveillance by PCR every 3 cycles while receiving study treatment. In 
addition, a final CMV test by PCR should be done upon treatment discontinuation. See Section 5. 
5. Baseline bone marrow aspirate/biopsy within 30 days prior to Cycle 1, Day 1, then follow 
Section 5 table, footnotes 11 and 12. 
6. β2-microglobulin at screening only. 
7.Coagulation lab tests to include PT/INR and PTT. 
8. Fluorescence in situ hybridization (FISH) of peripheral blood for 13q deletion, 11q deletion, 
17p deletion, trisomy 12, t(11:14). 
9. DNA sequencing for IgHV mutation status. 


24 | P a g e  
 
 
5.1.2 CENTRAL LABORATORY ASSESSMENTS 
 
The  PK  parameters  (including  AUC (0-∞),  AUC (0- τ),  Cmax,  tmax,  λz,   and  t½)  of  umbralisib  will  
be assessed by analysis of umbralisib plasma concentrations. 
 
PK blood (plasma) samples will be taken at the following timepoints. 
 
 
TABLE 1 
     PHARMACOKINETIC COLLECTION TIMES 
Visit 
Scheduled time point 
Cycle 1, Day 1 
Pre-dose 
0.5 hour post dose (± 5 minutes) 
1 hour post dose (± 10 minutes) 
2 hours post dose (± 10 minutes) 
4 hours post dose (± 30 minutes) 
6 hours post dose (± 30 minutes) 
Cycle 1, Day 2 
Pre-dose, 24 hours post Day 1 dose (± 2 hours) 
Cycle 2, Day 1 
Pre-dose 
2 hours post dose (± 10 minutes) 
4 hours post dose (± 30 minutes) 
Cycle 3, Day 1 
Pre-dose 
Cycle 4, Day 1 
Pre-dose 
Cycle 5, Day 1 
Pre-dose 
Cycle 6, Day 1 
Pre-dose 
 
5.1.3 PHARMACODYNAMICS 
 
The analyses for pharmacodynamic biomarkers are exploratory and will not be used to guide 
treatment decisions. 
 
   PHARMACODYNAMIC COLLECTION TIMES 
Visit 
Scheduled time point (hours) 
Cycle 1, Day 1 
Pre-dose 
2 Hours Post-dose 
4 Hours Post-dose 
6 Hours Post-dose 
Cycle 2, Day 1 
Pre-dose 
2 Hours Post-dose 
4 Hours Post-dose 
Cycle 3, Day 1 
Pre-dose 
Cycle 4, Day 1 
Pre-dose 
Cycle 5, Day 1 
Pre-dose 
Cycle 6, Day 1 
Pre-dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


25 | P a g e  
 
 
 
 
5.1.4 CORRELATIVE STUDIES (EXPLORATORY OBJECTIVE) 
 
Biological samples (Peripheral blood) will be collected at up to 6 time-points outlined in Section 
5, STUDY ASSESSMENTS AND TREATMENT SCHEDULE. Each red top tube will be 10 ml of 
peripheral blood. Each green top tube will be 10 ml of peripheral blood. Bone Marrow aspirate 
will  be collected at baseline and the end of Cycle 12. Each aspirate sample will be 8-10 ml of 
aspirate. As the correlative experiments are not the primary focus of the study and are more 
exploratory in nature, no sample size / power calculations were completed. Summary statistics 
will be used to summarize the quantitative measures (e.g., cytokine levels, expression levels) for 
the patients at the specified time-points with two-sample t-test use to determine if quantitative 
measurements differ between patients that respond and patients that do not respond at each 
time point. When assessing changes in quantitative measurements between time-points (e.g., pre 
and post treatment measurements) paired t-tests will be used. Longitudinal analysis with linear 
mixed models will also be used to look for statistical differences between the responders and 
non-responders using quantitative measurements at all time-points. Correlation between 
quantitative measurements will be assessed with Spearman correlation. 
 
If correlative lab samples are drawn at a required time point and treatment is delayed, the 
sample may be retained. When the subject re-starts the cycle, the sample will be re-collected for 
continuity with other subject samples. The research lab will be notified of the event if the 
treatment is delayed.  
 
 
 
 
 
 
  


26 | P a g e  
 
Immune-Profiling Studies 
 
1. T cell function will be assessed for changes in multiple characteristics including memory 
formation, TH-polarity, markers of exhaustion, and activation via flow cytometric  analysis. 
Naïve and memory sub-populations will be defined according to expression of CD45RA, 
CD62L, CCR5 and CCR7. TH-polarization, including TH1, TH2, TH17 and Treg subsets, 
will be determined by intracellular cytokine and FoxP3 profiles. Changes in T cell 
exhaustion phenotype will be tracked in terms of surface expression of several well-
defined markers, including CD160, CD200R, CD244, CD272, CD274, CD279, as well as the 
intracellular markers Lag3 and Tim3. Alterations in cellular activation will be measured 
in terms of phosphorylation of critical T cell signaling pathways, STAT 1, 3 and 5, as well 
as by surface expression of CD107a, correlating to secretory/cytotoxic activity. 
2. Global Immune function will be assessed. A) Patient peripheral blood will be assessed by 
multi parameter flow analysis for myeloid cells—specifically myeloid derived suppressor 
cells MDSCs both PMN-MDSCs and M-MDSCs using the following markers: CD3, CD14, 
CD19, CD56 HLA-DR, CD33, CD15, CD66b, and CD11b. B) Patient sera will be evaluated 
by flow cytometric means using cytokine bead arrays to measure serum cytokine levels 
quantitatively. The cytokine panel 
will include IFN-γ, TNF-α, IL-2, IL-4, IL-10, IL-6, IL-17A, allowing discrimination between 
TH1, TH2, and TH17 profiles. 
3. Peripheral blood to collect DNA and RNA will be processed for future assessments. 
 
4. Pharmacodynamics analysis of pAKT expression (Phos-Flow) for collected samples over 
time point of continued study. 
 
5 6 TREATMENT PLAN 
 
 
 
6.1 TREATMENT SUMMARY 
 
 
 
Treatment will be administered on an outpatient basis in 4-week (28 day) cycles. 
 
Umbralisib 
 
6.1.1 - 800 mg umbralisib once daily within 30 minutes of a meal until removal from study 
 
6.12-  Patient diary will be utilized 
 
 
6.2AGENT ADMINISTRATION 
 
 
 
Umbralisib will be self-administered orally, all on an outpatient basis. 
 
 
 
 
6.2.1 GUIDELINES FOR ADMINISTRATION OF UMBRALISIB 
 
 
 
• 
Method of Administration: Umbralisib  will  be  administered  orally  once  daily  within  


27 | P a g e  
 
30 minutes of a meal. 
• 
Potential Drug Interactions: No drug interactions have been reported to date. 
• 
Anti-microbial  prophylaxis:  Patients  are  required  to  start  prophylaxis  treatment  
with pneumocystis jiroveci pneumonia (PCP) and antiviral therapy prior to Cycle 1, Day 
1. 
o Anti-viral Prophylaxis: Valtrex 500 mg daily or Acyclovir 400 mg BID or equivalent. 
o PCP Prophylaxis: Final choice of PCP prophyalxis is per investigator discretion. 
Final choice of PCP and anti-viral prophylaxis therapy is per investigator discretion. 
If PCP or anti-viral therapy is not tolerated, alternate to a different PCP or anti-viral 
therapy, reduce the dose or modify the schedule for the prophylactic agent, or 
discontinue prophylaxis at investigator discretion. 
• 
Pre-medications: None 
Umbralisib will be stored in the Moffitt Investigational Pharmacy Department. It will be 
dispensed at the site by the clinical research staff under the direction of the PI or by a pharmacist 
at the site. Patients must be provided drug in its original container. Patients should be instructed 
to return all empty and partially filled bottles including any unused tablets when they 
return the site. Any unused study drug will be destroyed on site per Investigational Pharmacy 
standard procedures. Study drug compliance should be reviewed with the patient at the 
beginning of each new treatment cycle and as needed. Missed doses will be documented in the 
patients’ medical record. 
 
