Clinical trial NCT02612311
Conditions: Chronic Lymphocytic Leukemia
Sponsor: TG Therapeutics, Inc.
Start date: 2015-11-19; Completion date: 2023-02-22
Enrollment: 603 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the combination of ublituximab, a novel monoclonal antibody, and TGR-1202, a novel PI3K delta inhibitor compared to obinutuzumab and chlorambucil, and compared to ublituximab or TGR-1202 alone in Chronic Lymphocytic Leukemia (CLL) participants.

Detailed description:

Arms: arm 1: Participants received ublituximab, 150 milligrams (mg), intravenously (IV), on Day 1, 750 mg on Day 2, followed by 900 mg on Days 8 and 15 of Cycle 1 (cycle length=28 days), Day 1 of Cycles 2-6, and once every 3 cycles thereafter, along with umbralisib, 800 mg, orally, once daily during each cycle until disease progression, lack of tolerability, or until the treatment is commercially available or up to 87 months. arm 2: Participants received Obinutuzumab 100 mg, IV on Day 1, 900 mg on Day 2, followed by 1000 mg on Days 8 and 15 of cycle 1 (cycle length = 28 days), Day 1 of Cycle 2-6 along with Chlorambucil 0.5 milligram per kilogram (mg/kg) tablet orally on Days 1 and 15 once daily during each cycle until disease progression, lack of tolerability, or until the treatment is commercially available or up to 87 months. arm 3: Participants received ublituximab, 150 mg, IV, on Day 1, 750 mg on Day 2, followed by 900 mg on Days 8 and 15 of Cycle 1 (cycle length=28 days), Day 1 of Cycles 2-6, and once every 3 cycles thereafter, until disease progression, lack of tolerability, or until the treatment is commercially available or up to 87 months. arm 4: Participants received umbralisib, 800 mg tablets, orally, once daily during each cycle (cycle length= 28 days) until removal from study or up to 87 months.
Interventions: intervention 1: Obinutuzumab intervention 2: Ublituximab intervention 3: TGR-1202 intervention 4: Chlorambucil
Intervention descriptions: intervention 1: Obinutuzumab: IV infusion intervention 2: Ublituximab: IV infusion intervention 3: TGR-1202: Oral daily dose intervention 4: Chlorambucil: Oral dose

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Phase 3, Randomized Study to Assess the Efficacy and Safety of 
Ublituximab in Combination with TGR-1202 (Umbralisib) Compared to 
Obinutuzumab in Combination with Chlorambucil in Patients with 
Chronic Lymphocytic Leukemia (CLL) 
NCT Number: 
NCT02612311 
Document Date: 
Protocol Version 6: 20-April-2020 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UTX-TGR-304 
 
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Page 1 of 104 
Protocol version/Date:  
 
Version 6.0/ March 15, 2020 
Local Protocol #: 
 
 
Protocol UTX-TGR-304 
TITLE:  A Phase 3, Randomized Study to Assess the Efficacy and Safety of Ublituximab in 
Combination with TGR-1202 (Umbralisib) Compared to Obinutuzumab in Combination with 
Chlorambucil in Patients with Chronic Lymphocytic Leukemia (CLL) 
Sponsor: 
 
 
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort Street, 9th Floor 
 
 
 
 
New York, NY 10014 
 
 
 
 
 
Tel: (212) 554-4484 
 
IND Number:  
 
Ublituximab  
TGR-1202 (umbralisib) 
114,779 
 
116,762 
 
EudraCT Number: 
 
2015-005758-36 
 
 
 
 
 
 
Study Chair:   
 
MD, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tel 
  
 
Medical Monitor: 
 
MD 
 
 
 
 
Tel:
ext.
 
 
Study Coordination:  
TG Therapeutics, Inc. 
 
 
 
 
2 Gansevoort Street, 9th Floor,  New York, NY 10014 
 
 
 
 
Tel: (212) 554-4484 
 
Version: 1.0 
 
 
 
 
 
 
 
Date: 14 Sept 2015 
Version: 2.0 
 
 
 
 
 
 
 
Date: 10 June 2016 
Version: 3.0 
 
 
 
 
 
 
 
Date: 10 April 2017 
Version: 3.1 
 
 
 
 
 
 
 
Date: 18 June 2017 
Version: 4.0 
 
 
 
 
 
 
 
Date: 04 October 2017 
Version: 4.1 
 
 
 
 
 
 
 
Date: 20 December 2017 
Version: 5.0 
 
 
 
 
 
 
 
Date: 13 February 2019 
Version: 6.0 
 
 
 
 
 
 
 
Date: 15 March 2020 
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. 




  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
UTX-TGR-304 
 
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PROTOCOL ACCEPTANCE FORM 
Protocol Title: 
A Phase 3, Randomized Study to Assess the Efficacy and 
Safety of Ublituximab in Combination with TGR-1202 
(Umbralisib) Compared to Obinutuzumab in Combination 
with Chlorambucil in Patients with Chronic Lymphocytic 
Leukemia (CLL) 
Protocol Number: 
UTX-TGR-304 
IND Number: 
Ublituximab 
TGR-1202 (umbralisib) 
114,779 
 
116,762 
Date FINAL: 
15 March 2020 
 
I have read the attached protocol and agree that it contains all the necessary details for performing 
UTX-TGR-304. 
I will provide copies of the protocol and of the ublituximab and TGR-1202 Investigator’s Brochures, 
which were given to me by TG Therapeutics (Sponsor), to all members of the study team for whom I 
am responsible and who participate in the study.  I will discuss this material with them to ensure that 
they are fully informed regarding obinutuzumab, chlorambucil, ublituximab, and TGR-1202, 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 ................................................................................................................................. 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................... 22 
1 INTRODUCTION ................................................................................................................................ 24 
1.1 Chronic Lymphocytic Leukemia .......................................................................................................................... 24 
1.2 Ublituximab ................................................................................................................................................................. 24 
1.2.1 Pre-Clinical Evaluations of Ublituximab .................................................................................................................................................. 25 
1.2.2 Clinical Development of Ublituximab - CLL ............................................................................................................................................ 25 
1.3 TGR-1202 (umbralisib) .......................................................................................................................................... 27 
1.3.1 Pre-Clinical Development of TGR-1202 ................................................................................................................................................... 28 
1.3.2 Clinical Development of TGR-1202 ............................................................................................................................................................ 30 
1.4 Ublituximab in Combination with TGR-1202 ................................................................................................ 32 
2 OBJECTIVES AND ENDPOINTS ..................................................................................................... 34 
2.1 Study Objectives ........................................................................................................................................................ 34 
2.2 Efficacy Endpoints .................................................................................................................................................... 34 
3 ELIGIBILITY CRITERIA ................................................................................................................... 35 
3.1 Inclusion Criteria ....................................................................................................................................................... 35 
3.2 Exclusion Criteria ...................................................................................................................................................... 36 
4 STUDY DESIGN .................................................................................................................................. 38 
4.1 Overview of Study Design .......................................................................................................................... 38 
4.2 Registration and Randomization/Blinding .................................................................................................... 40 
4.3 Study Sites .................................................................................................................................................................... 41 
4.4 Discontinuation from Study Treatment ........................................................................................................... 41 
5 STUDY ASSESSMENTS AND TREATMENT SCHEDULE .......................................................... 42 
5.1 Laboratory Assessments ........................................................................................................................................ 43 
5.1.1 Local Laboratory Assessments ..................................................................................................................................................................... 43 
5.1.2 Central Laboratory Assessments ................................................................................................................................................................. 44 
........................................................................................... 44 
 ........................................................................................................................................................... 45 
 ........................................................................................................................................................................ 46 
6 TREATMENT PLAN .......................................................................................................................... 47 
6.1 Treatment Summary ................................................................................................................................................ 47 
6.2 Agent Administration .............................................................................................................................................. 48 
6.2.1 Guidelines for Administration of Obinutuzumab & Chlorambucil .............................................................................................. 48 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                        
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
   
 
       
 
  
  
 
 
  
  
 
  
 
 
  
   
 
  
    
   
    
 
 
   
 
   
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.2.2 Guidelines for Administration of Chlorambucil ................................................................................................................................... 50 
6.2.3 Guidelines for Administration of Ublituximab ...................................................................................................................................... 51 
6.2.4 Guidelines for Administration of TGR-1202 (umbralisib) .............................................................................................................. 54 
6.2.5 Criteria for Ongoing Treatment.................................................................................................................................................................... 55 
6.3 Dosing Delays and Modifications ........................................................................................................................ 55 
6.3.1 Dose Delay/Modifications: Obinutuzumab And/Or Chlorambucil ............................................................................................. 55 
6.3.2 Dose Delay: Ublituximab ................................................................................................................................................................................. 56 
6.3.3 Dose Delay/Modifications: TGR-1202 ...................................................................................................................................................... 57 
6.4 Ordering Obinutuzumab and Chlorambucil ................................................................................................... 59 
6.4.1 Obinutuzumab and Chlorambucil ............................................................................................................................................................... 59 
6.5 Ordering Ublituximab and TGR-1202 ............................................................................................................... 59 
6.6 Duration of Therapy ................................................................................................................................................. 59 
7 STUDY MEDICATION OVERVIEW AND SAFETY ...................................................................... 61 
7.1 Obinutuzumab ............................................................................................................................................................ 61 
7.2 Chlorambucil ............................................................................................................................................................... 61 
7.2.1 Adverse Events ..................................................................................................................................................................................................... 62 
7.3 Ublituximab ................................................................................................................................................................. 62 
7.3.1 Ublituximab - Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ......................................................... 63 
7.4 TGR-1202 (umbralisib) .......................................................................................................................................... 64 
7.4.1 TGR-1202 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ................................................................ 64 
7.4.2 Ublituximab + TGR-1202 – Comprehensive Adverse Events and Potential Risks List (CAEPRS) ............................... 65 
8 MEASUREMENT OF EFFECT .......................................................................................................... 67 
8.1 Method of Assessment ............................................................................................................................................ 67 
8.2 Response Review ....................................................................................................................................................... 67 
8.3 Identification and Measurement of Tumor Lesions and Organomegaly ............................................ 68 
8.3.1 Target Lesions ...................................................................................................................................................................................................... 68 
8.3.2 Spleen and Liver .................................................................................................................................................................................................. 68 
8.3.3 Non-Target Lesions ............................................................................................................................................................................................ 69 
8.4 Definitions of Tumor Response and Progression ........................................................................................ 69 
8.5 Complete Response .................................................................................................................................................. 70 
8.6 Partial Response ........................................................................................................................................................ 70 
8.7 Stable Disease ............................................................................................................................................................. 71 
8.8 Definitive Disease Progression ............................................................................................................................ 71 
8.9 Non-Evaluable ............................................................................................................................................................ 72 
8.10 Lymphocytosis During Therapy ....................................................................................................................... 72 
9 STATISTICAL CONSIDERATIONS ................................................................................................. 73 
9.1 Sample Size and Power ........................................................................................................................................... 73 


 
 
 
 
 
 
                                                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
    
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.2 General Analysis Convention ................................................................................................................................ 73 
9.3 Analysis Populations ................................................................................................................................................ 73 
9.4 Subjects Disposition ................................................................................................................................................. 74 
9.5 Subject Demographics and Baseline Characteristics .................................................................................. 74 
9.6 Medical History .......................................................................................................................................................... 74 
9.7 Extent of Exposure .................................................................................................................................................... 74 
9.8 Efficacy Analyses ....................................................................................................................................................... 74 
9.9 Missing Value Handling Procedures .................................................................................................................. 75 
9.10 Statistical Analyses ................................................................................................................................................ 75 
9.10.1 Primary efficacy variable .............................................................................................................................................................................. 75 
9.10.2 Secondary efficacy Outcomes ..................................................................................................................................................................... 75 
 .......................................................................................................................................................... 76 
9.11 Multiple Comparison Procedures .................................................................................................................... 77 
9.12 Interim analyses ...................................................................................................................................................... 77 
10 SAFETY REPORTING AND ANALYSIS ....................................................................................... 79 
10.1 Safety Analyses ........................................................................................................................................................ 79 
10.2 Adverse Event Characteristics .......................................................................................................................... 79 
10.3 Definitions of Adverse Events ........................................................................................................................... 79 
10.4 Adverse Events (AE’s) and Treatment Emergent Adverse Events (TEAE’s) ................................. 80 
10.5 Adverse Events / Serious Adverse Event Causality Assessment ........................................................ 80 
10.5.1 Recording of Adverse Events ...................................................................................................................................................................... 81 
10.5.2 Abnormal Laboratory Values and Vital Signs ..................................................................................................................................... 81 
10.5.3 Handling of Adverse Events ........................................................................................................................................................................ 81 
10.6 Serious Adverse Events ........................................................................................................................................ 82 
10.6.1 Definitions of Serious Adverse Events ................................................................................................................................................... 82 
10.6.2 Serious Adverse Event Reporting by Investigators ......................................................................................................................... 83 
10.7 Sponsor SAE Reporting Requirements .......................................................................................................... 84 
10.8 Recording of Adverse Events and Serious Adverse Events ................................................................... 84 
10.9 Diagnosis vs. Signs and Symptoms .................................................................................................................. 84 
10.9.1 Persistent or Recurrent Adverse Events ............................................................................................................................................... 84 
10.9.2 Abnormal Laboratory Values ..................................................................................................................................................................... 85 
10.9.3 Deaths .................................................................................................................................................................................................................... 85 
10.9.4 Hospitalization, Prolonged Hospitalization, or Surgery ................................................................................................................ 85 
10.9.5 Pre-Existing Medical Conditions ............................................................................................................................................................... 85 
10.9.6 Protocol-Defined Events of Special Interest ........................................................................................................................................ 86 
11 DATA SAFETY MONITORING BOARD (DSMB) ..................................................................... 87 


 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                           
 
 
 
 
 
 
 
 
 
 
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12 CLINICAL DATA COLLECTION AND MONITORING .............................................................. 88 
12.1 Site Monitoring Plan .............................................................................................................................................. 88 
12.2 Curricula Vitae and Financial Disclosures .................................................................................................... 88 
12.3 Data Ownership and Publication ..................................................................................................................... 88 
13 GCP, FINANCIAL, AND REGULATORY CONSIDERATIONS ................................................. 89 
13.1 IRB Approval ............................................................................................................................................................ 89 
13.2 Regulatory Approval ............................................................................................................................................. 89 
13.3 Insurance and Indemnity .................................................................................................................................... 89 
13.4 Informed Consent ................................................................................................................................................... 89 
13.5 Confidentiality.......................................................................................................................................................... 90 
13.6 Investigator and Staff Information .................................................................................................................. 91 
13.7 Financial Information ........................................................................................................................................... 91 
14 RECORD RETENTION AND DOCUMENTATION OF THE STUDY ...................................... 92 
14.1 Documentation Required to Initiate Study .................................................................................................. 92 
14.2 Study Documentation and Storage .................................................................................................................. 92 
14.3 Amendments to the Protocol ............................................................................................................................. 94 
14.4 Data Collection ......................................................................................................................................................... 94 
14.5 Study Monitoring, Auditing, and Inspecting ................................................................................................ 95 
14.6 Quality Assurance and Quality Control ......................................................................................................... 95 
14.7 Disclosure and Publication Policy.................................................................................................................... 96 
15 REFERENCES ................................................................................................................................... 97 
16 Appendix A – CLL Response Definition .................................................................................. 98 
17 Appendix B- Contraceptive Guidelines and Pregnancy ................................................ 101 
18 Appendix C – NYHA Classifications ...................................................................................... 103 
19 Appendix D – Hepatitis B Serologic Test Results ............................................................ 104 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Version 2.0 (Dated 10 June 2016) of this Protocol is the first amendment to this clinical trial and 
contains the following modifications: 
• 
Sponsor and study coordination address updated; 
• 
The exclusion criteria as been amended to now allow enrollment of subjects with prior 
chlorambucil treatment provided they are not refractory to chlorambucil; 
• 
Exclusion criteria #8 has been added to exclude subjects with prior live virus vaccines; 
• 
The phrasing of response assessment intervals has been revised for clarity from “prior to 
cycles 4, 7, 10, and 13 at Weeks 12, 24, 36, 48, and every 3 cycles after,” to “after the 
completion of cycles 3, 6, 9, 12, 15, 18 and every 3 cycles thereafter” and it was further 
clarified that subjects being followed for PFS off treatment should have evaluations done 
every 12 weeks; 
• 
Schedule of assessments and treatment schedule (Section 5) was updated, including: 
o Revised wording for Tumor Evaluation (as listed above) 
o Updated Urine Pregnancy Test, Sparse PK Sampling, Immunogenicity Sampling; 
• 
Further clarification was provided for exclusion criteria #3, now requiring evaluation for the 
presence of HBV, HCV or CMV by DNA (PCR) if HBc antibody, HCV antibody or CMV are 
positive during serum virology; 
• 
The pre-infusion medications for obinutuzumab administration was updated in a new table 
in section 6.2.1 which has been added to reflect the most recently available prescribing 
information; 
• 
Subjects randomized to Treatment Arms A and D (which include TGR-1202) are now 
required to start prophylaxis treatment with pneumocystis jiroveci pneumonia (PCP) and 
antiviral therapy within 7 days prior to randomization (Section 6.2.4), whereas this was 
previously at investigator discretion; 
• 
The shelf life of ublituximab has been increased to 36 months from 24 months when stored 
between +2 ͦC / +8 ͦC to reflect newly available stability data on ublituximab drug product; 
• 
Sections 7.3.1, 7.4.1, and 7.5.1 were updated to include the most recent adverse event 
information related to ublituximab and TGR-1202 corresponding to the latest Investigator 
Brochures; 
• 
Clarification was provided in Section 8.3.1 to better describe appropriate selection of target 
lesions; and 
• 
Appendix B – Contraceptive Guidelines and Pregnancy has been updated to require women 
physiologically capable of becoming pregnant to use highly effective contraception and all 
males physiologically capable of conceiving offspring must use a condom during the study 
and for 4 months after the last treatment dose if randomized to treatment Arms A, C, or D, or 
for 18 months after the last treatment dose if randomized to Arm B (obinutuzumab).  
Version 3.0 (Dated 10 April 2017) of this Protocol is the second amendment to this clinical trial and 
contains the following modifications: 
• 
Language was inserted to support the planned interim analysis for contribution amongst the 
first 200 subjects and facilitate the discontinuation of Arms C and D should the interim 
analysis indicate these arms are to be discontinued; 
• 
Overall Survival (OS) has been added to the efficacy endpoints; 
• 
Inclusion criteria #2 has been updated to include units (per microliter) in regards to absolute 
neutrophil count and platelet count; 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
MRD will now be evaluated in all subjects achieving a PR or CR following the Cycle 6 response 
assessment as opposed to previously only in subjects achieving a CR; 
• 
Inclusion Criteria # 7 was updated to reflect the appropriate contraception time period per 
Appendix B as well as for post chlorambucil therapy; 
• 
Exclusion Criteria # 8 was updated to include “4 weeks prior to” for the live virus 
administration; 
• 
The frequency of CT scans for efficacy evaluation after 36 months was lessened and is now 
required at least every 6 cycles.  Language was changed to state as follows: “After 36 months, 
subjects should be evaluated for response by CT and/or MRI every 6 cycles unless clinically 
indicated sooner” and “Subjects being followed for PFS off treatment should have scans done 
approximately every 3 months prior to 36 months and approximately every 6 months after 
36 months, unless clinically indicated sooner”; 
• 
As all countries are not participating in the Companion Trial (UTX-TGR-204), language was 
added to state “select countries only” in respect to the Companion Trial participation; 
• 
MRD sampling window was changed from a +/- 7 day window to +/- 14 day window; 
• 
Informed consent was removed from Section 5 table as is not a 21 day screening procedure; 
• 
Screening period was changed from 21 to 28 days; 
• 
TGR-1202 dose delay/modification section was updated for non-hematologic toxicity specific 
for diarrhea; 
• 
Ublituximab dose delay/modification section was updated for management of anaphylaxis; 
• 
Section 6.2.4 was updated to eliminate the “within 7 days” requirement for starting PCP and 
antivirals.  It was changed to “…prior to Day 1 of Cycle 1”; 
• 
Language was added in Section 6.2.3.1 to allow investigator discretion on infusion rate flow 
as follows: “If at any time during ublituximab treatment, an infusion related reaction is 
observed, the treating investigator may reduce the infusion flow rate at their discretion.” 
• 
The ublituximab risk profile (Section 7.3.1.3) was updated based on the most recently 
available safety information since the last study amendment; 
• 
Exclusion Criteria were updated with the addition of Exclusion Criteria # 9, which now 
excludes subjects with: “History of anaphylaxis (excluding infusion related reactions) in 
association with previous anti-CD20 administration”; 
• 
General grammatical and administrative updates throughout have been incorporated. 
Version 3.1 (Dated 18 June 2017) of this Protocol is the third amendment to this clinical trial and 
contains the following modifications: 
• 
Section 6.2.3.3.1 and Section 7.3 were both updated to include information regarding a new 
vial size for ublituximab; 
• 
Inclusion criteria 1d – added the micro symbol “µ” as was left off in error. 
 
