Clinical trial NCT04692155
Conditions: Mantle Cell Lymphoma
Keywords: Ublituximab Umbralisib TGR-1202 TG-1101
Sponsor: University of Alabama at Birmingham
Start date: 2021-08-31; Completion date: 2022-06-30
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm, multi-center, open label Phase Ib/II trial in adult patients with newly diagnosed Mantle Cell Lymphoma (MCL)(Stage II-IV). The Diagnosis of MCL (Stage II, III, IV) is supported by histology and over expression of cyclin D1 or by FISH (fluorescent in situ hybridization). In the proposed study, the primary endpoint is to estimate the biological response rate of the combination of Umbralisib at dose 800 mg with Ublituximab (900mg)-Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP), but a phase Ib portion with dose de-escalation at two does level (800 and 600 mg) will be built in to further confirm its safety and tolerability. Treatment will be administered on an outpatient basis in 3-week (21 day) cycles. Once Umbralisib dose is defined in phase Ib, the study will expand to phase II portion after SMC/DSMB (Safety monitoring committee/Data Safety Monitoring Committee) agreement.

Detailed description:
Mantle cell lymphoma (MCL) is an aggressive and incurable hematologic malignancy with incidence of MCL increases with age (average age is 68 years) and is more common in males. Majority of the patients presents with advanced systemic and symptomatic disease requiring aggressive chemotherapy. Although some patients with MCL can have indolent course, majority of them pursue an aggressive course. Most patients with MCL presents with non-bulky lymphadenopathy and advanced stage with frequent extra-nodal involvement. In general, MCL carries an aggressive course with very poor outcome. MCL has wide spectrum of clinical presentation ranging from indolent disease to symptomatic aggressive disease. The initial treatment of MCL depends on many disease and patient related factors. Advanced, biologically aggressive ( by histology markers) disease in a young and fit patient needs aggressive/intense induction, Autologus stem cell transplant (ASCT) consolidation and maintenance treatment. While unfit patient usually is offered less intense treatment followed by maintenance treatment.

Investigational drugs ublituximab \& umbralisib are highly active in various B cell lymphomas. Umbralisib is a highly-specific and orally available dual inhibitor of phosphoinositide-3-kinase (PI3K) delta (δ) and casein kinase 1 epsilon (CK1ε) with nanomolar inhibitory potency, and high selectivity over the alpha, beta, and gamma Class I isoforms of PI3K. The PI3Ks are a family of enzymes involved in various cellular functions, including cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta isoform of PI3K is highly expressed in cells of hematopoietic origin, and strongly upregulated, and often mutated in various hematologic malignancies.

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.

Pre-Clinical Development Of Ublituximab:

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 (Esteves IT, 2011).

Ublituximab in Combination with Umbralisib :

The combination of Ublituximab and Umbralisib is being evaluated in various clinical trials. The preliminary data suggests that the combination is safe and well tolerated. Results of a Phase I/Ib study of the combination of ublituximab + umbralisib (U2) in patients with relapsed or refractory Non-Hodgkin Lymphoma(NHL) and Chronic lymphocytic Leukemia(CLL) have been reported. Overall, results from this study suggest that the U2 regimen is well tolerated and active in patients with relapsed or refractory hematologic malignancies.

Rationale for this Study:

This is a Single arm, multi-center, open label Phase II trial with safety lead in Adult patients with newly diagnosed Mantle Cell Lymphoma (MCL)(Stage II-IV). MCL majority, is an aggressive and incurable lymphoma. As it is the lymphoma of elderly, aggressive treatment approaches like aggressive induction treatments and ASCT may be more risky in this population. Majority of these patients are treated with less intense approach like Rituximab-Bendamustine (BR), R-CHOP or VR-CAP. Nearly all the patients are treated with Rituximab maintenance after these induction approaches.

In this study, we will explore combination of novel CD20 monoclonal antibody (Ublituximab) with CHOP and a novel highly active PI3K inhibitor (Umbralisib) in ASCT ineligible untreated advanced MCL. Umbralisib is highly active in various B cell lymphomas. The combination of Ublituximab and Umbralisib is being evaluated in two signature clinical trials. The preliminary data suggests that the combination is safe and well tolerated. To improve upon the back bone of R-CHOP, we want to explore U2-CHOP (Ublituximab with Umbralixib)-CHOP followed by U2 maintenance in ASCT in eligible patients. Both the study agents (U2) are highly active in lymphomas. Study hypothesis is to improve rates of complete response at the end of induction treatment with this novel combination.

Study Objectives:

* To determine the safety of Umbralisib and Ublituximab in combination with CHOP chemotherapy for newly diagnosed MCL.
* To determine the efficacy of U2-CHOP in terms of Complete Response rates (CRR) in patients with untreated MCL after induction phase (6 cycles of U2-CHOP) by PET/CT response assessment criteria by Cheson 2014.
* To characterize the toxicity profile of U2-CHOP induction followed by U2 maintenance in newly diagnosed Mantle Cell Lymphoma (MCL) patients.
* To determine rates of Overall response rate, disease control rate
* Overall survival and progression free survival
* To explore minimal residual disease (MRD) negative rates at the end of induction treatment

Arms: arm 1: for phase 1 B portion, Ublitixumab will be given IV at dosage 900mg from Cycle 1 Day1 till cycle 6. If investigator decides to continue the treatment as maintenance, Ublitixumab will be given IV every 8 weeks for 24 months Umbralisib (800mg) will be given orally once a day within 30 minutes of a meal from Cycle 1 Day1 till cycle 6.If investigator decides to continue the treatment as maintenance,• Umbralisib will be given at orally daily for 24 months.

Chemotherapy combination of CHOP-cyclophosphamide IV 750mg/m2 for Age \<70 years, 500 mg/m2 for Age\>70 years doxorubicin IV 50mg/m2for Age \<70 years, 25 mg/m2 for Age\>70 years , and vincristine IV 1mg/m2 (max 2mg)) are administered on Cycle 1 day 1 till Cycle 6. Prednisone 50-100mg will be given orally on days 1 through 5 of every cycle.

For Phase II portion- Once Umbralisib dose is defined in phase Ib, the study will expand to phase II portion after SMC/DSMB (Safety monitoring committee/Data Safety Monitoring Committee) agrees.
Interventions: intervention 1: Ublituximab intervention 2: Umbralisib
Intervention descriptions: intervention 1: Ublituximab (900mg) will be administered as an intravenous infusion through a dedicated line. intervention 2: Umbralisib(800mg)will be administered orally once daily within 30 minutes of starting a meal.

Protocol documents:
Prot_SAP_002.pdf: 
Protocol Title 
Phase Ib/II trial of Ublituximab with CHOP (U2-CHOP) followed 
by U2 maintenance (U2-CHOP-U2) in previously untreated 
Mantle Cell Lymphoma (MCL) 
 
Study Protocol & Statistical Analysis Plan 
 
NCT#NCT04692155 
 
 
Date of Last Protocol Approval 
2/2/2022 
 
Amitkumar Mehta, MD 
Associate Professor, Dept of Medicine, 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 


 
 
1 
PROTOCOL TITLE:  Phase Ib/II trial of Ublituximab with CHOP (U2-CHOP) followed by U2 
maintenance (U2-CHOP-U2) in previously untreated Mantle Cell Lymphoma (MCL) 
 
NCT# 
UAB# 
TG Therapeutics# 
IND# 
 
Protocol version/Date: V 1.0, 3/19/18 
 
 
Protocol #: 
 
 
 
 
SPONSOR:  University of Alabama at Birmingham 
 
Investigators: Amitkumar Mehta, Luciano Costa, Olivia Hull, Andres Forero 
 
 
Principal Investigator:  Amitkumar Mehta, MD 
 
 
 
 
 
 
 
 
   
Support: 
TG Therapeutics (Funding and investigational agents) 
 