Umbralisib will be self-administered (by the patient). Tablets should be taken at approximately 
the same time each day with food (within 30 minutes of a meal). Patients 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 greater than 12 hours, it should not be replaced. If vomiting occurs, no attempt 
should be made to replace the vomited dose. 
 
6.2.1.1 DISPENSING OF UMBRALISIB 
 
 
Before dispensing, the site pharmacist or his/her representative must check that the 
umbralisib is in accordance with the product specifications and the validity is within the re-test 
date. 
The exact dose and the date of administration of umbralisib must be recorded within the 
patient’s medical records. Any error in drug administration should be recorded (e.g., missed 
dose). 
The  Investigational  Pharmacist  or  his/her  representative  should  complete  the  
accountability record with information concerning the dispensation of umbralisib. 
If a subject requires a dose reduction, the site pharmacist will dispense only the number of 
bottles of study drug required for the subject to have an adequate supply until the next 
dispensing visit. 
 
 


28 | P a g e  
 
6.2.2 CRITERIA FOR ONGOING TREATMENT 
 
 
 
Continue treatment as per protocol provided that patient has: 
• 
No intolerable toxicities related to study drug. 
o 
Treatment may be delayed to recover from toxicity for a maximum of eight 
weeks. Treatment delays of greater than 8 weeks may be allowed after discussion 
with the Principal Investigator. 
• 
No clinical or radiographic evidence of disease progression. 
• 
Not withdrawn from the study for other reasons. 
 
6.3 DOSING DELAYS AND MODIFICATIONS 
 
 
 
Patients should be assessed clinically for toxicity at each visit using the NCI CTCAE v5.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) grading scale. Dose delay and/or modification 
guidance is for adverse events considered at least possibly related to the study drug. If cytopenias 
are deemed related to the underlying disease rather than study drug, dose modifications are 
not required, or are per investigator discretion. 
Umbralisib should be discontinued if treatment is delayed for greater than 8 weeks due to 
toxicity 
unless the Principal Investigator approves restarting treatment. If the subject 
discontinues treatment but has not progressed, the subject should be followed for 
progression. If a patient withdraws consent or has documented progression, an end of study 
visit should be completed. 
 
 
6.3.1 DOSE DELAY/MODIFICATIONS: UMBRALISIB 
 
 
 
TABLE 2: UMBRALISIB DOSE DELAY AND/OR MODIFICATIONS GUIDANCE 
 
NCI-CTCAE Grade 
Dose Delay and/or Modification 
Hematologic Adverse Event 
Neutropenia 
Grade ≤ 2 neutropenia 
Maintain current dose. Consider supportive care as warranted. 
Grade 3 neutropenia 
Maintain  current  dose,  consider  supportive  care.    If  neutropenia recurs or 
persists at Grade 3 for more than 14 days ,  stop umbralisib until grade ≤ grade 2 
and resume at next lower dose level. 
Grade 4 neutropenia or 
occurrence of neutropenic fever 
or infection 
Delay umbralisib until Grade ≤ 3 and/or neutropenic fever or infection is 
resolved; thereafter, resume at full dose. Consider supportive care. If delay is >8 
weeks, permanently discontinue umbralisib. 
If recurrence after rechallenge, resume at next lower dose level. 
Thrombocytopenia 
Grade ≤ 3 thrombocytopenia 
Maintain current dose level and provide supportive care as clinically warranted. 
Grade 4 thrombocytopenia 
Delay umbralisib until Grade ≤ 3; thereafter, resume at full dose. Consider 
supportive care intervention as warranted. If recurrence after rechallenge, resume 
at next lower dose level. If delay is > 8 weeks, permanently discontinue 
umbralisib. 
 
Pulmonary & Related Infections* 


29 | P a g e  
 
Grade 1 & 2 
Stop all therapy and hold until complete resolution.   Restart umbralisib at one 
lower dose level. If recurrence after rechallenge, discontinue all treatment therapy. 
If delay is > 8 weeks, permanently discontinue umbralisib. 
 
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 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 prior to starting umbralisib. 
Diarrhea and/or Colitis 
Diarrhea Grade ≤ 2 
Maintain current dose level if tolerable or hold and then resume at current dose 
level once has resolved. 
NOTE: If persistent Grade 2 diarrhea, despite supportive care, delay umbralisib 
until ≤ Grade 1. If recurrence after rechallenge, resume at next lower dose level. 
If delay is > 8 weeks, permanently discontinue umbralisib. 
Diarrhea Grade ≥ 3 
Withhold umbralisib until Grade ≤ 2.  
If recurrence after rechallenge, resume at next lower dose level. 
If delay is > 8 weeks, permanently discontinue umbralisib.  
Colitis (all Grades) 
Hold umbralisib. Treat with supportive care and after resolution of colitis, resume 
umbralisib at next lower dose level 
If delay is > 8 weeks, permanently discontinue umbralisib.  
Liver Toxicity (ALT/SGPT, AST/SGOT, Bilirubin, Alkaline Phosphatase) 
Grade 1  
Maintain current umbralisib dose. 
Assess concomitant medications and risk 
factors*. Monitor labs every 1-2 weeks. 
 
 
 
 
 
 
 
 
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. 
 
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 
Once resolved to Grade ≤1 
o 
If umbralisib was delayed, restart umbralisib at current dose. 
o 
Taper prednisone by 10 mg per week until off. 
 
If  umbralisib  is delayed  for  > 8  weeks, permanently discontinue  umbralisib.  


30 | P a g e  
 
 
 
 
 
 
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  umbralisib  is delayed  for  > 8  weeks, permanently discontinue  umbralisib 
* 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 until Grade ≤ 2. 
 
If recurrence after rechallenge, resume at the next lower dose level. 
 
If delay is > 8 weeks, permanently discontinue umbralisib.  
TABLE 3: STUDY DRUG DOSE LEVELS 
 
Study Drug 
Starting Dose 
1st Dose Reduction 
2nd Dose Reduction 
Umbralisib 
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 should 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. 
 
6.4 ORDERING UMBRALISIB 
 
 
 
Umbralisib is available from TG Therapeutics. Please allow 5 to 7 business days between drug 
ordering and drug arrival. Please direct drug orders to ISTdrugorder@tgtxinc.com. The email 
should include the following: 
• 
Requested quantity of TG Therapeutics study drug(s) 
• 
Principal Investigator name 
• 
Study title 
• 
Investigational drug pharmacy shipping address 
 
Upon receipt of treatment supplies, the Pharmacist or the appropriate person of the site should 
update the accountability forms for umbralisib. If any abnormality on the supplied bottles 
(umbralisib) is observed, the Pharmacist or the appropriate person must document that on 
the acknowledgement of receipt and contact TG Therapeutics. 
 
