Clinical trial NCT03364231
Conditions: Marginal Zone Lymphoma Waldenstrom Macroglobulinemia Non Follicular Indolent Non-Hodgkin Lymphoma
Sponsor: TG Therapeutics, Inc.
Start date: 2017-11-30; Completion date: 2022-02-15
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This research study will evaluate the safety and efficacy of a study drug called Umbralisib (also known as TGR-1202) alone as a possible treatment for Waldenstrom's Macroglobulinemia that has come back or that has not responded to standard treatment.

Detailed description:

Arms: arm 1: Participants with non-follicular indolent non-Hodgkin's lymphoma (iNHL) with MZL as the histology type received umbralisib, 800 milligrams (mg), orally, once daily (QD), until disease progression, unacceptable toxicity, or withdrawal from the study whichever occurred first. arm 2: Participants with non-follicular iNHL with WM as the histology type received umbralisib, 800 mg, orally, QD, until disease progression, unacceptable toxicity, or withdrawal from the study whichever occurred first.
Interventions: intervention 1: Umbralisib
Intervention descriptions: intervention 1: Oral Daily Dose

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: A Phase 2 Study to Assess the Efficacy and Safety of TGR-1202
(Umbralisib) Monotherapy in Patients with Non-Follicular Indolent 
Non-Hodgkin’s Lymphoma
NCT Number: 
NCT03364231
Document Date: 
Protocol Version 2.0: 05-September-2017


TGR-1202-202 
 
 
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Page 1 of 68 
Protocol version/Date:  
 
Version 2.0 / 5 September, 2017 
Local Protocol #: 
 
 
Protocol TGR-1202-202 
TITLE: 
A Phase 2 Study to Assess the Efficacy and Safety of TGR-1202 (Umbralisib) Monotherapy in 
Patients with Non-Follicular Indolent Non-Hodgkin’s Lymphoma 
 
Sponsor: 
 
 
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort St., 9th Floor 
 
 
 
 
New York, NY 10014 
 
 
 
 
Tel: (212) 554-4484 
 
IND Number:  
 
TGR-1202 
116,762 
 
 
 
 
 
 
Study Chair:   
 
, M.D., FACP, FAAAS, FASCO 
 
 
 
 
 
 
Medical Monitor: 
 
, MD 
 
 
 
 
Tel: (212) 554-4484 
 
 
Study Coordination:  
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort Street, 9th Floor 
 
 
 
 
New York, NY 10019 
 
 
 
 
Tel: (212) 554-4484 
 
Version: 1.0 
 
 
 
 
 
 
 
Date:  4 April 2017 
Version: 2.0 
 
 
 
 
 
 
 
Date: 5 September 2017 
 
This document is a confidential communication of TG Therapeutics, Inc. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein shall be 
published or disclosed without prior written approval, except that this document may be disclosed to 
the appropriate Institutional Review Boards/ Independent Ethics Committees under the condition that 
they keep it confidential. 
  




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PROTOCOL ACCEPTANCE FORM 
Protocol Title: 
A Phase 2 Study to Assess the Efficacy and Safety of TGR-
1202 (Umbralisib) Monotherapy in Patients with Non-
Follicular Indolent Non-Hodgkin’s Lymphoma 
Protocol Number: 
TGR-1202-202 
IND Number: 
TGR-1202 
 
116,762 
 
Date FINAL: 
5 September 2017 
 
I have read the attached protocol and agree that it contains all the necessary details for performing 
TGR-1202-202. 
I will provide copies of the protocol and of the TGR-1202 (umbralisib) Investigator’s Brochure, which 
was given to me by TG Therapeutics (Sponsor), to all members of the study team for whom I am 
responsible and who participate in the study.  I will discuss this material with them to ensure that 
they are fully informed regarding TGR-1202, as well as the Standard of Care agents used in this trial, 
and the conduct of the study. 
Once the protocol has been approved by the IRB, I will not modify this protocol without obtaining the 
prior approval of TG Therapeutics and of the IRB.  I will submit the protocol modifications and/or 
any informed consent modifications to TG Therapeutics and the IRB, and approval will be obtained 
before any modifications are implemented. 
I understand the protocol and will work according to it, the principles of Good Clinical Practice 
(current ICH guidelines), and the Declaration of Helsinki (1964) including all amendments up to and 
including the Washington Clarification (2002). 
 
 
 
 
 
 
 
Print Name 
 
Signature 
 
Date 
 
 


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TABLE OF CONTENTS 
STUDY SYNOPSIS ................................................................................................................................... 9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................... 14 
1 INTRODUCTION ................................................................................................................................ 16 
1.1 Indolent non-Hodgkin’s Lymphoma .................................................................................................................. 16 
1.2 TGR-1202 (UMBRALISIB) ...................................................................................................................................... 17 
1.2.1 Pre-Clinical Development of TGR-1202 ................................................................................................................................................... 17 
1.2.2 Clinical Development of TGR-1202 ............................................................................................................................................................ 19 
1.3 Rationale for Recommended Phase 2 Dose of TGR-1202 ......................................................................... 21 
1.4 Rationale for Phase 2 Study .................................................................................................................................. 22 
2 OBJECTIVES AND ENDPOINTS ..................................................................................................... 23 
2.1 Study Objectives ........................................................................................................................................................ 23 
2.2 Efficacy Endpoints .................................................................................................................................................... 23 
3 ELIGIBILITY CRITERIA ................................................................................................................... 24 
3.1 Inclusion Criteria ....................................................................................................................................................... 24 
3.2 Exclusion Criteria ...................................................................................................................................................... 24 
4 STUDY DESIGN .................................................................................................................................. 26 
4.1 Overview of Study Design .......................................................................................................................... 26 
4.2 Registration ................................................................................................................................................................. 26 
4.3 Study Sites .................................................................................................................................................................... 26 
4.4 Discontinuation from Study Treatment ........................................................................................................... 26 
5 STUDY ASSESSMENTS AND TREATMENT SCHEDULE .......................................................... 28 
5.1 Study Assessments and Treatment Schedule ................................................................................................ 28 
5.2 Laboratory Assessments ........................................................................................................................................ 29 
5.2.1 Local Laboratory Assessments ..................................................................................................................................................................... 29 
5.2.2 Central Laboratory Assessments ................................................................................................................................................................. 29 
6 TREATMENT PLAN .......................................................................................................................... 30 
6.1 Treatment Summary ................................................................................................................................................ 30 
6.2 Agent Administration .............................................................................................................................................. 30 
6.2.1 Guidelines for Administration of TGR-1202(UMBRALISIB) .......................................................................................................... 30 
6.2.2 Criteria for Ongoing Treatment.................................................................................................................................................................... 31 
6.3 Dosing Delays and Modifications ........................................................................................................................ 31 
6.3.1 Dose Delay/Modification Recommendations: TGR-1202................................................................................................................ 31 
6.4 Ordering TGR-1202 .................................................................................................................................................. 33 


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6.5 Duration of Therapy ................................................................................................................................................. 33 
7 STUDY MEDICATIONS OVERVIEW AND SAFETY ................................................................... 34 
7.1 TGR-1202(UMBRALISIB) ....................................................................................................................................... 34 
7.1.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ....................................................................................... 34 
8 MEASUREMENT OF EFFECT .......................................................................................................... 36 
8.1 Method of Assessment ............................................................................................................................................ 36 
8.2 Response Review ....................................................................................................................................................... 36 
8.3 Antitumor Effect ........................................................................................................................................................ 36 
8.4 Definitions of Tumor Response and Progression ........................................................................................ 37 
8.4.1 Complete Response ............................................................................................................................................................................................ 37 
8.4.2 Very Good Partial Response ........................................................................................................................................................................... 37 
8.4.3 Partial Response .................................................................................................................................................................................................. 37 
8.4.4 Minor Response ................................................................................................................................................................................................... 38 
8.4.5 Stable Disease ....................................................................................................................................................................................................... 38 
8.4.6 Relapsed Disease or Progression of Disease .......................................................................................................................................... 38 
8.5 Definitions of Disease Parameters ..................................................................................................................... 38 
8.6 Evaluation of Best Overall Response ................................................................................................................. 39 
8.6.1 Duration of Response ........................................................................................................................................................................................ 39 
9 STATISTICAL CONSIDERATIONS ................................................................................................. 40 
9.1 Sample Size and Power ........................................................................................................................................... 40 
9.2 General Analysis Convention ................................................................................................................................ 40 
9.3 Analysis Populations ................................................................................................................................................ 40 
9.4 Patient Disposition ................................................................................................................................................... 40 
9.5 Patient Demographics and Baseline Characteristics .................................................................................. 41 
9.6 Medical History .......................................................................................................................................................... 41 
9.7 Extent of Exposure .................................................................................................................................................... 41 
9.8 Efficacy Analyses ....................................................................................................................................................... 41 
9.9 Missing Value Handling Procedures .................................................................................................................. 41 
9.10 Statistical Analyses ................................................................................................................................................ 41 
9.10.1 Primary Efficacy Variable ............................................................................................................................................................................. 41 
9.10.2 Efficacy Variable ............................................................................................................................................................................................... 42 
9.11 Multiple Comparison Procedures .................................................................................................................... 42 
9.12 Safety Analyses ........................................................................................................................................................ 42 
9.13 Adverse Event Characteristics .......................................................................................................................... 42 
9.14 Definitions of Adverse Events ........................................................................................................................... 42 
9.15 Adverse Events (AE’s) and Treatment Emergent Adverse Events (TEAE’s) ................................. 43 


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9.16 Adverse Events/Serious Adverse Event Causality Assessment .......................................................... 43 
9.16.1 Recording of Adverse Events ...................................................................................................................................................................... 44 
9.16.2 Abnormal Laboratory Values and Vital Signs ..................................................................................................................................... 44 
9.16.3 Handling of Adverse Events ........................................................................................................................................................................ 45 
9.17 Serious Adverse Events ........................................................................................................................................ 45 
9.17.1 Definitions of Serious Adverse Events ................................................................................................................................................... 45 
9.17.2 Serious Adverse Event Reporting by Investigators ......................................................................................................................... 46 
9.18 Sponsor SAE Reporting Requirements .......................................................................................................... 47 
9.19 Recording of Adverse Events and Serious Adverse Events ................................................................... 47 
9.20 Diagnosis vs. Signs and Symptoms .................................................................................................................. 47 
9.20.1 Persistent or Recurrent Adverse Events ............................................................................................................................................... 47 
9.20.2 Abnormal Laboratory Values ..................................................................................................................................................................... 48 
9.20.3 Deaths .................................................................................................................................................................................................................... 48 
9.20.4 Hospitalization, Prolonged Hospitalization, or Surgery ................................................................................................................ 48 
9.20.5 Pre-Existing Medical Conditions ............................................................................................................................................................... 48 
9.20.6 Protocol-Defined Events of Special Interest ........................................................................................................................................ 49 
10 CLINICAL DATA COLLECTION AND MONITORING .............................................................. 50 
10.1 Site Monitoring ........................................................................................................................................................ 50 
10.2 Amendments to the Protocol ............................................................................................................................. 50 
10.3 Curricula Vitae and Financial Disclosures .................................................................................................... 51 
10.4 Data Ownership and Publication ..................................................................................................................... 51 
11 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ....................................... 52 
11.1 IRB Approval ............................................................................................................................................................ 52 
11.2 Regulatory Approval ............................................................................................................................................. 52 
11.3 Informed Consent ................................................................................................................................................... 52 
11.4 Confidentiality.......................................................................................................................................................... 53 
11.5 Investigator and Staff Information .................................................................................................................. 54 
11.6 Financial Information ........................................................................................................................................... 54 
12 RECORD RETENTION AND DOCUMENTATION OF THE STUDY ...................................... 55 
12.1 Documentation Required to Initiate Study .................................................................................................. 55 
12.2 Study Documentation and Storage .................................................................................................................. 55 
12.3 Data Collection ......................................................................................................................................................... 57 
12.4 Study Monitoring, Auditing, and Inspecting ................................................................................................ 57 
12.5 Quality Assurance and Quality Control ......................................................................................................... 57 
12.6 Disclosure and Publication Policy.................................................................................................................... 58 
13 REFERENCES ................................................................................................................................... 59 