Version 4.0 (Dated 4 October 2017) of this Protocol is the fourth amendment to this clinical trial and 
contains the following modifications: 
• 
Section 4 was updated to reflect the closing of Arms C and D pursuant to the pre-specified 
interim analysis to establish contribution, conducted by the DSMB in May 2017; 
• 
Section 5.1.4 was updated to clarify that an additional post-baseline sparse PK sample could 
be collected from subjects; 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
Sections 6.3.2 and 6.3.3 were updated to provide the latest guidance for dose delay and 
modifications for ublituximab, TGR-1202, chlorambucil, and obinutuzumab; 
• 
Sections 7.3.1, 7.4.1, and 7.5.1 were updated to include the most recent adverse event 
information related to the ublituximab and umbralisib Investigator Brochures; 
• 
Sections 5.0 (Treatment Schedule) and 8.0 were updated to change the window for scans 
from +/- 7 days to +/- 14 days; 
• 
Updates were made throughout to include the generic name of TGR-1202: umbralisib; and 
• 
Minor administrative updates and typographical errors were corrected throughout. 
Version 4.1 (Dated 20 December 2017) of this Protocol is a correction to this clinical trial and 
contains the following modifications: 
• 
Sections 6.3 and 7.3:  Acknowledgement of the Adverse Event “Anaphylaxis” was mistakenly 
removed from Version 4.0 and has been re-inserted into the respected sections. 
Version 5.0 (Dated 13 February 2019) of this Protocol is the sixth amendment to this clinical trial and 
contains the following modifications: 
• 
Minor administrative and editorial changes. 
• 
Updated response assessment guidelines to state: “During the study period, Response 
assessments should be obtained every 3 cycles for the first 24 cycles.  After Cycle 24, evaluate 
for response approximately every 6 cycles unless clinically indicated sooner. Subjects 
followed for PFS off treatment should have response assessments done approximately every 
6 months unless clinically indicated sooner. 
• 
Section 4.4.  Added reasons for discontinuing a subject from the study to go along with 
reasons for discontinuing a subject from study treatment.  
• 
Section 5.0, Study Assessments and Treatment Schedule   
o Updated response assessments 
o Added CMV surveillance for all subjects on Arms A and D every 3 months through 30 days 
from last dose of study drug (EOT Visit)  
o Clarified End of Treatment (EOT) and End of Study (EOS) assessments and schedule.  
Added Table 3. 
• 
Section 5.1.1.  CMV surveillance added for all subjects on Arms A and D every 3 months 
through 30 days from last dose of study drug (EOT Visit) 
• 
Section 6.2.3 modified:  
o Recommendations for antihypertensives prior to Ublituximab infusion.  Window for 
holding antihypertensive is changed.  Consider holding antihypertensives 12-24 hours 
prior to infusion from previously stated 24 hours.    
o Premedication timing clarified.  Ublituximab should be started approximately 30 minutes 
after the conclusion of premedication infusions and should include an antihistamine 
(diphenhydramine 50 mg or equivalent), and a corticosteroid (dexamethasone 10-20 mg 
or equivalent). If pre-medication is given orally, administer oral pre-mediation 
approximately 45-60 minutes prior to the beginning of the ublituximab infusion. If 
subject has a negative reaction to a premedication the investigatory may consider 
decreasing its dose, using a different drug, or discontinue if not tolerated.  Additionally, if 
subject has other health conditions that are adversely impacted by a premedication the 
investigator may consider decreasing its dose, switching premedication to a different 
drug, or discontinue if medically appropriate. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
Section 6.2.4 was updated to remove Bactrim as a recommended anti-PCP prophylaxis, and 
additional instructions were given to switch to an alternate prophylaxis therapy, reduce dose, 
or discontinue prophylaxis at investigator discretion. 
• 
Section 6.3 was updated to remove the requirement to discontinue subjects from 
investigational product if held more than 28 days.  Treatment re-initiation after a treatment 
delay of greater than 2 cycles is at investigator discretion.  
• 
Section 6.3.3 Table 5  
o Respiratory/Infection section for Umbralisib clarified: *For sinopulmonary infections 
clearly not related to immune-mediated pneumonitis, TGR-1202 may be continued at 
investigator’s discretion.  While pneumonitis has been minimal with TGR-1202, it is a 
reported adverse event associated with other PI3K delta inhibitors.  Use of anti-
pneumocystis and anti-herpetic viral prophylaxis is required at start of therapy. 
o Added dose delays/modification and treatment instructions for Umbralisib related to 
liver injury 
• 
Section 7.3.1 Comprehensive Adverse Events and Potential Risks (CAEPRS) for Ublituximab 
to align with Ublituximab Investigator Brochure Version: 6.0 dated 20JUL2018.  
• 
Section 7.4.1 Comprehensive Adverse Events and Potential Risks (CAEPRS) for Umbralisib to 
align with Umbralisib Investigator Brochure Version: 6.0 dated 20JUL2018.  
• 
Language in protocol modified to utilize the term subject replacing patient.  
• 
Clarification throughout protocol confirming subjects will remain in follow up for PFS until 
progressive disease is confirmed by Independent Review Committee (IRC) through our 
central radiology vendor.  
• 
Overall Response Rate (ORR) analysis language has been included in Section 9.1. 
Version 6.0 (Dated 15 March 2020) of this Protocol is the seventh amendment to this clinical trial 
and contains the following modifications: 
• 
Response categories of CRi (complete response with incomplete marrow recovery) and nPR 
(nodular PR) were added throughout; 
• 
Terminology of tumor status and tumor assessment were changed to disease assessment 
throughout;  
• 
Updates to the statistical analysis plan were integrated throughout, including: 
o The interim analysis for purposes of futility at 75% of target events was converted 
to an interim analysis of efficacy consistent with updates to the Statistical Analysis 
Plan (SAP); 
o MRD negativity rate was modified to remove reference to “MRD positivity at 
baseline” since no baseline MRD samples are to be obtained in the study.  MRD 
was clarified as being assessed amongst responders only. 
o Clarification was made to specify that the primary and secondary efficacy 
analyses would occur in the ITT population. 
o The timing of the ORR analysis was clarified to be following a positive interim PFS 
analysis or, if the interim PFS analysis is negative, following the final PFS analysis; 
• 
Section 10.9.3 was updated to fix an error in the required reporting of deaths due to disease 
progression on study which should NOT be reported as an adverse event.   
• 
Minor administrative and editorial changes were incorporated. 
 








  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
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embolization) or any investigational drug within 21 days of Cycle 1/Day 1 
(contact sponsor for < 21- day washout period requests). 
a. Corticosteroid therapy started at least 7 days prior to Cycle 1/Day 1 
(prednisone ≤10 mg daily or equivalent) is allowed as clinically 
warranted.  Topical or inhaled corticosteroids are permitted. 
2. Autologous hematologic stem cell transplant within 3 months of study 
entry.  Prior Allogeneic hematologic stem cell transplant is excluded.  
3. Evidence of chronic active Hepatitis B (HBV, not including subjects 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 PCR - 
See Appendix D. 
4. Known histological transformation from CLL to an aggressive lymphoma 
(i.e. Richter’s transformation). 
5. Prior exposure to idelalisib (CAL-101), duvelisib (IPI-145), ACP-319, or any 
drug that specifically inhibits phosphoinositide-3-kinase (PI3K). 
6. Subjects who have received prior therapy with obinutuzumab.  Subjects 
who are refractory to prior chlorambucil (defined as disease progression 
while receiving or within 6 months of completion of a chlorambucil based 
regimen). 
7. Evidence of ongoing systemic bacterial, fungal or viral infection, except 
localized fungal infections of skin or nails.  NOTE:  Subjects may be receiving 
prophylactic antiviral or antibacterial therapies at investigator discretion.  
Use of anti-pneumocystis and antiviral prophylaxis is required for subjects 
on TGR-1202 arms. 
8. Live virus vaccines within 4 weeks prior to or during obinutuzumab or 
ublituximab therapy. 
9. History of anaphylaxis (excluding infusion related reactions) in association 
with previous anti-CD20 administration. 
10. Any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (NY 
Heart Association functional classification III-IV [see  Appendix C – 
NYHA Classifications]) 
b. Myocardial infarction within 6 months of randomization 
c. QTcF >470 msec 
d. Angina not well-controlled by medication 
e. Poorly controlled or clinically significant atherosclerotic vascular 
disease including cerebrovascular accident (CVA), transient ischemic 
attack (TIA), angioplasty, cardiac/vascular stenting within 6 months of 
randomization. 
11. 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. 
12. Women who are pregnant or lactating. 




  
     
   
  
  
 
 
 
 
 
 
 
 
 
 
 
 
   
  
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
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Enrollment 
Following Screening, qualified subjects will be randomized in a 1:1:1:1 ratio to 
one of the four arms: 
• 
Arm A: Ublituximab + TGR-1202 
• 
Arm B: Obinutuzumab + Chlorambucil 
• 
Arm C: Ublituximab 
• 
Arm D: TGR-1202 
 
Approximately 175 subjects will be enrolled into each of Arms A and B for the 
PFS analysis, and up to 175 subjects may be enrolled into each of Arms C and D 
unless contribution is established at the interim ORR analysis among the first 
50 subjects enrolled into each arm, in which case enrollment into Arms C or D 
may be terminated early.  
If contribution is established at the planned interim analysis and Arms C and D 
close for enrollment, qualified subjects will be randomized in a 1:1 ratio to one 
of two arms: 
• 
Arm A: Ublituximab + TGR-1202 
• 
Arm B: Obinutuzumab + Chlorambucil 
 
Contribution was established at the interim analysis and as of May 2017 Arms 
C and D are closed for enrollment.  
 
Stratification: 
Randomization will be stratified according to 17p deletion status (presence vs. 
absence) and treatment status (treatment naïve vs. previously treated).  For 
purposes of stratification, subjects will be considered “previously treated” only 








  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
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More details of efficacy analyses can be found in Section 9, Statistical 
Considerations Section. 
 
Sample Size: 
An approximate total number of 280 events between Treatments A and B will 
be required to provide 80% power to detect a treatment superiority of 
Treatment Arm A over Treatment Arm B at an overall two-sided significance 
level 0.04.  In the sample size calculation, it was assumed that the median PFS 
was 25 months for Treatment B and 35.5 months for Treatment A and that the 
subjects would be accrued within 24 months and followed for at least 48 
months.   
Safety Analyses: 
Treatment-emergent AEs through 30 days after last dose of study treatment will 
be summarized by Medical Dictionary for Regulatory Activities (MedDRA™), 
System Organ Class and preferred term.  The incidences and percentages of 
subjects experiencing each AE preferred term will be summarized with 
descriptive statistics.   
 
More details of safety analyses can be found in Section 10, Safety Reporting and 
Analysis Section. 
 






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


  
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2.1 PRE-CLINICAL EVALUATIONS OF UBLITUXIMAB 
1.2.1.1 IN VITRO ACTIVITY  
In an in-vitro assay using B-CLL cells from subject donors, ublituximab demonstrated an enhanced 
ability to kill CLL cells compared to rituximab.  Ublituximab demonstrated improved Fcγ receptor 
IIIA (FcγRIIIA)/CD16 binding and FcγRIIIA dependent effector functions compared to rituximab.  
Additionally, ublituximab induced higher in vitro ADCC against CLL cells, and a higher FcγRIIIA 
mediated interleukin-2 (IL2) production by FcγRIIIA+ Jurkat cells (de Romeuf C, 2008).  Ublituximab 
demonstrated high ADCC against both subject-derived CLL cells and NHL cell lines.  Ublituximab’ s 
engagement to FcγRIIIA triggers a stronger NK cell cytotoxicity against CLL as compared to Rituxan 
(in vitro) despite CD20 density, likely related to the glycosylation pattern (de Romeuf C, 2008).  
1.2.1.2 IN VIVO ACTIVITY 
The antitumor effect of ublituximab was compared to that of rituximab with chemotherapy in 
follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft murine models.  Single agent 
ublituximab demonstrated dose-related anti-tumor activity with 100% tumor growth inhibition in 
the FL xenograft at a dose of 100mg/kg, and a superior tumor growth delay (21 days) compared to 
rituximab. Ublituximab also demonstrated superior anti-tumor activity compared to rituximab 
against MCL xenografts at all dose levels (4).  
1.2.1.3 TOXICOLOGY 
In single-dose and repeat dose toxicology studies performed under GLP, ublituximab displayed a 
safety profile similar to what might be expected for anti-CD20 monoclonal antibodies. Single 
administration of up to 100 mg/kg ublituximab in cynomolgus monkeys was well tolerated, with no 
local irritation with intravenous administration.  Genotoxicity studies (Ames test) showed that 
ublituximab was not mutagenic.  Monkeys that received a single injection of 0.3 mg/kg of ublituximab 
developed an anti-ublituximab response, whereas anti-ublituximab antibodies were not detected in 
the animals which received 10 or 100 mg/kg (see Ublituximab Investigator Brochure). 
1.2.2 CLINICAL DEVELOPMENT OF UBLITUXIMAB - CLL 
Ublituximab has been studied in a variety of subject populations, both as a single agent, and in 
combination with other agents, with over 100 subjects having received ublituximab therapy to date 
across all studies.  Two Single-Agent Phase I/Ib trials have been conducted with ublituximab treating 
both NHL and CLL subjects, with a total of 41 subjects with relapsed or refractory CLL having been 
treated with single-agent ublituximab (TG-1101).  Further, following demonstration of safety and 
tolerability in these early single agent studies, Phase I and II combination studies were undertaken 
with a variety of agents.  Given the number of subjects who have received ublituximab in early-phase 
trials, the safety and side effect profile of the agent is well characterized.  Summaries of the single-
agent experience are provided below as well as data with use of ublituximab in combination with 
ibrutinib. 
In a two part, first-in human dose escalation study (protocol CD20-0703), subjects with relapsed or 
refractory CLL received one weekly infusion of single agent ublituximab for 4 doses in a 3+3 dose 
escalation design through 5 sequential dose levels.  Part II of the study was a dose-confirmation 
component which used an initial dose of 150 mg followed by 7 doses of 450 mg (total dose 3300 mg) 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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– the clinical summary will focus on the Part II part of the study as the dose is more relevant to the 
clinical application used in current clinical studies.  In Part II, 12 subjects were enrolled at 9 centers 
in France and followed for 12 months.  Demographic data for the 12 subjects enrolled in the study 
were as follows.  The median age was 69.5 years [62–77]; median time from diagnosis to inclusion 
was 10.4 years [4.0–23.6] and median prior therapies was 3 [1–8].  Seven subjects (58%) received at 
least one prior rituximab-containing regimen.  The median lymphocyte bone marrow infiltration was 
85% [40–94]. 
Most frequent drug-related adverse events (AE’s) reported were infusion related reactions (IRR) 
(75% of the subjects, including 33% of subjects with Grade 3 IRR).  Other Grade 3/4 AE’s > 10% 
included: neutropenia (67%) and increase ALT/AST (17%).  All AEs were reversible spontaneously 
or with supportive care intervention.  None of the reported adverse events were considered as a 
dose-limiting toxicity according the judgment of the study Safety Committee.  Therefore, the 
maximum tolerated dose was not reached in this study.  Significant blood lymphocyte depletion was 
observed in all subjects:  median lymphocyte count at baseline was 46.6 (x109/l); after 1 month (M1) 
= 1.5 (↓94%); M4=1.4 (↓91%) and M6=2.0 (↓89%). No cases of serum anti-ublituximab antibodies 
were detected at any time point.  
Clinical response was based on the criteria established by the National Cancer Institute (NCI)-
Working Group updated in 2008 (Hallek M, 2008).  All subjects but one received the planned 8 
infusions without any dose reduction--one subject was prematurely withdrawn due to a concomitant 
secondary leukemia unrelated to ublituximab therapy.  Response was evaluated at month 4 for the 
11 evaluable subjects, with an initial response rate of 64% (7/11) with a confirmed response at 
month 6 in 5/11 subjects (45%) subjects (all PRs).  Four of the 11 subjects achieved stable disease.  
At the 1-year follow-up, no responders had progressed, demonstrating all confirmed responses were 
durable despite no ublituximab maintenance therapy.  The median progression-free survival (PFS) 
was not reached at the 12-month follow-up (Cazin B, 2013). 
A Phase I trial of ublituximab (NCT01647971) was subsequently undertaken in subjects with B-cell 
lymphoma who were relapsed or refractory to a prior rituximab containing regimen, which included 
8 subjects with CLL.  This trial utilized a 3+3 design, assessing dose levels of 450, 600, 900, and 1200 
mg.  No DLTs were observed amongst the 12 subjects enrolled into the dose-escalation component, 
and expansion cohorts were subsequently undertaken at 600, 900, and 1200 mg.  Subjects with CLL 
were eligible to enroll into the expansion cohorts at 600 and 900 mg, receiving ublituximab on days 
1, 8 & 15 of Cycles 1 & 2, with monthly maintenance infusions starting in Cycle 3, followed by every 
3 months starting in Cycle 6.   
Of the 8 CLL subjects enrolled, 4 had infusion related reactions that were manageable with infusion 
interruptions only and all subjects received all schedule doses.  Other observed adverse events which 
were considered at least possibly related to study drug included neutropenia Grade 1/2 (n=1) and 
Grade 3/4 (n=3), as well as thrombocytopenia Grade 1/2 (n=1) and Grade 3/4 (n=1).  Six subjects 
were evaluable for efficacy as of data cutoff for ASCO 2014, with 4 out of 6 subjects achieving a partial 
response.  Rapid and profound circulating lymphocyte depletion (> 50% reduction) was noted with 
median time to peripheral response of 1 day (O'Connor OA, 2014). 
 