6.5 DURATION OF THERAPY 
 
 
 


31 | P a g e  
 
In the absence of treatment delays due to adverse event(s), treatment should continue through 
Cycle 1 and beyond unless one of the following criteria applies: 
• 
Disease progression or inter-current illness that prevents further treatment. 
• 
Patient decides to withdraw from the study, or changes in the patient's condition render 
the patient unacceptable for further treatment in the judgment of the investigator. 
• 
Study drug will be made available to responding patients until disease progression. If 
umbralisib becomes commercially available during the active period on study, an attempt 
will be made to obtain  this agent through commercial insurance.  If study drug continues 
past cycle 12, any laboratory or other testing procedures will be ordered at physician 
discretion and not considered a study procedure. Adverse events will be collected during 
this time, per guidance in Section 10.4.3.  
During the study period, all patients will be evaluated for response by CT or MRI within 14 days 
prior to Cycle 4, Day 1 for Cycle 3 assessment, and within 14 days prior to Cycle 13, Day 1 for Cycle 
12 assessment, and at any other time point to confirm progression. Patients who fail to achieve a 
partial or complete response to umbralisib at the Cycle 3 assessment will discontinue study 
treatment. At that time, patients- will be provided appropriate options to receive established 
frontline therapy. Patients who demonstrate a partial or complete response will be treated until 
disease progression, unacceptable toxicity, or the end of the study.Patients who discontinue from 
study treatment and have not progressed should continue to be followed for progression, if 
agreeable, approximately every 3 months. If the patient discontinues after Cycle 12 for reasons 
other than disease progression, they should continue to be followed for progression approximately 
every 6 months. 
 
6.6 STOPPING RULES 
In order to allow periodic review of safety data to ensure safety and limit potential toxicity, 
enrollment shall be conducted in consecutive groups of 10 patients.  The Principal Investigator (PI), 
Sub-Investigators, and the Moffitt Protocol Monitoring Committee (PMC) will be charged with 
reviewing safety data. Serious adverse events (SAEs) from this protocol will be reported to the IRB 
per their guidelines and concurrently to the PMC for review.  Following the final treatment dose in 
Cycle 3 (Day 28 of Cycle 3) of the last patient in a group set of 10 patients, the PI and PMC will decide 
whether or not it is possible to proceed to enroll the next group of 10 patients.  In order to ensure 
safety and limit toxicity for enrolled patients, dose modifications will be performed according to the 
schema described in Section 6.3.1.  This trial will be continuously monitored by the PI and the 
research team as well as being reviewed for safety at the weekly Lymphoma Section Research 
Meeting. All serious and non-serious adverse events will be documented, managed with protocol-
permitted dose reductions, followed until resolution or stabilization, and will also be reviewed by 
the PI, PMC and Sub-Investigators at the end of each group of 10 patients. 
 
In the event that >20% of patients (i.e. 3 of 10 patients, 5 of 20 patients, 7 of 30 patients, etc.) 
discontinue therapy due to a treatment-related serious adverse event or immune mediated toxicity 
(e.g. transaminitis, pneumonitis, rash, or colitis), study accrual will be suspended pending further 
investigation, and will only be resumed at the recommendation of the PI, PMC and the Sub-
Investigators. 
 
In the event of one (1) death attributed to the study drug, study accrual will be suspended pending 
further investigation, and will only be resumed at the recommendation of the PI, PMC, and the Co-


32 | P a g e  
 
Investigators. The PI, PMC, and the Sub-Investigators will have discretion to terminate the trial if an 
additional death occurs that can be attributed to the study drug. 
7   STUDY MEDICATION OVERVIEW AND SAFETY 
 
 
 
7.1 UMBRALISIB 
 
 
 
Chemical Name: 
Umbralisib 
 
Other Names: 
TGR-1202 
 
Classification: 
Dual inhibitor o phosphatidylinositol-3-Kinase (PI3K) Delta and  
                                             Casein kinase-1 epsilon (CK-1 E) 
 
Formulation: 
See Investigator Brochure 
 
Mode of Action: 
Irreversibly inhibits activity of the Class I Delta isoform of PI3K 
 
How Supplied: 
200 mg tablets 
 
Storage: 
Store in a secured limited-access area between 20o and  25°C. Excursions  
                                              permitted 15°C to 30°C.Do not freeze 
 
Stability: 
Expiration memorandums will be provided noting lot expiration dates.  For  
                                             questions about product expiry email productquality@tgtxinc.com 
Route of 
Administration: 
Oral 
 
Packaging: 
Umbralisib is provided in HDPE bottles each containing 30 tablets 
and a silica gel canister as a desiccant. 
 
Availability: 
Umbralisib is available from TG Therapeutics. 
 
 
7.1.1 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) 
 
 
 
The Investigator’s Brochure (IB) is the primary source for safety information. The umbralisib IB 
includes a summary of adverse event data and discussion on potential risks that have been 
observed or may be predicted to occur with this study drug. Refer to the most recent IB, which is 
updated periodically, for current information on umbralisib. 
7.1.1.1 VERY COMMON ≥ 10% 
 
 
• 
Blood and Lymphatic System Disorders: neutropenia 
• 
Gastrointestinal Disorders: Diarrhea, Nausea, vomiting 
 
7.1.1.2 GENERAL   DISORDERS   AND   ADMINISTRATION   SITE   CONDITIONS:   FATIGUE 
COMMON ≥ 2% AND < 10% 
 
 
• 
Blood and Lymphatic S ystem Disorders:  anemia, thrombocytopenia, leukocytosis, 
lymphocytosis 
• 
Ear and Labyrinth Disorders: tinnitus 


33 | P a g e  
 
• 
Eye Disorder: vision blurred 
• 
Gastrointestinal Disorder: constipation, abdominal pain, abdominal distension, 
dyspepsia, colitis, dry mouth 
• 
General Disorders and Administration Site Conditions: pyrexia, oedema peripheral 
• 
Infections and Infestations: pneumonia, oral candidiasis 
• 
Injury Poisoning and Procedural Complication: contusion 
• 
Investigations: weight decreased, alanine aminotransferase increased, aspartate 
aminotransferase increased, blood creatinine increased 
• 
Metabolism and Nutrition Disorders: decreased appetite, dehydration, hyperglycaemia, 
hypokalaemia, hypophosphatemia 
• 
 Musculoskeletal and Connective Tissue Disorder: muscle spasms, pain in extremity 
• 
Nervous System Disorders: dizziness, headache, dysgeusia, tremor 
• 
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 
 
 
8 MEASUREMENT OF EFFECT 
 
 
During the study period, all patients will be evaluated for response by CT or MRI within 14 
days prior to Cycle 4, Day 1 for Cycle 3 assessment, and within 14 days prior to Cycle 13, Day 1 
for Cycle 12 assessment, and at any other time point to confirm progression. The determination 
of response and progression will be based on iwCLL criteria (Hallek M, 2018). 
Patients who fail to achieve a partial or complete response to umbralisib at the Cycle 3 assessment 
will discontinue study treatment. At that time, patients- will be provided appropriate options to 
receive established frontline therapy. Patients who demonstrate a partial or complete 
response will be treated until disease progression, unacceptable toxicity, or the end of the 
study. 
Patients with a response should remain on study treatment until the occurrence of definitive 
disease progression, unacceptable toxicity, or withdrawal from the study due to investigator 
decision or other reasons. Patients who discontinue from study treatment (either for toxicity 
or physician choice) and have  not progressed will continue to be followed for progression as per 
the protocol. 
 
8.1 METHOD OF ASSESSMENT 
 
 
 
In addition to clinical examination, radiographic evaluation will be used in all patients enrolled. 
All baseline assessments to characterize disease will be performed within 30 days of Cycle 1, 
Day 1, prior to initiation of therapy. CT scan with iodinated IV contrast is the preferred 
method for radiographic tumor assessment. If iodinated contrast is contraindicated, a non-
contrast chest CT coupled with a gadolinium-enhanced MRI of the abdomen, pelvis and neck is 
an acceptable substitute. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, radionuclide 
scans, or tumor markers will not be considered for response assessment. 
 