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14 Appendix A –Criteria for Response Assessment ................................................................ 61 
15 Appendix B- Contraceptive Guidelines and Pregnancy ................................................... 65 
16 Appendix C – NYHA Classifications ......................................................................................... 67 
17 Appendix D – Hepatitis B Serologic Test Results ............................................................... 68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version 2. 0 (Dated 5 September 2017) of this Protocol is the second amendment to this clinical trial 
and contains the following modifications: 
• 
Section 2.1 has been updated to include 
 
• 
Section 3.2 has been updated to broaden the Exclusion Criteria to include any significant 
cardiovascular disease within 6 months 
• 
Sections 4.1, 6.5, and 8 have been updated to reflect the change in scan assessment schedule 
and to include response assessment for WM patients without nodal involvement. In addition, 
these sections have been updated to include the follow-up schedule for patients who 
discontinued from the study for reason other than disease progression.  
• 
Updates on the Study Assessment and Treatment Schedule in Section 5  
• 
Section 5.2.2 has been included to add Central Laboratory Assessments 
• 
Section 6.2.1 has been updated to require treatment with pneumocystis jiroveci pneumonia 
(PCP) and antiviral therapy 
• 
Section 6.3.1 has been updated to provide detailed guidance for TGR-1202 Dose Delays and 
Modifications 
• 
Section 7.1.1 has been updated to include the latest CAEPRS information for TGR-1202. 
• 
Appendix B has been updated for male patients to use highly effective contraception during 
the study period and for 30 days after.  
• 
Updated throughout to acknowledge the tradename for TGR-1202: umbralisib 
• 
Minor administrative updates and typographical errors were corrected throughout.   
 
 
















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1 INTRODUCTION 
1.1 INDOLENT NON-HODGKIN’S LYMPHOMA 
Non-Hodgkin’s lymphomas are a heterogeneous group of disorders with different pathophysiology, 
histology and clinical course. The indolent non-Hodgkin’s lymphomas (iNHL) are a subset of B-cell 
Non-Hodgkin’s Lymphomas characterized by prolonged median survival with a long relapsing and 
remitting clinical course. These indolent lymphomas are slow growing, spread slowly with few 
presenting symptoms. Follicular lymphoma grades I-IIIa tend to be slow growing and are the most 
prevalent lymphoma in this disease group. The remainder of indolent lymphomas are non- follicular 
indolent lymphomas comprising of small lymphocytic lymphoma, marginal zone B- cell lymphoma 
(nodal, splenic and extra nodal ) and lymphoplasmacytic lymphoma/ Waldenstrom’s 
macroglobulinemia1 . 
In the US, there are an estimated 16000 new cases of non-follicular indolent lymphomas diagnosed 
every year. Indolent non-Hodgkin’s lymphoma is a disease of the older population with the median 
age of diagnosis varying from 65 to 72 years. The average median survival for non–follicular indolent 
non-Hodgkin’s lymphomas is 10 – 15 years (SEER Stat Fact Sheets: Non-Hodgkin’s Lymphoma. 
Bethesda, MD: National Cancer Institute; 2013) For a disease with such a protracted course the goal 
of management has been to maintain a good quality of life and initiate treatment only when the 
patients become symptomatic. A wait and watch approach is used till the disease becomes 
symptomatic. 
2The foundation of treatment for indolent non-Hodgkin’s lymphomas is 
chemoimmunotherapy (mainly CD-20 antibody like rituximab ) used alone or in combination with 
chemotherapy consisting of anthracycline, alkylating and purine analogues for use as a first line agent 
and in relapsed or refractory disease. 3,4 The response rate and progression free survival of Rituximab 
monotherapy or combination therapy is reassuring however as many as 20-30% patients relapse 
within 3 years of treatment with first-line chemoimmunotherapy.5–7 Relapsed or refractory iNHL 
have poor overall survival. Furthermore, the responses to second line therapies are inferior 
suggesting a need for better salvage therapy after first line therapies 
Recently the FDA provided accelerated approval for the PI3K inhibitor, idelalisib to treat patients 
with relapsed follicular B-cell non-Hodgkin’s lymphoma (FL) and relapsed small lymphocytic 
lymphoma (SLL) who have received at least two prior systemic therapies. This was based on a 
randomized clinical trial involving 123 patients which showed an overall response rate of 57% and 
a median progression free survival of 11 months. However up to 54 % of patients in the clinical trial 
experienced a grade 3 or higher adverse event, with discontinuation of idelalisib in 20 % of the 
patients. Some of the most frequently reported adverse events of grade 3 or higher were diarrhea (in 
13% of the patients), pneumonia (in 7%), and dyspnea (in 3%).  Discontinuation or interruptions led 
to response durations that were shorter lived.8 Another clinical trial involving idelalisib for treatment 
of CLL showed a similar adverse effect profile.  Given the increasing rate of adverse effects including 
death, FDA has placed six clinical trials on hold for patients receiving idelalisib for chronic 
lymphocytic leukemia, small lymphocytic lymphoma and indolent non-Hodgkin’s lymphoma. 
Given an improved tolerability profile observed to date, we have selected TGR-1202(umbralisib) to 
study in patients with relapsed/refractory non-follicular indolent non-Hodgkin’s lymphomas. 
 




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FIGURE 2: REDUCTION OF PAKT BY TGR-1202 IN CELL LINES BY WESTERN BLOTTING 
 
1.2.1.1 IN-VIVO ACTIVITY 
In vivo efficacy of TGR-1202 was confirmed in a subcutaneous mouse MOLT-4 xenograft model.  Oral 
administration of 150 mg/kg/QD over a 25-day period resulted in a significant delay in tumor 
growth. 
FIGURE 3: TGR-1202 IN VIVO EFFICACY 
 
1.2.1.2 TOXICOLOGY  
To assess the safety and toxicity of TGR-1202 a 28-day repeat dose study with a 14-day recovery 
period was conducted in CD-1 mice and beagle dogs, to evaluate the potential reversibility of findings 
and to support the use in humans.  TGR-1202 was administered orally in order to mimic the planned 
mode of clinical administration.       
Once daily oral administration of TGR-1202 was tolerated in mice at free base dose levels of 50 and 
150 mg/kg/day.  Increases in liver weights, microscopic findings in the liver and the increases in 
serum cholesterol, and female only ALT, AST, and GGT levels were observed at 750 mg/kg/day of 
free base (the highest dose tested) and were considered adverse.  The no-observed-adverse-effect 
level (NOAEL) was considered to be 150 mg/kg/day in mice.  
Once daily oral administration by capsule of TGR-1202 was well tolerated in dogs at levels of 50 and 
150 mg/kg/day.  The gastrointestinal tract, based on clinical signs, was the target organ system.  
Based on effects on body weight and the incidence and severity of emesis and diarrhea, the NOAEL 
was considered to be 150 mg/kg/day (114.5 mg/kg/day as free base) in this species. 
Refer to the TGR-1202 Investigator’s Brochure (IB) for detailed information on toxicology studies 
conducted to date. 


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1.2.2 CLINICAL DEVELOPMENT OF TGR-1202  
1.2.2.1 SINGLE-AGENT IN PATIENTS WITH RELAPSED OR REFRACTORY HEMATOLOGIC 
MALIGNANCIES 
TGR-1202 was evaluated in a Phase I dose-escalation study in patients with relapsed and refractory 
hematologic malignancies (O’Connor et al, ASH 2015).  As of the latest cutoff date for this study of 
December 2015, 81 patients were enrolled and eligible for safety evaluation, with 63 patients 
evaluable for efficacy.  The median age was 65 years (range 22-85), 53/28 male and 14/81 enrolled 
patients had a diagnosis of DLBCL.  Among all patients, the median number of prior therapies was 3 
(range, 1-14), with 57% of patients having 3 or more prior therapies and 49% refractory to their 
immediate prior therapy.   
Patients have been 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 TGR-1202, 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 1.2.2.2 Healthy Subject Pharmacokinetic Studies below).  
Additionally, a healthy subject food effect study as well as data from the patients in the fed-state 
expansion cohorts revealed increased exposure in the fed state.  As a result of these improvements, 
dose-escalation has proceeded using the micronized formulation in a fed state.  This micronized 
formulation was introduced into dose escalation at 200 mg QD and dosed as high as 1200 mg QD, 
with no maximum tolerated dose (MTD) reached.  Intra-patient dose escalation rules have allowed 
patients enrolled into the study in early cohorts to increase their dose of TGR-1202 as subsequent 
higher cohorts have cleared safety evaluation.  A dose-dependent response has been observed with 
TGR-1202 (ASCO 2013), with a dose of 800 mg or higher of the initial formulation or any dose of the 
micronized formulation producing significant nodal reductions among CLL patients.  Of the 17 CLL 
patients treated at ≥800mg, 94% have achieved a nodal partial response, and nodal reductions show 
an improvement with time on TGR-1202 with a median time on study of 6 months.  Adverse events 
observed amongst all 55 patients included diarrhea, nausea, fatigue, cough, anorexia, headache, 
vomiting, rash, neutropenia, constipation, dyspnea, and thrombocytopenia.  One DLT event of Grade 
3 rash was observed at the 800 mg dose level of the initial formulation, which necessitated 
enrollment of an additional 3 patients.  The Grade 3 rash resolved upon suspension of TGR-1202 and 
concomitant medications and did not recur upon re-challenging the patient at 800 mg QD.  See 
Section 7.1.1 
 for a complete overview of the TGR-1202 side 
effect profile.   
1.2.2.2 HEALTHY SUBJECT PHARMACOKINETIC STUDIES 
In parallel with the Phase I single-arm, dose-escalation study in patients with relapsed or refractory 
hematologic malignancies; two healthy subject, crossover, bioequivalence pharmacokinetics studies 
have been completed.  The first pharmacokinetic study was a Phase I drug-food interaction study 
with a single 200 mg oral dose of TGR-1202 in healthy volunteers followed by a second single dose 
Phase I pharmacokinetic study evaluating the absorption, distribution, metabolism and excretion 
characteristics of two different oral formulations of 200 mg TGR-1202 (original formulation vs. 
micronized formulation) in healthy volunteers. 
 