 






 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
    
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
   
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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FIGURE 3: REDUCTION OF PAKT BY TGR-1202 IN CELL LINES BY WESTERN BLOTTING 
 
1.3.1.1 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 4: TGR-1202 IN VIVO EFFICACY 
 
1.3.1.2 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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1.3.2 CLINICAL DEVELOPMENT OF TGR-1202 
1.3.2.1 SINGLE-AGENT IN SUBJECTS WITH RELAPSED OR REFRACTORY HEMATOLOGIC 
MALIGNANCIES 
TGR-1202 is under evaluation in an ongoing single-agent Phase I dose-escalation study in subjects 
with relapsed and refractory hematologic malignancies (Burris et al, ASH 2014).  As of the latest 
cutoff date for this study of December 1, 2014, 55 subjects were enrolled and eligible for safety 
evaluation, with 43 subjects evaluable for efficacy.  The median age was 62 years (range 22-82), 73% 
male and 18/55 enrolled subjects had a diagnosis of CLL.  Among all subjects the median number of 
prior therapies was 3, with 80% receiving prior rituximab-based chemotherapy.  Other histological 
diagnoses included; FL (n=15), HL (n=9), DLBCL (n=7), MCL (n=2), MZL (n=2), HCL and WM (n=1 
each).  The majority of subjects had an ECOG of 1 and 51% received 3 or more prior therapies.     
Subjects 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 1.3.2.2 Healthy Subject Pharmacokinetic Studies below).  This 
micronized formulation was introduced into dose escalation at 200 mg QD and dosed as high as 1200 
mg QD, with no maximum tolerated dose (MTD) reached.  Intra-subject dose escalation rules have 
allowed subjects 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 ref), 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 
subjects.  Of the 14 evaluable CLL subjects treated at or above this therapeutic threshold, 93% 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 subjects 
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 
subjects.  The Grade 3 rash resolved upon suspension of TGR-1202 and concomitant medications and 
did not recur upon re-challenging the subject at 800 mg QD.  See Section 7.4.1 Comprehensive 
Adverse Events and Potential Risks Lists (CAEPRs) for a complete overview of the TGR-1202 side 
effect profile.   
Dosing of TGR-1202 initially occurred in the fasting state, but was transitioned mid-study to fed state 
dosing, with subjects instructed to take TGR-1202 with food.  All dosing of TGR-1202 is now 
conducted using the micronized formulation and in the fed state.   
Overall, TGR-1202 was well tolerated and displayed promising signs of clinical activity at the higher 
dosing cohorts.  No drug-related transaminase elevations or events of colitis have been reported to 
date.  No MTD has been reached and dose escalation continues. 
1.3.2.2 HEALTHY SUBJECT PHARMACOKINETIC STUDIES 
In parallel with the Phase 1 single-arm, dose-escalation study in subjects with relapsed or refractory 
hematologic malignancies; two healthy subjects, crossover, bioequivalence pharmacokinetics studies 
have been completed.  The first pharmacokinetic study was a Phase 1 drug-food interaction study 




  
  
  
  
  
  
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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AUC0-inf (ng∙hr/mL) 
7715.67 
12378.19 
160.43 
146.49 – 175.70 
Cmax (ng/mL) 
166.20 
371.70 
223.65 
202.33 – 247.20 
 
The micronized drug product formulation increased both the extent and rate of exposure of TGR-
1202 under fasted conditions. The extent (AUC0-t) and total extent (AUC0-inf) of exposure both 
increased by 60%, respectively, following administration of the modified drug product formulation 
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 
subjects 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 subjects administered equivalent doses of either 
the initial formulation in the fasting state or the micronized formulation in the fed state:   
 
 
1.4 UBLITUXIMAB IN COMBINATION WITH TGR-1202 
The combination of ublituximab and TGR-1202 is currently under evaluation in an ongoing Phase 
I/Ib study in subjects with relapsed or refractory NHL and CLL (Lunning et al., ASH 2014).  In this 
study, ublituximab is being dosed on Days 1, 8, and 15 of Cycle 1 & 2, and on Day 1 of Cycles 4, 6, 9 
and 12.  After Cycle 12, no further ublituximab is administered and TGR-1202 is continued until 
removal from study.   
A 3+3 dose-escalation design is being utilized to evaluate sequentially higher doses of the 
combination agents as illustrated below: 
 




 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2 OBJECTIVES AND ENDPOINTS 
2.1 STUDY OBJECTIVES 
PRIMARY OBJECTIVES 
• 
To establish that the combination of ublituximab + TGR-1202 is superior to the combination 
of obinutuzumab + chlorambucil as measured by duration of Progression-Free Survival (PFS) 
in subjects with CLL 
KEY SECONDARY OBJECTIVES 
• 
To evaluate and compare the combination of ublituximab + TGR-1202 to the combination of 
obinutuzumab + chlorambucil with respect to overall response rate in subjects with CLL 
• 
To establish that the combination of ublituximab + TGR-1202 provides clinical benefit over 
both ublituximab alone and TGR-1202 alone 
OTHER SECONDARY OBJECTIVES 
• 
To assess safety, tolerability and other efficacy outcomes. 
• 
 
 
2.2 EFFICACY ENDPOINTS 
Progression-free survival (PFS) 
PFS is defined as the interval from randomization to the earlier of the first documentation of 
definitive disease progression or death from any cause. 
Definitive disease progression based on standard criteria (Hallek et al. 2008) and occurring for any 
reason (i.e., increasing lymphadenopathy, organomegaly or bone marrow involvement; decreasing 
platelet count, hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other 
than lymphocytosis. 
 
Overall response rate (ORR) 
ORR is defined as sum of CR and PR rates. 
 
Complete Response (CR) Rate 
CR rate is defined as the proportion of subjects who achieve a CR. 
 
Minimal Residual Disease (MRD) Negativity Rate 
MRD negativity rate is defined as the proportion of subjects who are MRD negative. 
 
Duration of response (DOR) 
DOR is defined as the interval from the first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any cause. 
 
Overall Survival (OS) 
OS is defined as the interval from randomization to death from any cause. 


 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3 ELIGIBILITY CRITERIA 
Subjects must meet all the following inclusion criteria and none of the exclusion criteria to be eligible 
for participation in this study. 
3.1 INCLUSION CRITERIA 
Subjects must meet all the following inclusion criteria to be eligible for participation in this study: 
1. B-cell CLL that warrants treatment consistent with accepted IWCLL criteria (Hallek 2008) for 
initiation of therapy.  Any one of the following conditions constitute CLL that warrants 
treatment: 
a. Evidence of progressive marrow failure as manifested by the onset or worsening of 
anemia and/or thrombocytopenia, or 
b. Massive (i.e., lower edge of spleen ≥ 6 cm below the left costal margin), progressive, 
or symptomatic splenomegaly, or 
c. Massive (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic 
lymphadenopathy, or 
d. Progressive lymphocytosis in the absence of infection, with an increase in blood 
absolute lymphocyte count (ALC) >50% over a 2-month period or lymphocyte 
doubling time of <6 months (as long as initial ALC was ≥30,000/µL), or 
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy, or 
f. 
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs occurring in the absence of evidence of infection: 
i. Unintentional weight loss of ≥10% within the previous 6 months, or 
ii. Significant fatigue (≥ Grade 2), or 
iii. Fevers >100.5°F or 38.0°C for ≥2 weeks, or 
iv. Night sweats for >1 month. 
2. Adequate organ system function, defined as follows: 
a. Absolute neutrophil count (ANC) > 1,000/mm3 (µL) / platelet count > 50,000/mm3 
(µL). 
b. Total bilirubin ≤1.5 times the upper limit of normal (ULN)  
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if 
no liver involvement or ≤5 x the ULN if known liver involvement  
d. Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault 
formula.) 
3. Presence of measurable lymphadenopathy, defined as the presence of > 1 nodal lesion that 
measures > 2.0 cm in the longest diameter (LD) and > 1.0 cm in the longest perpendicular 
diameter (LPD) as assessed by computed tomography (CT) or magnetic resonance imaging 
(MRI). 
4. ECOG performance status ≤ 2. 
5. Male or female ≥ 18 years of age. 
6. Ability to swallow and retain oral medication. 
7. Female subjects who are not of child-bearing potential (see Appendix B- Contraceptive 
Guidelines and Pregnancy), and female subjects of child-bearing potential who have a 
negative serum pregnancy test within 3 days prior to Cycle 1, Day 1.  Female subjects of child-
bearing potential, and male partners must consent to use a medically acceptable method of 
contraception throughout the study period and for 4 months after the last dose of 


 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
    
 
 
   
 
 
 
   
   
 
 
 
 
  
 
 
        
 
 
  
    
 
 
     
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ublituximab or TGR-1202, or 18 months after the last dose of obinutuzumab or 4 weeks after 
the last dose of chlorambucil. 
8. Willingness and ability to comply with trial and follow-up procedures, and give written 
informed consent. 
3.2 EXCLUSION CRITERIA 
Subjects who meet any of the following exclusion criteria are not to be enrolled to this study: 
1. Subjects receiving cancer therapy (i.e., chemotherapy, radiation , immunotherapy, biologic 
therapy, hormonal therapy, surgery and/or tumor embolization) or any investigational drug 
within 21 days of Cycle 1/Day 1 (contact sponsor for < 21-day washout period requests) 
a. Corticosteroid therapy started at least 7 days prior to Cycle 1/Day 1 (prednisone 
≤10 mg daily or equivalent) is allowed as clinically warranted.  Topical or inhaled 
corticosteroids are permitted. 
2. Autologous hematologic stem cell transplant within 3 months of study entry.  Prior 
Allogeneic hematologic stem cell transplant is excluded.  
3. Evidence of chronic active Hepatitis B (HBV, not including subjects 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 IgM is positive the subject must be evaluated for the presence of HBV, HCV, or CMV by 
DNA (PCR).  - See Appendix D. 
4. Known histological transformation from CLL to an aggressive lymphoma (i.e. Richter’s 
transformation). 
5. Prior exposure to idelalisib (CAL-101), duvelisib (IPI-145), ACP-319, or any drug that 
specifically inhibits phosphoinositide-3-kinase (PI3K) 
6. Subjects who have received prior therapy with obinutuzumab.  Subjects who are refractory 
to prior chlorambucil (defined as disease progression while receiving or within 6 months of 
completion of a chlorambucil based regimen) 
7. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal 
infections of skin or nails.  NOTE:  Subjects may be receiving prophylactic antiviral or 
antibacterial therapies at investigator discretion.  Use of anti-pneumocystis and antiviral 
prophylaxis is required for subjects on TGR-1202 arms. 
8. Live virus vaccines within 4 weeks prior to or during obinutuzumab or ublituximab therapy. 
9. History of anaphylaxis (excluding infusion related reactions) in association with previous 
anti-CD20 administration. 
10. Any severe and/or uncontrolled medical conditions or other conditions that could affect 
their participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (NY Heart 
Association functional classification III-IV [see  Appendix C – NYHA Classifications]) 
b. Myocardial infarction within 6 months of randomization 
c. QTcF >470 msec 
d. Angina not well-controlled by medication 
e. Poorly controlled or clinically significant atherosclerotic vascular disease including 
cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, 
cardiac/vascular stenting within 6 months of randomization. 
11. 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 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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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. 
12. 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 3, randomized, four-arm trial to evaluate the efficacy and safety of 
ublituximab in combination with TGR-1202 compared to that of obinutuzumab in combination with 
chlorambucil (CHL), and to ublituximab alone and to TGR-1202 alone in subjects with CLL.  While the 
primary objective of the study is to demonstrate the superiority of Arm A (Ublituximab + TGR-1202) 
over Arm B (Obinutuzumab + Chlorambucil) as measured by progression-free survival (PFS) and 
overall response rate (ORR), an interim analysis of ORR among the first 50 subjects enrolled into each 
arm is planned to assess the contribution of each single agent in the ublituximab + TGR-1202 
combination regimen. 
During the study, subjects from Treatment Arms B, C, and D with disease progression confirmed by 
the independent review committee (IRC), may be enrolled into a Companion Study (select 
participating countries only) immediately.  At the end of the study, non-progressed subjects from all 
treatment arms may also be enrolled to the above mentioned Companion Study.  In the Companion 
Study, subjects from Treatment Arms B, C, and D may start treatment with ublituximab + TGR-1202 
as described in this protocol, while subjects entering the Companion Study from Treatment Arm A 
may continue their treatment per specified by this protocol.  These subjects enrolled to the open 
Companion Study will receive ublituximab in combination with TGR-1202 (at the same dose as the 
Treatment Arm A in this current study) until they show disease progression, are unable to continue 
treatment for any reason such as lack of tolerability, or until the treatment is commercially available. 
Enrollment 
Following Screening, qualified subjects will be randomized in a 1:1:1:1 ratio to one of the four arms: 
• 
Arm A: Ublituximab + TGR-1202 (umbralisib) 
• 
Arm B: Obinutuzumab + Chlorambucil 
• 
Arm C: Ublituximab 
• 
Arm D: TGR-1202 (umbralisib) 
 
Approximately 175 subjects will be enrolled into each of Arms A and B for the PFS analysis, and up 
to 175 subjects may be enrolled into each of Arms C and D unless contribution is established at the 
interim ORR analysis among the first 50 subjects enrolled into each arm, in which case enrollment 
into Arms C or D will be terminated early. 
If contribution is established at the planned interim analysis and Arms C and D close for enrollment, 
qualified subjects will be randomized in a 1:1 ratio to one of two arms: 
• 
Arm A: Ublituximab + TGR-1202 (umbralisib) 
• 
Arm B: Obinutuzumab + Chlorambucil 
 
Contribution was established at the interim analysis and as of May 2017 Arms C and D are closed for 
enrollment.  
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
  
  
 
 
 
  
  
  
 
 
  
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
    
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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Stratification: 
Randomization will be stratified according to 17p deletion status (presence vs. absence) and 
treatment status (treatment naïve vs. previously treated).  For purposes of stratification, subjects will 
be considered “previously treated” only if they have previously received at least 2 cycles of one or 
more prior treatment regimens.   
 
During the study period, response assessments should be obtained every 3 cycles for the first 24 
cycles.  After Cycle 24, evaluate for response approximately every 6 cycles unless clinically indicated 
sooner. Subjects followed for PFS off treatment should have response assessments done 
approximately every 6 months unless clinically indicated sooner.  Date of progression, beginning of 
new treatment, and/or death should be entered in the eCRF. 
The best clinical response as well as disease progression will be determined by an Independent 
Review Committee (IRC).  Subjects will remain on study treatment until the occurrence of definitive 
disease progression confirmed by central radiology, unacceptable toxicity, or withdrawal from the 
study due to investigator decision or other reasons.  Subjects who discontinue from study treatment 
(either for toxicity or physician choice) and have not progressed will continue to be followed for 
progression is confirmed by central radiology review. 
An independent DSMB has been established to advise the Sponsor on safety and provide benefit/risk 
oversight of the study as described in the DSMB Charter Once the database has been locked, the 
independent DSMB will review the primary and secondary efficacy analyses and safety data.   
Study Schema 
 


 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.2 REGISTRATION AND RANDOMIZATION/BLINDING 
Subjects who are eligible and who have signed an informed consent will be randomized in a 1:1:1:1 
ratio to one of four treatment arms: ublituximab in combination with TGR-1202 (Arm A), 
obinutuzumab in combination with chlorambucil (Arm B), ublituximab alone (Arm C), or TGR-1202 
alone (Arm D).  Randomization will be stratified according to 17p deletion status (presence vs. 
absence) and treatment status (treatment naïve vs. previously treated).  For purposes of stratification, 
subjects will be considered “previously treated” only if they have previously received at least 2 cycles 
of one or more prior treatment regimens.   
Investigators will use an interactive web response system (IWRS) to assign subjects to one of four 
treatment arms as follows: 
• 
Arm A: Ublituximab + TGR-1202 
• 
Arm B: Obinutuzumab + Chlorambucil 
• 
Arm C: Ublituximab 
• 
Arm D: TGR-1202 
 
If contribution is established at the planned interim analysis and Arms C and D close for enrollment, 
qualified subjects will be randomized in a 1:1 ratio to one of two arms: 
• 
Arm A: Ublituximab + TGR-1202 
• 
Arm B: Obinutuzumab + Chlorambucil 
 
Contribution was established at the interim analysis and as of May 2017 Arms C and D are closed for 
enrollment.  
 
Subjects must begin study treatment within 7 days of randomization.  Please see the Study 
Manual for additional information on randomization.  Of note, randomization to treatment 
must occur within the 28-day screening period. 
Upon entering subject information into the IWRS, investigators will receive an enrollment approval 
and a unique subject identifier that will include the randomization assignment.  This confirmation 
must be received by the site prior to dispensing study drug to the participant.  Further details about 
the subject registration process using the IWRS system will be outlined in the Study Manual. 
As this is an open-label study, to protect data integrity, the following procedures will be implemented 
to ensure all clinical and statistical decisions are made in a treatment blinded manner. The Sponsor, 
except for Clinical Operations personnel monitoring the study and the Medical Monitor, will be 
blinded to treatment assignment and specific dosing data within the four individual treatment arms. 
In addition, unblinded Clinical Operations personnel will not be involved in any discussions 
regarding the analysis of data after enrollment of the first subject into the trial or any protocol 
amendment, except those related to safety. 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.3 STUDY SITES 
 
Up to 200 centers in the United States and select ex-US sites may be asked to participate in this study.  
Enrollment is expected to be completed approximately 24 months after the first subject is 
randomized.  
4.4 DISCONTINUATION FROM STUDY TREATMENT 
Discontinuation from study treatment and discontinuation from the study might be linked or might 
be separate events, depending on the triggering action, decision or outcome.  Subjects will be 
discontinued from study treatment for any of the following reasons: 
• 
Disease progression confirmed by central radiology 
• 
Intolerable toxicity related to study drug 
• 
Subject requests to withdraw consent or discontinue treatment 
• 
Pregnancy 
• 
Initiation of therapeutic intervention not permitted by the protocol 
• 
Investigator discretion 
• 
Discontinuation of the study by the Sponsor 
 
Subjects will be discontinued from the study for any of the following reasons: 
• 
Disease progression confirmed by central radiology 
• 
Subject requests to withdraw consent  
• 
Initiation of therapeutic intervention not permitted by the protocol 
• 
Discontinuation of the study by the Sponsor 
Subjects who discontinue from study treatment (for reasons other than progressive disease) will 
continue to be followed for progression until PD is confirmed by central radiology or until a new 
treatment regimen has begun. 
Subjects who discontinue all study treatment but remain on study for disease progression 
assessment, will have an End of Treatment visit (EOT) and will continue to be followed for  adverse 
events (treatment-related AEs and disease-related AEs), disease progression and other protocol 
required procedures (see Section 5, Table 3 for EOT and follow up assessment schedule).  All new 
treatment-related AEs occurring within 30 calendar days from treatment discontinuation must be 
reported and followed until resolution, unless, in the opinion of the investigator, these events are not 
likely to improve because of the underlying disease.  In this case the investigators must record the 
reason for not conducting the 30-day safety evaluation in the subject’s medical records and as a 
comment on the electronic Case Report Form (eCRF). 
All subjects who have CTCAE Grade 3 or 4 laboratory abnormalities at the time of withdrawal should 
be followed until the laboratory values have returned to Grade 1 or 2, unless in the opinion of the 
investigator, it is not likely that these values are to improve because of the underlying disease.  In this 
case, the investigator must record his or her reasoning for making this decision in the subject’s 
medical records and as a comment on the eCRF. 
Subjects who discontinue from the study will have an End of Study visit (EOS - see Section 5, Table 
3). 
 






 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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3. Coagulation lab tests to include PT and INR. 
4. Beta2-microglobulin  
5. Serum Virology to include HBsAG, HBc antibody, HCV antibody, and CMV IgG and IgM.   If HBc 
antibody, HCV antibody or CMV IgG and/or IgM are positive the subject must be evaluated 
for the presence of active HBV, HCV or CMV by PCR - See Appendix D.  CMV surveillance 
every 3 months for all subjects on Arm A and Arm D.  CMV surveillance will discontinue 
30 days after last dose of umbralisib.  
6. Baseline bone marrow aspirate/biopsy (if applicable) 
7. Fluorescence in situ hybridization (FISH) of peripheral blood for 13q deletion, 11q deletion, 
17p deletion, trisomy 12, t(11:14); DNA sequencing for IgHV mutation status. 
 
5.1.2 CENTRAL LABORATORY ASSESSMENTS 
The following assessments will be shipped to and analyzed at a central laboratory.  Please see Lab 
Manual for processing, handling, and shipping instructions. 
1. Minimal Residual Disease (MRD) assessment for subjects in PR or CR beginning at Cycle 6 
response assessment.  
 