Statistician: 
Name: Young-il Kim 
Address: 1717 11th Ave S, Birmingham, AL 35294-4410 
Phone No: 205.934.3679, Fax No: 205.934.4262 
       Email: youngkim@uabmc.edu 
 
 
TG Therapeutics, Inc. Tracking Number:   
 
Sites: 
1. University of Alabama at Birmingham 
2. TBD 
3. TBD 
4. TBD 
5. TBD 
 
 
University of Alabama at Birmingham, Clinical Trials Network and Monitoring Office – UAB 
CTNMO 
(Multicenter Operations) 
 
Name: Pam Dixon, RN, OCN, CCRP 
Address: 1802 6th Avenue South; NP 2515, Birmingham, AL 35294 
Phone: (205) 975-5387 
Fax No:(205) 975 9875 
Email Address: pamdixon@uab.edu 
 
Name: Trina Lucas-Chancey 


 
 
2 
Address: 1802 6th Avenue South; NP 2515, Birmingham, AL 35294 
Phone: (205) 996-5976 
Fax No: (205) 975-9875 
Email Address: tlucas@uab.edu 
 
 
 
Protocol Version History: 
 
Original Protocol 
March 2018 
 
 
 
 
 
 
 
 


 
 
3 
Table of Contents 
 
 
Sr No 
Content 
Page 
1. 
PROTOCOL SYNOPSIS 
5 
2. 
PROTOCOL SCHEMA 
12 
 
ABBREVIATIONS 
13 
3. 
INTRODUCTION 
15 
 
3.1 
Disease specific Background 
15 
 
3.2 
Umbralisib Background 
17 
 
3.3 
Ublituximab background 
22 
 
3.4 
Minimal Residual Disease in MCL 
25 
 
3.5 
Study Rationale 
26 
4. 
OBJECTIVES 
26 
 
4.1 
Primary Objective 
26 
 
4.2 
Secondary Objectives 
27 
 
4.3 
Explorative Objective 
27 
 
4.4 
Efficacy Endpoints 
27 
5. 
SUBJECT SELECTION 
27 
 
5.1 
Eligibility Criteria 
27 
 
5.2 
Inclusion Criteria 
27 
 
5.3 
Exclusion Criteria 
28 
 
5.4 
Subject Enrolment 
30 
6. 
TREATMENT AND PROCEDURES 
30 
 
6.1 
Phase Ib 
30 
 
6.2 
Dose Limiting Toxicities 
30 
 
6.3 
Induction Treatment 
31 
 
6.4 
Phase II 
31 
 
6.5 
Maintenance Treatment 
31 
7. 
AGENT ADMINISTRATION AND DOSING GUIDELINES 
33 
 
7.1 
Umbralisib administration and dosing guidelines 
33 
 
7.2 
Ublituximab administration and dosing guidelines 
33 
 
7.3 
CHOP administration and dosing guidelines 
42 
 
7.4 
CHOP dosing guidelines for Elderly (>70 years) 
44 
8. 
CONCOMITANT MEDICATIONS AND SUBSEQUENT THERAPY 
44 
 
8.1 
Concomitant and Supportive Medications 
44 
 
8.2 
Excluded Medications 
44 
 
8.3 
Subsequent Therapy 
44 
9. 
DISCONTINUATION 
45 
 
11.1 
Sudy Discontinuation 
45 
 
11.2 
Treatment Discontinuation 
45 
 
11.3 
Participation Discontinuation 
45 
10. 
STUDY ASSESSMENT AND SCHEDULE 
45 
 
10.1 
Induction Phase 
46 
 
10.2 
Maitenance Phase 
48 
11. 
STATISTICAL ANALYSIS 
49 
 
11.1 
Study Design 
49 
 
11.2 
Sample size and Power Calculations 
49 


 
 
4 
 
11.3 
Statistical Plan 
49 
12. 
DEFINITION OF TUMOR RESPONSE ASSESSMENT 
50 
13. 
MRD ASSESSEMENT 
50 
14. 
SAFETY REPORTING 
51 
15. 
REGULATORY, ADMINISTRATIVE AND LEGAL OBLIGATIONS 
52 
 
15.1 
Prestudy Documentation Requirements 
52 
 
15.2 
Compliance with Laws and Regulations 
53 
 
15.3 
Protocol Amendments 
54 
 
15.4 
Ethical, Financial and Regulatory Considerations 
54 
 
15.5 
IRB approval 
54 
 
15.6 
Informed Consent 
54 
 
15.7 
Patient confidentiality 
55 
 
15.8 
Data Recording 
55 
 
15.9 
Study Monitoring 
55 
 
15.10 
Frequency of Reviews 
55 
 
15.11 
Protocol Deviations and Safety Reporting 
56 
 
15.12 
Data Collection 
56 
 
15.13 
Study Completion 
57 
 
15.14 
Record Retention 
57 
 
15.15 
Publication 
57 
16. 
REFERENCES 
58 
17. 
APPENDIX 
61 
 
A 
Contraception Guidelines and Pregnancy 
62 
 
B 
 NYHA Classification 
64 
 
C 
Hepatitis B serology Interpretation 
65 
 
D 
MIPI and ECOG Performance status score 
66 
 
E 
PET/CT CRITERIA FOR LYMPHOMA (Cheson et al, 2014) 
67 
 
F 
NCI-CTACAE VERSION 4.0 
68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
5 
 
PROTOCOL SYNOPSIS 
 
PROTOCOL INFORMATION 
Title: U2-CHOP-U2 in MCL: Phase Ib/II trial of Ublituximab with CHOP (U2-CHOP) followed 
by U2 maintenance (U2-CHOP-U2) in previously untreated Mantle Cell Lymphoma (MCL) 
 
Objectives 
Primary Objective: 
 
Phase Ib: 
 
To determine the safety of Umbralisib and Ublituximab in 
combination with CHOP chemotherapy for newly diagnosed 
MCL 
 
Phase II: 
 
CRR: To determine the efficacy of U2-CHOP in terms of Complete 
Response rates (CRR) in patients with untreated MCL after 
induction phase (6 cycles of U2-CHOP) by PET/CT response 
assessment criteria by Cheson 2014 (appendix) 
 
Secondary Objectives: 
 
Phase II: 
 
To determine Overall response rate (ORR=CR+PR) of the 
induction treatment with U2-CHOP in untreated MCL 
 
To determine Overall Survival (OS) at 3 years  
 
To determine Progression Free Survival (PFS) at 3 years 
 
To determine the rate of disease control (CR+PR+SD) at 3 years 
 
 
Exploratory: 
 
To determine the frequency of MRD negative (MRD-) disease at 
the end of induction treatment with U2-CHOP. 
 
 
 
Study Design 
Single arm, multi-center, open label Phase II trial with safety lead 
in Phase Ib. 
 
Study Population 
Adult patients with newly diagnosed MCL (Stage II-IV). 
 
Inclusion Criteria 
• 
Males or female patients >18 years of age 


 
 
6 
• 
Diagnosis if MCL (Stage II, III, IV) as supported by 
histology and over expression of cyclin D1 (in 
association with CD20 and CD5) or evidence of t(11;14) 
by FISH (fluorescent in situ hybridization) with 
indication of initiation of therapy. 
• 
At least one LN of >1.5 cm size as index/measurable site 
of disease 
• 
No prior therapy for MCL 
• 
Not eligible for bone marrow transplantation (assessed 
by treating physician due to comorbidities) or not 
interested in bone marrow transplant (clear 
documentation of patient’s unwillingness to pursue 
transplant) 
• 
Eastern cooperative Oncology Group (ECOG): 0,1 or 2 
(Appendix) 
• 
Absolute neutrophil count (ANC) >1500 (>1000 if bone 
marrow involvement with MCL) within 28 days prior to 
initiation of therapy 
• 
Platelets >100000 cells/µL (>75000 cells/µL if bone 
marrow involvement with MCL) within 28 days prior to 
initiation of therapy 
• 
Hemoglobin >9.0 gm/dL (>8.0 gm/dL if bone marrow 
involvement with MCL) within 28 days prior to 
initiation of therapy 
• 
Alanine transaminase (ALT)/Aspartate Transaminase 
(AST) <3.0 X Upper limit of Normal (ULN) within 28 
days prior to initiation of therapy 
• 
Total Bilirubin <2 X ULN within 28 days prior to 
initiation of therapy 
• 
Calculated Creatinine Clearance >35 mL/min by 
Cockcroft-Gault Equation 
• 
Male patients must agree to use an acceptable method 
of contraception for the entire duration of study. 
• 
All patients (or their legal representative) must have 
signed an informed consent indicating that they are 
willing to participate in the study and are willing to 
follow the procedure required by the study in 
accordance with federal, local and institutional 
guidelines. 
• 
Female patients who are not of child-bearing potential 
(see Appendix: CONTRACEPTION GUIDELINES AND 
PREGNANCY), and female patients of child-bearing 
potential who have a negative serum pregnancy test 
within 72 hours prior to initial trial treatment.  Female 
patients of child-bearing potential and all 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 either study drug.  
 