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relative to original drug product formulation. The Peak plasma (Cmax) levels of TGR-1202 increased 
by over 124% following administration of the micronized drug product formulation relative to 
original drug product formulation under fasted conditions. 
Using these mean values, a 320 mg oral dose of TGR-1202 in the original formulation under fasted 
condition can be extrapolated to be equivalent to an oral dose of 200 mg of the original formulation 
TGR-1202 under fasted conditions in term of exposure based on AUC0-inf.  
The improved exposure seen with the micronized formulation of TGR-1202 was confirmed in 
patients in the Phase 1 dose escalation as well.  The chart below illustrates the pre-dose plasma 
concentrations of TGR-1202 on Day 1 of Cycle 2 in patients administered equivalent doses of either 
the initial formulation in the fasting state or the micronized formulation in the fed state:   
 
1.3 RATIONALE FOR RECOMMENDED PHASE 2 DOSE OF TGR-1202 
In this Phase 2 study, 800 mg dose of TGR-1202 will be orally administered under fed conditions 
using the micronized drug product formulation.  The two Phase I pharmacokinetic studies have 
elucidated that: 
• 
The systemic exposure to TGR-1202 increases approximately 67% based on total extent 
(AUC0-inf) under fed condition; and 
• 
The systemic exposure to TGR-1202 increases approximately 60% based on the modified 
drug product formulation when compared to the original drug product formulation.  
To evaluate the improvement in the absorption of TGR-1202 with the modified drug product 
formulation under fed condition, the Phase I dose-escalation study with TGR-1202 includes the 
following dose groups: 
• 
Administration of original drug product formulation under fasted and fed conditions; and 
• 
Administration of the modified drug product formulation under fed conditions.  
Based on the results from the completed Phase 1 dose-escalation study and the two Phase I 
pharmacokinetics studies in healthy volunteers, a dose of 800 mg of TGR-1202 using the modified 
drug product formulation under fed condition was selected.  


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1.4 RATIONALE FOR PHASE 2 STUDY  
Based on the success of Phase I trials of PI3K inhibitor idelalisib in patients with iNHL Gopal et al 
performed a Phase 2 randomized clinical trial involving 123 patients with relapsed and refractory 
iNHL with prior rituximab and alkylator based therapy.  After a median follow-up of 9.7 months, the 
median time to a response was 1.9 months, the median duration of response was 12.5 months, and 
the median progression-free survival was 11 months. The response rate was 57% (71 of 125 
patients), with 6% meeting the criteria for a complete response. However up to 54 % of patients in 
the clinical trial experienced a grade 3 or higher adverse event, with discontinuation of idelalisib in 
20 % of the patients. Some of the most frequently reported adverse events of grade 3 or higher were 
diarrhea (in 13% of the patients), pneumonia (in 7%), and dyspnea (in 3%)8. Combining idelalisib 
with other agents resulted in greater episodes of grade 3 or higher events including death. In addition 
to autoimmune toxicity multiple episodes of severe sepsis were reported with increasing 
opportunistic infections suggesting possible immune deficiency.11–13 A recent safety analysis of 3 
Phase III studies in subjects with previously untreated CLL (bendamustine /rituximab ± idelalisib) 
and previously treated indolent B-cell NHL (rituximab ± idelalisib and bendamustine/rituximab ± 
idelalisib) were recently halted because of an excess of deaths and serious adverse events among 
patients treated in the idelalisib-containing groups (combined mortality rate, 49/664 [7.4%] vs 
14/402 [3.5%]) 
TGR-1202 (umbralisib) is a PI3K inhibitor with an improved safety profile. In an integrated analysis 
of two Phase I studies, 165 patients with non-Hodgkin’s lymphoma, including CLL, were treated with 
TGR-1202.  Adverse events such as nausea, diarrhea, fatigue, headache, vomiting and cough were the 
most commonly reported events, the majority of which were Grade 1 and 2.  The only Grade ≥3 
adverse event in more than 10% of patients was neutropenia (18%).  Discontinuation due to an 
adverse event with TGR-1202 was reported 8% of patients. 
 
The purpose of this study is to evaluate the safety and efficacy of TGR-1202 in previously treated 
non-follicular indolent non-Hodgkin’s lymphoma patients.   


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2 OBJECTIVES AND ENDPOINTS 
2.1 STUDY OBJECTIVES 
PRIMARY OBJECTIVES 
• 
To evaluate the overall response rate (CR + PR + VGPR + MR) and duration of response for 
TGR-1202 in patients with relapsed or refractory non-follicular indolent non-Hodgkin’s 
lymphoma.   
SECONDARY OBJECTIVES 
• 
To determine the progression free survival of TGR-1202 in patients with relapsed or refractory 
non-follicular indolent non-Hodgkin’s lymphoma. 
• 
To evaluate time to treatment failure with TGR-1202. 
• 
To evaluate the safety profile of TGR-1202 
 
 
2.2 EFFICACY ENDPOINTS 
Progression-free survival (PFS) 
 
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. Definitive disease progression based on revised 
response criteria for malignant lymphoma (Cheson et al, 2014 and Owen et al 2013).  
 
Time to treatment failure (TTF)  
TTF is defined as a composite endpoint measuring time from Cycle 1/Day 1 to discontinuation of 
treatment for any reason, including disease progression, treatment toxicity, and death.  
Overall response rate (ORR) 
 
ORR is defined as sum of CR and PR (and VGPR, MR for patients with WM) rates.  
 
Duration of response (DOR) 
 
DOR is defined as the interval from the first documentation of CR or PR or VGPR or MR to the earlier 
of the first documentation of definitive disease progression or death from any cause. 


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3 ELIGIBILITY CRITERIA 
Patients must meet all of the following inclusion criteria and none of the exclusion criteria to be 
eligible for participation in this study. 
 
3.1 INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for participation in this study: 
1. Histologically confirmed diagnosis of B-cell non-follicular indolent non-Hodgkin’s lymphoma 
meeting following requirements.   
a. World Health Organization 2008 classification criteria warranting therapy as per 
investigator discretion for histologies limited to splenic marginal zone lymphoma 
(SMZL), nodal marginal zone Lymphoma (NMZL), or extra-nodal marginal zone 
lymphoma (ENMZL), and lymphoplasmacytic lymphoma. 
b. Presence of CD20+ lymphoplasmacytic lymphoma involving the bone marrow, positive 
serum immunofixation for monoclonal IgM and atleast one criteria for initiation of 
treatment as per Consensus panel of International Workshops on Waldenstrom’s 
macroglobulinemia. 
2. Relapsed or refractory after at least one prior treatment regimen, with no limit on prior 
therapies. 
3. At least 1 measurable disease lesion >1.5 cm in at least one diameter by CT/CT-PET or 
magnetic resonance imaging (MRI) in an area of no prior radiation therapy, or in an area that 
was previously irradiated that has documented progression. 
a. Exceptions include for Waldenstrom’s macroglobulinemia patients without nodal 
involvement. 
4. Waldenstrom’s macroglobulinemia patients must have measurable quantitative IgM 
monoclonal protein greater than normal value. 
5. Adequate organ system function, defined as follows: 
a. Absolute neutrophil count (ANC) > 1,000 / platelet count > 50,000. 
b. Total bilirubin ≤1.5 times the upper limit of normal (ULN) 
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if 
no liver involvement or ≤5 x the ULN if known liver involvement 
d. Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault or 
MDRD formula, 24- hour urine Cr clearance also acceptable) 
6. ECOG performance status ≤ 2 
7. Male or female ≥ 18 years of age 
8. Ability to swallow and retain oral medication 
9. 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. 
10. 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. Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, 
biologic therapy, hormonal therapy, surgery and/or tumor embolization) or any investigational 
drug within 21 days of Cycle 1/Day 1. 


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a. Corticosteroid therapy started at least 7 days prior to study entry (prednisone ≤10 mg daily 
or equivalent) is allowed as clinically warranted.  Topical or inhaled corticosteroids are 
permitted 
2. Refractory to idelalisib, duvelisib, or any drug that specifically inhibits phosphoinositide-3-
kinase (PI3K).   
3. Prior autologous stem cell transplant within 6 months.  Prior allogeneic hematologic stem cell 
transplant is excluded.   
4. Evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B 
vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C infection (HCV), 
cytomegalovirus (CMV), or known history of HIV. If HBc antibody, HCV antibody or CMV is 
positive the subject must be evaluated for the presence of HBV, HCV, or CMV by DNA (PCR) - See 
Appendix D. 
5. Known histological transformation to an aggressive lymphoma  
6. Known Central Nervous System (CNS) lymphoma; patients with symptoms of CNS disease must 
have a negative CT scan and negative diagnostic lumbar puncture.  
7. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infection 
of skin or nails.  NOTE:  Patients may be receiving prophylactic antiviral or antibacterial therapies 
at investigator discretion. 
8. Any severe and/or uncontrolled medical conditions or other conditions that could affect their 
participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (NY Heart Association 
functional classification III-IV) – See Appendix C 
b. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of randomization 
c. QTc Interval >470  
d. Angina not well-controlled by medication 
e. Poorly controlled or clinically significant atherosclerotic vascular disease including 
cerebrovascular 
accident 
(CVA), 
transient 
ischemic 
attack 
(TIA), 
angioplasty, 
cardiac/vascular stenting within 6 months of enrollment 
9. Malignancy within 3 years of study enrollment except for adequately treated basal, squamous 
cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the cervix, superficial 
bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, localized 
prostate cancer and PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart 
with the most recent one being within 4 weeks of study entry. 
10. Women who are pregnant or lactating. 


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4 STUDY DESIGN 
4.1 OVERVIEW OF STUDY DESIGN 
This study is designed as a Phase 2 trial to evaluate the efficacy and safety of TGR-1202 (umbralisib) 
monotherapy in previously treated non-follicular indolent non-Hodgkin’s lymphoma. Patients are 
required to have non-follicular indolent non-Hodgkin’s lymphoma that is relapsed or refractory 
following at least one prior standard therapy regimen.   
 
Enrollment 
Following Screening, qualified patients will be administered TGR-1202 monotherapy at 800 mg QD. 
 