 
 
 
 
 


  
  
 
 
 
 
 
 
 
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ARM D: TGR-1202 (if applicable) 
Cycle 1, and Onward: 
• 
800 mg TGR-1202 once daily until removal from study 
6.2 AGENT ADMINISTRATION 
Ublituximab and obinutuzumab treatment will be administered as an IV infusion while TGR-1202 
and chlorambucil will be self-administered orally, all on an outpatient basis. 
6.2.1 GUIDELINES FOR ADMINISTRATION OF OBINUTUZUMAB & CHLORAMBUCIL 
Guidelines for administration of obinutuzumab and chlorambucil are per the FDA approved 
prescribing information.  Please refer to www.gazyva.com (U.S. only) or www.gazyvaro.com (ex-U.S. 
sites) for the most up to date information. 
• 
Method of Administration:  Obinutuzumab will be administered as an IV infusion and 
chlorambucil will be administered orally, each in accordance with prescribing 
information 
• 
Potential Drug Interactions:  There are no known drug-interactions with 
obinutuzumab or chlorambucil 
• 
Pre-medications: Pre-medicate before each dose of obinutuzumab according to the 
following table:   
Day of 
Treatment 
Cycle 
Subjects requiring 
premedication 
Premedication 
Administration 
Cycle 1: Day 1, 
Day 2 
All subjects 
Intravenous glucocorticoid: 
20 mg dexamethasone or 
80 mg methylprednisolone1 
Completed at least 1 
hour prior to GAZYVA 
infusion. 
650–1000 mg 
acetaminophen 
At least 30 minutes 
before GAZYVA infusion 
anti-histamine (e.g., 50 mg 
diphenhydramine) 
All subsequent 
infusions 
All subjects 
650–1000 mg 
acetaminophen 
At least 30 minutes 
before GAZYVA infusion. 
Subjects with an IRR 
(Grade 1-2) with the 
previous infusion 
650–1000 mg 
acetaminophen 
At least 30 minutes 
before GAZYVA infusion. 
anti-histamine (e.g., 50 mg 
diphenhydramine) 
Subjects with a 
Grade 3 IRR with the 
previous infusion OR 
with a lymphocyte 
count > 25 x 109 /L 
prior to next 
treatment 
Intravenous glucocorticoid: 
20 mg dexamethasone or 
80 mg methylprednisolone1 
Completed at least 1 
hour prior to GAZYVA 
infusion 
650–1000 mg 
acetaminophen 
At least 30 minutes 
before GAZYVA infusion. 
anti-histamine (e.g., 50 mg 
diphenhydramine) 
1 Hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion 
reactions. 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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• 
Subjects with high tumor burden and/or high circulating absolute lymphocyte counts (greater 
than 25 x 109/L) should be pre-medicated with anti-hyperuricemics (e.g., allopurinol) beginning 
12–24 hours prior to start of therapy.  Ensure adequate hydration for prophylaxis of tumor lysis 
syndrome. Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is 
recommended for subjects with CLL during treatment and for up to 12 months following 
treatment as per investigator discretion.  See prescribing information for more information.   
 
6.2.1.1 INFUSION RELATED REACTIONS AND INFUSION RATE GUIDANCE -OBINUTUZUMAB 
General Concomitant Medication and Supportive Care Guidelines 
Obinutuzumab can cause severe and life-threatening infusion reactions. Two thirds of subjects 
experienced a reaction to the first 1000 mg infused of obinutuzumab. Infusion reactions can also 
occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and 
respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). 
Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, 
pyrexia, and chills. 
Pre-medicate subjects with acetaminophen, antihistamine, and a glucocorticoid. Institute medical 
management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion 
reactions as needed. Closely monitor subjects during the entire infusion. Infusion reactions within 24 
hours of receiving obinutuzumab have occurred. 
For subjects with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-
threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the 
obinutuzumab infusion.  Permanently discontinue obinutuzumab therapy. 
For subjects with Grade 1, 2, or 3 infusion reactions: Interrupt obinutuzumab for Grade 3 reactions 
until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions 
and manage symptoms. 
For subjects with preexisting cardiac or pulmonary conditions, monitor more frequently throughout 
the infusion and the post-infusion period since they may be at greater risk of experiencing more 
severe reactions. Hypotension may occur as part of the obinutuzumab infusion reaction. Consider 
withholding antihypertensive treatments for 12 hours prior to, during each obinutuzumab infusion, 
and for the first hour after administration until blood pressure is stable. For subjects at increased 
risk of hypertensive crisis, consider the benefits versus the risks of withholding their 
antihypertensive medication as is suggested. 
Please refer to the FDA approved prescribing information and www.gazyva.com (U.S. sites) or 
www.gazyvaro.com (ex-U.S. sites) for the most up to date information including warnings and 
precautions, adverse reactions, and boxed warnings. 
6.2.1.2 DISPENSING OF OBINUTUZUMAB 
Before use, the obinutuzumab vials should be inspected for particulate matter or discoloration.  Any 
vial with evidence of particulates or discoloration should not be used. 
 
The exact dose and the date and time of administration of obinutuzumab must be recorded within 
the eCRF, subject’s medical records, and/or in the drug accountability records. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The Pharmacist or his/her representative should record the date dispensed and subject’s number 
and initials, as well as complete the accountability forms with information concerning the 
dispensation of obinutuzumab. Preparation should be done by the Pharmacist or his/her 
representative according to instructions for sterile dilution. 
6.2.1.2.1 DILUTION OF OBINUTUZUMAB 
Prepare the solution for infusion, using aseptic technique, as follows: 
• 
Inspect visually for any particulate matter and discoloration prior to administration. 
• 
Dilute into a 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. Do not use other 
diluents such as dextrose (5%). 
• 
Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1: 
o Withdraw 40 mL of GAZYVA solution from the vial. 
o Dilute 4 mL (100 mg) of GAZYVA into a 100 mL 0.9% sodium chloride infusion 
bag for immediate administration. 
o Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% sodium chloride 
infusion bag at the same time for use on day 2 and store at 2°C to 8°C (36°F to 
46°F) for up to 24 hours. After allowing the diluted bag to come to room 
temperature, use immediately. 
o Clearly label each infusion bag. 
• 
Preparation of solution for infusion on day 8 and 15 of Cycle 1 and day 1 Cycles 2–6: 
o Withdraw 40 mL of GAZYVA solution from the vial. 
o Dilute 40 mL (1000 mg) into a 250 mL 0.9% sodium chloride infusion bag. 
• 
Mix diluted solution by gentle inversion. Do not shake or freeze. 
• 
For microbiological stability, the diluted GAZYVA infusion solution should be used 
immediately. Dilute under appropriate aseptic conditions. If not used immediately, the 
solution may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior 
to use. 
• 
The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL. 
The intravenous solution should be prepared and dispensed by the clinical research center 
pharmacist and should be infused by a qualified nurse with experience in monitoring the 
administration of chemotherapeutic agents. 
6.2.2 GUIDELINES FOR ADMINISTRATION OF CHLORAMBUCIL 
• 
Method of Administration: Chlorambucil will be administered orally Days 1 & 15 of Cycles 1 - 
6 
• 
Potential Drug Interactions:  There are no known drug-interactions with obinutuzumab in 
combination with chlorambucil.  See chlorambucil prescribing information more information. 
• 
Pre-medications: None 
Chlorambucil will be self-administered (by the subject).  Subjects should be instructed to swallow the 
tablets as a whole and should not chew or crush them. 
If a dose of chlorambucil is missed, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should be taken the next day.  If vomiting occurs, no attempt should be 
made to replace the vomited dose. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
  
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
      
 
 
 
 
   
 
 
     
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study drug compliance should be reviewed with the subject at the beginning of each new treatment 
cycle.  Missed doses should be documented. 
6.2.3 GUIDELINES FOR ADMINISTRATION OF UBLITUXIMAB 
• 
Method of Administration: Ublituximab will be administered as an intravenous infusion 
through a dedicated line. 
• 
Potential Drug Interactions:  No Drug Interactions have been reported to date. 
• 
Pre-medications: Ublituximab should be started approximately 30 minutes after the 
conclusion of the last pre-medication infusion and should include an antihistamine 
(diphenhydramine 50 mg or equivalent), and a corticosteroid (dexamethasone 10-20 mg or 
equivalent). If pre-medication is given orally, administer pre-medication approximately 45-60 
minutes prior to the beginning of the ublituximab infusion. If the subject has a negative 
reaction to a pre-medication, the investigator may consider decreasing its dose, using a 
different drug or discontinue if not tolerated.  Additionally, if a subject has other health 
conditions that are adversely impacted by a pre-medication, the investigator may consider 
decreasing its dose, switching premedication to a different drug or discontinue if clinically 
appropriate. 
o Use of oral acetaminophen 650 mg (or equivalent) should be restricted to subjects who 
experience fever or pyrexia after week 1 dose, or as clinically warranted. 
• 
Hypersensitivity and Infusion Reaction Precautions: Medication and resuscitation equipment 
must be available per institutional guidelines prior to ublituximab administration for the 
emergency management of potential anaphylactic reactions.   
• 
Subject Care Implications:   
o Ublituximab should not be administered as an IV push or bolus. 
o Diluted ublituximab should be checked before administration for cloudiness, color, or deposits.  
Ublituximab should not be administered if does not conform to the specifications. Immediately 
inform the Monitor/Sponsor with any product quality concerns or questions. 
o It is recommended that ublituximab be administered immediately after dilution. 
o No other treatment may be co-administered with ublituximab (other than for immediate 
intervention for adverse event). 
o Concurrent glucocorticoid therapy if started at least 7 days prior to study entry (< 10 mg per 
day of prednisone or equivalent) is allowed as clinically warranted.  
o Since infusion-related hypotension may occur, consider holding antihypertensive 
medications 12-24 hours prior to and throughout infusion of ublituximab. 
o For subjects at risk for tumor lysis syndrome in the opinion of the treating investigator, 
prophylaxis with allopurinol or per recommended institutional standards should be 
considered. 
 
 
 
 






  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.2.4 GUIDELINES FOR ADMINISTRATION OF TGR-1202 (UMBRALISIB) 
• 
Method of Administration: TGR-1202 will be administered orally once daily with food 
• 
Potential Drug Interactions:  No Drug Interactions have been reported to date. 
• 
Pre-medications: For subjects randomized to Treatment Arms A and D which include TGR-
1202, subjects are required to start prophylaxis treatment with pneumocystis jiroveci 
pneumonia (PJP) and antiviral therapy prior to Cycle 1, Day 1.  Choice and dose of PJP and 
anti-viral prophylaxis therapy is at the investigator discretion. Recommended prophylactic 
agents are provided below: 
o Anti-viral Prophylaxis:  Valtrex 500 mg daily or Acyclovir 400 mg BID or equivalent  
o PJP Prophylaxis: Dapsone 100 mg daily or equivalent. 
If anti-viral or anti-bacterial prophylaxis is not tolerated, the investigator may consider an 
alternate dose and/or dosing regimen, using a different prophylactic agent as well as 
discontinuing prophylaxis.  Final choice of PJP and anti-viral prophylaxis therapy is per 
investigator discretion. 
 
TGR-1202 will be dispensed at the sites by the research coordinator or designee under the direction 
of the PI or by a pharmacist at the site.  Subjects must be provided drug in its original container.  
Subjects should be instructed to return any unused tablets when they return the bottle to the site. 
Study drug compliance should be reviewed with the subject at the beginning of each new treatment 
cycle and as needed.  Missed doses will be documented in the subjects’ medical record. 
TGR-1202 will be self-administered (by the subject).  Tablets should be taken at approximately the 
same time each day with food (within 30 minutes of a meal).   Subjects should be instructed to 
swallow the tablets whole and should not chew or crush them. 
If a dose of TGR-1202 is missed, it should be taken as soon as possible on the same day.  If it is missed 
for a period greater than 12 hours, it should not be replaced.  If vomiting occurs, no attempt should 
be made to replace the vomited dose. 
6.2.4.1 DISPENSING OF TGR-1202 
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, 
subject’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 subject’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. 
 
 


  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.2.5 CRITERIA FOR ONGOING TREATMENT 
Continue treatment as per protocol provided that subject has: 
• 
No drug-related toxicity that warrants permanent study treatment discontinuation. 
• 
No radiographic evidence of disease progression that is confirmed by central radiology 
review.  
• 
Not withdrawn consent from the study for other reasons. 
6.3 DOSING DELAYS AND MODIFICATIONS 
Subjects should be assessed clinically for toxicity at each visit using the NCI CTCAE v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) grading scale.  Dose delay and/or modification 
guidance is for adverse events considered at least possibly related to 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. 
If greater than 2 cycle delay is necessary for recovery of toxicities to levels outlined in Sections 6.3.1, 
6.3.2 and 6.3.3, re-initiation of treatment is at the discretion of the investigator.  Contact TG 
Therapeutics prior to re-initiating treatment with any questions. If a subject discontinues treatment 
due to toxicity, then the subject should continue to be followed for progression as described for end 
of treatment (EOT) assessments (Section 5, Table 3).  If a subject withdraws consent from the study, 
begins a non-study treatment or has documented progression by central radiology, an end of study 
(EOS) visit should be completed (Section 5, Table 3). 
6.3.1 DOSE DELAY/MODIFICATIONS: OBINUTUZUMAB AND/OR CHLORAMBUCIL 
No reduction in the dose of obinutuzumab is permitted.  Chlorambucil dose reductions are described 
below.  A dose delay is permitted for chlorambucil or obinutuzumab to allow recovery of hematologic 
toxicities to ≤ Grade 2 or non-hematologic toxicities to Grade 1 or baseline level. If chlorambucil is 
discontinued, obinutuzumab may continue at the discretion of the investigator.  
If obinutuzumab is discontinued, the subject is withdrawn from study treatment. If a subject 
discontinues treatment due to toxicity or has completed 6 cycles of treatment with obinutuzumab 
(and  chlorambucil, if applicable), and the subject does not have disease progression that is confirmed 
by central radiology review, then the subject should continue to be followed for progression as 
described for end of treatment (EOT) assessments (Section 5, Table 3).  If a subject withdraws 
consent from the study, begins a non-study treatment or has documented progression by central 
radiology, an end of study (EOS) visit should be completed (Section 5, Table 3).  If a Grade 3 or 4 
cytopenia prevents treatment on day 15 of any cycle, the day 15 chlorambucil dose will be skipped. 
Obinutuzumab + Chlorambucil administration on day 1 of the following cycle will be given if the 
cytopenia has resolved to ≤ Grade 2.  If the cytopenia persists, obinutuzumab + chlorambucil 
administration will be delayed until the cytopenia has improved to ≤ Grade 2. 
If a subject experiences Grade 3 or 4 cytopenia, the guidelines for dose delay (chlorambucil and 
obinutuzumab) and dose reduction recommendations (chlorambucil only) are outlined the table 
below: 
 










 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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For subjects in Arms B, C and D with definite disease progression (as confirmed by the IRC), a single-
arm companion study will be available in select participating countries only.  In this companion 
study, compliant subjects who are tolerating primary study therapy are eligible to receive 
ublituximab in combination with TGR-1202, at the dose used in Arm A. 


 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7 STUDY MEDICATION OVERVIEW AND SAFETY 
7.1 OBINUTUZUMAB 
Chemical Name: 
obinutuzumab 
Other Names:    
Gazyva®, Gazyvaro® 
Classification:   
Humanized monoclonal antibody 
Mode of Action: 
Targets CD20 antigen on B-cells 
 
Description: 
Glycoengineered humanized monoclonal IgG1 kappa antibody directed 
against the CD20 antigen found on pre-B and mature B cells.   
How Supplied:  
Supplied in 1000-mg (40-mL) single-use vials. 
Storage: 
Obinutuzumab vials are stable at 2°C–8°C (36°F–46°F).   Vials should be 
protected from direct sunlight and should not be frozen or shaken. 
Stability: 
Diluted obinutuzumab solutions for infusion may be stored at 2°C–8°C (36°F–
46°F) for 24 hours and are known to be stable for an additional 48 hours at 
room temperature.  
Route of  
Administration: 
Intravenous 
Availability: 
 
Obinutuzumab is commercially available from Genentech/Roche. 
7.2 CHLORAMBUCIL 
Chemical Name: 
chlorambucil  
Other Names:    
Leukeran® 
Classification:    
alkylating agent of the nitrogen mustard type 
Mode of Action: 
interferes with DNA replication and induces cellular apoptosis 
 
How Supplied:  
Supplied as brown, film-coated tablets, containing 2 mg chlorambucil 
Storage: 
Refer to chlorambucil prescribing information 
Route of  
Administration: 
Oral 
Availability: 
 
Chlorambucil is available commercially. 
 


  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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7.2.1 ADVERSE EVENTS  
Please see obinutuzumab and chlorambucil full prescribing information for detailed information.  
Common adverse reactions (≥25%) in clinical trials of CLL for obinutuzumab in combination with 
chlorambucil were infusion reactions and neutropenia.  Warnings and Precautions for obinutuzumab 
include; infusion reactions, tumor lysis syndrome, neutropenia, thrombocytopenia, infections, 
anemia, pyrexia, cough, nausea, diarrhea, and cytopenias.  Fatal infusion reactions, severe 
mucocutaneous 
reactions, 
hepatitis 
B 
virus 
reactivation 
and 
Progressive 
Multifocal 
Leukoencephalopathy (PML) can occur in subjects receiving obinutuzumab.  Additionally, do not 
administer live virus vaccines prior to or during obinutuzumab therapy. 
7.3 UBLITUXIMAB 
Chemical Name: 
ublituximab 
 
Other Names:    
TG-1101 
Classification:    
Recombinant chimeric anti-CD20 monoclonal antibody    
Mode of Action: 
Targets CD20 antigen on B-cells 
 
Description: 
Ublituximab is a genetically engineered chimeric murine/human mAb 
directed against the CD20 antigen found on the surface of B lymphocytes.  
Ublituximab displays the typical structure of immunoglobulins, consisting of 
two gamma (γ) heavy chains and two kappa (κ) light chains linked by disulfide 
bridges. It is composed of a murine variable region (37.2% of total amino 
acids) fused onto human constant regions. 
How Supplied: 
Concentration of 10 mg/mL in 15 mL (150 mg) or 25 mg/mL in 6 mL (150 mg) 
single-use glass vials.  
Storage: 
Ublituximab must be stored in a secured limited-access refrigerated area at a 
temperature ranging from 2°C - 8°C.  Ublituximab must not be frozen. 
Stability: 
Once a vial of ublituximab has been opened and/or diluted it must be used 
immediately.  After dilution, ublituximab is stable in static conditions for 24 
hours at 25°C, and in dynamic conditions it is stable for 8 hours at 25°C.   
Ublituximab has a shelf-life of 36 months if stored between 2°C - 8°C, based 
on stability data. 
Route of  
Administration: 
Intravenous 
Packaging: 
 
Ublituximab is packed in kits. Each kit contains:  
• 
Six vials containing 150 mg solution of ublituximab each 
or 
• 
One vial containing 150 mg solution of ublituximab (for replacement 
if needed) 


 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The container closure system for the vials containing 6 mL is a type I glass vial 
closed by a siliconized chlorobutyl rubber stopper sealed with an aqua plastic 
and aluminum cap. 
The container closure system for the vials containing 15 mL is a Type I plus 
borosilicate vial closed by a siliconized bromobutyl rubber stopper sealed 
with a white plastic and aluminum cap. 
Availability: 
 
Ublituximab is available from TG Therapeutics. 
7.3.1 UBLITUXIMAB - COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS 
(CAEPRS) 
The following adverse events were observed in subjects treated with single agent ublituximab and 
were considered at least possibly related to the study medication.  The preliminary safety data as of 
May 01, 2018 is provided for a total of 117 subjects exposed to single agent ublituximab with a 
maximum follow up of 2+ years.  See the latest ublituximab Investigator’s Brochure for updated 
safety information a complete list of all adverse events reported regardless of causality. 
7.3.1.1 VERY COMMON (≥ 10%) 
Blood and Lymphatic System Disorders: neutropenia, thrombocytopenia 
General Disorders and Administration Site Conditions: pyrexia 
Injury, Poisoning and Procedural Complications: infusion related reaction 
Nervous System Disorders: headache 
7.3.1.2 COMMON (≥ 2% - < 10%) 
Blood and Lymphatic System Disorders: anemia, pancytopenia 
Gastrointestinal Disorders: diarrhea, abdominal pain, nausea, oral pruritus 
General Disorders and Administration Site Conditions: fatigue, asthenia, chills, oedema 
peripheral, pain 
Hepatobiliary Disorders: cytolytic hepatitis 
Infections and Infestations: herpes zoster 
Investigations: aspartate aminotransferase increased, blood bilirubin increased, gamma-
glutamyltransferase increased 
Musculoskeletal and Connective Tissue Disorders: muscular weakness 
Nervous System Disorders: dysgeusia 
Respiratory, Thoracic and Mediastinal Disorders: throat irritation, throat tightness 