For radiographic evaluations, the same method of assessment and the same technique (e.g., 


34 | P a g e  
 
scan 
type, patient position, dose of contrast, injection/scan interval) should be used to 
characterize each identified and reported lesion at baseline and during study treatment and 
follow-up. However, if a patient is imaged without contrast at baseline, subsequent assessments 
should be performed with contrast, unless medically contraindicated. 
 
All relevant clinical and radiographic information required to make each tumor status 
assessment must be made available for source verification. 
 
8.2 RESPONSE REVIEW 
 
 
 
The review of radiographic and clinical data by the study investigators will be performed on 
an ongoing basis. De-identified images should be available if TG Therapeutics requests to confirm 
any objective response observed. 
 
8.3 IDENTIFICATION 
AND 
MEASUREMENT 
OF 
TUMOR 
LESIONS
 
AND ORGANOMEGALY 
 
 
 
8.3.1 TARGET LESIONS 
 
 
At baseline, up to 6 lymph nodes should be selected as target lesions (if measurable disease is 
present) that will be used to quantitate the status of the disease during study treatment. Ideally, the 
target lesions should be located in disparate regions of the body. Only peripheral nodes need be 
selected as target lesions. However, it is optimal if mediastinal and retroperitoneal areas of disease 
are assessed whenever these sites are involved. 
 
Target lesions should be measured and recorded at baseline and as per the study assessment 
schedule. The cross-sectional dimensions (the largest cross-sectional diameter, i.e., the LD × LPD) 
will be recorded (in cm) for each target lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each target lesion and the sum of the products (SPD) (in cm2) for all target lesions will 
be calculated and recorded. The baseline SPD will be used as references by which objective tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and LPD 
diameters will be reported in centimeters and all PPDs and SPDs will be reported in centimeters 
squared. 
 
A nodal mass may be selected as a measurable nodal target lesion if it is > 1.5 cm in the longest 
diameter (Hallek M, 2018). 
 
Progressive disease will be determined using the 2018 iwCLL criteria. Transient increases of lymph 
node size during treatment with novel inhibitors may occur (Hallek M, 2018). 
 
 
8.3.2 SPLEEN AND LIVER 
 
 
Both the spleen and liver will be assessed by CT/MRI scan and/or by physical examination 
(method of measurement should be consistent throughout study participation) at baseline and 
as per the study assessment schedule. The baseline and nadir values for the longest vertical 
dimension (LVD) of each organ will be used as reference to further characterize the objective 
tumor response of the measurable dimensions of the CLL during treatment. All spleen and liver 


35 | P a g e  
 
LVD measurements should be recorded in centimeters. 
 
By imaging, the spleen will be considered normal if <13 cm using craniocaudal  measurement 
(Hallek M, 2018). 
 
There is no international consensus on the size of a normal liver (Hallek M, 2018). For the purpose 
of this trial, a decrease to < 18 cm in the longest diameter on CT scan will be considered a normal 
liver. The iwCLL 2018 criteria will be utilized to determine the response. 
 
 
 
 
 
8.3.3 NON-TARGET LESIONS 
 
 
Any other measurable and abnormal nodal lesions not selected for quantitation as target lesions 
may be considered non-target lesions. In addition, non-measurable evidence of CLL such as nodal 
lesions with both diameters < 1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal disease, 
ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal masses that 
are not confirmed and followed by imaging techniques, cystic lesions, previously irradiated 
lesions, and lesions with artifacts may be considered as non-target disease. 
The presence or absence of non-target disease should be recorded at baseline and as per the study 
assessment schedule. If present at baseline, up to 6 non-target lesions should be recorded. The 
non- target disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment.  Measurements are not required and these lesions should be followed as “present” or 
“absent”. 
 
8.4 DEFINITIONS OF TUMOR RESPONSE AND PROGRESSION 
 
 
 
Responses will be categorized as CR, PR, SD, or PD. Response criteria for this protocol will be 
per iwCLL 2018 criteria (see Appendix D). Response to therapy includes 2 groups of parameters 
that need to be documented. Group A assesses the lymphoid tumor load (CT) and constitutional 
symptoms; group B assesses the hematopoietic criteria. The hemataopoietic criteria will be 
evaluated using the lab testing on Cycle 4 Day 1 and Cycle 13 Day 1. 
For the purpose of this study, the bone marrow biopsy response criterion will be calculated using 
the following formula: 
Cellularity x % involvement of CLL= percent of response 
If the reporting pathologist provides a range for B-cell or lymphocytic leukemia involvement 
(i.e.,80-85%), the higher number of the range will be used for the calculation. 
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference 
for disease progression the smallest measurements recorded since treatment started). Where 
imaging data are available, these data will supersede physical examination data in determining 
tumor status. 
 
8.5 LYMPHOCYTOSIS DURING THERAPY 
 
 
 


36 | P a g e  
 
Upon initiation of umbralisib, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase 
from baseline and above absolute lymphocyte count of 5,000/mcL) may occur. The onset of 
isolated lymphocytosis usually occurs during the first few weeks of umbralisib therapy and 
usually resolves within three to four months. Patients with lymphocytosis should be continued 
on study drug until the occurrence of definitive disease progression (i.e., disease progression that 
is manifest by worsening CLL-related signs other than lymphocytosis alone), or the occurrence 
of another reason to discontinue study therapy.7 
9 STATISTICAL CONSIDERATIONS 
 
 
 
9.1 SAMPLE SIZE 
 
 
 
This is a phase 2 study designed to assess the overall response rate (CR + PR) and progression-
free survival (PFS) of Umbralisib in treatment naïve patients with CLL.  The primary endpoint is 
the overall response rate (ORR) from the time of treatment.  The study will plan to enroll up to 
40 subjects, and assuming 10% attrition, the study will have approximately 35 subjects 
remaining for analysis. Any subjects who are screen failures are not considered enrolled and 
may be replaced to meet the accrual goal. Enrollment is expected to be completed in 
approximately 18 months with 24 months follow up.  The ORR for the standard of care is about 
60%.  We expect that Umbralisib treatment could lead to 80% ORR.  A Simon 2-stage minimax 
design that differentiates ORRs of 0.60 (null hypothesis) and 0.80 (alternative hypothesis) will 
be used to assess treatment efficacy, with the probabilities of a type I error (falsely accepting a 
non-promising therapy) and type II error (falsely rejecting a promising therapy) both set at 
0.10.  Twenty seven patients will be accrued in the first stage of the study.  If 18 or fewer 
patients have a response, then the study will be terminated and declared negative.  If 19 or 
more patients have a response, then an additional 8 patients will be accrued to the second 
stage.  At the conclusion of the study, if 25 or more patients have a response out of a total of 35 
patients enrolled, the regimen will be considered worthy of further investigation. 
 
 
9.2 GENERAL ANALYSIS CONVENTION 
 
 
 
Unless otherwise stated, all analyses will be performed using SAS Version 9.2 or higher and 
all hypothesis tests will be conducted at a two-sided significance level of 0.05. 
In general, summary tabulations will display the number of observations, mean, standard 
deviation, median, minimum, maximum, and appropriate percentiles for continuous variables, 
and the number and percentage by category for categorical data. Summaries will be presented. 
The data listings will include all available efficacy and safety data. 
 