During the study period, all patients will be evaluated for response by CT, PET-CT and/or MRI every 
3 cycles. For patients with WM without nodal involvement, response will be assessed by quantitative 
monoclonal IgM protein every 3 cycles. The best clinical response as well as disease progression will 
be determined by local investigator. Patients will remain on study treatment until the occurrence of 
definitive disease progression, unacceptable toxicity, or withdrawal from the study due to 
investigator decision or other reasons.  Patients who discontinue from study treatment (either for 
toxicity or physician choice) and have not progressed should continue to be followed for progression 
every 6 months or per standard of care. 
An independent DSMB will be established to advise the Sponsor on safety and ethical issues of the 
study.  Once the database has been locked, the independent DSMB will review the primary and 
secondary efficacy analyses and safety data. 
4.2 REGISTRATION  
Patients who are eligible and who have signed an informed consent will be enrolled in the trial with 
TGR-1202 monotherapy.  
4.3 STUDY SITES 
 
Up to 5 centers in the United States may be asked to participate in this study.   
4.4 DISCONTINUATION FROM STUDY TREATMENT 
Patients may be discontinued from study treatment for any of the following reasons: 
• 
Disease progression 
• 
Intolerable toxicity related to study drug 
• 
Patient requests to withdraw consent or discontinue treatment 
• 
Pregnancy 
• 
Inability of the patient to comply with study requirements 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Non-compliance/lost to follow-up 


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• 
Investigator discretion 
• 
Discontinuation of the study by the Sponsor 
Patients who discontinue from study treatment (for reasons other than progressive disease) will 
continue to be followed for progression. 
After discontinuation from protocol treatment, patients should be followed for AEs for 30 calendar 
days after their last dose of either study drug.  All new AEs occurring during this period must be 
reported and followed until resolution, unless, in the opinion of the investigator, these values are not 
likely to improve because of the underlying disease.  In this case the investigators must record his or 
her reasoning for this decision in the patient’s medical records and as a comment on the electronic 
Case Report Form (eCRF). 
All patients who have CTCAE grade 3 or 4 laboratory abnormalities at the time of withdrawal should 
be followed until the laboratory values have returned to grade 1 or 2, unless in the opinion of the 
investigator, it is not likely that these values are to improve because of the underlying disease.  In this 
case, the investigator must record his or her reasoning for making this decision in the patient’s 
medical records and as a comment on the eCRF. 








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Before dispensing, the site pharmacist or his/her representative must check that the TGR-1202 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 TGR-1202 must be recorded within the eCRF, 
patient’s medical records, and/or in the drug accountability records.  For the purpose of drug 
accountability and dosing subjects should record any missed doses of TGR-1202 on a drug diary.  Any 
error in drug administration should be recorded (e.g., missed dose) in the eCRF. 
The Pharmacist or his/her representative should record the date dispensed and patient’s number 
and initials, as well as complete the accountability record in the electronic drug accountability system 
with information concerning the dispensation of TGR-1202.  
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 one cycle. 
• 
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 v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf) 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. 
A maximum one cycle delay of treatment (28 days) for recovery from toxicity is allowed to recover 
from hematologic toxicities to ≤ Grade 3 or non-hematologic toxicities to ≤ Grade 2 or to baseline 
level.  If greater than a one cycle delay is necessary, then the patient should discontinue treatment 
and continue to be followed for progression.  If a patient withdraws consent or has documented 
progression, an end of study visit should be completed. 
6.3.1 DOSE DELAY/MODIFICATION RECOMMENDATIONS: TGR-1202 
Supportive care should be considered for any patient who experiences Grade ≥ 2 cytopenias, or Grade 
≥ 1 non-hematologic toxicities.  A maximum 28 day (1 cycle) delay for recovery from toxicity is 
allowed to allow recovery of hematologic toxicities to ≤Grade 3 or non-hematologic toxicities to ≤ 
Grade 2 or to baseline level.  If greater than a 28- day delay is necessary, then the patient should 
discontinue treatment and continue to be followed for progression.  If the patient withdraws consent 
or has documented progression, an end of study visit should be completed. 
 
 






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7 STUDY MEDICATIONS OVERVIEW AND SAFETY 
7.1 TGR-1202(UMBRALISIB) 
Chemical Name: 
Umbralisib 
Other Name: 
 
TGR-1202 
Classification:    
Phosphatidylinositol-3-Kinase (PI3K) Delta Inhibitor  
Formulation: 
 
See Investigator Brochure 
 
Mode of Action: 
Irreversibly inhibits activity of the Class I Delta isoform of PI3K 
 
How Supplied:  
TGR-1202: 200 mg tablets 
Storage: 
Store at 25°C.  Excursions permitted 15°C to 30°C. 
Stability: 
Retest dates will be provided periodically by Sponsor. 
Route of  
Administration: 
Oral 
Packaging: 
TGR-1202 is provided in HDPE bottles each containing 30 tablets and a silica 
gel canister as a desiccant.  
Availability: 
 
TGR-1202 is available from TG Therapeutics. 
7.1.1 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) 
The following adverse events were observed in patients treated with single agent TGR-1202 and 
were considered at least possibly related to study medication.  See the TGR-1202 investigator 
brochure for a complete list of all adverse events reported regardless of causality. 
7.1.1.1 COMMON (>20%) 
• 
Gastrointestinal Disorders: Diarrhea, Nausea 
• 
General Disorders and Administration Site Conditions: Fatigue 
 
7.1.1.2 LESS COMMON (≥10% - ≤ 20%) 
• 
Blood and Lymphatic System Disorders: Neutropenia 
• 
Gastrointestinal Disorders: Vomiting 
• 
Metabolism and Nutrition Disorders: Decreased Appetite 
• 
Skin and Subcutaneous Tissue Disorders: Rash 
 
7.1.1.3 UNCOMMON (≥1 - <10%) 
• 
Blood and Lymphatic System Disorders: Anemia, Febrile neutropenia, Leukocytosis, 
Thrombocytopenia 
• 
Eye Disorders: Vision Blurred 


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• 
Gastrointestinal Disorders: Abdominal distension, Abdominal pain, Constipation, Dry 
mouth, Dyspepsia, Colitis 
• 
General Disorders and Administration Site Conditions: Asthenia, Chills, Oedema 
peripheral, Pyrexia 
• 
Infections and infestations Oral candidiasis, Pneumonia, Upper respiratory tract infection 
• 
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, 
Blood creatinine increased, Lymphocyte count increased, Weight decreased 
• 
Metabolism and Nutrition Disorders: Dehydration, Hyperglycemia, Hypokalemia, 
Hypophosphatemia,  
• 
Musculoskeletal and Connection Tissue Disorders: Arthralgia, Muscle spasms, Pain in 
extremity 
• 
Nervous System Disorders: Dizziness, Dysgeusia, Headache, Neuropathy peripheral, 
Tremor 
• 
Psychiatric Disorders: Insomnia 
• 
Respiratory, Thoracic and Mediastinal Disorders: Cough  
• 
Skin and Subcutaneous Tissue Disorders: Alopecia, Night sweats, Pruritus  
 
 
7.1.1.4 EVENTS REPORTED IN LESS THAN 1% OF SUBJECTS 
• 
Blood and Lymphatic System Disorders: Leukopenia, Hyperbilirubinemia, Bacteremia  
• 
Ear and Labyrinth Disorders: Tinnitus  
• 
Eye Disorders: Visual Impairment, Visual acuity reduced   
• 
Gastrointestinal Disorders: Eructation, Flatulence, Gastrooesophageal Reflux Disease, 
Abdominal Pain Upper, Mouth Ulceration, Anal Hemorrhage, Hypoaesthesia Oral, 
Paraesthesia Oral, Pancreatitis  
• 
General Disorders and Administration Site Conditions:  Malaise, Mucosal Inflammation,  
• 
Hepatobiliary Disorders: Hypocalcemia 
• 
Infections and Infestations:  Candida infection, Fungal skin infection, Lung infection, 
Sinusitis 
• 
Investigations: International Normalized Ratio Increase, Blood lactate dehydrogenase 
increase, Blood phosphorus increased, Blood sodium increased, Blood uric acid increased, 
White blood cell count decreased 
• 
Injury, Poisoning and Procedural Complications: Contusion 
• 
Metabolism 
and 
Nutrition 
Disorders: 
Hyperlipidemia, 
Hypertriglyceridemia, 
Hyponatremia 
• 
Musculoskeletal and Connective Tissue Disorders: Muscular Weakness, Myalgia, Pain in 
Jaw  
• 
Nervous System Disorders: Somnolence, Peripheral Sensory Neuropathy, Memory 
Impairment  
• 
Psychiatric Disorders: Anxiety, Libido Decrease, Delirium, Parasomnia 
• 
Reproductive System and Breast Disorders: Erectile Dysfunction 
• 
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Epistaxis, Hypoxia, Influenza, 
Respiratory Failure  
• 
Skin and Subcutaneous Tissue Disorders: Dermatitis, Dermatitis Acneiform,  
• 
Vascular Disorders: Hot Flush 
 


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8 MEASUREMENT OF EFFECT 
During the study period, all patients will be evaluated for response by CT, PET-CT and/or MRI every 
3 cycles.  All baseline assessments to characterize disease will be performed within 30 days of Cycle 
1 Day 1, prior to initiation of therapy.  During the treatment period, all efficacy assessments have a 
+/- 7 day window.  The determination of response and progression will be based on the Response 
Criteria for non-Hodgkin’s lymphoma, Lugano Classification (Cheson et al., 2014) and IWWM-6 
(Owen et al 2013) consensus for respective disease histology. The best clinical response as well as 
disease progression will be determined by the independent central radiology group (ICRG).  The 
findings of the ICRG will be considered primary for analyses of ORR, PFS, and other tumor control 
endpoints.  Patients who discontinue from study treatment (either for toxicity or physician choice) 
and have not progressed will continue to be followed for progression approximately every 6 months 
or per standard of care. 
8.1 METHOD OF ASSESSMENT 
CT scan is the preferred method for radiographic tumor assessment. CT with iodinated IV contrast is 
preferred.  If iodinated contrast is contraindicated, a non-contrast chest CT coupled with a 
gadolinium-enhanced MRI of the abdomen/pelvis is an acceptable substitute.  Contrast-enhanced 
scanning is preferred, but iodine-containing or gadolinium contrast material may be omitted in 
patients for whom use of a contrast agent would be medically contraindicated. Chest x-ray, 
ultrasound, endoscopy, laparoscopy, or tumor markers will not be considered for response 
assessment.  PET-CT may also be used if per standard of care by investigator. 
 
Bone marrow assessment should be used to assess response to therapy if the patient was deemed to 
have disease in the bone marrow prior to initiation of protocol therapy, per standard of care and at 
the discretion of the investigator. 
 
For radiographic evaluations, the same method of assessment and the same technique (e.g., 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. 
8.2 RESPONSE REVIEW 
All responses will be made by local investigator assessment. 
8.3 ANTITUMOR EFFECT  
Assessment of lymphoma response (CR, PR, VGPR or MR) and disease progression will be evaluated 
as outlined in the schedule of events, according to the Response Criteria for non-Hodgkin’s 
lymphoma, Lugano Classification (Cheson et al., 2014) and IWWM-6 consensus (Owen et al 2013) for 
respective disease histology. Overall response rate, CR, PR, VGPR, MR, SD, PFS and DOR will be 
calculated as detailed below.  