 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis 
Vascular Disorders: hypertension 
7.4 TGR-1202 (UMBRALISIB) 
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. 
7.4.1 TGR-1202 COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS 
(CAEPRS) 
The following adverse events were observed in subjects treated with single agent umbralisib and 
were considered at least possibly related to the study medication.  The preliminary safety data as of 
May 01, 2018 is provided for a total of 136 subjects exposed to single agent umbralisib with a 
maximum follow up of 5+ years.  See the latest umbralisib Investigator’s Brochure for updated safety 
information a complete list of all adverse events reported regardless of causality.  
7.4.1.1 VERY COMMON (≥10%) 
Blood and Lymphatic System Disorders: neutropenia 
Gastrointestinal Disorders: nausea, diarrhoea, vomiting 
General Disorders and Administration Site Conditions: fatigue 
7.4.1.2 COMMON (≥ 2% - < 10%) 
Blood and Lymphatic System Disorders: anaemia, thrombocytopenia, leukocytosis, lymphocytosis 
Ear and Labyrinth Disorders: tinnitus 
Eye Disorders: vision blurred 
Gastrointestinal Disorders: constipation, abdominal pain, abdominal distension, dyspepsia, colitis, 
dry mouth 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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General Disorders and Administration Site Conditions: pyrexia, oedema peripheral  
Infections and Infestations: pneumonia, oral candidiasis 
Injury, Poisoning and Procedural Complications: contusion 
Investigations: weight decreased, alanine aminotransferase increased, aspartate aminotransferase 
increased, blood creatinine increased 
Metabolism and Nutrition Disorders: decreased appetite, dehydration, hyperglycaemia, 
hypokalaemia, hypophosphataemia 
Musculoskeletal and Connective Tissue Disorders: muscle spasms, pain in extremity 
Nervous System Disorders: dizziness, headache, dysgeusia, tremor 
Psychiatric Disorders: insomnia 
Respiratory, Thoracic and Mediastinal Disorders: cough 
Skin and Subcutaneous Tissue Disorders: rash maculo-papular, alopecia, night sweats, pruritus, 
rash 
7.4.2 UBLITUXIMAB + TGR-1202 – COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL 
RISKS LIST (CAEPRS) 
The following adverse events were observed in subjects treated with the combination of ublituximab 
+ umbralisib and were considered at least possibly related to one or both of the study medications.  
The preliminary safety data as of May 01, 2018 is provided for a total of 75 subjects exposed to 
ublituximab + umbralisib with a maximum follow up of 3+ years.  See the latest ublituximab and 
umbralisib Investigator’s Brochures for updated safety information a complete list of all adverse 
events reported regardless of causality. 
7.4.2.1 VERY COMMON (≥ 10%) 
Blood and Lymphatic System Disorders: anemia, neutropenia 
Gastrointestinal Disorders: diarrhea, nausea, vomiting 
General Disorders and Administration Site Conditions: fatigue 
Injury, Poisoning and Procedural Complications: infusion related reaction 
Metabolism and Nutrition Disorders: decreased appetite 
7.4.2.2 COMMON (≥ 1% - < 10%) 
Blood and Lymphatic System Disorders: thrombocytopenia 
Cardiac Disorders: cardiac failure congestive 
Ear and Labyrinth Disorders: ear congestion, ear discomfort 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Eye Disorders: conjunctival pallor, conjunctivitis, corneal oedema, vision blurred 
Gastrointestinal Disorders: abdominal discomfort, abdominal distension, abdominal pain, 
constipation, dyspepsia, flatulence, gastrooesophageal reflux disease, haematochezia, salivary 
hypersecretion, stomatitis 
General Disorders and Administration Site Conditions: asthenia, chills, face oedema, infusion site 
pain, local swelling, odedema peripheral, pyrexia, systemic inflammatory response syndrome 
Hepatobiliary Disorders: hyperbilirubinaemia 
Immune System Disorders: hypogammaglobulinaemia 
Infections and Infestations: bronchitis, cellulitis, clostridium difficile colitis, enterocolitis 
infectious, oral candidiasis, oral herpes, otitis media, pneumonia, pneumonia streptococcal, 
rhinovirus infection, sepsis, sepsis syndrome, sinusitis, skin infection, upper respiratory tract 
infection, urinary tract infection 
Injury, Poisoning and Procedural Complications: wound 
Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood 
alkaline phosphatase increased, blood creatinine increased, computerised tomogram thorax 
abnormal, immunoglobulins decreased, weight decreased 
Metabolism and Nutrition Disorders: dehydration, failure to thrive, hyperglycaemia, 
hyperuricaemia, hypokalaemia, hypophosphataemia 
Musculoskeletal and Connective Tissue Disorders: joint swelling, muscle spasms, muscular 
weakness, myalgia, pain in extremity 
Nervous System Disorders: dizziness, dysgeusia, headache, lethargy, sinus headache, somnolence 
Psychiatric Disorders: agitation, anxiety 
Renal and Urinary Disorders: micturition urgency, renal failure, renal failure acute 
Reproductive System and Breast Disorders: scrotal cyst, semen discolouration 
Respiratory, Thoracic and Mediastinal Disorders: choking, cough, dysphonia, dyspnea, epistaxis, 
hypoxia, oropharyngeal pain, pneumonitis, productive cough, sinus congestion 
Skin and Subcutaneous Tissue Disorders: alopecia, cold sweat, dermatitis acneiform, dermatitis 
bullous, dry skin, ecchymosis, pruritus, rash, maculo-papular, rosacea, urticaria 
Vascular Disorders: hypertension 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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8 MEASUREMENT OF EFFECT 
During the study period, response assessments should be obtained every 3 cycles for the first 24 
cycles.  After Cycle 24, evaluate for response approximately every 6 cycles unless clinically indicated 
sooner. Subjects followed for PFS off treatment should have response assessments done 
approximately every 6 months unless clinically indicated sooner.  Date of progression, beginning of 
new treatment, and/or death should be entered in the eCRF.  After baseline assessment, all efficacy 
assessments have a +/- 14-day window.  The determination of response and progression will be 
based on IWCLL criteria (Hallek M, 2008).  Radiographic and clinical disease assessments will be 
subject to independent confirmation by the Independent Review Committee (IRC).  The findings of 
the IRC will be considered primary for analyses of ORR, PFS, and other efficacy endpoints. 
CT scan is the preferred method of tumor assessment, but MRI may be used at the investigator’s 
discretion.  The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and throughout the study.  Please see study manual 
for detailed instructions for disease assessment, and submission of scans for independent review. 
 
All baseline assessments to characterize disease will be performed within 30 days of Cycle 1 Day 1, 
prior to initiation of therapy. 
  
Subjects will remain on study treatment until the occurrence of definitive disease progression 
confirmed by IRC, unacceptable toxicity, or withdrawal from the study due to investigator decision 
or other reasons. Subjects who discontinue from study treatment (either for toxicity or physician 
choice) and have not progressed will continue to be followed for progression as per the protocol. 
8.1 METHOD OF ASSESSMENT 
In addition to clinical examination, radiographic evaluation will be used in all subjects enrolled. CT 
scan is the preferred method for radiographic tumor assessment. MRI scanning may be used at the 
investigator’s discretion in subjects for whom this may be a preferred alternative to CT scanning; 
however, if MRI is performed, a non-contrast CT of the chest should be performed.  Contrast-
enhanced scanning is preferred, but iodine-containing or gadolinium contrast material may be 
omitted in subjects for whom use of a contrast agent would be medically contraindicated. Chest x-
ray, ultrasound, endoscopy, laparoscopy, PET, radionuclide scans, or tumor markers will not be 
considered for response assessment. 
 
For radiographic evaluations, the same method of assessment and the same technique (e.g., scan type, 
subject position, dose of contrast, injection/scan interval) should be used to characterize each 
identified and reported lesion at baseline and during study treatment and follow-up. However, if a 
subject is imaged without contrast at baseline, subsequent assessments should be performed with 
contrast, unless medically contraindicated. 
 
All relevant clinical and radiographic information required to make each disease assessment must be 
made available for source verification and for submission to the IRC. 
 
8.2 RESPONSE REVIEW 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
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An Independent Review Committee (IRC) will provide a blinded review of radiographic data and 
pertinent clinical data in order to provide expert interpretation of changes in disease status.  The 
subject should continue study treatment pending confirmation of progression status.   
 
The review of radiographic and clinical data by the IRC will be performed on an ongoing basis.  The 
specifics of the IRC’s processes and reading methods will be described in an independent review 
charter developed by the contracted imaging facility in conjunction with the Sponsor.   
8.3 IDENTIFICATION 
AND 
MEASUREMENT 
OF 
TUMOR 
LESIONS 
AND 
ORGANOMEGALY 
8.3.1 TARGET LESIONS 
At baseline, up to 6 lymph nodes should be selected as target lesions that will be used to quantify the 
status of the disease during study treatment. Ideally, the target lesions should be located in disparate 
regions of the body. Only peripheral nodes need be selected as target lesions. However, it is optimal 
if mediastinal and retroperitoneal areas of disease are assessed whenever these sites are involved. 
 
Target lesions will be measured and recorded at baseline and as per the study assessment schedule.  
The cross-sectional dimensions (the largest cross-sectional diameter, i.e., the LD × LPD) will be 
recorded (in cm) for each target lesion. The product of the perpendicular diameters (PPD) (in cm2) 
for each target lesion and the sum of the products (SPD) (in cm2) for all target lesions will be 
calculated and recorded. The baseline SPD will be used as references by which objective tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and LPD 
diameters will be reported in centimeters and all PPDs and SPDs will be reported in centimeters 
squared. 
 
A nodal mass may be selected as a measurable nodal target lesion if it is > 1.5 cm in long axis diameter 
and > 1.0 cm in short axis diameter.  At follow-up time points, the LDs for individual lesions and the 
SPD of all nodal target lesions will be considered.  
 
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered progressive 
disease. 
 
In cases in which a large lymph node mass has split into multiple components, all subcomponents 
regardless of size will be used in calculating the SPD. Progression of the lesion will be based on the 
SPD of sub-components. Lesion sub-components will have the true PPDs calculated. Similarly, lesion 
sub-components that are visible but neither abnormal nor measurable will have the default PPD of 
1.0 cm2 (1.0 cm × 1.0 cm) used in calculating the SPD. 
 
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer be 
separated by this boundary, the newly merged lesion will be measured bi-dimensionally. 
 
8.3.2 SPLEEN AND LIVER 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Both the spleen and liver will be assessed by CT/MRI scan and/or by physical examination at baseline 
and as per the study assessment schedule. The baseline and nadir values for the longest vertical 
dimension (LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters. 
 
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD, with the LVD being obtained 
by multiplying the number of sections on which the spleen is visualized by the thickness of the 
sections (e.g., if the spleen is seen in 14 contiguous cross-sectional images with 0.5-cm thickness, the 
LVD is recorded as 7 cm). 
 
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of the 
spleen at baseline or nadir, not changes relative to the total splenic LVD. 
 
A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the spleen in its LVD 
or decrease to ≤ 12 cm by imaging is required for declaration of a splenomegaly response. Conversely, 
an increase in splenic enlargement by ≥ 50% from nadir (minimum increase of 2 cm) is required for 
declaration of splenic progression.  By imaging, the liver will be considered enlarged if it is >18 cm in 
LVD. 
 
A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the liver in its LVD 
or decrease to ≤ 18 cm is required for declaration of a hepatomegaly response.  Conversely, an 
increase in liver enlargement by ≥ 50% from nadir (minimum increase of 2 cm) is required for 
declaration of hepatic progression. 
8.3.3 NON-TARGET LESIONS 
Any other measurable and abnormal nodal lesions not selected for quantitation as target lesions may 
be considered non-target lesions. In addition, non-measurable evidence of CLL such as nodal lesions 
with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal disease, ascites, 
pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal masses that are not 
confirmed and followed by imaging techniques, cystic lesions, previously irradiated lesions, and 
lesions with artifacts may be considered as non-target disease. 
 
The presence or absence of non-target disease should be recorded at baseline and as per the study 
assessment schedule. If present at baseline, up to 6 non-target lesions should be recorded. The non-
target disease at baseline will be used as a general reference to further characterize regression or 
progression of CLL during assessments of the objective tumor response during treatment. 
Measurements are not required, and these lesions should be followed as “present” or “absent”. 
8.4 DEFINITIONS OF TUMOR RESPONSE AND PROGRESSION 
Responses will be categorized by the IRC as CR, CRi, nPR, PR, SD, or PD. In addition, a response 
category of not evaluable (NE) is provided for situations in which there is inadequate information to 
otherwise categorize response status. 
 
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference for 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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disease progression the smallest measurements recorded since treatment started). Where imaging 
data are available, these data will supersede physical examination data in determining tumor status. 
8.5 COMPLETE RESPONSE 
 
To satisfy criteria for a CR, all of the following criteria must be met: 
• 
No evidence of new disease 
• 
ALC in peripheral blood of <4 x 109/L 
• 
Regression of all target nodal masses to normal size ≤1.5 cm in the LD 
• 
Normal spleen and liver size 
• 
Regression to normal of all nodal non-target disease and disappearance of all detectable non-
nodal, non-target disease 
• 
Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age 
• 
Peripheral blood counts meeting all of the following criteria: 
o ANC >1.5 x 109/L without need for exogenous growth factors (e.g., G-CSF) 
o Platelet count ≥100 x 109/L without need for exogenous growth factors 
o Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (e.g., erythropoietin) 
 
Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who have a persistent 
anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow that is related to prior or 
ongoing drug toxicity (and not to CLL) will be considered as a CR with incomplete marrow recovery 
(CRi). 
 
8.6 PARTIAL RESPONSE 
 
To satisfy criteria for a PR, all of the following criteria must be met: 
• 
No evidence of new disease 
• 
A change in disease status meeting ≥2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: 1) only lymphadenopathy is present at baseline; 2) only 
lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:   
o In a subject with baseline lymphocytosis (ALC ≥4 x 109/L), a decrease in peripheral 
blood ALC by ≥50% from baseline or a decrease to <4 x 109/L 
o A decrease by ≥50% from the baseline in the SPD of the target nodal lesions 
o In a subject with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Section 8.3.2 
o In a subject with enlargement of the liver at baseline, a hepatomegaly response as 
defined in Section 8.3.2 
o A decrease by ≥50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules 
• 
No target, splenic, liver, or non-target disease with worsening that meets the criteria for 
definitive PD 
• 
Peripheral blood counts meeting 1 of the following criteria: 
o ANC >1.5 x 109/L or >50% increase over baseline without need for exogenous growth 
factors (e.g., G-CSF) 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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o Platelet count ≥100 x 109/L or ≥50% increase over baseline without need for 
exogenous growth factors 
o Hemoglobin ≥110 g/L (11.0 g/dL) or ≥50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (e.g., erythropoietin) 
8.7 STABLE DISEASE 
 
To satisfy criteria for SD, the following criteria must be met: 
 
• 
No evidence of new disease 
• 
There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD 
8.8 DEFINITIVE DISEASE PROGRESSION 
 
The occurrence of any of the following events indicates definitive PD: 
• 
Evidence of any new disease: 
o A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD 
o New or recurrent splenomegaly, with a minimum LVD of 14 cm 
o New or recurrent hepatomegaly, with a minimum LVD of 20 cm 
o Unequivocal reappearance of an extra-nodal lesion that had resolved 
o A new unequivocal extra-nodal lesion of any size  
o *New non-target disease (e.g., effusions, ascites, or other organ abnormalities related to 
CLL). 
 
*Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence alone of PD 
unless histologically confirmed. Thus, a declaration of PD should not be made if this is the only 
manifestation of apparently new disease. 
 
• 
Evidence of worsening of target lesions, spleen or liver, or non-target disease: 
o Increase from the nadir by ≥50% from the nadir in the SPD of target lesions 
o Increase from the nadir by ≥50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm 
o Splenic progression, defined as an increase in splenic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm) 
o Hepatic progression, defined as an increase in hepatic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm) 
o Unequivocal increase in the size of non-target disease (e.g., effusions, ascites, or other 
organ abnormalities related to CLL) 
o Transformation to a more aggressive histology (e.g., Richter’s syndrome) as established 
by biopsy (with the date of the biopsy being considered the date of CLL progression if the 
subject has no earlier objective documentation of CLL progression). 
 
• 
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells 
o The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
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o The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by >20 
g/L (2 g/dL) from the highest on-study hemoglobin 
 
If there is uncertainty regarding whether there is true progression, the subject should continue study 
treatment and remain under close observation pending confirmation of progression status by the 
IRC. In particular, worsening of constitutional symptoms in the absence of objective evidence of 
worsening CLL will not be considered definitive disease progression; in such subjects, both CLL-
related and non-CLL-related causes for the constitutional symptoms should be considered.  
 
Worsening of disease during temporary interruption of study treatment (e.g., for intercurrent illness) 
is not necessarily indicative of resistance to study treatment. In these instances, CT/MRI or other 
relevant evaluations should be considered in order to document whether definitive disease 
progression has occurred. If subsequent evaluations suggest that the subject has experienced 
persistent definitive CLL progression, then the date of progression should be the timepoint at which 
progression was first objectively documented. 
8.9 NON-EVALUABLE 
 
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 
• 
There are no images or inadequate or missing images 
• 
Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have undergone 
splenectomy). 
 
A time-point will be considered to have a response of NE if any target lesion is missing. PD may be 
assigned at any time point regardless of the extent of missing target or non-target lesions. Missing 
non-target lesions will not impact the ability to assess for response or disease progression. 
8.10 LYMPHOCYTOSIS DURING THERAPY 
 
Upon initiation of TGR-1202, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from 
baseline and above absolute lymphocyte count of 5,000/mcL) may occur. The onset of isolated 
lymphocytosis usually occurs during the first few weeks of TGR-1202 therapy and usually resolves 
within three to four months.  Subjects with lymphocytosis should be continued on study drug until 
the occurrence of definitive disease progression (i.e., disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another reason 
to discontinue study therapy. 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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. 
9.3 ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) population will consist of all randomized subjects, regardless of 
administration of study treatment (ublituximab, TGR-1202, obinutuzumab + chlorambucil or 
ublituximab + TGR-1202).  Analyses of this population will assign subjects the treatment they were 
scheduled to receive, regardless of any errors of dosing or dose modifications.  Subjects who received 
treatment in the group that is different from what they have been randomized to, will be noted in the 
Clinical Study Report.  The ITT population is the primary analysis population for efficacy analyses.   