 
 
7 
Exclusion Criteria 
• 
Any prior anti-neoplastic therapy for MCL 
• 
CNS involvement by MCL  
• 
Non-hematologic malignancy within the past 3 years 
with the exception of a) adequately treated basal cell 
carcinoma, squamous cell skin cancer, or localized 
thyroid cancer; b) carcinoma in situ of the cervix or 
breast; c) prostate cancer of Gleason Grade 6 or less 
with stable prostate-specific antigen levels; or d) cancer 
considered cured by surgical resection or unlikely to 
impact survival during the duration of the study, such 
as localized transitional cell carcinoma of the bladder or 
benign tumors of the adrenal or pancreas. 
• 
If patient has received prior anthracycline therapy, the 
cumulative anthracycline dose should be <150mg/m2 
of doxorubicin equivalent 
• 
H/O prior Allogeneic transplantation or autologous 
stem cell transplantation for any other reason. 
• 
Use of immunosuppressive therapy (e.g. cyclosporine A, 
tacrolimus or high dose steroids). Patients receiving 
steroids must be at a dose of <10mg/day prednisone 
(or equivalent) within 7 days of the first day of the 
study treatment administration. Patients are allowed to 
use topical or inhaled corticosteroids. 
• 
Concurrent any anticancer therapy for any other cancer 
(chemotherapy, radiation, surgery, immunotherapy, 
biologic therapy, hormonal therapy, investigational 
therapy or tumor embolization). 
• 
Use or expected use during the study of any prohibited 
medications including potent CYP3A4 inhibitors, 
inducers, substrates (appendix) within 14 days or 5 
half-lives (whichever is longer) before the study 
treatment administration. 
• 
Significant concurrent, uncontrolled medical condition 
including but not limited to renal, hepatic, 
hematological, GI, endocrine, pulmonary, neurological, 
cerebral or psychiatric disease. 
• 
History of stroke or intracranial hemorrhage within 6 
months of the date of study treatment administration 
(unless complete and full recovery) 
• 
Chronic or current active infections requiring systemic 
antibiotics, antifungal or antiviral treatment or 
exposure to live vaccines within 30 days of study 
treatment. 
• 
Known HIV infection. 


 
 
8 
• 
Evidence of Hepatitis B or Hepatitis C infection or risk 
of reactivation. HBV DNA and HCV RNA Evidence of 
chronic active Hepatitis B (HBV, not including patients 
with prior hepatitis B vaccination; or positive serum 
Hepatitis B antibody) or chronic active Hepatitis C 
infection (HCV), active cytomegalovirus (CMV), or 
known history of HIV.  If HBc antibody is positive or 
CMV IgM is reactive the subject must be evaluated for 
the presence of HBV or CMV DNA (by PCR) 
• 
Known history of drug-induced liver injury, alcoholic 
liver disease, non-alcoholic steatohepatitis, primary 
biliary cirrhosis, ongoing extrahepatic obstruction 
caused by stones, cirrhosis of the liver 
• 
Any severe and/or uncontrolled medical conditions or 
other conditions that could affect participation in the 
study such as: 
• Symptomatic, or history of documented 
congestive heart failure (New York Heart 
Association functional classification III-
IV)[see Appendix:  NYHA Classifications] 
• Significant cardiovascular disease such as 
uncontrolled or symptomatic arrhythmias, 
CHF, or myocardial infarction within 6 
months of enrollment.  
• Concomitant use of medication known to 
cause QT prolongation or torsades de pointes 
should be used with caution and at 
investigator discretion. 
• Poorly controlled or clinically significant 
atherosclerotic vascular disease including 
cerebrovascular accident (CVA), transient 
ischemic attack (TIA), angioplasty, cardiac 
or vascular stenting within 6 months of 
enrollment. 
• 
Cardiac ejection fraction (EF) <45%. 
• 
Current NY heart association Class II to IV congestive 
heart failure or uncontrolled arrhythmia 
• 
Presence of an abnormal ECG that is clinically 
meaningful. Patients with QTc interval >450 
milliseconds are excluded (corrected by Fridericia). 
• 
Currently pregnant or breast feeding. 
• 
Unable to swallow and retain oral medication, 
malabsorption syndrome, disease significantly affecting 
GI function, total resection of stomach or small bowel, 


 
 
9 
ulcerative colitis, symptomatic IBD or complete or 
partial obstruction. 
• 
Anaphylaxis to monoclonal antibody/Rituximab in past. 
• 
Any condition that would, in investigator’s judgment, 
interfere with full participation in the study, including 
administration of study medication/chemotherapy, 
attending study visits, pose a risk to the patient or 
interfere with interpretation of study data. 
• 
Inability to comprehend or unwilling to sign the ICF. 
• 
Subjects with pleural effusions requiring thoracentesis 
or ascites requiring paracentesis within 21 days prior to 
registration 
• 
Contraindication or intolerance to required supportive 
care medications (neulasta, acyclovir or 
bactim/dapson/pentamidine/atovaquone) 
• 
 Females who are pregnant or lactating. 
 
STUDY PROCEDURES 
Phase IB: 
Initially, 3 patients will be enrolled in Phase Ib safety lead in with 
maximum dose of Ublituximab (900mg) and Umbralisib 
(800mg) with Cyclophosphamide, Doxorubicin, Vincristine and 
Prednisone (CHOP) for the Cycle#1 of induction. These patients 
will be followed for 21 days and safety will be reviewed by Safety 
monitoring committee (SMC). If no one develops Dose Limiting 
Toxicities (DLT), the trial will expand into phase II portion. If one 
of three develops DLT, 3 additional patients will be enrolled on 
same dose level. If none or 1, develops DLT, the trial will expand 
into phase II portion.  If 2 or more patients develop DLT, 
Umbralisib dose will be lowered to 600mg repeating similar 
steps per SMC’s recommendations. Once the safe dose of 
Umrbalisib is identified, study will expand into Phase II portion 
with that identified and SMC approved dose. 
 
 
Induction Therapy: 
 
Screening: Subjects likely to meet eligibility criteria will be 
offered participation in the study after investigator verifies UAB 
CTNMO registration. Subjects will sign informed consent prior to 
any protocol associated procedures. Screening procedures are 
outlined in Table and will ensure that subject meets all eligibility 
criteria, obtain disease assessment at base line to allow efficacy 
assessment, assess baseline toxicity and provide identification 
sample(s) for MRD assessment at the end of induction treatment. 
 
U2-CHOP induction therapy: 
The total duration of induction is total of 6, 3 weekly cycles each. 
In all cycles, subjects will receive Ublituximab (for C#1: day 1,8 
and 15, C#2-6: day 1), Umbralisib (daily continuous, day 1-21), 


 
 
10 
CHO (on day 1) and Prednisone (100mg daily from Day 1-5) 
(Refer to dose adjusting guidelines in table for CHOP) 
 
 
Response Assessment: 
 
All subjects will have base line PET/CT scan and Response 
assessment scan 5-6 weeks post C#6. The response will be 
assessed by PET/CT criteria for Lymphoma (Cheson et al, 2014, 
Appendix E). 
 