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8.4 DEFINITIONS OF TUMOR RESPONSE AND PROGRESSION 
Evaluable for objective response.  Only those patients who have had a pre-treatment baseline 
efficacy evaluation and at least one post-treatment efficacy evaluation will be considered evaluable 
for response.  These patients will have their response classified according to the definitions stated 
below. 
8.4.1 COMPLETE RESPONSE 
Complete response (CR) is defined as the complete disappearance of all evidence of disease and 
disease-related symptoms.  The spleen and/or liver, if considered enlarged before therapy, on the 
basis of physical exam or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should disappear.    
Bone marrow infiltrate cleared on repeat biopsy, if indeterminate by morphology, 
immunohistochemistry should be negative (Cheson et al., 2014 Lugano Classification).   
Previously involved nodes that were 1.1 to 1.5 cm in the long axis and more than 1.0 cm on their short 
axis before treatment must have decreased to ≤ 1.0 cm in their short axis after treatment (Cheson et 
al., 2014 Lugano Classification). 
For Waldenstrom’s macroglobulinemia patients, complete response is defined as disappearance of 
serum monoclonal IgM protein by immunofixation with a normal serum IgM level. The spleen and/or 
liver, if considered enlarged before therapy, on the basis of physical exam or CT scan, should not be 
palpable on physical examination and should be considered normal size by imaging studies, and 
nodules related to WM should disappear. Bone marrow infiltrate cleared on repeat biopsy, if 
indeterminate by morphology, immunohistochemistry should be negative. (Owen et al 2013) 
8.4.2 VERY GOOD PARTIAL RESPONSE 
A response criteria exclusive for Waldenstrom’s macroglobulinemia patients, Very Good Partial 
Response (VGPR) is defined as reduction of Monoclonal IgM protein greater than 90 % from baseline. 
The spleen and/or liver, if considered enlarged before therapy, on the basis of physical exam or CT 
scan, should not be palpable on physical examination and should be considered normal size by 
imaging studies, and nodules related to WM should disappear. (Owen et al 2013) 
8.4.3 PARTIAL RESPONSE 
Partial response (PR) is defined as the regression of measurable disease and no new sites of disease.  
Regression is defined as greater than or equal to 50% decrease in the sum of the products of the 
diameters (SPD) of the index lesions, coupled with no unequivocal increase in size of other lymph 
nodes, liver or spleen.    No new sites of disease should be observed.  If bone marrow was involved 
prior to therapy and a clinical CR was achieved but no bone marrow assessment is completed after 
treatment, then these patients are considered partial responders (Cheson et al., 2014 Lugano 
Classification). 
For Waldenstrom’s macroglobulinemia patients, partial response is defined as reduction of 
Monoclonal IgM protein between 50-90 % from baseline with regression of measurable disease. 
Regression is defined as greater than or equal to 50% decrease in the sum of the products of the 


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diameters (SPD) of the index lesions, coupled with no unequivocal increase in size of other lymph 
nodes, liver or spleen.    No new sites of disease should be observed. (Owen et al 2013) 
8.4.4 MINOR RESPONSE 
A response criteria exclusive for Waldenstrom’s macroglobulinemia patients, Minor Response (MR) 
is defined as presence of detectable Monoclonal IgM protein with reduction of monoclonal IgM 
protein greater than 25 % but less than 50 % from baseline. No new sites of disease should be 
observed. (Owen et al 2013) 
8.4.5 STABLE DISEASE 
Stable disease is defined as the failure to attain CR/PR but does not fulfill the criteria for progressive 
disease.  For those with disease evaluated by CT only, there must be no unequivocal change in the 
size of the previous lesions on the post-treatment CT scan (Cheson et al., 2014 Lugano Classification) 
For Waldenstrom’s macroglobulinemia patients, stable disease is defined as presence of detectable 
Monoclonal IgM protein with less than 25% reduction and less than 25% increase in serum IgM level 
from baseline. No unequivocal increase in size of other lymph nodes, liver or spleen. No new sites of 
disease should be observed. (Owen et al 2013) 
8.4.6 RELAPSED DISEASE OR PROGRESSION OF DISEASE 
 
Any of the following conditions will constitute relapsed or progressive disease: 
Appearance of any new lesion more than 1.5 cm in any axis, even if other lesions are decreasing in 
size will be considered relapsed or progressive disease.  Increase in FDG uptake in a previously 
unaffected site should be confirmed with other modalities, a therapeutic decision should not be made 
solely on the basis of PET without histologic confirmation (Cheson et al., 2014 Lugano Classification). 
There is at least a 50% increase from nadir in one of the following:  
• 
The SPD of index lesions,  
• 
The greatest transverse diameter (GTD) of any individual previously involved node, or  
• 
The GTD of any previously involved node provided that the GTD of that node is now ≥ 1.5 cm. 
(Cheson et al., 2014 Lugano Classification). 
For Waldenstrom’s macroglobulinemia patients, progressive disease is defined as more than 25% 
increase in serum IgM level from lowest nadir and/or progression in clinical features attributable the 
disease. (Owen et al 2013) 
8.5 DEFINITIONS OF DISEASE PARAMETERS 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in at 
least two dimensions with conventional techniques (CT, PET/CT, MRI, x-ray) and meet one of the 
following criteria: nodal lesion with a long axis > 1.5 cm regardless of short axis, nodal lesion with 


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long and short axes > 1.0 cm, or extra-nodal lesions with long and short axes > 1.0 cm with spiral CT 
scan.  All tumor measurements should be recorded in centimeters.   
Non-measurable disease (evaluable disease):  All other lesions (or sites of disease) including 
small lesions, (< 1.0 cm using spiral CT scan) are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis, and cystic lesions are all 
non-measurable.   
Index lesions:  All measurable lesions up to a maximum of 6 nodal and extra-nodal lesions total, 
representative of all involved organs, should be identified as index lesions and recorded and 
measured at baseline. For patients with splenic marginal zone lymphoma without lymphadenopathy, 
the spleen size should be used as an index lesion. Index lesions should be selected on the basis of 
their size (clearly measurable in two perpendicular dimensions) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  A baseline sum of product of 
the diameters (SPD) for all index lesions will be calculated and reported as the baseline SPD.  The 
baseline SPD will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.  
 
Non-index lesions:  All other lesions (or sites of disease) including any measurable lesions over and 
above the 6 index lesions should be identified as non-index lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
8.6  
EVALUATION OF BEST OVERALL RESPONSE 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria as per the NHL established criteria used 
in this study (See Appendix A). 
8.6.1 DURATION OF RESPONSE 
Duration of response is defined as the time from documentation of a response to treatment to the 
first documentation of tumor progression or death due to any cause, whichever comes first.  Duration 
of the response will be summarized using n (sample size), mean, standard deviation, median, 
minimum, and maximum for the responders. 
Duration of stable disease: 
Stable disease is measured from the start of the treatment (Cycle 1/Day1) until the criteria for 
progression are met. 
Progression-Free Survival: 
Progression free survival (PFS) is defined as the time from Cycle 1/Day1 to the first documentation 
of tumor progression or death due to any cause, whichever comes first.  This variable will be analyzed 
via Kaplan-Meier methodology.  The median PFS will be estimated. 


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9 STATISTICAL CONSIDERATIONS 
The sections of the Statistical Considerations describe the statistical methods to be used to analyze 
the efficacy and safety. These methods may be revised and updated due to reasons such as regulatory 
requirements or need for further clarifications. The final analysis plan will be documented in a formal 
statistical analysis plan (SAP) that must be finalized before database lock. The SAP will include details 
on how variables will be derived, how missing data will be handled, and how censoring procedures 
will be applied to time to event related variables as well as the details on statistical methods to be 
used for safety and efficacy analyses. The final clinical study report will discuss deviations from the 
SAP, if any. 
9.1 SAMPLE SIZE AND POWER 
 
 
 
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. 
Summary tabulations will display the number of observations, mean, standard deviation, median, 
minimum, maximum, and appropriate percentiles for continuous variables, and the number and 
percentage by category for categorical data. Summaries will present data by treatment arm and 
overall, if appropriate.  The data listings will include all available efficacy and safety data. 
In general, safety and efficacy data will be presented by histology type and overall. 
9.3 ANALYSIS POPULATIONS 
The safety population will include all enrolled patients who have received at least one dose of study 
treatment.  The safety analyses will be based on this safety population. 
The modified Intent-to-Treat (mITT) population will consist of all safety patient who have provided 
at least some post baseline efficacy assessments.  The efficacy analyses will be based on this mITT 
population. 
9.4 PATIENT DISPOSITION 
Patient disposition summaries will be presented by histology type and overall and will include the 
number of patients enrolled and the number and percentage of enrolled patients in the mITT and 
safety populations.  The summaries will also include the reasons for permanent discontinuation of 
study treatment and study.   


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9.5 PATIENT DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline demographic and clinical characteristics will be summarized as percentages for categorical 
variables and as mean, standard deviation, median, minimum and maximum for continuous 
measures.  The analyses of baseline characteristics will be performed for the mITT Population.   
9.6 MEDICAL HISTORY 
Medical history will be captured at the Screening visit.  Medical history will be coded using MedDRA 
and will be summarized by MedDRA system organ class and preferred term for the Safety population. 
9.7 EXTENT OF EXPOSURE 
The dose (mg) of study drugs administered, the total number of doses of study drugs, and the 
duration of treatment (number of study cycles) will be summarized with descriptive statistics.  The 
number and percentage of patients whose dose is modified at any time will be summarized by each 
type of modification by cycle and overall.  The proportion of patients completing each cycle of 
treatment will be summarized. 
9.8 EFFICACY ANALYSES   
Each patient will be assigned to one of the following categories:  1) complete response, 2) partial 
response, 3) very good partial response, 4) minor response, 5) stable disease, 6) progressive disease, 
7) early death from malignant disease, 8) early death from toxicity, 9) early death because of other 
cause, or 10) 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 an independent central radiology group (ICRG) 
which will be blinded to treatment arm assignment.  Definitive disease progression will be based on 
standard criteria (Cheson, B 2014 Lugano Classification; Appendix A –Criteria for Response 
Assessment and Owen et al 2013 Appendix B). 
9.9 MISSING VALUE HANDLING PROCEDURES   
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing.  The algorithms for imputation of partial dates vary depending upon the parameter and are 
presented in the Statistical Analysis Plan.   
9.10 STATISTICAL ANALYSES   
9.10.1 PRIMARY EFFICACY VARIABLE 
The primary efficacy outcome is Overall Response Rate (ORR).  The ORR is defined as percent of 
patients who achieve CR or PR for MZL histology type patients and is defined as percent of patients 


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who achieve CR, VGPR, PR or MR for WM histology type patients.  The estimated response rates as 
well as the two-sided 95% confidence interval of the response rate will be presented.   
9.10.2 EFFICACY VARIABLE 
The secondary efficacy variable will include: 
• 
Complete Response (CR) rate; 
• 
Progression free survival (PFS); 
• 
Duration of response (DOR); 
• 
Time to Treatment Failure (TTF). 
These variables will be analyzed as appropriate. 
9.11 MULTIPLE COMPARISON PROCEDURES   
The study is a single treatment arm study.  No formal claims will be made.   
9.12 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.   Exposure to study treatment 
and reasons for discontinuation of study treatment will also be tabulated. 
9.13 ADVERSE EVENT CHARACTERISTICS 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy 
of 
the 
CTCAE 
version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.     
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only. 
Expected AEs are defined as those described in the TGR-1202(umbralisib) Investigator Brochure.  
Please refer to prescribing information for a listing of expected AEs. 
9.14 DEFINITIONS OF ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product. An AE does not necessarily have to have a causal 
relationship with this treatment.  An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporarily associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition. 