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The safety population will include all randomized subjects who received at least one dose of study 
treatment (ublituximab, TGR-1202, obinutuzumab + chlorambucil, or ublituximab + TGR-1202).  
Subjects who are included in a treatment group that is different from what they have been 
randomized to will be noted. 
The per protocol population will include all ITT subjects without major protocol violations.  Major 
protocol violations will be documented.  Analyses based on per protocol population may be 
performed. 
9.4 SUBJECTS DISPOSITION 
Subject disposition summaries will be presented by treatment arm and will include the number of 
subjects enrolled, randomized, and the number and percentage of randomized subjects in the ITT 
and safety populations.  The summaries will also include the reasons for permanent discontinuation 
of study treatment and study.  Disposition by investigational sites will also be presented. 
9.5 SUBJECT DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline demographic and clinical characteristics will be summarized as percentages for categorical 
variables and as mean, standard deviation, median, minimum and maximum for continuous 
measures. The analyses of baseline characteristics will be performed for the ITT Population.   
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 subjects whose dose is modified at any time will be summarized by each 
type of modification by cycle and overall.  The proportion of subjects completing each cycle of 
treatment will be summarized. 
9.8 EFFICACY ANALYSES   
Each subject will be assigned to one of the following categories:  1) complete response (CR or CRi), 
2) partial response (PR or nPR), 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown 
(not assessable, insufficient data). 
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 review committee (IRC) which 
will be blinded to treatment arm assignment.   Definitive disease progression will be based on 
standard criteria (Hallek et al. 2008, Appendix A – CLL Response Definition) occurring for any reason 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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(e.g., increasing lymphadenopathy, organomegaly or bone marrow involvement; decreasing platelet 
count, hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other than 
lymphocytosis. 
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 duration of progression-free survival (PFS).   
9.10.1.1 PROGRESSION-FREE SURVIVAL 
Duration of PFS is defined as the number of days between randomization and the date of progression 
(as confirmed by the IRC) or death due to any cause.  The duration of PFS for subjects who progress 
and then subsequently die will be the number of days between randomization and the date of 
progression is first observed. 
Hypothesis testing for comparison between the treatment arms will be performed using a stratified 
(by randomization stratification factors) log-rank test via 
  For each 
treatment arm, the median duration of PFS and the proportion of subjects alive and progression-free 
at 6, 12, and 18 months will be estimated using the Kaplan-Meier method.  For each estimate, a 95% 
confidence interval will be reported. 
The primary objective that Treatment A is superior to Treatment B will be tested at an overall two-
sided 0.04 level of significance. 
Unless earlier established at the interim analysis for ORR, contribution of the individual components 
will be analyzed according to the testing plan described in the UTX-TGR-304 Statistical Analysis Plan 
which will be conducted in agreement with the FDA.   
9.10.2 SECONDARY EFFICACY OUTCOMES 
Other secondary efficacy outcomes include: Overall Response Rate (ORR), CR rate, Minimal Residual 
Disease (MRD) negativity, Duration of response (DOR), and overall survival (OS).  
9.10.2.1 OVERALL RESPONSE RATE 
ORR will be determined according to the criteria of the International Workshop on Chronic 
Lymphocytic Leukemia (Hallek et al. 2008). 
Overall Response Rate (ORR) is defined as percent of subjects who achieve CR, CRi, nPR, or PR.  The 
response rate will be analyzed using a Cochran-Mantel-Haenzel (CMH) test stratified by the 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
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randomization factors.  The 95% confidence intervals for the response rates as well as for the 
differences of the response rate will be presented.   
The key secondary objective that Treatment A provides additional clinical benefit over treatments C 
alone and D alone will be tested a two-sided 0.01 level of significance at the interim (when the first 
50 subjects enrolled into each arm provided ORR assessment). 
Contribution of the individual components based on ORR will be analyzed according to the testing 
plan described in the UTX-TGR-304 Statistical Analysis Plan which will be conducted in agreement 
with the FDA. 
If contributions of individual components based on ORR is established at the interim ORR analysis, a 
formal test of ORR between Treatment A will be tested conducted at a two- sided 0.01 level following 
a positive interim PFS analysis or, if the interim PFS analysis is negative, following the final PFS 
analysis. 
9.10.2.2 CR RATE 
CR rate is defined as the percent of subjects who achieve a CR or CRi.  CR rate will be analyzed using 
a Cochran-Mantel-Haenzel (CMH) test stratified by the randomization factors.  The 95% confidence 
intervals for the response rates as well as for the differences of the complete response rate will be 
presented. 
9.10.2.3 MINIMAL RESIDUAL DISEASE NEGATIVITY 
The MRD negativity rate is defined as the proportion of subjects who achieve MRD negativity post-
baseline.  MRD is assessed only amongst responders, defined as subjects achieving CR/CRi/PR/nPR.  
Subjects who do not have an MRD assessment at any post-baseline visits will be considered non-
responders and will be included in the denominator when calculating MRD negativity rate.  MRD 
negativity rate will be analyzed in the ITT population using a Cochran-Mantel-Haenzel (CMH) test 
stratified by the randomization factors.  The 95% confidence intervals for the MRD negativity rates 
as well as for the differences of the MRD negativity rate will be presented. 
9.10.2.4 DURATION OF RESPONSE 
Duration of response (DOR) defined as the interval from the first documentation of CR, CRi, nPR, or 
PR to the earlier of the first documentation of definitive disease progression or death from any cause.  
The Kaplan-Meier estimator for DOR will be presented for patients who achieve an objective 
response in each treatment arm. The same censoring rules will be applied as for PFS.   
9.10.2.5 OVERALL SURVIVAL 
Overall Survival (OS) is defined as the interval from randomization to death from any cause.  As 
subjects are expected to survive for a long time relative to the duration of the study, OS analysis may 
not be reliable due to heavily censored data.  OS will be evaluated if, for example, sufficient data are 
available.  OS data will be censored at the last documented date that the subject is confirmed alive for 
subjects who withdraw consent or are lost to follow-up prior to the end of the study, and for subjects 
whose vital status in the study cannot be determined.  The Kaplan-Meier estimator for OS will be 
presented for all subjects in the ITT population.   
 


 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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9.11 MULTIPLE COMPARISON PROCEDURES   
The study has the following three pre-specified primary efficacy evaluations: 
 
1. Assessing whether Treatment A is superior to Treatment B based on PFS; 
2. Assessing contributions of individual components in Treatment A established based on PFS; 
3. Assessing contributions of individual components in Treatment A established based on ORR; 
 
Contributions of individual components of Treatment A will be established if positivity is established 
for either #2 or #3, above.   
 
To control for the overall Type I error rate at 0.05, an overall two-sided p-value of 0.01 will be used 
to evaluate #3, at the interim analysis when the first 50 patients in Treatment Arms A, C, and D have 
provided adequate ORR data (at least one post-baseline disease assessment).  If contributions of 
individual components in Treatment A based on ORR is established at the interim ORR analysis, a 
formal test of ORR between Treatment A and Treatment B will be conducted at a two-sided 0.01 level 
following a positive interim PFS analysis or, if the interim PFS analysis is negative, following the final 
PFS analysis.  Analysis of CR rate and MRD negativity rate will also be conducted sequentially at the 
two-sided 0.01 level.    
 
The remaining overall two-sided p-value of 0.04 will be used to evaluate #1 (and to evaluate #2 if #3 
is not earlier established to be positive).  If #1 is established to be positive and #3 has not been 
established to be positive at the interim ORR analysis for contribution, the following assessments will 
be evaluated at the overall two-sided 0.04 significance level to establish #2: 
1. Assessing whether treatment A is superior to Treatment C regarding PFS; and 
2. Assessing whether treatment A is superior to Treatment D regarding PFS. 
 
To control for the overall Type I error rate, a claim cannot be made unless all proceeding claims, if 
any, are made.   For completeness, all p-values will be presented. 
 
9.12 INTERIM ANALYSES   


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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One interim analysis based on ORR will be performed when approximately 50 subjects each in Arms 
A, B, C and D have provided disease assessments to determine ORR status.  If contributions of 
individual components in Treatment A based on ORR is established at the interim ORR analysis, a 
secondary claim that Treatment A is superior over Treatment B based on ORR will be tested at a two-
side 0.01 level following a positive interim PFS analysis or, if the interim PFS analysis is negative, 
following the final PFS analysis.   Further, should contribution be established at the interim ORR 
analysis, enrollment into both Arms C and D will be terminated, however enrollment into Arms A and 
B will continue until 175 patients have been enrolled into each arm. If contribution was unable to be 
established by ORR at the interim analysis, both single agent arms C and D will be evaluated for PFS. 
One interim analysis based on PFS will be performed solely for purposes of assessing futility at 
approximately 50% information time (140 events).    A second interim PFS analysis will be conducted 
at the later to occur of i) 75% information time (210 events), and ii) December 10, 2019, to evaluate 
the superiority hypothesis for Arm A compared to Arm B.  At this interim analysis, early study 
termination will be guided by an O'Brien-Fleming monitoring boundary that is preserving the (one-
sided) 0.0005 false positive error rate.  At 75% of the events (i.e., 210 PFS events), the corresponding 
Z-value would be 3.81, with corresponding nominal two-sided p=0.00013.  If early termination does 
not occur, nearly all of the two sided 0.04 false positive error rate allocated to PFS would have been 
preserved, statistical significance for PFS at the 280 event final analysis would be achieved with Z-
value 2.06.  The study will end either at the second interim PFS analysis or at the final PFS analysis.   
 
An independent DSMB has been established and will conduct all interim analyses in addition to 
reviewing clinical data periodically throughout the trial.  The DSMB may recommend stopping or 
modifying the trial for safety.  


 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10 SAFETY REPORTING AND ANALYSIS 
10.1 SAFETY ANALYSES 
Safety evaluations will be based on the incidence, intensity, and type of adverse events, as well as on 
clinically significant changes in the subject’s physical examination, vital signs, and clinical laboratory 
results.  Safety analyses will be performed using the safety population.  Safety variables will be 
tabulated and presented by the dose of ublituximab, TGR-1202, obinutuzumab + chlorambucil 
and/or the combination of ublituximab + TGR-1202 study drug actually received.  Exposure to study 
treatment and reasons for discontinuation of study treatment will also be tabulated. 
10.2 ADVERSE EVENT CHARACTERISTICS 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy 
of 
the 
CTCAE 
version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.     
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes only. 
Expected AEs are defined as those described in the ublituximab Investigator Brochure and the TGR-
1202 Investigator Brochure.  Please refer to the obinutuzumab as well as chlorambucil prescribing 
information for a listing of expected AEs. 
10.3 DEFINITIONS OF ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product. An AE does not necessarily have to have a causal 
relationship with this treatment.   An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporarily associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition. 
In clinical studies, an AE can include an undesirable medical condition occurring at any time, 
including run-in or washout periods, even if no study treatment has been administered.  The NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0 is to be used for the grading of 
severity of symptoms and abnormal findings.  For adverse events not covered by the NCI-CTCAE 
Version 4.0 grading system, the following definitions will be used: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.4 ADVERSE EVENTS (AE’S) AND TREATMENT EMERGENT ADVERSE EVENTS 
(TEAE’S) 
All AEs and SAEs occurring on study will be listed by subject.  The frequency and percentages of 
subjects 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 subject 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. 
 
10.5 ADVERSE EVENTS / SERIOUS ADVERSE EVENT CAUSALITY ASSESSMENT 
The Investigator must also assess the relationship of any adverse event to the use of study drugs 
(whether none, one, or both), based on available information, using the following guidelines: 
• 
Not Related: Clear-cut temporal and/or mechanistic relation to a cause other than the study 
drug(s). 
• 
Doubtful: There is no reasonable possibility that the event is related to the study drug(s) but 
a definite cause cannot be ascertained. 
• 
Possible: There is still a reasonable possibility that the cause of the event was the study 
drug(s) but there exists a more likely cause of the event such as complications of progressive 
disease. 
• 
Probable: The most likely cause of the event is the study drug(s) but other causes cannot be 
completely excluded. 
• 
Definite: Clear cut temporal and/or mechanistic relation to the study drug(s).  All other 
causes have been eliminated.  Events classified as definite will often be confirmed by 
documenting resolution on discontinuation of the study drug and recurrence upon 
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10.5.1 RECORDING OF ADVERSE EVENTS 
All adverse events of any subject during the course of the study will be reported on the case report 
form, and the investigator will give his or her opinion as to the relationship of the adverse event to 
study drug treatment (i.e., whether the event is related or unrelated to study drug administration – 
either ublituximab, TGR-1202, obinutuzumab + chlorambucil or ublituximab + 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 ublituximab, TGR-1202, obinutuzumab + 
chlorambucil or ublituximab + TGR-1202 treatment spanning from Cycle 1/Day 1 until 30 calendar 
days after discontinuation or completion of either protocol-specific treatment (Arm B subjects 
should complete at end of study (EOS) visit) as defined by the protocol for that subject, are to be 
recorded on the eCRF. 
10.5.2 ABNORMAL LABORATORY VALUES AND VITAL SIGNS 
The reporting of abnormalities of vital signs as adverse events should be avoided.  Abnormalities of 
vital signs should not be reported unless any criterion for an SAE is fulfilled, the vital signs 
abnormalities cause the subject 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.  Subjects 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.  Subject incidence of abnormal laboratory 
results will be summarized by treatment group and maximum grade for each abnormal laboratory 
finding. 
10.5.3 HANDLING OF ADVERSE EVENTS 
All adverse events resulting in discontinuation from the study should be followed until resolution or 
stabilization.  Subjects should be followed for AEs for 30 calendar days after discontinuation or 
completion of protocol-specific treatment (either ublituximab, TGR-1202, obinutuzumab + 
chlorambucil or ublituximab + TGR-1202).  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 subject’s medical record and as a comment on the eCRF.  After 


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


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


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.7  SPONSOR SAE REPORTING REQUIREMENTS 
Sponsor is responsible for reporting relevant SAEs to the competent authority, other applicable 
regulatory authorities, and participating investigators, in accordance with ICH guidelines, FDA 
regulations, and/or local regulatory requirements. 
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). 
10.8 RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on the 
SAE Report Forms and AE eCRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE eCRF; AEs 
that meet the definition of an SAE should additionally be reported. 
10.9 DIAGNOSIS VS. SIGNS AND SYMPTOMS 
All AEs should be recorded individually in the subject’s own words (verbatim) unless, in the opinion 
of the Principal Investigator or designated physician, the AEs constitute components of a recognized 
condition, disease, or syndrome.  In the latter case, the condition, disease, or syndrome should be 
named rather than each individual sign or symptom.  If a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an AE or SAE as appropriate on the relevant form(s) (SAE 
Report Form and/or AE eCRF).  If a diagnosis is subsequently established, it should be reported as 
follow-up information is available.  If a diagnosis is determined subsequent to the reporting of the 
constellation of symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
10.9.1 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between subject evaluation time 
points.  Such events should only be recorded once on the SAE Report Form and/or the AE eCRF.    If 
a persistent AE becomes more severe (changes from a Grade 1 or 2 AE to a Grade 3 or 4 AE) or lessens 
in severity (changes from a Grade 3 or 4 AE to a Grade 1 or 2 AE), it should be recorded on a separate 
SAE Report Form and/or AE eCRF.   


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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A recurrent AE is one that occurs and resolves between subject evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE eCRF 
for each recurrence. 
10.9.2 ABNORMAL LABORATORY VALUES 
Abnormal laboratory results should be noted in the eCRF as an adverse event if they are associated 
with an overdose, require or prolong inpatient hospitalization, or are otherwise considered clinically 
significant by the investigator. If an abnormal laboratory value or vital sign is associated with clinical 
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. 
10.9.3 DEATHS 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of the subject’s CLL for up to 30 days post the last dose of study 
drug will be recorded on the appropriate study eCRF and not reported on the 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. 
10.9.4 HOSPITALIZATION, PROLONGED HOSPITALIZATION, OR SURGERY 
Any AE that results in hospital admission of >24 hours or prolongs hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this protocol.  There 
are some hospitalization scenarios that do not require reporting as an SAE when there is no 
occurrence of an AE.  See section 10.6.1.   
10.9.5 PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing relevant medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the study’s appropriate medical history eCRF.  A pre-existing 
medical condition should be recorded as an AE or SAE only if the frequency, severity, or character of 
the condition worsens during the study.  When recording such events on the appropriate SAE Report 
Form and/or AE eCRF, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
 
 


  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.9.6 PROTOCOL-DEFINED EVENTS OF SPECIAL INTEREST 
The following are events of special interest, and will need to be reported expeditiously: 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
During the course of the study, all female subjects of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix B- Contraceptive Guidelines and Pregnancy) 
must contact the treating investigator immediately if they suspect that they may be pregnant (a 
missed or late menstrual period should be reported to the treating investigator).   
If an investigator suspects that a subject may be pregnant prior to administration of study drug(s), 
the study drug(s) must be withheld until the result of the pregnancy test is confirmed.  If a pregnancy 
is confirmed, the subject must not receive any study drug(s) and must be discontinued from the study.   
If an investigator suspects that a subject may be pregnant after the subject has been receiving study 
drug(s), the study drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed.  If a pregnancy is confirmed, the study drug(s) must be immediately and permanently 
stopped, the subject must be discontinued from the study, and the investigator must notify the Study 
Chair or Medical Monitor as soon as possible.   
If a subject becomes pregnant while enrolled in the study, an SAE form should be completed and 
submitted to the Sponsor.  Abortions (spontaneous, accidental, or therapeutic) must also be reported 
to the Sponsor. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be expeditiously 
reported as an SAE, using the previously described process for SAE reporting. 
Study Drug Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment (either ublituximab, TGR-1202, obinutuzumab + 
chlorambucil or ublituximab + TGR-1202) 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, 
subjects should stop study drug dosing and be clinically monitored as appropriate, managing 
symptoms/side effects that may occur. 
Secondary/Second Primary Malignancy  
Any secondary and/or second primary 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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11 DATA SAFETY MONITORING BOARD (DSMB) 
An independent Data Safety Monitoring Board (DSMB) has be established to advise the Sponsor on 
safety and provide benefit/risk oversight of the study as described in the DSMB Charter.  This 
independent DSMB will review the study clinical data at regular intervals or as necessary.  The DSMB 
may advise the Sponsor to terminate the study early or modify the protocol to address safety signals 
that they may identify.  
 


 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12 CLINICAL DATA COLLECTION AND MONITORING 
12.1 SITE MONITORING PLAN 
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 subject 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 subject confidentiality is 
maintained. 
Site monitoring shall be conducted to ensure the human subject protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality and 
meet the Sponsor, GCP/ICH and, when appropriate, regulatory guidelines.  The Site Monitoring Plan 
shall define aspects of the monitoring process. 
12.2 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. 
12.3 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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13 GCP, 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).  
 
13.1 IRB APPROVAL 
The study protocol, ICF, IB, available safety information, subject documents (e.g., study diary), subject 
recruitment procedures (e.g., advertisements), information about payments (i.e., PI payments) and 
compensation available to the subjects and documentation evidencing the PI’s qualifications must be 
submitted to the IRB 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. 
13.2 REGULATORY APPROVAL 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and approval 
of the appropriate regulatory bodies obtained, prior to study initiation. If required, the Sponsor will 
also ensure that the implementation of substantial amendment to the protocol and other relevant 
study documents happen only after approval by the relevant regulatory authorities. 
Safety updates for ublituximab and/or TGR-1202 will be prepared by the Sponsor or its 
representative as required, for submission to the relevant regulatory authority.   
13.3 INSURANCE AND INDEMNITY 
Details of insurance and/or indemnity will be contained within the written agreement between the 
PI or site and the Sponsor. 
13.4 INFORMED CONSENT 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study that are 
relevant to the subject's decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
    
   
 
    
 
 
 
 
  
 
 
 
 
    
 
 
 
 
  
 
  
  
  
   
 
  
 
    
   
 
 
     
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
   
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The ICF will be submitted for approval to the IRB that is responsible for review and approval of the 
study.  Each consent form must include all of the relevant elements currently required by the 
responsible regulatory authority, as well as local county authority or state regulations and national 
requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the study.  Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications of 
participating in this study, the candidate will be asked to give consent to participate in the study by 
signing an informed consent form.  A notation that written informed consent has been obtained will 
be made in the subject’s medical record.  A copy of the informed consent form, to include the subject’s 
signature, will be provided by the investigator to the subject.   
If an amendment to the protocol substantially alters the study design or the potential risks to the 
subjects, the subject’s consent to continue participation in the study must be obtained. 
13.5 CONFIDENTIALITY 
Subject Confidentiality 
Confidentiality of subject’s personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), and national data protection laws. HIPAA 
regulations require that, in order to participate in the study, a subject 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 subjects 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 subject’s 
medical records, but the subject 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 subject to revoke his or her authorization.  
In the event that a subject revokes authorization to collect or use his or her PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should be 
made to obtain permission to collect at least vital status (i.e., that the subject is alive) at the end of 
their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that the 
investigator and institution permit authorized representatives of the Sponsor, the regulatory 


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


 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
    
      
 
    
  
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
    
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
  
 
     
  
 
   
  
  
  
 
 
  
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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14 RECORD RETENTION AND DOCUMENTATION OF THE STUDY 
14.1 DOCUMENTATION REQUIRED TO INITIATE STUDY 
Before the study may begin, certain documentation required by FDA regulations and/or local 
regulatory authorities 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 Vitae 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. 
14.2 STUDY DOCUMENTATION AND STORAGE 
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated study 
duties and should ensure that all persons assisting in the conduct of the study are informed of their 
obligations. All persons authorized to make entries and/or corrections on the eCRFs are to be 
included on this document. All entries in the subject’s eCRF are to be supported by source 
documentation 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 subject’s eCRF data are obtained. 
These can include, but are not limited to, hospital records, clinical and office charts, laboratory, 
medico-technical department and pharmacy records, diaries, microfiches, EKG traces, copies or 
transcriptions certified after verification as being accurate and complete, photographic negatives, 
microfilm or magnetic media, X-rays, and correspondence. 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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, subject 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 subjects (sufficient information to link records e.g., medical records), all original, signed 
informed consent forms, and copies of all eCRFs, SAE Reporting forms, source documents, detailed 
records of treatment disposition, and related essential regulatory documents.  The documents listed 
above must be retained by the investigator for as long as needed to comply with national and 
international regulations (generally 2 years after discontinuing clinical development or after the last 
marketing approval).  The Sponsor or its representative will notify the investigator(s)/institutions(s) 
when the study-related records are no longer required.   
If the investigator relocates, retires, or for any reason withdraws from the study, either the Sponsor 
or its representative should be prospectively notified.  The study records must be transferred to an 
acceptable designee, such as another investigator, another institution, or to sponsor.  The 
investigator must obtain the sponsor written permission before disposing of any records, even if 
retention requirements have been met.  All study files will be maintained by the Sponsor or its 
representative throughout the study, and will be transferred to the Sponsor at the conclusion of the 
study. 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
  
 
 
 
    
  
 
  
  
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.3 AMENDMENTS TO THE PROTOCOL 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation.   
If an amendment to the protocol is required, the amendment will be originated and documented by 
the Sponsor.  All amendments require review and approval of the Sponsor and the Principal 
Investigator supporting the study.  The written amendment must be reviewed and approved by the 
Sponsor, and submitted to the IRB at the investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to subject, increase to dosing or 
exposure, subject 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 subject exposure and/or subject number 
has been proposed; or, when the addition or removal of an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and REC and/or FDA and Competent Authority 
approval include, but are not limited to, the following: 
• 
Change to study design  
• 
Risk to subject 
• 
Increase to dose or subject exposure to drug  
• 
Subject 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 subjects, their consent to continue participation in the study should be 
obtained. 
14.4 DATA COLLECTION 
The study eCRF is the primary data collection instrument for the study. An electronic case report 
form will be utilized for the collection of all data and all data will be entered using the English 
language and should be kept current to enable the monitor to review the subjects’ status throughout 
the course of the study. 
In order to maintain confidentiality, only study number, subject number, initials and date of birth will 
identify the subject in the eCRF.  If the subject’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 subject number and subject’s initials.  The investigator will maintain a 
personal subject identification list (subject numbers with corresponding subject identifiers) to 
enable records to be identified and verified as authentic. Subject data/information will be kept 
confidential, and will be managed according to applicable local, state, and federal regulations. 