9.3 STUDY POPULATIONS 
 
 
 
Two study populations, intent-to-treat (ITT) and safety populations, are pre-defined for this 
study. The ITT population will include all enrolled patients who provide some efficacy 
assessments and the safety population will include all patients who take at least one dose of 
study medication. The efficacy analyses will be based on ITT population and the safety analyses 
will be based on the safety population. 
 
9.4 PATIENT DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
 
 
 


37 | P a g e  
 
Baseline demographic and clinical characteristics will be summarized as percentages for 
categorical variables and as mean, standard deviation, median, minimum and maximum for 
continuous measures. The analyses of baseline characteristics will be performed for the ITT 
population. 
9.5 MEDICAL HISTORY 
 
 
 
Medical history will be captured at the Screening visit. 
 
9.6 EXTENT OF EXPOSURE 
 
 
 
The dose (mg) of study drugs administered, the total number of doses of study drug, and the 
duration of treatment (number of study cycles) will be summarized with descriptive statistics. The 
number and percentage of patients whose dose is modified at any time will be summarized by each 
type of modification by cycle and overall. The proportion of patients completing each cycle of 
treatment will be summarized. 
 
 
9.7 EFFICACY ANALYSES 
 
 
 
Each patient will be assigned to one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 8) unknown (not assessable, 
insufficient data). 
Many of the efficacy measures will be based on disease assessments. The best clinical response 
as well as disease progression will be determined by the treating investigator. Scans should be 
kept on file in cases where independent review or confirmation may be warranted. Definitive 
disease progression will be based on standard criteria (Hallek et al. 2018) occurring for any 
reason (e.g., 
increasing lymphadenopathy, organomegaly or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of disease-related 
symptoms) other than lymphocytosis. 
During the study period, all patients will be evaluated for response by CT or MRI within 14 
days prior to Cycle 4, Day 1 for Cycle 3 assessment, and within 14 days prior to Cycle 13, Day 1 
for Cycle 12 assessment, and at any other time point to confirm progression. Patients who fail 
to achieve a partial or complete response to umbralisib at the Cycle 3 assessment will discontinue 
study treatment. At that time, patients- will be provided appropriate options to receive 
established frontline therapy. Patients who demonstrate a partial or complete response 
will be treated until disease progression, unacceptable toxicity, or the end of the study. 
 
9.8 MISSING VALUE HANDLING PROCEDURES 
 
 
 
In general, other than for partial dates, missing data will not be imputed and will be treated 
as missing. The algorithms for imputation of partial dates may vary depending upon the 
parameter. 
 
9.9 STATISTICAL ANALYSES 
 
 


38 | P a g e  
 
 
 
9.9.1 PRIMARY EFFICACY VARIABLE - PFS 
 
 
 
The two primary efficacy outcomes are overall response rate (ORR) and progression-free survival 
(PFS). Time to progression event “Survival” curve will be presented using Kaplan-Meier method. 
Median time to event and the 95% confidence interval of the median times will be presented, 
if estimable. Median time to event will be tested against the null hypothesis value using a one-
sample (one-sided) log-rank test. 
PFS is defined as the interval from Cycle 1, Day 1 to the earlier of the first documentation 
of definitive disease progression or death from any cause. 
Overall Response Rate (ORR) will be determined according to the criteria of the International 
Workshop on Chronic Lymphocytic Leukemia (Hallek et al. 2018). 
 
We will estimate Overall Response Rate (ORR), which is defined as percent of patients who achieve 
CR or PR. We will also estimate exact 95% confidence intervals for the response rates. These will 
be followed by additional logistic regression analyses model to adjust for demographic and baseline 
parameters. 
 
10 SAFETY REPORTING AND ANALYSIS 
 
 
 
10.1 SAFETY ANALYSES 
 
 
 
Safety evaluations will be based on the incidence, intensity, and type of adverse events, as well 
as on clinically significant changes in the patient’s physical examination, vital signs, and clinical 
laboratory results. Safety analyses will be performed using the safety population. Safety variables 
will be tabulated and presented by the dose of umbralisib study drug actually received. Exposure 
to study treatment and reasons for discontinuation of study treatment will also be tabulated. 
 
10.2 ADVERSE EVENT CHARACTERISTICS 
 
 
 
CTCAE term (AE description)  and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of 
the CTCAE version 5.0. A  copy  of  the  CTCAE  version  5.0  can  be  downloaded  from  the  
CTEP  web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only. 
Expected AEs are defined as those described in the Umbralisib Investigator Brochure. 
 
Definitions of Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product. An AE does not necessarily have to have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporarily associated with the use of a medicinal product, whether or not considered related 


39 | P a g e  
 
to the medicinal product. This includes any occurrence that is new in onset or aggravated in 
severity or frequency from the baseline condition. 
In clinical studies, an AE can include an undesirable medical condition occurring at any time, 
including run-in or washout periods, even if no study treatment has been administered. The 
NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 is to be used for the 
grading of severity of symptoms and abnormal findings. For adverse events not covered by the 
NCI-CTCAE Version 4.0 grading system, the following definitions will be used: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated. 
• 
Grade 3: Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
10.3 ADVERSE  EVENTS  (AES)  AND  TREATMENT  EMERGENT  ADVERSE  
EVENTS (TEAES) 
 
 
All AEs and SAEs occurring on study will be listed by patient. Adverse events will be collected 
per the Moffitt SOP for adverse events, serious adverse events, and unanticipated problems. For 
the purpose of this trial, adverse event collection: 
• 
Occurs after first dosing of study medication (Cycle 1, Day 1) and through the end of 
the study or up through 30 days  after the last dose of study treatment, or 
• 
Is considered treatment-related regardless of the start date of the event, or 
• 
Is  present  before  first  dosing  of  study  medication  but  worsens  in  intensity  or  
the investigator subsequently considers treatment-related. 
 
Adverse Events that are considered at least possibly related to study treatment will be tabulated 
as well as deaths, SAEs, and events resulting in treatment discontinuation. 
 
10.4 ADVERSE EVENTS/SERIOUS ADVERSE EVENT CAUSALITY ASSESSMENT 
 
 
 
The Investigator must also assess the relationship of any adverse event to the use of study 
drugs (whether none, one, or both), based on available information, using the following 
guidelines: 
• 
Not Related: Clear-cut temporal and/or mechanistic relation to a cause other than 
the study drug(s). 
• 
Doubtful: There is no reasonable possibility that the event is related to the study drug(s) 
but a definite cause cannot be ascertained. 
• 
Possible: There is still a reasonable possibility that the cause of the event was the study 
drug(s) but there exists a more likely cause of the event such as complications of 
progressive disease. 
• 
Probable: The most likely cause of the event is the study drug(s) but other causes cannot 
be completely excluded. 
• 
Definite: Clear cut temporal and/or mechanistic relation to the study drug(s). All other 


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causes have been eliminated. Events classified as definite will often be confirmed by 
documenting resolution on discontinuation of the study drug and recurrence upon  
resumption. 
 
 
 
 
 
10.4.1 RECORDING OF ADVERSE EVENTS 
 
 
 
All adverse events of any patient during the course of the study will be recorded in the Moffitt 
On Core electronic database.  The investigator will give his or her opinion as to the relationship 
of the adverse event to study drug treatment (i.e., whether the event is related or unrelated to 
study drug administration – umbralisib). If the adverse event is serious, it should be reported as 
described in Sections 10.5.2 and 10.6. Other untoward events occurring in the framework of a 
clinical study are also to be recorded as AEs (i.e., AEs that occur prior to assignment of study 
treatment that are related to a protocol-mandated intervention, including invasive procedures 
such as biopsies, medication washout, or no treatment run-in). 
All AEs regardless of seriousness or relationship to umbralisib treatment spanning from Cycle 
1, Day 1 until 30 calendar days (+/-7 days) after discontinuation or completion of protocol-
specific treatment as defined by the protocol for that patient, are to be recorded. 
 