Maintenance Therapy: 
Those subjects with objective response (CR, PR and Stable 
disease (SD)), will initiate maintenance treatment with U2 
(Ublituximab and Umbralisib). Ublituximab will be infused every 
8 weeks and Umbralisib will be orally daily for 2 years. 
 
Supportive Therapy: 
 
Growth Factor 
All subjects will receive growth factor during the induction 
chemotherapy. Peg-filgrastim will be administered either on 
same day or day#2 of chemotherapy per center’s standards. 
Short acting growth factors are also allowed (starting on Day2-9 
of every induction treatment). 
 
Prophylaxis:  
Viral and Pneumocystis Jirovecii prophylaxis will be given all 
through the treatment (both induction and maintenance phase) 
 
Viral Prophylaxis: All patients will receive Ayclovir (400 BID 
orally daily) or famciclovir (250mg orally twice a day) or 
Valacyclovir (500mg orally twice or thrice a day) for 
prophylaxis.  
 
PJP Prophylaxis: Bactrim DS Monday, Wednesday and Friday 
every week or Dapsone (100mg daily orally)/Atovaquone 
(1500mg orally daily)/Pentamidine (300mg NEB every 4 
weeks) per institution standard. G6PD testing should be done in 
patients going on Bactrim/Dapsone. 
 
 
 
Primary Endpoint 
Rate of complete remission at the end of induction treatment 
(U2-CHOP X 6 cycles) per PET/CT assessment criteria for 
Lymphoma (Cheson et al, 2014) 
Secondary Endpoints 
• 
Rate of Overall Response Rate (CR+PR) 
• 
Rate of PFS at 3 years 
• 
Rate of OS at 3 years 


 
 
11 
• 
Rate of disease control rate (CR+PR+SD) at 3 years 
• 
Rate of MRD negativity at the end of induction 
• 
PFS and OS of MRD- subjects 
Statistical Methods 
Phase IB safety study will use 3+3 dose de-escalation design at 
two dose cohorts assuming the DLT is no more than (<) 33% in 
the combination. The sample size in this portion will range from 
3-12. We expect that Umbralisib in combination with 
Ublituximab-CHOP will improve the CRR to 70%  comparing to 
the standard treatment with R-CHOP alone at 40% response 
rate. Using Single-Stage Phase II design for Testing H0: P < P0 
versus H1: P > P1, A sample size of 25 achieves 90% power to 
detect a difference (P1-P0) of 0.3 using a one-sided binomial test. 
If the number of responses is 15 or more, the hypothesis that P 
<= 0.4 is rejected with a target error rate of 0.050 and an actual 
error rate of 0.034. If the number of responses is 14 or less, the 
hypothesis that P >= 0.7 is rejected with a target error rate of 0.1 
and an actual error rate of 0.098. Thus, a total of 28-37 of 
patients will be required to both portions of the study. 
 
 
 
 


 
 
12 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
13 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
°C 
degrees Centigrade 
°F 
degrees Fahrenheit 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time (also PTT) 
AST 
aspartate aminotransferase 
BID 
twice daily 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CR 
complete response 
CrCl 
Creatinine Clearance 
CRF 
case report form(s) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
Females of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice  
GLP 
Good Laboratory Practice  
GM-CSF 
granulocyte macrophage colony stimulating factor 
h 
hour(s) 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram(s) 


 
 
14 
LDH 
lactate dehydrogenase 
mg 
milligram(s) 
min 
minute(s) 
mIU 
Milli International Units 
mL 
milliliter(s) 
MM 
multiple myeloma 
mm2 
millimeter(s) squared 
mm3 
millimeter cubed 
MCL 
Mantle Cell Lymphoma 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
per os (oral) 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QIU 
Qualified Investigator Undertaking Form 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SEER 
Surveillance, Epidemiology, and End Results 
SPEP 
serum protein electrophoresis  
STD10 
severely toxic dose in 10% of animals 
TLS 
Tumor lysis syndrome 
TTP 
time to tumor progression 
ULN 
upper limit of the normal range 
UPEP 
urine protein electrophoresis 
WBC 
white blood count 
 
 
 
 
 
 
 
 
 


 
 
15 
 
3.0       INTRODUCTION 
 
Mantle cell lymphoma (MCL) is an incurable hematologic malignancy arising from CD5+ antigen 
naïve pre-germinal center B cells that comprises approximately 6-7% of all adult Non Hodgkin 
Lymphoma (NHL)1. The incidence of MCL increases with age (average age is 68 years) and is more 
common in males1,2. Although some patients with MCL can have indolent course, majority of them 
pursue an aggressive course.  Most patients of MCL presents with non-bulky lymphadenopathy and 
advanced stage with frequent extra-nodal involvement. In general, MCL pursue an aggressive course 
with very poor outcome. The median survival reported in various series is between 3-5 years3.  
The MCL is characterized by unique molecular characteristic of over expression of cell cycle regulator 
protein cyclin D1 (the first event in lymphomagenesis). This over expression is due to the 
chromosomal translocation of t(11;14) (q13;q32) which juxtaposes cyclin D1 gene, B-cell 
leukemia/lymphoma (bcl-1), under control of immunoglobulin heavy chain enhancer. Apart from 
this characteristic molecular feature, other markers such as CD20 and CD5 expression, inactivating 
p53 mutations and decreased expression of p27 are also evident in MCL. 4 
Apart from common lymphoma indicators (extra-nodal involvement, age, performance status and 
LDH), Ki-67 proliferation index has proven to be powerful predictor of survival in MCL in post 
Rituximab era. Mantle Cell International Prognostic Index (MIPI) identified four independent 
prognostic factors (age, performance status, LDH and WBC count). Based on these prognostic factors, 
the patients can be classified into high risk (OS of 2 years), intermediate risk (OS of 4 years) and low 
risk (OS of 6 years). 5 6 7-9 
MCL is still considered incurable with currently available treatment options. MCL has wide spectrum 
of clinical presentation ranging from indolent disease to symptomatic aggressive disease. Indolent 
disease usually presents with limited stage disease, low tumor burden, without high risk features and 
low Ki67 expression and has better overall ourtome.10-13 Unfortunately, majority of the patients will 
present with advanced systemic and symptomatic disease and symptomatic disease requiring 
aggressive induction, consolidative and maintenance treatment depending on their physiological 
status.  
The initial treatment of MCL depends on many disease and patient related factors. Advanced, 
biologically aggressive (high Ki67 index, p53 mutated and blastoid) disease in a young and fit patient 
needs aggressive/intense induction, ASCT consolidation and maintenance treatment. While unfit 
patient usually is offered less intense treatment (R-CHOP, R-B, VR-CAP) followed by maintenance 
treatment.  
Rituximab combined with high dose cytarabine (R-Hyper CVAD or R-DHAP) followed by autologous 
stem cell transplantation (ASCT) is currently considered standard in treatment of MCL for fit 
patients14. The addition of rituximab to multi-agent chemotherapy backbone has improved response 
rates and outcomes. 15In a randomized controlled trial of CHOP vs R-CHOP, addition of rituximab lead 
to better outcomes.16  
Over the past decade multiple studies have revealed the role of cytarabine in treatment of MCL. 
Treatment regimens containing high dose cytarabine are shown to produce better complete response 
rates and PFS17-20. In a phase III trial comparing RCHOP(6 cycles) vs RCHOP(3 cycles) alternating with 
RDHAP(rituximab, dexamethasone, cytarabine and cisplatin)(3 cycles) followed by autologous 
transplantation, the R-DHAP arm had better CR rate(25% vs 36%, p=0.012), longer response 
duration (46 vs. 48 months, p=0.0382) and longer OS(82 mths vs. not reached, p=0.045)21. In a phase 
II trial, R-HyperCVAD (rituximab, cyclophosphamide, doxorubicin, vincristine and dexamethasone) 
alternating with R-MA (rituximab, methotrexate and cytarabine) was was associated with 97% RR 