 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.5 STUDY MONITORING, AUDITING, AND INSPECTING 
The investigator will permit study-related monitoring, quality audits, and inspections by government 
regulatory authorities, the Sponsor or its representative(s) of all study-related documents (e.g., 
source documents, regulatory documents, data collection instruments, case report forms).  The 
investigator will ensure the capability for inspections of applicable study-related facilities.  The 
investigator will ensure that the study monitor or any other compliance or QA reviewer is given 
access to all study-related documents and study-related facilities.   
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities and the sponsor or its representative(s).  
At the Sponsor’s discretion, Source Document Verification (SDV) may be performed on all data items 
or a percentage thereof. 
14.6 QUALITY ASSURANCE AND QUALITY CONTROL 
In addition to the Clinical Monitoring component of this protocol, the Sponsor’s Quality Assurance 
(QA) department shall establish an Auditing Plan document separate from the protocol to establish 
the criteria by which independent auditing shall be conducted during the conduct of the study to 
assess compliance with GCP and applicable regulatory requirements.  Data or documentation audited 
shall be assessed for compliance to the protocol, accuracy in relation to source documents and 
compliance to applicable regulations. 
Each study site shall be required to have Standard Operating Procedures (SOP’s) to define and ensure 
quality assurance/control processes for study conduct, data generation & collection, recording of 
data/documentation and reporting according to the protocol, GCP and any applicable local, national 
or international regulations. 
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. 
As this is an open-label study, to protect data integrity, the following procedures will be implemented 
to ensure all clinical and statistical decisions are made in a treatment blinded manner. The Sponsor, 
except for Clinical Operations personnel monitoring the study and the Medical Monitor, will be 
blinded to treatment assignment and specific dosing data within the three individual treatment arms. 
In addition, unblinded Clinical Operations personnel will not be involved in any discussions 
regarding the analysis of data after enrollment of the first subject into the trial or any protocol 
amendment, except those related to safety. 
 
 
 


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


 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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15 REFERENCES 
 
Altekruse SF, K. C. (2010, November). SEER Cancer Statistics Review. Retrieved from seer.cancer.gov: 
http://seer.cancer.gov/csr/1975.2007 
American Cancer Society. (2014). American Cancer Society. Retrieved June 5, 2014, from 
www.cancer.org: 
http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-
042151.pdf 
Cazin B, L. S. (2013). Final results of a multicenter phase Ib single agent study with the novel anti-
CD20 monoclonal antibody ublituximab (TG-1101) in patients with relapsed chronic 
lymphocytic leukemia (CLL). European Hematology Assocation, (p. abstractP111). Stockholm. 
de Romeuf C, D. C.-T.-B. (2008). Chronic lymphocytic leukaemia cells are effeciently killed by an anti-
CD20 monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16. 
British Journal of Haematology, 6(140), 635-643. 
Esteves IT, D. C. (2011). LFB-R603 (ublituximab), a third-generation monoclonal anti-CD20 antibody, 
displays additive antitumor activity with antileukemic chemotherpeutic agents in mouse 
xenograft models. American Society of Hematology, abstract 1660. 
Genentech Inc. (2013, September). Rituxan (rituximab) Prescribing Information. South San 
Francisco, CA. 
Hallek M, C. B.-C. (2008). Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: 
a report from the International Wrokshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institue - Wroking Group 1996 Guidelines. blood, 12(111), 5446-5456. 
Lin K, S. P. (2002). Relationship between p53 dysfunction, CD38 expression and IgVH mutatin in 
chronic lymphcytic leukemia. blood, 1404. 
O'Connor OA, D. C. (2014). A phase I trial of ublituximab (TG-1101), a novel anti-CD20 monoclonal 
antibody (MAB) in B-cell lymphoma patients with prior exposure to rituximab. American 
Society of Clinical Oncology, (p. abstract 8524). Chicago. 
 (2011). PI3Kgamma enzyme assay. Shameerpet, India: Incozen Therapeutics. 
 (2011). AKT phosphorylation in MOLT-4 cells. June Study Report IVT-5264-APM-10. 
Shameerpet, India: Incozen Therapeuticis PVT Ltd. 
 (2011). AKT phosphorylation in THP-1 cells. Study Report IVT-5264-ATP-08. Shameerpet, 
India: Incozen Therapeuticis PVT Ltd. 
 


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


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


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


 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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17 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 a) 4 months after the last 
treatment dose if randomized to treatment Arms A, C, or D; or b) 18 months after the last treatment 
dose of obinutuzumab and 4 weeks after the last dose of chlorambucil if randomized to Arm B. The 
highly effective contraception is defined as either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
2. Sterilization:  have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least 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 subjects on the study, the vasectomised male 
partner should be the sole partner for that subject. 
4. Oral contraception, injected or implanted hormonal methods. 
5. Use of a combination of any 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 pregnancy test ≤ 72 hours prior to 
initiating treatment. 
Fertile Males: 
Fertile males, defined as all males physiologically capable of conceiving offspring must use a condom 
during treatment, and for a) 4 months after the last treatment dose if randomized to treatment Arms 
A, C, or D; or b) 18 months after the last treatment dose of obinutuzumab and 4 weeks after the last 
dose of chlorambucil if randomized to Arm B, and should not father a child in this period. 
Pregnancies 
To ensure subject safety, each pregnancy in a subject 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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18 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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19 APPENDIX D – HEPATITIS B SEROLOGIC TEST RESULTS 
 

SAP_001.pdf: 


  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Protocol UTX-TGR-304 
Phase 3 
 
A Phase 3, Randomized Study to Assess the Efficacy 
and Safety of Ublituximab in Combination with TGR-
1202 Compared to Obinutuzumab in Combination 
with Chlorambucil in Patients with Chronic 
Lymphocytic Leukemia (CLL) 
 
Statistical Analysis Plan 
 
 
Sponsor 
TG Therapeutics, Inc. 
2 Gansevoort St., 9th Floor 
New York, NY 10014 
Tel: (212) 554-4484 
 
 
Study Coordination 
TG Therapeutics, Inc. 
2 Gansevoort St., 9th Floor 
New York, NY 10014 
Tel: (212) 554-4484 
 
Medical Monitor 
Tel:
 
Study Chair 
Tel 
 
 
Version Final 2.0 
 
March 15, 2020 
 
 
 




 
 
 
  
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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TABLE OF CONTENTS 
1.0 
DOCUMENT HISTORY ............................................................................................................................. 5 
2.0 
LIST OF ABBREVIATIONS ...................................................................................................................... 6 
3.0 
INTRODUCTION ........................................................................................................................................ 7 
4.0 
STUDY DESCRIPTION ............................................................................................................................. 8 
4.1 
Study Objectives ........................................................................................................................ 8 
4.2 
Study Treatment ........................................................................................................................ 9 
4.3 
Study Design ............................................................................................................................ 10 
4.4 
Randomization and Blinding ............................................................................................. 11 
5.0 
ANALYSIS POPULATIONS ................................................................................................................... 12 
5.1 
Intent-to-Treat Population ................................................................................................. 12 
5.2 
Safety Population ................................................................................................................... 12 
5.3 
Per protocol Population ...................................................................................................... 12 
6.0 
GENERAL CONVENTIONS ................................................................................................................... 12 
6.1 
Definition of Baseline ........................................................................................................... 13 
6.2 
Definition of Time .................................................................................................................. 13 
6.3 
Missing and Partial Data ...................................................................................................... 13 
7.0 
DESCRIPTION OF THE STUDY POPULATIONS ............................................................................ 13 
7.1 
Disposition ............................................................................................................................... 13 
7.2 
Demographic and Baseline Characteristics .................................................................. 14 
7.3 
Medical History ....................................................................................................................... 14 
7.4 
History of Chronic Lymphocytic Leukemia................................................................... 14 
8.0 
TREATMENTS AND MEDICATIONS ................................................................................................. 14 
8.1 
Prior and Concomitant Medications ............................................................................... 14 
8.2 
Study Treatment Exposure ................................................................................................. 15 
9.0 
EFFICACY ANALYSES ............................................................................................................................ 15 
9.1 
Primary Efficacy Outcomes ................................................................................................ 15 
9.1.1 
Progression-Free Survival .................................................................................................. 15 
9.2 
KEY Secondary Efficacy Outcomes ................................................................................... 17 
9.2.1 
Overall Response Rate ......................................................................................................... 17 
9.3 
Other Secondary Efficacy Outcomes ............................................................................... 17 
9.3.1 
Complete Response Rate ..................................................................................................... 17 
9.3.2 
Minimal Residual Disease Negativity Rate .................................................................. 17 
9.3.3 
Duration of Response ........................................................................................................... 18 
18 
9.5 
Multiplicity ............................................................................................................................... 18 
9.6 
interim analysis ...................................................................................................................... 20 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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9.7 
sample size ............................................................................................................................... 20 
10.0 
SUMMARIES OF MEASURES OF SAFETY ........................................................................................ 21 
10.1 
Adverse Events ........................................................................................................................ 21 
10.2 
Laboratory Assessments ..................................................................................................... 21 
10.2.1 Variables .................................................................................................................................... 22 
10.2.2 Statistical Analysis ................................................................................................................. 22 
10.3 
Vital Signs ................................................................................................................................. 23 
10.3.1 Variables .................................................................................................................................... 23 
10.3.2 Statistical Analysis ................................................................................................................. 23 
10.4 
Physical Exam .......................................................................................................................... 23 
10.5 
ECOG Performance Status ................................................................................................... 23 
11.0 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS ........................................... 23 
12.0 
DATA QUALITY ASSURANCE ............................................................................................................. 23 
13.0 
REFERENCES ........................................................................................................................................... 23 
14.0 
APPENDICES ........................................................................................................................................... 25 
14.1 
Appendix A - Imputation Rules for Missing Dates ...................................................... 25 
 
 
 






 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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3.0 
INTRODUCTION 
The statistical analysis plan (SAP) is based on: 
• 
Protocol UTX-TGR-304, version 6.0 for FDA’s Special Protocol Assessment, dated March 15, 
2020, 
• 
FDA Guidance On Cancer Trial Endpoints (Guidance for Industry Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics), 
• 
FDA guidance on the co-development of two or more new investigational drugs used in 
combination (Guidance for Industry Co-development of Two or More New Investigational 
Drugs for Use in Combination) 
• 
ICH guidelines E9 (Statistical Principles for Clinical Trials). 
 
The purpose of this document is to provide details on study populations and on how the 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 details on statistical methods to be used to analyze the safety 
and efficacy data from the study.   
 
 
 
An Independent Data Safety Monitoring Board (DSMB) will be established to monitor clinical data on 
a regular basis during the study.  The DSMB may recommend modifications to the study conduct to 
the Sponsor as specified in the DSMB charter. 
 
An Independent Review Committee (IRC) will be established to provide a blinded review of 
radiographic data and pertinent clinical data in order to provide expert interpretation of changes in 
disease status and to confirm or refute the determination of the Principal Investigator at the site.  CLL 
response and progression data collected from this study will be subjected to review by the IRC which 
will be blinded to treatment arm assignment.  The review of radiographic and clinical data by the IRC 
will be performed on an ongoing basis.  The specifics of the IRC’s processes and reading methods will 
be described in an Independent Review Charter developed by the contracted imaging facility in 
conjunction with the Sponsor.  The findings of the IRC will be considered primary for analyses of PFS 
and other efficacy endpoints. 
 
The SAP may evolve over time, for example, to reflect the requirements of protocol amendments or 
regulatory requests.  However, the final SAP must be finalized, approved by the Sponsor, and placed 
on file before the database is locked.  Deviations from the approved plan will be noted in the clinical 
study report. 


 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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4.0 
STUDY DESCRIPTION 
4.1 
STUDY OBJECTIVES 
PRIMARY OBJECTIVES 
• 
To establish that the combination of ublituximab + TGR-1202 is superior to the combination 
of obinutuzumab + chlorambucil as measured by Progression-Free Survival (PFS) in patients 
with CLL 
KEY SECONDARY OBJECTIVES 
• 
To establish that the combination of ublituximab + TGR-1202 provides clinical benefit over 
both ublituximab alone and TGR-1202 alone 
• 
To evaluate and compare the combination of ublituximab + TGR-1202 to the combination of 
obinutuzumab + chlorambucil with respect to overall response rate in patients with CLL 
OTHER SECONDARY OBJECTIVES 
• 
To assess safety, tolerability and other efficacy outcomes. 
 




 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
    
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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• 
900 mg Ublituximab on Day 1 
 
After Cycle 6: 
• 
900 mg Ublituximab on Day 1, every 3 cycles (i.e. Cycle 9, 12, 15, etc.) 
 
 
ARM D: TGR-1202 
Cycle 1, and Onward: 
• 
800 mg TGR-1202 once daily until removal from study 
 
 
Additional information, including premedication procedures can be found in Section 8 of the 
protocol. 
4.3 
STUDY DESIGN 
This study is designed as a Phase 3, randomized, four-arm trial to evaluate the efficacy and safety of 
ublituximab in combination with TGR-1202 compared to that of obinutuzumab in combination with 
chlorambucil (CHL), and to ublituximab alone and to TGR-1202 alone in patients with CLL.  While 
the primary objective of the study is to demonstrate the superiority of Arm A (Ublituximab + TGR-
1202) over Arm B (Obinutuzumab + Chlorambucil) as measured by progression-free survival (PFS) 
and overall response rate (ORR), an interim analysis of ORR among the first 50 patients enrolled 
into each arm is planned to assess the contribution of each single agent in the ublituximab + TGR-
1202 combination regimen. 
 
 
Following Screening, qualified patients will be randomized in a 1:1:1:1 ratio to one of the four arms: 
• 
Arm A: Ublituximab + TGR-1202 
• 
Arm B: Obinutuzumab + Chlorambucil 
• 
Arm C: Ublituximab 
• 
Arm D: TGR-1202 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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Randomization will be stratified according to 17p deletion status (presence vs. absence) and 
treatment status (treatment naïve vs. previously treated).  For purposes of stratification, patients 
will be considered “previously treated” only if they have previously received at least 2 cycles of one 
or more prior treatment regimens. 
 
During the study period, response assessments should be obtained every 3 cycles for the first 24 
cycles.  After Cycle 24, evaluate for response approximately every 6 cycles unless clinically 
indicated sooner. Subjects followed for PFS off treatment should have response assessments done 
approximately every 6 months unless clinically indicated sooner.  The best clinical response as well 
as disease progression will be determined by an Independent Review Committee (IRC).  Patients 
will remain on study treatment until the occurrence of definitive disease progression, unacceptable 
toxicity, or withdrawal from the study due to investigator decision or other reasons.  Patients who 
discontinue from study treatment (either for toxicity or physician choice) and have not progressed 
will continue to be followed for progression. 
 
The study will include a non-binding interim analysis for ORR at 50 patients per arm, and an 
interim analysis for PFS solely for purposes of assessing futility at 50% information time 
(approximately 140 events).  A second interim PFS analysis will be conducted at the later to occur 
of i) 75% information time (210 events), and ii) December 10, 2019, to evaluate the superiority 
hypothesis for Arm A compared to Arm B.  The study will end either at the second interim PFS 
analysis or at the final PFS analysis after approximately 280 PFS events are observed between Arms 
A & B.  The interim analyses will be performed by the independent DSMB.      
4.4 
RANDOMIZATION AND BLINDING 
The patient must consent after being informed of the procedures to be followed, the experimental 
nature of the treatment, potential benefits, alternatives, side-effects, risks and discomforts.  Patients 
who are eligible and who have signed an informed consent will be randomized in a 1:1:1:1 ratio to 
one of four treatment arms: ublituximab in combination with TGR-1202 (Arm A), obinutuzumab in 
combination with chlorambucil (Arm B), ublituximab alone (Arm C), or TGR-1202 alone (Arm D).  
Randomization will be stratified according to 17p deletion status (presence vs. absence) and 
treatment status (treatment naïve vs. previously treated).  For purposes of stratification, patients 
will be considered “previously treated” only if they have previously received at least 2 cycles of one 
or more prior treatment regimens.   
Investigators will use an interactive web response system (IWRS) to assign patients to one of four 
treatment arms as follows: 
• 
Arm A: Ublituximab + TGR-1202 
• 
Arm B: Obinutuzumab + Chlorambucil 
• 
Arm C: Ublituximab 
• 
Arm D: TGR-1202 
Patients must begin study treatment within 7 days of randomization.  Please see the Study 
Manual for additional information on randomization. 
Upon entering patient information into the IWRS, investigators will receive an enrollment approval 
and a unique patient identifier that will include the randomization assignment.  This confirmation 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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must be received by the site prior to dispensing study drug to the participant.  Further details about 
the patient registration process using the IWRS system will be outlined in the Study Manual. 
As this is an open-label study, to protect data integrity, the following procedures will be implemented 
to ensure all clinical and statistical decisions are made in a treatment blinded manner. The Sponsor, 
except for Clinical Operations personnel monitoring the study and the Medical Monitor, will be 
blinded to treatment assignment and specific dosing data within the four individual treatment arms. 
In addition, unblinded Clinical Operations personnel will not be involved in any discussions 
regarding the analysis of data after enrollment of the first patient into the trial or any protocol 
amendment, except those related to safety. 
5.0 
ANALYSIS POPULATIONS 
5.1 
INTENT-TO-TREAT POPULATION 
The Intent-to-Treat (ITT) population will consist of all randomized patients, regardless of 
administration of study treatment (ublituximab, TGR-1202, obinutuzumab + chlorambucil, or 
ublituximab + TGR-1202).  Analyses of this population will assign patients the treatment they were 
scheduled to receive, regardless of any errors of dosing or dose modifications.  Patients who received 
treatment in the group that is different from what they have been randomized to, will be noted in the 
CSR.  The ITT population is the primary analysis population for efficacy analyses.  
5.2 
SAFETY POPULATION 
The safety population will include all randomized patients who received at least one dose of study 
treatment (ublituximab, TGR-1202, obinutuzumab + chlorambucil, or ublituximab + TGR-1202).  
Patients who are included in a treatment group that is different from what they have been 
randomized to will be noted. 
5.3 
PER PROTOCOL POPULATION 
The per protocol population will include all ITT patients without major protocol violations and who 
have had at least one post-baseline response assessment.  Major protocol violations will be 
documented prior to database lock.  Analyses based on per protocol population may be performed. 
 