 
10.4.1 ABNORMAL LABORATORY VALUES AND VITAL SIGNS 
 
 
 
The reporting of abnormalities of vital signs as adverse events should be avoided. Abnormalities 
of vital signs should not be reported unless any criterion for an SAE is fulfilled, the vital signs 
abnormalities cause the patient to discontinue study treatment, or the investigator insists that 
the abnormality should be reported as an AE. Abnormal laboratory results should be recorded 
as an adverse event if they are associated with an overdose, require or prolong inpatient 
hospitalization, or are otherwise considered clinically significant by the investigator. If an 
abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, the sign 
or symptom should be recorded as an AE, and the associated laboratory value or vital sign should 
be considered additional information to record related to the AE. If the laboratory abnormality 
is a sign of a disease or syndrome, only the diagnosis needs to be recorded on the SAE Report 
Form or AE eCRF. 
Clinical Laboratory Results will be summarized. Summary statistics for actual values and  for 
changes from baseline will be tabulated for laboratory results by scheduled visit. Patients with 
laboratory values outside of the normal reference range at any post-baseline assessment will 
be summarized and graded per NCI CTCAE Version 5.0 when applicable. Patient incidence of 
abnormal laboratory results will be summarized by treatment group and maximum grade for 
each abnormal laboratory finding. 
 
 
10.4.2 HANDLING OF ADVERSE EVENTS 
 
 
 
All adverse events resulting in discontinuation from the study should be followed until resolution 
or stabilization. Patients should be followed for AEs for 30 calendar days (+/-7 days) after 


41 | P a g e  
 
discontinuation or completion of protocol-specific treatment (umbralisib). All new AEs occurring 
during this period 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. In this 
case, the investigators must record his or her reasoning for this decision in the patient’s medical 
record]. After 30 days, only AEs, SAEs, or deaths assessed by the investigator as treatment related 
are to be reported. 
 
10.5 SERIOUS ADVERSE EVENTS 
 
 
10.5.1 DEFINITIONS OF SERIOUS ADVERSE EVENTS 
 
 
 
The definitions of serious adverse events (SAEs) are given below. The investigator is responsible 
for ensuring that all staff involved in the study are familiar with the content of this section. 
An SAE or reaction is defined as any untoward medical occurrence that: 
 
• 
results in death, is immediately life-threatening, 
• 
requires   at   least   a   24-hour   in-patient   hospitalization   or   prolongation   of   
existing hospitalization, 
• 
results in persistent or significant disability/incapacity, and/or 
• 
causes a congenital anomaly/birth defect. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be immediately 
life- threatening or result in death or hospitalization, but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the previous definition. 
These should also usually be considered serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency or drug 
abuse. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per iwCLL Hallek et al. 2018), should not be reported as a serious adverse 
event. 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an SAE that is suspected 
to be at least possibly related to study medication and is an unexpected event. SUSAR reporting 
is encompassed within SAE reporting guidelines as defined in this section. 
Treatment within or admission to the following facilities is not considered to meet the criteria 
of “in-patient hospitalization” (although if any other SAE criteria are met, the event must 
still be treated as an SAE and immediately reported): 
• Emergency Department or Emergency Room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 


42 | P a g e  
 
• Hospice or skilled nursing facility, Nursing homes, Custodial care or Respite care facility  
• Hospitalization during the study for a pre-planned surgical or medical procedure (one 
which was planned prior to entry in the study), does not require reporting as a serious 
adverse event. 
 


43 | P a g e  
 
It is important to distinguish between “serious” and “severe” adverse events, as the terms are 
not synonymous. Severity is a measure of intensity; however, an AE of severe intensity need 
not necessarily be considered serious. For example, nausea which persists for several hours 
may be considered severe nausea but may not be considered an SAE. On the other hand, a 
stroke which results in only a limited degree of disability may be considered only a mild stroke, 
but would be considered an SAE. Severity and seriousness should be independently assessed 
when recording AEs and SAEs. 
Adverse events classified by the treating investigator as serious require expeditious handling 
and reporting to TG Therapeutics in order to comply with regulatory requirements. Serious 
adverse events may occur at any time from signing of the consent form through the 30-day follow-
up period after the last study treatment. TG Therapeutics should be notified of all SAEs, regardless 
of causality, within 24 hours of the first knowledge of the event by the treating physician or 
research personnel. Report SAEs to TG Therapeutics at safety@tgtxinc.com (copy gabriel.green-
lemons@tgtxinc.com and donna.gesumaria@tgtxinc.com on an SAE Form (MedWatch FORM FDA 
3500 or equivalent). Include the TG Therapeutics, Inc. tracking number (TGR-NTG-006) on the 
SAE report .SAEs are to be followed until resolution (with autopsy report, if applicable). 
CLL progression or death due to CLL progression should be reported by the investigator as 
a serious adverse event only if it is assessed that umbralisib caused or contributed to the CLL 
progression (i.e. by a means other than lack of effect). 
 
The investigator must review and sign off on the SAE data on the SAE report. 
 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to TG Therapeutics as soon as it is available; these reports should be submitted 
using the appropriate SAE form. 
 
10.6 SAE REPORTING REQUIREMENTS BY INVESTIGATOR TO FDA AND IRB 
 
 
 
The investigator is responsible for reporting SAEs to the FDA in accordance with ICH guidelines, 
FDA regulations, and/or local regulatory requirements. 
The investigator is responsible for reporting unexpected fatal or life-threatening events 
associated with the use of the study drugs to the FDA within 7 calendar days of the first 
knowledge of the event by the treating physician or research personnel. The investigator will 
report all related but unexpected SAEs including non-death/non-life-threatening related but 
unexpected SAEs (SUSAR) associated with the use of the study medications to the FDA by a 
written safety report within 15 calendar days of the first knowledge of the event by the treating 
physician or research personnel. 
Investigators must report SAEs, SUSARs and follow-up information to their responsible 
Institutional Review Board (IRBs)/Independent Ethics Committee according to the policies of 
the responsible IRB (Research Ethics Committee). 
 
10.7 RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
 
 


44 | P a g e  
 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on the 
SAE Report Forms and within medical records. Avoid colloquialisms and abbreviations. All AEs, 
including those that meet SAE reporting criteria, should be recorded; AEs that meet the definition of 
an SAE should additionally be reported. 
 
 
10.8 DIAGNOSIS VS. SIGNS AND SYMPTOMS 
 
 
 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Principal Investigator or designated physician, the AEs constitute components of 
a recognized condition, disease, or syndrome. In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom. If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s). If a diagnosis is subsequently established, it should be reported as 
follow-up information is available. If a diagnosis is determined subsequent to the reporting of the 
constellation of symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
 
 
10.8.1 PERSISTENT OR RECURRENT ADVERSE EVENTS 
 
 
 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or as an 
AE. If a persistent AE becomes more severe (changes from a Grade 1 or 2 AE to a Grade 3 or 4 
AE) or lessens in severity (changes from a Grade 3 or 4 AE to a Grade 1 or 2 AE), it should be 
recorded on a separate SAE Report Form and/or as a separate AE. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs. All recurrent AEs should be recorded on an SAE Report Form and/or as 
an AE for each recurrence. 
 