 
 
16 
with 87% CR. Impressively, at 10 years follow up the median OS was not reached with median time 
to failure of 4.6 years. The regimen was associated with higher toxicity profile.22 Another phase II 
study of the same regimen confirmed higher CR rates with good survival rates.23 Although highly 
active, R-HyperCVAD is associated with significant treatment related toxicity and interruption in 
therapy.  
For unfit patients or who are ASCT ineligible, the treatment options are limited. Most commonly used 
chemo-immunotherapy regimens are R-CHOP, BR or VR-CAP. A phase II by European MCL network 
tested RCHOP against FCR (fludarabine, cyclophosphamide and rituximab) followed by second 
maintenance randomization between Interferon and rituximab.24 The median OS at 4 years was 
significantly in favor of the RCHOP arm (62% vs 47%, p=0.005). In second randomization, rituximab 
maintenance reduced risk of progression or death by 45 %( 68% vs 29%), improved duration of 
response and OS. 24 
Bendamustine in combination with rituximab have shown promising results in first line and relapse 
refractory setting. In a randomized phase III trial of BR vs RCHOP, BR showed significant 
improvement in PFS (35.4vs 22.1months) although there was no statistically significant difference in 
OS25. The combination of bendamustine and rituximab with cytarabine was evaluated in a Phase II 
study of patients older than 65 who were not eligible for aggressive chemotherapy26. Among 
previously untreated MCL patients, the ORR was 100% and the 2 year PFS was 95%. A phase III 
double-blind study of ibrutinib in combination with BR versus BR for the treatment of patients with 
newly diagnosed MCL is currently ongoing (NCT01776840)27.  
Bortezomib, a proteasome inhibitor, inhibits 26S proteasome. By doing so, it inhibits NF-kB pathway 
making it rationale for activity in MCL. It was approved as a single agent, by US food and drug 
administration (US FDA) in MCL in relapse refractory setting in December 2006. In the registration 
phase III trial, newly diagnosed MCL patients, not eligible for aggressive chemotherapy were 
randomized to receive VR-CAP or RCHOP28. At follow-up of 4 years VR-CAP patients had better PFS 
(24.7 vs 14.4 months, p=<0.001) and median OS at 4 years (64% vs 54%) compared to R-CHOP. Based 
on this trial, US FDA approved VR-CAP in newly diagnosed MCL patients. 
Intensive consolidation chemotherapy and high dose chemotherapy followed by autologous 
transplantation are usually not recommended for patients who above age 65 or who are unfit for 
such regimens. In much selected elderly patients however, this may be an acceptable option29. 
Autologous HSCT is now considered a standard consolidation strategy for young and fit patients with 
MCL. In a prospective study of frontline RCHOP/RDHAP followed by ASCT the 3 year even free 
survival and overall survival were 84% and 90% respectively but the median overall survival not 
reached30. In this trial, the molecular reemission (MRD negative disease) at 2 years post ASCT was 
associated with improvement in PFS and OS.  
The MD Anderson group published a study of Hyper CVAD induction followed by consolidative 
autoHSCT which showed fiver year disease free survival of 42% and OS of 77%.31In the Nordic MCL-
2 phase II trial, 160 MCL patients younger than 66 years were given 6 cycles of rituximab and high-
dose cytarabine containing induction regimen followed by BEAM (carmustine, etoposide, cytarabine 
and melphalan) conditioning regimen and ASCT. The CR rate increased from 56% to 90% after 
myeloablative chemotherapy stressing the role of intensive consolidation therapy in improving the 
response rate17. In the European MCL Network phase III trial, the response rate after autoHSCT was 
97% in the two arms but the rate of molecular remission that is a powerful and independent 
prognostic factor for the duration of the response rose from 55 to 72% after ASCT (p=0.0116)21,32. 
 
Maintenance therapy with rituximab may provide extended disease control in patients who are 
unable to undergo aggressive chemotherapy and/or ASCT. In a pilot phase II study, previously 


 
 
17 
untreated patients with MCL were treated with modified less intense HyperCVAD followed by 
rituximab maintenance for 5 years. The median PFS was 37 months and median OS was not reached 
in favor of rituximab maintenance 33. In another study of modified HyperCVAD with bortezomib 
followed by rituximab maintenance, median PFS and OS were not reached at 4 years34.  
 
Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) are a class of drugs that inhibit the 
phosphoinositide 3 kinase enzymes which are part of the Pi3K/AKT/mTOR pathway. The 
phosphatidylinositol-3-kinase pathway is known to have a significant role in B-cell function including 
B-cell antigen receptor signaling. Inhibition of PI3K delta dependent signaling has been shown to 
have antitumor effect by inducing apoptosis and affecting the tumor microenvironment. Two class I 
PI3K isoforms inhibitors have been tested for relapsed MCL, the oral isoform-selective inhibitor PI3K 
(CAL-101/ GS-1101, idelalisib) that blocks survival signals, induces apoptosis and disrupts signals 
between the tumor microenvironment and B-cell malignancies35-37 and the more pleiotropic PI3K- 
(Copanlisib / BAY 80 – 6946) that exhibits preferential inhibition of AKT phosphorylation, superior 
antitumor activity and potent apoptosis inducing activity38. A phase I trial of Idelalisib, in heavily 
pretreated patients with MCL confirmed the activity of this compound with an ORR of 40% (5% CR) 
and a 1-year PFS of 22%39. Copanlisib, an intravenous formulations has been evaluated in a phase II 
study in various lymphomas, including 7 patients with MCL with ORR of 71% (1 uCR / 4 PR)40. 
 
 
 
 
3.1  UMBRALISIB  
Umbralisib is a highly-specific and orally available phosphoinositide-3-kinase (PI3K) delta (δ) 
inhibitor with nanomolar inhibitory potency, and high selectivity over the alpha, beta, and gamma 
Class I isoforms of PI3K.  The PI3Ks are a family of enzymes involved in various cellular functions, 
including cell proliferation and survival, cell differentiation, intracellular trafficking and immunity.  
The delta isoform of PI3K is highly expressed in cells of hematopoietic origin, and strongly 
upregulated, and often mutated in various hematologic malignancies.   
 
In the Phase I study, to-date, a total of 81 patients have been treated with umbralisib, including 22 FL 
and 21 CLL patients.  In all treated patients, the most commonly-occurring (≥18% patients) adverse 
events (AEs; all grades, all causality) were nausea, diarrhea, fatigue, rash, headache, cough and 
vomiting, the majority of which were Grade 1/2.  The only Grade ≥3 AE occurring in < 5% of patients 
was anemia (9%).  Discontinuation due to an adverse event with TGR-1202 was reported in 6/81 
(7%) of patients.  Of the 17 evaluable CLL patients, 16 (94%) achieved a nodal PR of which 10 (59%) 
achieved a PR per Hallek 2008 criteria.   Clinical activity was also observed in FL, with 12/16 (75%) 
evaluable patients experiencing tumor reductions, and a preliminary 38% ORR (6/16) with an 
additional 2 patients achieving 49% reductions in tumor burdens (patients continuing to receive 
ongoing therapy).  The longest period of treatment on the study to-date is 34 cycles (over 2.5 years), 
and 27% of patients have received more than 12 cycles of treatment. The Phase I study is closed as 
umbralisib is now in Phase 3 development for patients with CLL (UNITY-CLL study). 
 
Preclinical Evaulations of Umbralisib  
The potency of umbralisib against the human and mouse δ isoform of PI3K was evaluated in 
a homogeneous time resolved fluorescence (HTRF) based enzyme assay in the presence of ATP at 
its Km value (100 μM) (Umbralisib Investigator Brochure). Selectivity over the other three 
isoforms, namely, α, β, and γ was also determined (Prasanna R, 2011; Seeta N, 2011a, 2011b).  
 