6.0 
GENERAL CONVENTIONS 
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.  P-values will be 
presented with 3 decimals and p-values that are less than 0.001 will be presented as <0.001. 
 
Continuous (non-survival related) data will be summarized using descriptive statistics: number of 
observations (n), mean, standard deviation (SD), median, 25th and 75th percentiles, minimum, and 
maximum.  Frequencies and percentages will be used to summarize categorical (discrete) data.  
Presentations of categorical data will generally suppress percentages for items where the count is 
zero in order to draw attention to the nonzero counts.  In general, mean, standard deviation, median, 
25th and 75th percentiles, minimum, maximum, and percentages will be presented with one decimal. 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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Unless otherwise stated, confidence intervals, when presented, will be constructed at the two-sided 
95% level.  For binomial variables, the 95% confidence intervals will be constructed using the normal 
approximation without continuity correction. 
 
Data listings will present all data collected on eCRFs by study drug, center, and patient number. 
6.1 
DEFINITION OF BASELINE 
In general, the last observed measurement prior to, or on the first administration of study treatment 
will be considered the baseline measurement. 
6.2 
DEFINITION OF TIME 
For the purpose of summarizing/analyzing efficacy data, time will be defined relative to the date of 
randomization.  Unless otherwise stated, for visits (or events) that occur on or after randomization, 
time is calculated as: 
time (days) = visit date (event date) – date of randomization + 1. 
For visits (or events) that occur prior to randomization, time is calculated as: 
time (days) = visit date (event date) – date of randomization. 
For listings (such as for adverse events) of the quantity “days since first/last dose” is defined as: 
days since first/last dose = event date – date of first/last dose. 
Events that occur on the same day as the first/last dose will therefore be described as occurring zero 
days from the first/last dose.  In most cases, listings will include the number of days since first/last 
dose of either study treatment. Labels and footnotes in the data presentations will specify clearly 
which reference date and therapeutic agent are used. 
6.3 
MISSING AND PARTIAL DATA 
In general, other than for partial dates, missing data will not be imputed and will be treated as 
missing.  The algorithms for imputation of partial dates vary depending upon the parameter and are 
presented in 14.1 Appendix A - Imputation Rules for Missing Dates. 
 
7.0 
DESCRIPTION OF THE STUDY POPULATIONS 
The paragraphs below specify presentations of data for both the ITT and safety populations.  If, 
however, the two populations are almost the same (i.e., safety population is 95% of the ITT 
population), then only the ITT tables will be presented.  A summary of differences between the two 
populations will be noted in the CSR. 
7.1 
DISPOSITION 
Patient disposition summaries will be presented by treatment arm and will include the number of 
patients enrolled, randomized, and the number and percentage of randomized patients in the ITT 
and safety populations.  The summaries will also include the reasons for permanent discontinuation 
of study treatment and study.  Disposition by investigational sites will also be presented. 


 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
A summary of demographics and baseline characteristics will be presented by treatment arm for the 
ITT and safety populations. 
 
The demographic characteristics consist of age, age category (defined below), sex, ethnicity, race, and 
Eastern Cooperative Oncology Group (ECOG) performance status.  Baseline height and weight will 
also be presented using standard descriptive statistics. 
 
Age (years) will be calculated as (date of informed consent – date of birth) / 365.25. 
 
Age categories, < 65 years and 65 years or older, will be presented using frequencies and percentages. 
 
The number and percentage of patients’ ethnicity, race category, cytogenetics category, prior 
therapies, 17p deletion status (present vs. absent), and Immunoglobulin heavy chain variable region 
(IgHV) Mutation Status (unmutated (or IgHV3-21) vs mutated) will also be summarized. 
7.3 
MEDICAL HISTORY 
A data listing will present medical history.  If useful for interpretation of the results of the study, a 
table will summarize the data. 
7.4 
HISTORY OF CHRONIC LYMPHOCYTIC LEUKEMIA 
Tables will present information regarding the patients’ history of Chronic Lymphocytic Leukemia, 
including time since initial diagnosis, and if applicable, most recent relapse, to randomization.  
 
8.0 
TREATMENTS AND MEDICATIONS 
8.1 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications recorded on the eCRFs will be coded using the WHO or MedDRA dictionary.  Prior 
and concomitant medications will be summarized by treatment arm in the safety population by 
anatomical therapeutic chemical (ATC) Class Level 4 and WHO Drug base substance preferred name. 
 
Prior medications are defined as medications with stop dates occurring before the date of first 
administration of any study treatment component.  Concomitant medications are defined as 
medications with start dates occurring on or after the date of first administration of any study 
treatment component and no more than 30 days after the last administration of any study treatment 
component.  Medications with start and stop dates that bracket the date of first administration of any 
study treatment component will be summarized as both prior and concomitant medications. 
 
For the purpose of summarizing prior and concomitant medications, incomplete medication start 
and stop dates will be imputed as detailed in Appendix A.  Based on imputed start and stop dates, 
medications that clearly stopped prior to date of first administration of any study treatment 
component will be included in the prior medications table, and medications that clearly started on or 
after date of first administration of any study treatment component will be included in the 
concomitant medications table.  All other medications will be included in both the prior and 
concomitant medications tables. 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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8.2 
STUDY TREATMENT EXPOSURE 
Study treatment exposure will be summarized by treatment arm.  Study treatment consists of the 
following four therapeutic agents: 
 
• 
Obinutuzumab; 
• 
Chlorambucil; 
• 
Ublituximab; and 
• 
TGR-1202. 
 
The following will be summarized by treatment arm for each of the above study treatment 
components using descriptive statistics: 
 
• 
number and percentage of patients complete each cycle; 
• 
number and percentage of patients who received at least one dose; 
• 
number and percentage of patients who had dose interruptions and frequency of dose 
interruptions; 
• 
duration of exposure, calculated as (date of last dose – date of first dose + 1); 
• 
number of doses received; 
• 
number of doses reductions (for chlorambucil and TGR-1202 only); and 
• 
cumulative dose received. 
 
 
9.0 
EFFICACY ANALYSES 
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 review committee (IRC) which 
will be blinded to treatment arm assignment.   Definitive disease progression will be based on 
standard criteria (Hallek et al. 2008, see Appendix A in the protocol) occurring for any reason (e.g., 
increasing lymphadenopathy, organomegaly or bone marrow involvement; decreasing platelet 
count, hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other than 
lymphocytosis.  Detailed procedures to assess response and progression are discussed in Section 10 
in the protocol.  
9.1 
PRIMARY EFFICACY OUTCOMES 
9.1.1 PROGRESSION-FREE SURVIVAL 
Progression-free survival is defined as the time from the date of randomization until the date of first 
documentation of definitive disease progression or date of death from any cause, whichever occurs 
first.  Patients who die without a reported prior progression will be considered to have progressed 
on the day of their death.  Patients who did not progress or are lost to follow-up will be censored at 
the day of their last disease assessment.  If no baseline or post-baseline assessment is available, the 
patient will be censored at the date of randomization.  If death or PD occurs after 2 or more 
consecutive missing disease assessments, censoring will occur at the date of the last disease 
assessment prior to the missed assessments.  The use of a new anticancer therapy prior to the 
occurrence of PD will result in censoring at the date of last disease assessment prior to initiation of 
new therapy.  Censoring rules for PFS are summarized in TABLE 1. 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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For each treatment arm, the median duration of PFS and the proportion of patients progression-free 
at 6, 12, and 18 months will be estimated using the Kaplan-Meier method.  For each estimate, a 95% 
confidence interval will be reported. 
The primary objective that Treatment A is superior to Treatment B will be tested at an overall two-
sided 0.04 level of significance. 
9.2 
KEY SECONDARY EFFICACY OUTCOMES 
9.2.1 OVERALL RESPONSE RATE 
ORR will be determined according to the criteria of the International Workshop on Chronic 
Lymphocytic Leukemia (Hallek et al. 2008). 
Overall Response Rate (ORR) is defined as percent of patients who achieve complete response (CR), 
complete response with incomplete marrow recovery (CRi), partial response (PR) or nodular partial 
response (nPR).  The response rate comparison between the two treatment arms will be analyzed 
via a Cochran-Mantel-Haenzel (CMH) test stratified by the randomization factors.   The 95% 
confidence intervals for the response rates as well as for the differences of the response rate based 
on normal approximations will be presented.  Additional logistic analyses model may be used to 
assess the impact of demographic and baseline parameters as well as the stratification factors. 
The key secondary objective that Treatment A provides additional clinical benefit over treatments C 
alone and D alone will be tested at a two-sided 0.01 level of significance at the interim based on ORR 
(when approximately the first 50 patients enrolled into each arm provided ORR assessment). 
  
 
 
 
9.3 
OTHER SECONDARY EFFICACY OUTCOMES 
9.3.1 COMPLETE RESPONSE RATE 
The CR rate is defined as the proportion of patients with a best overall response of complete response 
(CR) or complete response with incomplete marrow recovery (CRi).  Patients who do not have a 
disease response assessment for any reason will be considered non-responders and will be included 
in the denominator when calculating the CR rate.  For each treatment group, the number of patients 
achieving a CR or CRi will be divided by the total of patients randomized to yield the proportion 
responding. 
The CR rate will be analyzed using a Cochran-Mantel-Haenzel (CMH) test stratified by the 
randomization factors.   The 95% confidence intervals for the CR rate and the treatment difference 
based on normal approximation (Active – Control) will be presented. 
9.3.2 MINIMAL RESIDUAL DISEASE NEGATIVITY RATE 
The MRD negativity rate is defined as the proportion of patients who achieve MRD negativity post-
baseline.  MRD is assessed only amongst responders, defined as subjects achieving CR/CRi/PR/nPR.  
Patients who do not have an MRD assessment post-baseline will be considered non-responders and 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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will be included in the denominator when calculating MRD negativity rate.  For each treatment group, 
the number of patients achieving MRD negativity will be divided by the total number of patients 
randomized to yield the proportion responding. 
The rate of MRD negativity will be analyzed in the ITT population using a Cochran-Mantel-Haenzel 
(CMH) test stratified by the randomization factors.   The 95% confidence intervals for the rate of MRD 
negativity and the treatment difference (Active – Control) in rate of MRD negativity will be presented 
9.3.3 DURATION OF RESPONSE 
Duration of Response (DOR) defined as the interval from the first documentation of CR, CRi, PR, or 
nPR to the earlier of the first documentation of definitive disease progression or death from any 
cause.  The Kaplan-Meier estimator for DOR will be presented for patients who achieve an objective 
response in each treatment arm. The same censoring rules will be applied as for PFS. 
 
9.5 
MULTIPLICITY 
The study has the following three pre-specified primary efficacy evaluations: 
 
1. Assessing whether Treatment A is superior to Treatment B based on PFS; 
2. Assessing contributions of individual components in Treatment A established based on PFS; 
3. Assessing contributions of individual components in Treatment A established based on ORR; 
 
Contributions of individual components of Treatment A will be established if positivity is 
established for either #2 or #3, above.   
 
To control for the overall Type I error rate at 0.05, an overall two-sided p-value of 0.01 will be used 
to evaluate #3, at the interim analysis when the first 50 patients in Treatment Arms A, C, and D have 
provided adequate ORR data (at least one post-baseline disease assessment).  If contributions of 
individual components in Treatment A based on ORR is established at the interim ORR analysis, a 
formal test of ORR between Treatment A and Treatment B will be conducted at a two-sided 0.01 
level following a positive interim PFS analysis or, if the interim PFS analysis is negative, following 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
    
   
  
  
    
   
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
   
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
   
  
  
  
  
   
   
   
   
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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the final PFS analysis.  Analysis of CR rate and MRD negativity rate will also be conducted 
sequentially at the two-sided 0.01 level (See Figure 1).    
 
The remaining overall two-sided p-value of 0.04 will be used to evaluate #1 (and to evaluate #2 if 
#3 is not earlier established to be positive).  If #1 is established to be positive and #3 has not been 
established to be positive at the interim ORR analysis for contribution, the following assessments 
will be evaluated at the overall two-sided 0.04 significance level to establish #2: 
1. Assessing whether treatment A is superior to Treatment C regarding PFS; and 
2. Assessing whether treatment A is superior to Treatment D regarding PFS. 
 
 
 
 
 
Figure 1 below illustrates the testing schema for primary and secondary analyses.   
 
Figure 1. Study UTX-TGR-304 Testing Schema to Control Type I Error for Multiple Analyses 
 
*Contribution test based on ORR is not tested sequentially from PFS, but represents previous testing 
based on ORR at α=0.01 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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To control for the overall type I error rate, a claim cannot be made unless all proceeding claims, if 
any, are made.   For completeness, all p-values will be presented. 
9.6 
INTERIM ANALYSIS 
One interim analysis based on ORR will be performed when approximately 50 subjects each in Arms 
A, B, C and D have provided disease assessments to determine ORR status.  If contributions of 
individual components in Treatment A based on ORR is established at the interim ORR analysis, a 
secondary claim that Treatment A is superior over Treatment B based on ORR will be tested at a two-
side 0.01 level following a positive interim PFS analysis or, if the interim PFS analysis is negative, 
following the final PFS analysis.   Further, should contribution be established at the interim ORR 
analysis, enrollment into both Arms C and D will be terminated, however enrollment into Arms A and 
B will continue until 175 patients have been enrolled into each arm. If contribution was unable to be 
established by ORR at the interim analysis, both single agent arms C and D will be evaluated for PFS. 
 
One interim analysis based on PFS will be performed solely for purposes of assessing futility at 
approximately 50% information time (140 events).    A second interim PFS analysis will be 
conducted at the later to occur of i) 75% information time (210 events), and ii) December 10, 2019, 
to evaluate the superiority hypothesis for Arm A compared to Arm B.  At this interim analysis, early 
study termination will be guided by an O'Brien-Fleming monitoring boundary that is preserving the 
(one-sided) 0.0005 false positive error rate.  At 75% of the events (i.e., 210 PFS events), the 
corresponding Z-value would be 3.81, with corresponding nominal two-sided p=0.00013.  If early 
termination does not occur, nearly all of the two sided 0.04 false positive error rate allocated to PFS 
would have been preserved, statistical significance for PFS at the 280 event final analysis would be 
achieved with Z-value 2.06.  The study will end either at the second interim PFS analysis or at the 
final PFS analysis.      
 
An independent DSMB will be established and will conduct all interim analyses in addition to 
reviewing clinical data periodically throughout the trial.  The DSMB may recommend stopping or 
modifying the trial for safety reasons. 
9.7 
SAMPLE SIZE 
 
 
 
 
 
 
 
 
 
    
 
 
 
 


 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.0 SUMMARIES OF MEASURES OF SAFETY 
Safety analyses will be performed for the safety population.  Safety evaluations will be based on the 
incidence, intensity, and type of adverse events, as well as on clinically significant changes in the 
patient’s physical examination, vital signs, and clinical laboratory results.  Safety variables will be 
tabulated and presented by study drug actually received. 
 
Because there is no pre-specified safety outcome defined in terms of AEs, clinically relevant 
laboratory parameters, or vital signs, any formal comparisons between the treatment arms with 
respect to specific safety parameters will be post-hoc. 
10.1 ADVERSE EVENTS 
Each AE and SAE term recorded on eCRFs will be mapped to a preferred term (PT) using the MedDRA 
dictionary.  The investigator will classify the severity of AEs and SAEs using the NCI CTCAE v4.0 and 
will assess the relationship of each event to study treatment. 
 
All AEs and SAEs occurring on study will be listed by treatment drug, center, and patient.  The 
frequency and percentages of patients with treatment-emergent adverse events (TEAEs) will be 
tabulated by system organ class (SOC) and PT, where treatment-emergent is defined as any AE that; 
 
• 
occurs after randomization and through the end of the study or, if serious, up through 30 days 
after the last dose of study treatment; 
• 
is present before randomization but worsens in intensity or the investigator subsequently 
considers treatment-related. 
 
For the purpose of calculating treatment emergence and inclusion in summary tables, incomplete 
onset dates will be imputed as detailed in Appendix A.  Summaries will display incidence by study 
drug received and total incidence, and PTs within each SOC will appear in decreasing order of total 
incidence as well as in alphabetical order.  At each level of summarization, a patient will be counted 
only once for each AE, SOC, or PT experienced within that level. 
Related TEAEs, serious TEAEs, Grade 3 or higher TEAEs, related serious TEAEs, related Grade 3 or 
higher TEAEs, and TEAEs resulting in discontinuation of study treatment will be similarly 
summarized.  Summaries of TEAEs by relationship to the study treatment will also be prepared. 
 
At each level of summarization, a patient will be counted only once for each AE, SOC, or PT 
experienced within that level.  In the summation for AE severity, within each level of AE, SOC, or PT 
experienced, the one with the highest severity will be included.  In the summation for AE’s 
relationship to the study drug, within each level of AE, SOC, or PT experienced, the one with the 
closest relationship to the study drug will be included. 
 
10.2 LABORATORY ASSESSMENTS 
Laboratory data for hematology and serum chemistry tests will be reported in International Units. 
Individual values outside the central laboratory reference ranges will be identified (by “H” for high 
and “L” for low) in the data listings displaying the absolute values for each patient. 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Abnormalities in laboratory tests that the investigator considers clinically significant will be 
recorded and summarized as AEs. 
10.3 VITAL SIGNS 
10.3.1 
VARIABLES 
The following vital signs will be summarized: 
• 
Blood pressure (systolic and diastolic, mmHg) 
• 
Pulse rate (beats/min) 
• 
Respiration rate (breaths/min) 
10.3.2 
STATISTICAL ANALYSIS 
Summary tables of vital signs and change from baseline will be presented for all scheduled visits 
where vital signs were assessed.  All recorded vital sign data will be listed. 
10.4 PHYSICAL EXAM 
Physical examination data will be presented in a data listing. 
10.5 ECOG PERFORMANCE STATUS 
ECOG Performance Status will be summarized as shift from baseline tables by visit using frequencies 
and percentages at all scheduled visits where performance status was assessed. 
 
11.0 IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS 
Major protocol deviations from entry criteria and treatment compliance will be summarized as far as 
they can be extracted from numeric or coded study data. 
 
12.0 DATA QUALITY ASSURANCE 
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. 
 
As this is an open-label study, to protect data integrity, the following procedures will be implemented 
to ensure all clinical and statistical decisions are made in a treatment blinded manner. The Sponsor, 
except for Clinical Operations personnel monitoring the study and the Medical Monitor, will be 
blinded to treatment assignment and specific dosing data within the three individual treatment arms. 
In addition, unblinded Clinical Operations personnel will not be involved in any discussions 
regarding the analysis of data after enrollment of the first patient into the trial or any protocol 
amendment, except those related to safety. 
 
13.0 REFERENCES 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Hallek M, et al. (2008). Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: 
a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National 
Cancer Institute-Working Group 1996 guidelines. Blood 2008;111: (12):5446-56. 
 




 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 if month < month of first dose then set day to last day of month. 
 if month > month of first dose then set day to 1st day of month. 
o if year < year of first dose then set day to last day of month. 
o if year > year of first dose then set day to 1st day of month. 
• 
For all other cases, set onset date to date of first dose. 
 
Concomitant Medications/Medical History 
• 
If start date is completely missing, start date will not be imputed. 
• 
If (year is present and month and day are missing) or (year and day are present and month 
is missing), set month and day to January 1. 
• 
If year and month are present and day is missing, set day to 1st day of month. 
• 
If end date is completely missing, end date will not be imputed. 
• 
If (year is present and month and day are missing) or (year and day are present and month 
is missing), set month and day to December 31. 
• 
If year and month are present and day is missing, set day to last day of the month.