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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. 
9.15 ADVERSE EVENTS (AE’S) AND TREATMENT EMERGENT ADVERSE EVENTS 
(TEAE’S) 
All AEs and SAEs occurring on study will be listed by patient.  The frequency and percentages of 
patients with treatment-emergent adverse events (TEAEs) will be tabulated by system organ class 
(SOC) and preferred term (PT), where treatment-emergent is defined as any AE that: 
• 
Occurs after first dosing of study medication and through the end of the study or up through 
30 days after the last dose of study treatment, or 
• 
Is considered treatment-related regardless of the start date of the event, or  
• 
Is present before first dosing of study medication but worsens in intensity or the investigator 
subsequently considers treatment-related.  
 
TEAEs that are considered at least possibly related to study treatment will be tabulated as well as 
deaths, SAEs, and events resulting in treatment discontinuation. 
AEs that occur after informed consent but before first dosing of study medication will not be 
summarized but will be listed.   
At each level of summarization, a patient will be counted only once for each AE, SOC, or PT 
experienced within that level.  In the summation for AE severity, within each level of AE, SOC, or PT 
experienced, the one with the highest severity will be included.  In the summation for AE’s 
relationship to the study drug, within each level of AE, SOC, or PT experienced, the one with the 
closest relationship to the study drug will be included. 
9.16 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. 


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• 
Possible: There is still a reasonable possibility that the cause of the event was the study 
drug(s) but there exists a more likely cause of the event such as complications of progressive 
disease. 
• 
Probable: The most likely cause of the event is the study drug(s) but other causes cannot be 
completely excluded. 
• 
Definite: Clear cut temporal and/or mechanistic relation to the study drug(s).  All other 
causes have been eliminated.  Events classified as definite will often be confirmed by 
documenting resolution on discontinuation of the study drug and recurrence upon 
resumption. 
9.16.1 RECORDING OF ADVERSE EVENTS 
All adverse events of any patient during the course of the study will be reported on the case report 
form, and the investigator will give his or her opinion as to the relationship of the adverse event to 
study drug treatment (i.e., whether the event is related or unrelated to study drug administration –
TGR-1202).  If the adverse event is serious, it should be reported as soon as possible and no greater 
than 24 hours to the sponsor or designee.  Other untoward events occurring in the framework of a 
clinical study are also to be recorded as AEs (i.e., AEs that occur prior to assignment of study 
treatment that are related to a protocol-mandated intervention, including invasive procedures such 
as biopsies, medication washout, or no treatment run-in). 
All AEs regardless of seriousness or relationship to study drug treatment spanning from Cycle 1/Day 
1 until 30 calendar days after discontinuation or completion of protocol-specific treatment as defined 
by the protocol for that patient, are to be recorded on the eCRF. 
9.16.2 ABNORMAL LABORATORY VALUES AND VITAL SIGNS 
The reporting of abnormalities of vital signs as adverse events should be avoided.  Abnormalities of 
vital signs should not be reported unless any criterion for an SAE is fulfilled, the vital signs 
abnormalities cause the patient to discontinue study treatment, or the investigator insists that the 
abnormality should be reported as an AE.  Abnormal laboratory results should be noted in the eCRF 
as an adverse event if they are associated with an overdose, require or prolong inpatient 
hospitalization, or are otherwise considered clinically significant by the investigator. If an abnormal 
laboratory value or vital sign is associated with clinical signs and/or symptoms, the sign or symptom 
should be reported as an AE, and the associated laboratory value or vital sign should be considered 
additional information that must be collected in the relevant eCRF.  If the laboratory abnormality is 
a sign of a disease or syndrome, only the diagnosis needs to be recorded on the SAE Report Form or 
AE eCRF. 
Clinical Laboratory Results will be summarized.  Summary statistics for actual values and for changes 
from baseline will be tabulated for laboratory results by scheduled visit.  Patients with laboratory 
values outside of the normal reference range at any post-baseline assessment will be summarized, 
and graded per NCI CTCAE Version 4.0 when applicable.  Patient incidence of abnormal laboratory 
results will be summarized by treatment group and maximum grade for each abnormal laboratory 
finding. 
 


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9.16.3 HANDLING OF ADVERSE EVENTS 
All adverse events resulting in discontinuation from the study should be followed until resolution or 
stabilization.  Patients should be followed for AEs for 30 calendar days after discontinuation or 
completion of protocol-specific.  All new AEs occurring during this period must be reported and 
followed until resolution unless, in the opinion of the investigator, these values are not likely to 
improve because of the underlying disease.  In this case, the investigators must record his or her 
reasoning for this decision in the patient’s medical record and as a comment on the eCRF.  After 30 
days, only AEs, SAEs, or deaths assessed by the investigator as treatment related are to be reported. 
9.17 SERIOUS ADVERSE EVENTS 
9.17.1 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 IWG Cheson et al. 2014, should not be reported as a serious adverse event.   
A suspected unexpected serious adverse reaction (SUSAR) is defined as an SAE that is suspected to 
be at least possibly related to study medication(s) and is an unexpected event. SUSAR reporting is 
encompassed within SAE reporting guidelines as defined in this section. 
Treatment within or admission to the following facilities is not considered to meet the criteria of “in-
patient hospitalization” (although if any other SAE criteria are met, the event must still be treated as 
an SAE and immediately reported): 
• 
Emergency Department or Emergency Room 
• 
Outpatient or same-day surgery units 


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• 
Observation or short-stay unit 
• 
Rehabilitation facility 
• 
Hospice or skilled nursing facility 
• 
Nursing homes, Custodial care or Respite care facility 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as a serious adverse event to the 
Sponsor. 
9.17.2 SERIOUS ADVERSE EVENT REPORTING BY INVESTIGATORS 
It is important to distinguish between “serious” and “severe” adverse events, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke, but would be 
considered an SAE.  Severity and seriousness should be independently assessed when recording AEs 
and SAEs on the eCRF. 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to the Sponsor in order to comply with regulatory requirements.  Serious adverse events 
may occur at any time from the signing of the informed consent form through the 30-day follow-up 
period after the last study treatment.  Sponsor or designee should be notified of all SAEs, regardless 
of causality, within 24 hours of the first knowledge of the event by the treating physician or research 
personnel.   
To report an SAE, see the appropriate form. 
All SAEs (regardless of causality assessment) occurring on study or within 30 days of last study 
treatment should be immediately reported to the sponsor as SAEs within the CRF and followed until 
resolution (with autopsy report if applicable). 
NHL progression or death due to NHL progression should be reported by the investigator as a serious 
adverse event only if it is assessed that the study drugs caused or contributed to the NHL progression 
(i.e. by a means other than lack of effect).  Unrelated events of NHL progression should be captured 
on the appropriate eCRF. 
The investigator must review and sign off on the SAE data on the SAE report.  The SAE should be 
reported to the Sponsor (or Sponsor designee).   
When an SAE is reported to the sponsor or designee, the same information should be entered on the 
eCRF within 24 hours (1 business day).  Transmission of the SAE report should be confirmed by the 
site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should also 
be reported to the sponsor or designee as soon as it is available; these reports should be submitted 
using the appropriate SAE form.  The detailed SAE reporting process will be provided to the sites in 
the Safety Monitoring Plan. 


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Investigators must report SAEs and follow-up information to their responsible Institutional Review 
Board (IRBs)/Independent Ethics Committee according to the policies of the responsible IRB 
(Research Ethics Committee). 
9.18  SPONSOR SAE REPORTING REQUIREMENTS 
Sponsor is responsible for reporting relevant SAEs to the competent authority, other applicable 
regulatory authorities, and participating investigators, in accordance with ICH guidelines, FDA 
regulations, and/or local regulatory requirements. 
Sponsor is responsible for reporting unexpected fatal or life-threatening events associated with the 
use of the study drugs to the regulatory agencies and competent authorities within 7 calendar days 
after being notified of the event.  The Sponsor will report all related but unexpected SAEs including 
non-death/non-life-threatening related but unexpected SAEs (SUSAR) associated with the use of the 
study medications to the regulatory agencies and competent authorities by a written safety report 
within 15 calendar days of notification.  Following the submission to the regulatory agencies and 
competent authorities, Investigators and trial sites will be notified of the SUSAR.  Investigators must 
report SUSARs and follow-up information to their responsible Institutional Review Board 
(IRBs)/Independent Ethics Committee according to the policies of the responsible IRB (Research 
Ethics Committee). 
9.19 RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on the 
SAE Report Forms and AE eCRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE eCRF; AEs 
that meet the definition of an SAE should additionally be reported. 
9.20 DIAGNOSIS VS. SIGNS AND SYMPTOMS 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the opinion 
of the Principal Investigator or designated physician, the AEs constitute components of a recognized 
condition, disease, or syndrome.  In the latter case, the condition, disease, or syndrome should be 
named rather than each individual sign or symptom.  If a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an AE or SAE as appropriate on the relevant form(s) (SAE 
Report Form and/or AE eCRF).  If a diagnosis is subsequently established, it should be reported as 
follow-up information is available.  If a diagnosis is determined subsequent to the reporting of the 
constellation of symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
9.20.1 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between patient evaluation time 
points.  Such events should only be recorded once on the SAE Report Form and/or the AE eCRF.    If 
a persistent AE becomes more severe (changes from a Grade 1 or 2 AE to a Grade 3 or 4 AE) or lessens 