 
 
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Data demonstrated the specificity of umbralisib towards PI3Kδ with >1000, 50 and 48-fold 
selectivity over α, β, and γ, respectively in an enzyme based assay, indicating that the primary mode 
of action of this compound is via inhibition of the δ isoform. 
 
FIGURE 1: UMBRALISIB POTENCY AGAINST 
HUMAN AND MOUSE PI3K  ISOFORMS 
PI3K isoforms 
(Human) 
IC50 (nM) 
Α 
>10,000 
Β 
1,116 
Γ 
1,065 
Δ 
22.23 
 
Proliferation of immortalized leukemic cells representative of various indications was determined 
by a MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay (Umbralisib 
Investigator Brochure). Cells were incubated with umbralisib for different time-periods (72 -96 h) 
based on their doubling time. Data demonstrated the ability of umbralisib to inhibit leukemic 
cell proliferation albeit with different potencies based on the cell type. 
Overall, a 50% growth inhibition for majority of B, T, and monocytic cell lines was achieved at 
a concentration between 0.5 -7.5 μM of umbralisib. 
Subsequent to cell viability, the effect of umbralisib on AKT phosphorylation (Umbralisib 
Investigator Brochure) was determined. AKT, a serine threonine kinase mediates the downstream 
effects of PI3K activity and modulates several cell processes including survival and growth. 
Reduction of phosphorylated AKT by umbralisib in representative cell lines was determined by 
Western blotting using a phospho-AKT (Ser473) antibody. 
FIGURE 2: REDUCTION OF PAKT BY UMBRALISIB IN CELL LINES BY WESTERN BLOTTING 
 
In vivo efficacy of umbralisib was confirmed in a subcutaneous mouse MOLT-4 xenograft model. Oral 
administration of 150 mg/kg/QD over a 25-day period resulted in a significant delay in tumor 
growth. 
FIGURE 3: UMBRALISIB IN VIVO EFFICACY 


 
 
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Toxicology 
To assess the safety and toxicity of umbralisib 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.  Umbralisib was administered orally in order to mimic the planned 
mode of clinical administration.       
Once daily oral administration of umbralisib 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 umbralisib 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 Umbralisib Investigator’s Brochure (IB) for detailed information on toxicology studies 
conducted to date. 
 
CLINICAL DEVELOPMENT OF UMBRALISIB  
Single-Agent in Patients with Relapsed or Refractory Hematologic Malignancies 
Umbralisib is under evaluation in a single-agent Phase I dose-escalation study in patients with 
relapsed and refractory hematologic malignancies (Burris et al, 2015).  A total of 81 patients were 
enrolled and eligible for safety evaluation, with 63 patients evaluable for efficacy.  The median age 
was 65 years (range 22-85) and 53% were male.  Among all patients the median number of prior 
therapies was 3 (with a range of 1-14), with 80% receiving prior rituximab-based chemotherapy.  
Histological diagnoses were as follows: FL (n=22), CLL (n=21), diffuse large B-cell lymphoma 
(DLBCL; n=14), Hodgkin’s lymphoma (HL; n=9), mantle cell lymphoma (MCL; n=6), MZL (n=5), WM 
(n=2) and one each of hairy-cell leukemia (HCL) and T-cell lymphoma.  The majority of patients had 
an ECOG of 1 and 40/81 (49%) were refractory to prior therapy.     
Patients have been enrolled in a 3+3 dose-escalation design starting at 50 mg QD with subsequent 
cohorts evaluating doses as high as 1800 mg QD.  In an effort to further improve the oral 
bioavailability of umbralisib, the particle size of the drug product was reduced through a 
micronization process, resulting in greater absorption when tested in a bioequivalence crossover 
study in healthy subjects  .  This micronized formulation was introduced into dose escalation at 200 
mg QD and dosed as high as 1200 mg QD, with no maximum tolerated dose (MTD) reached.  Intra-
patient dose escalation rules have allowed patients enrolled into the study in early cohorts to 
increase their dose of umbralisib as subsequent higher cohorts have cleared safety evaluation. 
A dose-dependent response has been observed with umbralisib, with a dose of 800 mg or higher of 
the initial formulation or any dose of the micronized formulation producing significant nodal 


 
 
20 
reductions among CLL patients.  Of the 17 evaluable CLL patients treated at or above this therapeutic 
threshold, 16/17 (94%) have achieved a nodal partial response, and nodal reductions show an 
improvement with time on umbralisib with a median time on study of 6 months.  Clinical activity was 
also observed in FL, with 12/16 (75%) evaluable patients experiencing tumor reductions, and a 
preliminary 38% ORR (6/16) with an additional 2 patients achieving 49% reductions in tumor 
burdens (patients continuing to receive ongoing therapy). 
In all treated patients (81), the most commonly-occurring (≥18% patients) adverse events (AEs; all 
grades, all causality) were nausea, diarrhea, fatigue, rash, headache, cough and vomiting, the majority 
of which were Grade 1/2.  The only Grade ≥3 AE occurring in >10% of patients was neutropenia 
(11%). No events of colitis have been observed. Discontinuation due to an AE was reported in only 
6/81 (7%) of patients.  Less commonly-occurring AEs (9-12%) included constipation, decreased 
appetite, hypokalemia, anemia, dizziness, dyspnea, pyrexia, abdominal pain, arthralgia and insomnia.  
Dosing of umbralisib initially occurred in the fasting state, but was transitioned mid-study to fed state 
dosing, with patients instructed to take umbralisib with food.  All dosing of umbralisib is now 
conducted using the micronized formulation and in the fed state.   
Overall, umbralisib was well tolerated and displayed promising signs of clinical activity at the higher 
dosing cohorts with 800 mg QD selected as the Phase 2 dose in patients with previously treated CLL 
and NHL. 
Healthy Subject Pharmacokinetic Studies 
In parallel with the Phase 1 single-arm, dose-escalation study in patients with relapsed or refractory 
hematologic malignancies; two healthy subject, crossover, bioequivalence pharmacokinetics 
studies have been completed. The first pharmacokinetic study was a Phase 1 drug-food interaction 
study with a single 200 mg oral dose of umbralisib in healthy volunteers followed by a second single 
dose Phase 1 pharmacokinetic study evaluating the absorption, distribution, metabolism and 
excretion characteristics of two different oral formulations of 200 mg umbralisib (original 
formulation vs. micronized formulation) in healthy volunteers. 
 
TGR-1202-PK101: Food Effect 
Study TGR-1202-PK 101 was two-period, randomized, two-way crossover, drug-food, drug-gender 
interaction study in 24 healthy subjects (12 males and 12 females) to assess the mean plasma 
umbralisib concentration over time following a single oral dose of 200 mg of umbralisib under 
fasting and fed condition using the original formulation. In general, administration of umbralisib 
under fed conditions results in a higher rate of exposure relative to when the product was given 
under fasting conditions. 
The statistical comparisons of umbralisib pharmacokinetic parameters under fasted and fed 
condition are shown below. 
 
Parameters 
Geometric LS Means 
% Geometric 
Mean Ratio 
Confidence Interval 
Fasting 
Fed 
AUC0-t (ng∙hr/mL) 
6029.87 
9692.02 
160.73 
140.25 – 184.21 
AUC0-inf  (ng∙hr/mL) 
8391.35 
14047.17 
167.40 
141.59 – 197.92 
Cmax  (ng/mL) 
176.78 
483.15 
273.31 
234.04 – 319.17 
 
Food increased both the extent and rate of exposure of umbralisib. The extent (AUC0-t) and total 
extent (AUC0-inf) of exposure increased by 61% and 67%, respectively, when umbralisib was 


 
 
21 
administered under fed conditions compared to fasting conditions. The peak plasma levels of 
umbralisib increased by over 173% when umbralisib was administered with food. 
 