 
 
 
10.8.2 ABNORMAL LABORATORY VALUES 
 
 
 
Abnormal laboratory results should be recorded as an adverse event if they are associated with 
an overdose, require or prolong inpatient hospitalization, or are otherwise considered clinically 
significant by the investigator. If an abnormal laboratory value or vital sign is associated 
with clinical signs and/or symptoms, the sign or symptom should be reported as an AE, and the 
associated laboratory value or vital sign should be considered additional information to record 
related to the AE. If the laboratory abnormality is a sign of a disease or syndrome, only the 
diagnosis needs to be recorded on the SAE Report Form or as an AE. 
 
 
10.8.3 DEATHS 
 
 
 
Deaths that occur during the protocol-specified AE reporting period that are attributed by 
the investigator solely to progression of the patient’s CLL for up to 30 days post the last dose of 
study drug  will  be  recorded,  but  are  exempted  from expedited  reporting.  All other on-study 


45 | P a g e  
 
deaths, regardless of attribution, will be recorded on an SAE Report Form and expeditiously 
reported as described in Sections 10.5.2 and 10.6. 
When recording a serious adverse event with an outcome of death, the event or condition that 
caused or contributed to the fatal outcome should be recorded. If the cause of death is unknown 
and cannot be ascertained at the time of reporting, record “Death NOS”. 
 
 
10.8.4 HOSPITALIZATION, PROLONGED HOSPITALIZATION, OR SURGERY 
 
 
 
Any AE that results in hospital admission of > 24 hours or prolongs hospitalization should 
be documented and reported as an SAE unless specifically instructed otherwise in this protocol. 
There are some hospitalization scenarios that do not require reporting as an SAE when there is 
no occurrence of an AE. See section 10.5.1. 
 
 
10.8.5 PRE-EXISTING MEDICAL CONDITIONS 
 
 
 
A pre-existing relevant medical condition is one that is present at the start of the study. Such 
conditions should be recorded in the subject’s medical history. A pre-existing medical condition 
should be recorded as an AE or SAE only if the frequency, severity, or character of the condition 
worsens during the study. When recording such events on the appropriate SAE Report Form 
and/or as an AE, it is important to convey the concept that the pre-existing condition has changed 
by including applicable descriptors. 
 
 
10.8.6 PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST 
 
 
 
The following are events of special interest, and will need to be reported expeditiously: 
 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
 
During the course of the study, all female patients of childbearing potential (the definitions 
of “women of childbearing potential” are listed in Appendix A- Contraceptive Guidelines and 
Pregnancy) must contact the treating investigator immediately if they suspect that they may 
be pregnant (a missed or late menstrual period should be reported to the treating investigator). 
If an investigator suspects that a patient may be pregnant prior to administration of study drug(s), 
the study drug(s) must be withheld until the result of the pregnancy test is confirmed. If a 
pregnancy is confirmed, the patient must not receive any study drug(s), and must be discontinued 
from the study. 
If an investigator suspects that a patient may be pregnant after the patient has been receiving study 
drug(s), the study drug(s) must immediately be withheld until the result of the pregnancy test 
is confirmed. If a pregnancy is confirmed, the study drug(s) must be immediately and 
permanently stopped, the patient must be discontinued from the study, and the investigator 
must notify the Study Chair and TG Therapeutics as soon as possible.  
If a patient becomes pregnant while enrolled in the study , , submit a Pregnancy Report Form to TG 
Therapeutics, Inc. within 24 hours of the first knowledge of the event by the investigator or 
research personnel following the same process described for reporting SAEs to TG Therapeutics, 
Inc.  Include the TG Therapeutics, Inc. tracking number (TGR-NTG-006) on the Pregnancy Report 
Form and include an assessment of the causal relationship to the study drug.  Male subjects must 


46 | P a g e  
 
contact the investigator immediately if their female partner becomes pregnant, and the investigator 
must submit a Pregnancy Report Form to TG Therapeutics, Inc. within 24 hours as described above.  
Consent should be obtained from the pregnant female subject/male subject’s partner to allow the 
pregnancy to be followed up for the full duration of the pregnancy (or until spontaneous abortion 
or voluntary termination), to collect the outcome with details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications, 
as applicable. Additionally, medical information should be collected on the newborn for 6 months 
after birth, as permitted by local regulations.  
Any SAE experienced during pregnancy must be reported to TG Therapeutics, Inc.  SAEs 
experienced during pregnancy must be reported to TG Therapeutics, Inc. on the SAE Report Form 
within 24 hours of the first knowledge of the event by the investigator or research personnel 
following the same process as described above for SAEs.  Abortions (spontaneous, accidental, or 
therapeutic) must also be reported to TG Therapeutics. 
 
Study Drug Overdose 
 
Symptomatic and non-symptomatic overdose must be recorded. Any accidental or intentional 
overdose with the study treatment (umbralisib) that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to TG Therapeutics immediately (within 24 hours) using 
the corresponding SAE form, and following the same process described for SAEs. If a study 
drug overdose occurs, patients should stop study drug dosing and be clinically monitored as 
appropriate, managing symptoms/side effects that may occur. 
 
Secondary / Second Primary Malignancy 
 
Any secondary malignancy event must be reported via the SAE form as previously described 
(in addition to the routine AE reporting mechanisms). Any malignancy possibly related to 
cancer treatment should also be reported via the routine reporting mechanisms outlined in the 
protocol. 
 
11 CLINICAL DATA COLLECTION AND MONITORING 
 
 
 
11.1 AMENDMENTS TO THE PROTOCOL 
 
 
 
Proposed amendments to the protocol require review and approval by TG Therapeutics prior 
to implementation. After approval by TG Therapeutics, the amendment will be submitted 
formally to the FDA by the Principal Investigator. The protocol amendment must also be reviewed 
and approved by the institutional IRB prior to implementation. If an amendment to the protocol 
substantially alters the study design or the potential risks to patients, patients’ consent to 
continue participation in the study should be obtained per institutional policies. 
 
11.2 DATA OWNERSHIP AND PUBLICATION 
 
 
 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential. By conducting this study, the 


47 | P a g e  
 
Investigator affirms to TG Therapeutics that he or she will maintain, in strict confidence, 
information furnished by TG Therapeutics, except as exempted for regulatory purposes. 
All manuscripts, abstracts, or other presentation materials generated by site investigators must 
be reviewed and approved by TG Therapeutics prior to submission. 
 
11.3 STUDY RECORDS RETENTION 
Study records will be retained for 2 years after a marketing application is approved for the drug; or, 
if an application is not approved for the drug, until 2 years after shipment and delivery of the drug 
for investigational use is discontinued and FDA has been so notified.  
11.4 CLINICAL MONITORING 
 
 
 
Data will be captured in OnCore, Moffitt’s electronic Clinical Trials Database. For each 
participant enrolled, the electronic CRF must be completed by the assigned data manager 
or other authorized study staff. Any paper forms should be typed or filled out using indelible 
ink and must be legible. Errors should be crossed out but not obliterated, the correction 
inserted, and the change initialed and dated by the investigator or his/her authorized 
delegate. This also applies to records for those patients who fail to complete the study. 
If a patient stops dosing or terminates from the study, the dates and reasons must be 
noted on the CRF. If a patient terminates from the study because of a dose limiting toxicity, 
thorough efforts should be made to clearly document the outcome. Regulatory documents 
and case reports forms will be monitored internally according to the Moffitt Cancer Center 
monitoring policies. Monitoring will be performed regularly by the MCC Clinical 
Monitoring Core for accuracy, completeness, and source verification on data entry, 
validation of appropriate consent process, reporting on SAEs, and adherence of the 
protocol, GCP guidelines and applicable regulatory requirements. 
 