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in severity (changes from a Grade 3 or 4 AE to a Grade 1 or 2 AE), it should be recorded on a separate 
SAE Report Form and/or AE eCRF.   
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE eCRF 
for each recurrence. 
9.20.2 ABNORMAL LABORATORY VALUES 
Abnormal laboratory results should be noted in the eCRF as an adverse event if they are associated 
with an overdose, require or prolong inpatient hospitalization, or are otherwise considered clinically 
significant by the investigator. If an abnormal laboratory value or vital sign is associated with clinical 
signs and/or symptoms, the sign or symptom should be reported as an AE, and the associated 
laboratory value or vital sign should be considered additional information that must be collected in 
the relevant eCRF.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form or AE eCRF. 
9.20.3 DEATHS 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of the patient’s NHL for up to 30 days post the last dose of study 
drug will be recorded on the appropriate study eCRF and reported on the Adverse Event page of the 
eCRF, i.e. are exempted from expedited reporting. All other on-study deaths, regardless of attribution, 
will be recorded on an SAE Report Form and expeditiously reported to the Sponsor. 
When recording a serious adverse event with an outcome of death, the event or condition that caused 
or contributed to the fatal outcome should be recorded as the single medical concept on the Adverse 
Event page of the eCRF.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, record “Death NOS” on the eCRF Adverse Event page. 
9.20.4 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 9.17.1.   
9.20.5 PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing relevant medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the study’s appropriate medical history eCRF.  A pre-existing 
medical condition should be recorded as an AE or SAE only if the frequency, severity, or character of 
the condition worsens during the study.  When recording such events on the appropriate SAE Report 
Form and/or AE eCRF, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
 


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


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


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• 
Patient number increase of more than 20% 
• 
Addition or removal of tests and/or procedures  
• 
Addition/removal of a new Investigator  
It should be further noted that, if an amendment to the protocol substantially alters the study design 
or the potential risks to the patients, their consent to continue participation in the study should be 
obtained. 
10.3 CURRICULA VITAE AND FINANCIAL DISCLOSURES 
All Principal Investigators will be required to submit to the Sponsor or its designee an up-to-date 
signed curriculum vitae (CV), current within two years, a current copy of their medical license, and a 
completed FDA form 1572 and financial disclosure statement.  In addition, all sub-investigators will 
be required to submit to the Sponsor or its designee an up-to-date signed CV, current within two 
years, a current copy of their medical license, and a completed financial disclosure statement. 
10.4 DATA OWNERSHIP AND PUBLICATION 
By conducting this study, the Investigator affirms to Sponsor that he or she will maintain, in strict 
confidence, information furnished by the Sponsor including data generated from this study and 
preliminary laboratory results, except as exempted for regulatory purposes.  
All data generated during the conduct of this study is owned by the Sponsor and may not be used by 
the Investigator or affiliates without the expressed written consent of the Sponsor. 
All manuscripts, abstracts, or other presentation materials generated by site investigators must be 
reviewed and approved by the Sponsor prior to submission. 


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11 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).  
11.1 IRB APPROVAL 
The study protocol, ICF, IB, available safety information, patient documents (e.g., study diary), patient 
recruitment procedures (e.g., advertisements), information about payments (i.e., PI payments) and 
compensation available to the patients and documentation evidencing the PI’s qualifications must be 
submitted to the IRB for ethical review and approval prior to the study start.   
The PI/Sponsor and/or designee will follow all necessary regulations to ensure initial and ongoing, 
IRB study review. The PI/Sponsor (as appropriate) must submit and, where necessary, obtain 
approval from the IRB for all subsequent protocol amendments and changes to the informed consent 
document.  Investigators will be advised by the sponsor or designee whether an amendment is 
considered substantial or non-substantial and whether it requires submission for approval or 
notification only to an IRB. 
If applicable, the PI will notify the IRB within 90 days of the end of the study, or if the study 
terminates early, the PI must notify the IRB within 15 days of the termination.  A reason for the early 
termination must be provided (as defined in Directive 2001/20/EC). The Sponsor will either prepare 
or review all submission documents prior to submission to the IRB. 
11.2 REGULATORY APPROVAL 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and approval 
of the appropriate regulatory bodies obtained, prior to study initiation. If required, the Sponsor will 
also ensure that the implementation of substantial amendment to the protocol and other relevant 
study documents happen only after approval by the relevant regulatory authorities. 
Safety updates for TGR-1202 (umbralisib) will be prepared by the Sponsor or its representative as 
required, for submission to the relevant regulatory authority.   Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI or site and the Sponsor. 
11.3 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.  Each consent form must include all of the relevant elements currently required by the 


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responsible regulatory authority, as well as local county authority or state regulations and national 
requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the study.  Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications of 
participating in this study, the candidate will be asked to give consent to participate in the study by 
signing an informed consent form.  A notation that written informed consent has been obtained will 
be made in the patient’s medical record.  A copy of the informed consent form, to include the patient’s 
signature, will be provided by the investigator to the patient.   
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study must be obtained. 
11.4 CONFIDENTIALITY 
Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), and national data protection laws. HIPAA 
regulations require that, in order to participate in the study, a patient must sign an authorization 
from the study that he or she has been informed of following: 
• 
What protected health information (PHI) will be collected from patients in this study; 
• 
Who will have access to that information and why; 
• 
Who will use or disclose that information;  
• 
That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal or 
state privacy laws;  
• 
The information collected about the research study will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the 
conclusion of the study; 
• 
Whether the authorization contains an expiration date; and 
• 
The rights of a research patient to revoke his or her authorization.  
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should be 
made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the end of 
their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that the 
investigator and institution permit authorized representatives of the Sponsor, the regulatory 
authorities and the IRB direct access to review the patient’s original medical records at the site for 
verification of study-related procedures and data.  


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Measures to protect confidentiality include: only a unique study number and initials will identify 
patients on the eCRF or other documents submitted to the Sponsor. This information, together with 
the patient’s date of birth, will be used in the database for patient identification. Patient names or 
addresses will not be entered in the eCRF or database. No material bearing a patient’s name will be 
kept on file by the Sponsor. Patients will be informed of their rights within the ICF. 
11.5 INVESTIGATOR AND STAFF INFORMATION 
Personal data of the investigators and sub-investigators may be included in the Sponsor database, 
and shall be treated in compliance with all applicable laws and regulations.  When archiving or 
processing personal data pertaining to the investigator or sub-investigator, the Sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized party. 
11.6 FINANCIAL INFORMATION  
The finances for this study will be patient to a separate written agreement between the Sponsor and 
applicable parties.  Any Investigator financial disclosures as applicable to 21CFR Part 54 shall be 
appropriately provided. 


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


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The PI and study staff are responsible for maintaining a comprehensive and centralized filing system 
(Site Study File/SSF or ISF) of all study-related (essential) documentation, suitable for inspection at 
any time by representatives from the Sponsor and/or applicable regulatory authorities.  The ISF/SSF 
must consist of those documents that individually or collectively permit evaluation of the conduct of 
the study and the quality of the data produced.  The ISF/SSF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 13 and 21 CFR Part 312.57, including 
key documents such as the IB and any amendments, protocol and any amendments, signed ICFs, IRB 
approval documents, Financial Disclosure forms, patient identification lists, enrollment logs, 
delegation of authority log, staff qualification documents, laboratory normal ranges, records relating 
to the study drug including accountability records.  Drug accountability records should, at a 
minimum, contain information regarding receipt, shipment, and disposition.  Each form of drug 
accountability record, at a minimum, should contain PI name, date drug shipped/received, date, 
quantity and batch/code, or lot number for identity of each shipment.  In addition, all original source 
documents supporting entries in the eCRF must be maintained and be readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest records 
as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing application 
has been approved by FDA; or, in the event that the marketing application has not been approved by 
FDA, for no less than 2 years after the last shipment / delivery of the drug for investigational use is 
discontinued and FDA has been notified of the discontinuation. 
The IRB shall maintain adequate documentation / records of IRB activities as per 21CFR Part 56.115 
for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not been 
approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., medical records), all original, signed 
informed consent forms, and copies of all eCRFs, SAE Reporting forms, source documents, detailed 
records of treatment disposition, and related essential regulatory documents.  The documents listed 
above must be retained by the investigator for as long as needed to comply with national and 
international regulations (generally 2 years after discontinuing clinical development or after the last 
marketing approval).  The Sponsor or its representative will notify the investigator(s)/institutions(s) 
when the study-related records are no longer required.   
If the investigator relocates, retires, or for any reason withdraws from the study, either the Sponsor 
or its representative should be prospectively notified.  The study records must be transferred to an 
acceptable designee, such as another investigator, another institution, or to sponsor.  The 
investigator must obtain the sponsor written permission before disposing of any records, even if 
retention requirements have been met.  All study files will be maintained by the Sponsor or its 
representative throughout the study, and will be transferred to the Sponsor at the conclusion of the 
study. 


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12.3 DATA COLLECTION 
The study eCRF is the primary data collection instrument for the study. An electronic case report 
form will be utilized for the collection of all data and all data will be entered using the English 
language and should be kept current to enable the monitor to review the patients’ status throughout 
the course of the study. 
In order to maintain confidentiality, only study number, patient number, initials and date of birth will 
identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g. laboratory 
report), it must be obliterated on the copy of the document to be supplied to the investigator site and 
replaced instead with the patient number and patient’s initials.  The investigator will maintain a 
personal patient identification list (patient numbers with corresponding patient identifiers) to 
enable records to be identified and verified as authentic. Patient data/information will be kept 
confidential, and will be managed according to applicable local, state, and federal regulations. 
12.4 STUDY MONITORING, AUDITING, AND INSPECTING 
The investigator will permit study-related monitoring, quality audits, and inspections by government 
regulatory authorities, the Sponsor or its representative(s) of all study-related documents (e.g., 
source documents, regulatory documents, data collection instruments, case report forms).  The 
investigator will ensure the capability for inspections of applicable study-related facilities.  The 
investigator will ensure that the study monitor or any other compliance or QA reviewer is given 
access to all study-related documents and study-related facilities.   
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities and the sponsor or its representative(s).  
At the Sponsor’s discretion, Source Document Verification (SDV) may be performed on all data items 
or a percentage thereof. 
12.5 QUALITY ASSURANCE AND QUALITY CONTROL 
In addition to the Clinical Monitoring component of this protocol, the Sponsor’s Quality Assurance 
(QA) department shall establish an Auditing Plan document separate from the protocol to establish 
the criteria by which independent auditing shall be conducted during the conduct of the study to 
assess compliance with GCP and applicable regulatory requirements.  Data or documentation audited 
shall be assessed for compliance to the protocol, accuracy in relation to source documents and 
compliance to applicable regulations. 
Each study site shall be required to have Standard Operating Procedures (SOP’s) to define and ensure 
quality assurance/control processes for study conduct, data generation & collection, recording of 
data/documentation and reporting according to the protocol, GCP and any applicable local, national 
or international regulations. 
Accurate and reliable data collection will be ensured by verification and cross check of the eCRFs 
against the investigator’s records by the study monitor (source document verification) and by the 
maintenance of a drug–dispensing log by the investigator.  Collected data will be entered into a 
computer database and subject to electronic and manual quality assurance procedures. 