Using these mean values, a 334 mg oral dose of umbralisib under fasted condition can be 
extrapolated to be equivalent to an oral dose of 200 mg of umbralisib under fed conditions in 
terms of exposure based on AUC0-inf. 
 
 
 
TGR-1202-PK102: Formulation Effect 
Study TGR-1202-PK 102 was a two-period, randomized, two-way cross over, relative bioavailability 
and pharmacokinetic bioequivalence study with two different drug product formulations of 
umbralisib. In this study, umbralisib was administered under fasted conditions in 24 healthy 
subjects (12 males and 12 females) to assess the mean plasma umbralisib concentration over time 
following a 200 mg single dose of the original drug product formulation and modified 
(micronized) drug product formulation of umbralisib. The mean rate and extent of exposure to 
umbralisib were higher following administration of the micronized drug product formulation 
compared to the original drug product formulation as mean concentrations were higher throughout 
most of the sampling interval. 
 
 
Parameters 
Geometric LS Means 
% 
Geometric 
Mean Ratio 
 
Confidence 
Interval 
Original 
Formulatio
n
Micronized 
Formulatio
n
AUC0-t (ng∙hr/mL) 
5906.11 
9439.82 
159.83 
149.43 – 170.95 
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 
umbralisib 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 
umbralisib 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 umbralisib in the original formulation under fasted 
condition can be extrapolated to be equivalent to an oral dose of 200 mg of the original formulation 
umbralisib under fasted conditions in term of exposure based on AUC0-inf. 
The improved exposure seen with the micronized formulation of umbralisib was confirmed in 
patients in the Phase 1 dose escalation as well. The chart below illustrates the pre-dose plasma 
concentrations of umbralisib on Day 1 of Cycle 2 in patients administered equivalent doses of either 
the initial formulation in the fasting state or the micronized formulation in the fed state: 


 
 
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3.2 UBLITUXIMAB 
Ublituximab is a novel third generation chimeric anti-CD20 monoclonal antibody bioengineered for 
potent activity, exhibiting a unique glycosylation profile with a low fucose content, designed to induce 
superior antibody-dependent cytotoxicity (ADCC).  Ublituximab exhibits competitive complement-
dependent cytotoxicity (CDC), on par with rituximab, and has also been demonstrated to induce 
programmed cell death (PCD) upon binding to the CD20 antigen on B-lymphocytes.  Ublituximab has 
a unique protein sequence, and targets epitopes on CD20 not targeted by rituximab or ofatumumab, 
both currently approved anti-CD20 antibodies (Esteves IT, 2011). 
 
Pre-Clinical Development Of Ublituximab 
In-Vitro Activity 
In an in-vitro assay using B-CLL cells from patient donors, ublituximab demonstrated an enhanced 
ability to kill CLL cells compared to rituximab.  Ublituximab demonstrated improved Fcγ receptor 
IIIA (FcγRIIIA)/CD16 binding and FcγRIIIA dependent effector functions compared to rituximab.  
Additionally, ublituximab induced higher in vitro ADCC against CLL cells, and a higher FcγRIIIA 
mediated interleukin-2 (IL2) production by FcγRIIIA+ Jurkat cells (de Romeuf C, 2008).  Ublituximab 
demonstrated high ADCC against both patient-derived CLL cells and NHL cell lines.  Ublituximab’s 
engagement to FcγRIIIA triggers a stronger NK cell cytotoxicity against CLL as compared to rituxan 
(in vitro) despite CD20 density, likely related to the glycosylation pattern (de Romeuf C, 2008).  
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 (Esteves IT, 2011). 
 
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). 


 
 
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Clinical Development of Ublituximab 
Ublituximab has been studied in a variety of patient populations, both as a single agent, and in 
combination with other agents, with over 100 patients having received ublituximab therapy to date 
across all studies.  Two Single-Agent Phase I/Ib trials have been conducted with ublituximab treating 
both NHL and CLL patients, with a total of 41 patients with relapsed or refractory CLL having been 
treated with single-agent ublituximab (TG-1101).  Further, following demonstration of safety and 
tolerability in these early single agent studies, Phase I and II combination studies were undertaken 
with a variety of agents.  Given the number of patients who have received ublituximab in early-phase 
trials, the safety and side effect profile of the agent is well characterized.  Summaries of the single-
agent experience are provided below as well as data with use of ublituximab in combination with 
ibrutinib. 
In a two part, first-in human dose escalation study (protocol CD20-0703), patients with relapsed or 
refractory CLL  received one weekly infusion of single agent ublituximab for 4 doses in a 3+3 dose 
escalation design through 5 sequential dose levels.  Part II of the study was a dose-confirmation 
component which used an initial dose of 150 mg followed by 7 doses of 450 mg (total dose 3300 mg) 
– the clinical summary will focus on the Part II part of the study as the dose is more relevant to the 
clinical application used in current clinical studies.  In Part II, 12 patients were enrolled at 9 centers 
in France and followed for 12 months.  Demographic data for the 12 patients enrolled in the study 
were as follows.  The median age was 69.5 years [62–77]; median time from diagnosis to inclusion 
was 10.4 years [4.0–23.6] and median prior therapies was 3 [1–8].  Seven patients (58%) received at 
least one prior rituximab-containing regimen.  The median lymphocyte bone marrow infiltration was 
85% [40–94]. 
Most frequent drug-related adverse events (AE’s) reported were infusion related reactions (IRR) 
(75% of the patients, including 33% of patients with Grade 3 IRR).  Other Grade 3/4 AE’s > 10% 
included: neutropenia (67%) and increase ALT/AST (17%).  All AEs were reversible spontaneously 
or with supportive care intervention.  None of the reported adverse events were considered as a 
dose-limiting toxicity according the judgment of the study Safety Committee.  Therefore, the 
maximum tolerated dose was not reached in this study.  Significant blood lymphocyte depletion was 
observed in all patients:  median lymphocyte count at baseline was 46.6 (x109/l); after 1 month (M1) 
= 1.5 (↓94%); M4=1.4 (↓91%) and M6=2.0 (↓89%). No cases of serum anti-ublituximab antibodies 
were detected at any time point.  
Clinical response was based on the criteria established by the National Cancer Institute (NCI)-
Working Group updated in 2008 (Hallek M, 2008).  All patients but one received the planned 8 
infusions without any dose reduction--one patient was prematurely withdrawn due to a concomitant 
secondary leukemia unrelated to ublituximab therapy.  Response was evaluated at month 4 for the 
11 evaluable patients, with an initial response rate of 64% (7/11) with a confirmed response at 
month 6 in 5/11 patients (45%) patients (all PRs).  Four of the 11 patients achieved stable disease.  
At the 1 year follow-up, no responders had progressed, demonstrating all confirmed responses were 
durable despite no ublituximab maintenance therapy.  The median progression-free survival (PFS) 
was not reached at the 12 month follow-up (Cazin B, 2013). 
A Phase I trial of ublituximab (NCT01647971) was subsequently undertaken in patients with B-cell 
lymphoma who were relapsed or refractory to a prior rituximab containing regimen, which included 
8 patients with CLL.  This trial utilized a 3+3 design, assessing dose levels of 450, 600, 900, and 1200 
mg.  No DLTs were observed amongst the 12 patients enrolled into the dose-escalation component, 
and expansion cohorts were subsequently undertaken at 600, 900, and 1200 mg.  Patients with CLL 
were eligible to enroll into the expansion cohorts at 600 and 900 mg, receiving ublituximab on days 
1, 8 & 15 of Cycles 1 & 2, with monthly mainte/nance infusions starting in Cycle 3, followed by every 
3 months starting in Cycle 6.   
Of the 8 CLL patients enrolled, 4 had infusion related reactions that were manageable with infusion 


 
 
24 
interruptions only and all patients received all schedule doses.  Other observed adverse events 
which were considered at least possibly related to study drug included neutropenia Grade 1/2 
(n=1) and Grade 3/4 (n=3), as well as thrombocytopenia Grade 1/2 (n=1) and Grade 3/4 (n=1).  Six 
patients were evaluable for efficacy as of data cutoff for ASCO 2014, with 4 out of 6 patients 
achieving a partial response.  Rapid and profound circulating lymphocyte depletion (> 50% 
reduction) was noted with median time to peripheral response of 1 day (O'Connor OA, 2014). 
 