11.5 QUALITY ASSURANCE AND QUALITY CONTROL 
 
 
Quality control procedures will be implemented beginning with the OnCore data entry system 
and QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the staff for clarification/resolution. 
Following written SOPs, the Moffitt internal monitors will verify that the clinical trial 
is conducted and data are generated, documented, and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements (e.g., good laboratory 
practices (GLP), good manufacturing  practices (GMP). 
 
The investigational site will provide direct access to source data/documents, and reports 
for the purpose of monitoring and auditing, and inspection by local and regulatory 
authorities. 
All staff will be trained by the PI through a site initiation presentation which may be 
performed by a  power point training or a summary document for training on the initial 
protocol. This will be provided to those staff unable to attend the initiation presentation 
. Training will be performed by self-study for approved amendments and documented per 
the Moffitt CTO SOP . Documentation of training will befiled in the electronic regulatory 
binder. 
 


48 | P a g e  
 
11.6 PROTOCOL DEVIATIONS 
 
 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, of MOP 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly. 
It is the responsibility of the study staff   to identify and report deviations as defined by the 
Moffitt Clinical Trials Office standard.  Protocol deviations must be sent to the local IRB per their 
guidelines. The site PI/study staff is responsible for knowing and adhering to their IRB 
requirements. 
  12 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
 
 
 
This study will be conducted according to the standards of Good Clinical Practice outlined in 
the ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, 
institutional research policies and procedures and any other local applicable regulatory 
requirement(s). 
 
12.1 IRB APPROVAL 
 
 
 
The study protocol, ICF, and other necessary study documents must be submitted to the IRB 
for ethical review and approval prior to the study start. Principal Investigator is also responsible 
for insuring IRB renewals, and IRB approval for all subsequent protocol amendments and 
changes to the informed consent document.  
 
12.2 INFORMED CONSENT 
 
 
 
Informed consent is a process by which a patient voluntarily confirms his or her willingness 
to participate in a particular study, after having been informed of all aspects of the study that 
are relevant to the patient's decision to participate. Informed consent is documented by means 
of a written, signed and dated informed consent form. The ICF will be submitted for approval to 
the IRB that is responsible for review and approval of the study. 
Before recruitment and enrollment into the study, each prospective candidate will be given a 
full explanation of the study. Once the essential information has been provided to the 
prospective candidate, and the investigator is sure that the individual candidate understands the 
implications of 
participating in this study, the candidate will be asked to give consent to 
participate in the study by signing an informed consent form. A notation that written informed 
consent has been obtained will be made in the patient’s medical record. A copy of the informed 
consent form, to include the patient’s signature, will be provided by the investigator or his 
designee to the patient. 
 
If an amendment to the protocol substantially alters the study design or the potential risks to 
the patients, the patient’s consent to continue participation in the study must be obtained. 
 
12.3 CONFIDENTIALITY 
 
 
 


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Patient Confidentiality 
 
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA), and national data protection laws. 
HIPAA regulations require that, in order to participate in the study, the patient should be 
informed of following: 
• 
What protected health information (PHI) will be collected from patients in this study; 
• 
Who will have access to that information and why; 
• 
Who will use or disclose that information; 
• 
That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws; 
• 
The information collected about the research study will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the 
conclusion of the study; 
• 
Whether the authorization contains an expiration date; and 
• 
The rights of a research patient to revoke his or her authorization. 
 
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
patient authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e., that the patient is alive) 
at the end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorized representatives of TG Therapeutics, the 
regulatory authorities and the IRB direct access to review the patient’s original medical records 
at the site for verification of study-related procedures and data. Patients will be informed of 
their rights within the ICF. 
 
 
 
 
 
 
 
 


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  12 REFERENCES 
 
 
 
1. 
Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus Ofatumumab in Previously Treated 
Chronic Lymphoid Leukemia. New England Journal of Medicine;0(0):null. 
2. 
Barr PM, Brown JR, Hillmen P, et al. Dose adherence and baseline exposure analysis of 
the ibrutinib 420 mg dose administered to patients with previously treated chronic lymphocytic 
leukemia (CLL). ASCO Annual Meeting Proceedings; 2015:7012. 
3. 
Friedman DR, Simms T, Allgood SD, et al. The PI3K-δ inhibitor TGR-1202 induces 
cytotoxicity and inhibits phosphorylation of AKT in 17p deleted and non-17p deleted CLL cells 
in vitro. Cancer Research. 2014;74(19 Supplement):4518-4518. 
4. 
Burris HA, Patel MR, Brander DM, et al. TGR-1202, a novel once daily pi3kδ inhibitor, 
demonstrates clinical activity with a favorable safety profile, lacking hepatotoxicity, in patients 
with chronic lymphocytic leukemia and B-cell lymphoma. Blood. 2014;124(21):1984-1984. 
5. 
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and Rituximab in Relapsed Chronic 
Lymphocytic Leukemia. New England Journal of Medicine. 2014. 


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6. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and  treatment  of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. 
Blood. 2008;111(12):5446-5456. 
7. 
Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical 
end points in chronic lymphocytic leukemia. Journal of Clinical Oncology;30(23):2820-2822. 
8. 
Hallek, M., et al., Guidelines for diagnosis, indications for treatment, response 
assessment and supportive management of chronic lymphocytic leukemia. Blood, 2018. Jun 
21;131(25):2745- 2760. doi: 10.1182/blood-2017-09-806398. Epub 2018 Mar 14. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 APPENDIX A- CONTRACEPTIVE GUIDELINES AND PREGNANCY 
 
 
 
Women Not of Childbearing Potential are Defined as Follows: 
 
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea  with 
serum FSH levels > 40 mIU/mL [for US only:  and estradiol < 20 pg/mL] or have had surgical 
bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential. 
 
Contraceptive Guidelines for Women of Child-Bearing Potential: 
 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 30 days after stopping 
treatment. The highly effective contraception is defined as either: 


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1. True abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
2. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) 
or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment. 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female patients on the study, the vasectomised 
male partner should be the sole partner for that patient. 
4. 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 unacceptable forms of contraception for women of childbearing potential: 
 
• 
Female condom 
• 
Natural family planning (rhythm method) or breastfeeding 
• 
Fertility awareness 
• 
Withdrawal 
• 
Cervical shield 
 
Women of child-bearing potential must have a negative serum or urine pregnancy test ≤ 3 days 
prior to initiating treatment. 
Fertile Males: 
 
Fertile males, defined as all males physiologically capable of conceiving offspring, must use 
condoms during treatment and for 30 days after discontinuation of the study drug. They should 
not father a child in this period. 
 
Pregnancies 
 
To ensure patient safety, each pregnancy, either in a female patient or the female partner of a male 
patient on study treatment, must be reported to TG Therapeutics Inc. within 24 hours of learning 
of its occurrence. The pregnancy must be followed until term. Both the mother and the infant 
child must be followed for 6 months after termination of 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 follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the study drug and reported by the investigator to TG Therapeutics 
Inc. Any SAE experienced during pregnancy must be reported to TG Therapeutics Inc. 


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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 APPENDIX B – NYHA CLASSIFICATIONS 
 
 
New York Heart Association (NYHA) Classifications 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation 
of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
Objective 
evidence 
of 
minimal 
cardiovascular 
disease. 


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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 APPENDIX C – HEPATITIS B SEROLOGIC TEST RESULTS 
 
 


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17 APPENDIX D – IWCLL RESPONSE CRITERIA VERSION 2018 
 


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