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12.6 DISCLOSURE AND PUBLICATION POLICY 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right to 
release literature publications based on the results of the study. 
A clinical study report will be prepared upon completion of the study.  The Sponsor will disclose the 
study results, in the form of a clinical study report synopsis, to the IEC and the applicable regulatory 
authorities within one year of the end of the study.  The format of this synopsis and that of the clinical 
study report and its addendum will comply with ICH E3 guidelines for structure and content of a 
clinical study report. 
The financial disclosure information will be provided to the Sponsor prior to study participation from 
all PIs and Sub-Investigators who are involved in the study and named on the FDA 1572 form. 
By conducting this study, the Investigator affirms to the Sponsor that he or she will maintain, in strict 
confidence, information furnished by the Sponsor including data generated from this study and 
preliminary laboratory results, except as exempted for regulatory purposes.  
All data generated during the conduct of this study is owned by the Sponsor and may not be used by 
the Investigator or affiliates without the expressed written consent of the Sponsor. 
All manuscripts, abstracts, or other presentation materials generated by site investigators must be 
reviewed and approved by the Sponsor prior to submission. 


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13 REFERENCES 
Cheson, B. D., Pfistner, B., Juweid, M. E., Gascoyne, R. D., Specht, L., Horning, S. J., . . . Diehl, V. (2007). Revised 
response criteria for malignant lymphoma. Journal of Clinical Oncology, 25(5), 579-586. doi: 
10.1200/JCO.2006.09.2403 
Cheson, B.C., Fisher, R.I., Barrington, S.F., Cavalli, F., Schwartz, L.H., Zucca, E., Lister, T.A. (2014). 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and Non-
hodgkin lymphoma: The Lugano classification. Journal of Clinical Oncology, 32, (1-10). doi: 
10.1200/JCO.2013.54.8900 
de Romeuf C, D. C., Le Garff-Tavernier M, Fournier N, Gaucher C, Glacet A, Jorieux S, Bihoreau N, Behrens CK, 
Beliard R, Vieillard V, Cazin B, Bourel D, Prost JF, Teillaud JC, Merle-Beral H. (2008). Chronic 
lymphocytic leukaemia cells are effeciently killed by an anti-CD20 monoclonal antibody selected for 
improved engagement of FcgammaRIIIA/CD16. British Journal of Haematology, 6(140), 635-643.  
Esteves IT, D. C., Herveau S, Reslan L, Brune F, Van Overtvelt L, Salcedo M, Fournes B. (2011). LFB-R603 
(ublituximab), a third-generation monoclonal anti-CD20 antibody, displays additive antitumor activity 
with antileukemic chemotherpeutic agents in mouse xenograft models. American Society of 
Hematology, abstract 1660.  
Friedberg, J. W. (2011). Relapsed/Refractory diffuse large b-cell lymphoma. Hematology, 498-505.  
Genentech. (2014). Rituxan® prescribing information. 
Lunning, M. A., Vose, J. M., Schreeder, M. T., Fowler, N., Nastoupil, L., Siddiqi, T., . . . O'Brien, S. (2014). 
Ublituximab, a novel glycoengineered anti-CD20 mAb, in combination with TGR-1202, a next generation 
once daily PI3Kdelta inhibitor, demonstrates activity in heavily pre-treated and high-risk chronic 
lymphocytic leukemia and B-cell lymphoma. Paper presented at the American Society of Hematology, 
San Francisco, CA. 
NCCN. (2015). NCCN guidelines: Non-Hodgkin's Lymphomas (Vol. Version 2.2015). 
O'Connor, O. A., Schreeder, M. T., Deng, C., Amengual, J. E., Boccia, R., Khalil, M. Y., . . . Farber, C. M. (2014). 
Ublituximab (TG-1101), a novel anti-cd20 monoclonal antibody for rituximab relapsed/refractory B-cell 
malignancies. Paper presented at the European Hematology Association, Milan, Italy. 


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 (2011). PI3Kgamma enzyme assay. Shameerpet, India: Incozen Therapeutics. 
Rosenwald, A., Wright, G., Chan, W. c., Connors, J. M., Campo, E., Fisher, R. I., . . . Staudt, L. M. (2002). The use of 
molecular profiling to predict survival after chemotherapy for diffuse large-b-cell lymphoma. New 
England Journal of Medicine, 346(25), 1937-1947.  
 (2011a). AKT phosphorylation in MOLT-4 cells. June Study Report IVT-5264-APM-10. Shameerpet, 
India: Incozen Therapeuticis PVT Ltd. 
 (2011b). AKT phosphorylation in THP-1 cells. Study Report IVT-5264-ATP-08. Shameerpet, India: 
Incozen Therapeuticis PVT Ltd. 
Therapeutics, T. (2014). Ublituximab (TG-1101) Investigator's Brochure (Vol. Version 3.0). 
Owen, R. G. et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: Consensus Panel 
Recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. 
Seminars in Oncology 30, 110–115 (2003). 
.Owen, R. G., et al Response assessment in Waldenström macroglobulinaemia: update from the VIth 
International Workshop. Br J Haematol, 160: 171–176. doi:10.1111/bjh.12102 (2013)  
 
 


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14 APPENDIX A –CRITERIA FOR RESPONSE ASSESSMENT 
Revised Response Criteria for Non- Hodgkin’s Lymphoma (Cheson et. al. 2014 Lugano 
Classification) 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete Response 
 
 
Lymph nodes and extra-
lymphatic sites 
 
Score 1, 2, or 3* with or without a 
residual mass on 5PS† 
It is recognized that in Waldeyer's 
ring or extra-nodal sites with high 
physiologic 
uptake 
or 
with 
activation within spleen or marrow 
(eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake 
may 
be 
greater 
than 
normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic 
response may be inferred if uptake 
at sites of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
No extra-lymphatic sites of disease 
Non- measured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal 
by 
morphology; 
if 
indeterminate, IHC negative 
Partial Response 
 
 
Lymph nodes and extra-
lymphatic sites 
Score 4 or 5† with reduced uptake 
compared 
with 
baseline 
and 
residual mass(es) of any size 
At interim, these findings suggest 
responding disease 
At end of treatment, these findings 
indicate residual disease 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and extra-
nodal sites 
When a lesion is too small to measure 
on CT, assign 5 mm × 5 mm as the 
default value 
When no longer visible, 0 × 0 mm 


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For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Non- measured lesion 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 
50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes 
from 
chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in the 
context 
of 
a 
nodal 
response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan 
Not applicable 
No response or stable 
disease 
 
 
Target nodes/nodal masses, 
extra-nodal lesions 
Score 4 or 5 with no significant 
change in FDG uptake from baseline 
at interim or end of treatment 
< 50% decrease from baseline in SPD 
of up to 6 dominant, measurable 
nodes and extra-nodal sites; no 
criteria for progressive disease are 
met 
Non-measured lesions 
Not applicable 
No 
increase 
consistent 
with 
progression 
Organ enlargement 
Not applicable 
No 
increase 
consistent 
with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
 
 
Individual target 
nodes/nodal masses, Extra-
nodal lesions 
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or  new FDG-avid foci 
consistent with lymphoma at 
PPD Progression: 
An individual node/lesion must be 
abnormal with: 
- LDi > 1.5 cm  
- Increase by ≥ 50% from PPD nadir. 


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Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance 
imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular 
diameters for multiple lesions.*A score of 3 in many patients indicates a good prognosis with 
standard treatment, especially if at the time of an interim scan. However, in trials involving PET 
where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant 
nodes, nodal masses, and extra-nodal lesions selected to be clearly measurable in two diameters. 
Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, 
spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Non-
measured lesions: Any disease not selected as measured, dominant disease and truly assessable 
disease should be considered not measured. These sites include any nodes, nodal masses, and extra-
nodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site 
of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions 
that cannot be confirmed and followed by imaging. In Waldeyer's ring or in extra-nodal sites (eg, GI 
interim or end-of-treatment 
assessment 
An increase in LDi or SDi from nadir 
- 0.5 cm for lesions ≤ 2 cm 
- 1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 
50% of the extent of its prior 
increase beyond baseline (eg, a 15-
cm spleen must increase to > 16 cm). 
If no prior splenomegaly, must 
increase by at least 2 cm from 
baseline. 
New or recurrent splenomegaly. 
Non-measured lesions 
None 
New or clear progression of 
preexisting non-measured lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (eg, infection, 
inflammation). If uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extra-nodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 


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tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 
metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, with 
marrow activation as a result of chemotherapy or myeloid growth factors).†PET 5PS: 1, no uptake 
above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma 
Consensus-based uniform response criteria for WM developed by the IWWM, updated 
in the sixth IWWM 
Complete response (CR) 
Absence of serum monoclonal IgM protein by immunofixation. 
Normal serum IgM level.  
Complete 
resolution 
of 
extramedullary 
disease, 
i.e., 
lymphadenopathy and splenomegaly if present at baseline. 
Morphologically normal bone marrow aspirate and trephine 
biopsy 
Very good partial response (VGPR) 
Monoclonal IgM protein is detectable ≥90% reduction in serum 
IgM level from baseline 
Complete 
resolution 
of 
extramedullary 
disease, 
i.e., 
lymphadenopathy/splenomegaly if present at baseline. No new 
signs or symptoms of active disease 
Partial response (PR) 
Monoclonal 
IgM 
protein 
is 
detectable.≥50% 
but<90% 
reduction in serum IgM level from baseline. Reduction in 
extramedullary disease, i.e., lymphadenopathy/splenomegaly if 
present at baseline. No new signs or symptoms of active disease 
Minor response (MR) 
Monoclonal IgM protein is detectable 
≥25% but<50% reduction in serum IgM level from baseline 
No new signs or symptoms of active disease 
Stable disease 
Monoclonal IgM protein is detectable 
<25% reduction and <25% increase in serum IgM level from 
baseline 
 
No 
progression 
in 
extramedullary 
disease, 
ie, 
lymphadenopathy/splenomegaly 
 
No new signs or symptoms of active disease 
Progressive disease 
≥25% increase in serum IgM level* †from lowest nadir (requires 
confirmation) 
and/or 
progression 
in 
clinical 
features 
attributable the disease 
 


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15 APPENDIX B- CONTRACEPTIVE GUIDELINES AND PREGNANCY 
Women Not of Childbearing Potential are Defined as Follows: 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum 
FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral 
oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of child bearing potential. 
Contraceptive Guidelines for Women of Child-Bearing Potential: 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 30 days after stopping 
treatment. The highly effective contraception is defined as either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
2. Sterilization:  have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks ago.  In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment. 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female patients on the study, the vasectomised male 
partner should be the sole partner for that patient. 
4. 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 


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Women of child-bearing potential must have a negative serum or urine pregnancy test ≤ 72 hours 
prior to initiating treatment. 
Fertile Males: 
Fertile males, defined as all males physiologically capable of conceiving offspring, must use condoms 
during the treatment period and for 30 days after study drug discontinuation and should not father 
a child in this period.  
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to TG 
Therapeutics Inc. within 24 hours of learning of its occurrence. The pregnancy should be followed up 
for 3 months after the termination of the pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the investigator 
to TG Therapeutics Inc.  Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study drug and reported by the investigator 
to TG Therapeutics Inc.  Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 


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


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17 APPENDIX D – HEPATITIS B SEROLOGIC TEST RESULTS