Pharmacokinetics 
After infusion of ublituximab (previously known as LFB-R603) at a 150 mg dose followed by seven 
weekly injection infusions at 450 mg, results suggested non-linear pharmacokinetics with respect to 
dose (450 mg vs. 150 mg) and time (week 4 vs. week 8) and more than proportional increase of Cmax 
and AUC∞ due to a clearance decrease.  The volume of distribution at steady state was small (~5 L), 
approximately equal to blood volume.   These non-linear pharmacokinetics may be explained by 
binding of ublituximab to its target, with a large component of target-mediated elimination after the 
first dose that is decreased after subsequent infusions due to a reduction in the available target.  
However, limited data for each dose level cohort and considerable variability in baseline patient 
characteristics, particularly in terms of tumor burden, make firm conclusions difficult. 
The linear mean serum concentration-times profile after the first, the fourth and the eighth infusion 
of ublituximab are presented in Figure 1.  A summary of non-compartmental PK parameters after the 
first, the fourth and the eighth infusion of ublituximab are presented in Table 1. 
FIGURE 4: LINEAR MEAN SERUM CONCENTRATION-TIMES PROFILE AFTER THE FIRST, THE 
FOURTH AND THE EIGHT INFUSION OF UBLITUXIMAB 
 
TABLE 1: PHARMACOKINETIC RESULTS AFTER THE 1ST (150 MG), THE 4TH (450 MG) AND 
THE 8TH (450 MG) INFUSION OF UBLITUXIMAB 
PK 
Parameters a 
1st Infusion 
150 mg  (Day 1) 
4th Infusion 
450mg  (Day 22) 
8th Infusion 
450 mg  (Day 50) 
N 
12 
11 
11 
Cmax (mg/L) 
23.4 ± 11.2 
168.6 ± 61.8 
220.5 ± 141.9 
tmax (h) 
9.0 (5.0-30.3) 
5.00 (3.1-52.0) 
5.1 (3.1-23.5) 
AUC∞ (mg.h/L) 
732.1 ± 590 
17890 ± 17730* 
50760 ± 74460 
t1/2term (h) 
13.43± 10.2 
80.7 ± 58.5* 
147.8 ± 133.8 
CL (mL/h) 
424.2 ± 389.3 
57.69 ± 42.91 
38.62 ± 26.63 
Vd/Vdss, (L) 
4.8 ± 2.1 
4.9 ± 2.3* 
5.7 ± 3.3 
a mean ± SD, tmax: median (range) , with respect to the start of infusion                                                    *Accurate determination not possible 
Concentration was still measurable in at least one patient of the cohort up to day 169. Values for Cmax 
and AUC¥ increased from the first to the eighth infusion whereas t1/2 term decreased. 
 
 
Ublituximab in Combination with TGR-1202 


 
 
25 
The combination of ublituximab and TGR-1202 is currently under evaluation in registration trials in 
CLL and various B cell NHL histologies.  Preliminary results of an ongoing Phase I/Ib study in patients 
with relapsed or refractory NHL and CLL have been reported (Lunning et al., 2015).  In early cohorts, 
patients received ublituximab on days 1, 8 and 15 of Cycles 1 & 2, then on day 1 of Cycles 4, 6, 9, and 
12.  In later cohorts, the ublituximab administration schedule was amended to infusions on days 1, 8, 
and 15 of Cycle 1, followed by Day 1 of Cycles 2 through 6.  CLL patients receive Cycle 1, Day 1 
infusions split over Days 1 and 2.  TGR-1202 is taken once daily until patients are removed from study 
as per the protocol.    
A 3+3 dose-escalation design is being utilized to evaluate sequentially higher doses of the 
combination agents as illustrated below: 
Cohort 
Ublituximab NHL Dose 
Ublituximab CLL Dose 
TGR -1202 Dose (QD) 
1 
900 mg 
600 mg 
800 mg 
2 
900 mg 
600 mg 
1200 mg 
3 
900 mg 
900 mg 
400 mg (micronized) 
4 
900 mg 
900 mg 
600 mg (micronized) 
5 
900 mg 
900 mg 
800 mg (micronized) 
6 
900 mg 
900 mg 
1200 mg (micronized) 
 
As of December 1, 2015, 71 patients have been enrolled and are evaluable for safety, with 58 patients 
evaluable for efficacy.  The median age was 65 years (range 26 – 86), 47 Male/24 Female, with 
histologies as follows: 24 DLBCL, 19 CLL/SLL, 19 FL, 6 MZL, 2 MCL, and 1 patient with Richter’s 
Transformation.  Patients had a median of 3 prior therapies, and 58% were refractory to prior 
therapy.   
Among the 71 patients evaluable for safety, nausea was the most prevalent adverse event (46%), 
followed by diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion related reaction 
(25%).  Seven patients had their dose of TGR-1202 reduced due to various adverse events.  IRR and 
neutropenia were managed through dose delays, with 1 CLL patient having a neutropenia related 
dose delay which met the criteria for a DLT, necessitating enrollment of additional CLL patients into 
Cohort 1.  Overall 8% of patients have discontinued TGR-1202 due to an adverse event.   
Sixteen DLBCL patients treated with ublituximab + TGR-1202 were treated with therapeutic doses, 
amongst whom, the overall response rate was 31% with three patients experiencing a complete 
remission as confirmed by independent review. Amongst the five patients who responded, three 
had GCB subtype, while the other two patients subtype was not known.   
Overall, the preliminary data suggests the combination of ublituximab and TGR-1202 is well 
tolerated and active in patients with relapsed or refractory hematologic malignancies, including 
those with DLBCL. 
 
Minimal Residual Disease  in MCL 
The most frequently used methods for monitoring treatment response in lymphoma is PET and CT 
imaging. However, both these modalities have limitation of detecting disease at micro levels. 
Minimal residual disease (MRD) assessments in MCL by various methods have been explored but 
allel specific quantitative polymerase chain reaction method have been very sensitive and specific. 
Compared to other MRD detection methods (flow cytometry, PCR) the clonoSEQ assay is 10-100x 
more sensitive. The assay has the capability of identifying one cancer in one million healthy cells 
(Sala Torra et al 2017). This assay has undergone clinical validation and fulfills the requirements 
for regulatory review. It uses next generation DNA sequencing (NGS) and can serve as a 
standardized way to determine treatment effect.  Panel directed NGS MRD detection uses the 


 
 
26 
genetic features of lymphoma to identify tumor specific DNA in the patient’s blood. 
(https://www.adaptivebiotech.com/) 
 
MRD assessment in MCL has been prognostic as well as can be used as surrogate for efficacy of the 
induction treatment. Here in this study, our exploratory objective is to assess the rates of MRD 
negativity at the end of the induction treatmnet (after C#6 of U2-CHOP). 
 
3.3  Rationale for this Study 
MCL majoritily, is an aggressive and incurable lymphoma. As it is the lymphoma of elderly, 
aggressive treatment approaches like aggressive induction treatments and ASCT may be more risky 
in this population. Majority of these patients are treated with less intense approach like Rituximab-
Bendamustine (BR), R-CHOP or VR-CAP. Nearly all the patients are treated with Rituximab 
maintenance after these induction approaches. 
In this proposal, we want to explore combination of novel CD20 monoclonal antibody 
(Ublituximab) with CHOP and a novel highly active PI3K inhibitor (Umbralisib) in ASCT ineligible 
untreated advanced MCL.  Ublituximab, a novel third generation chimeric anti-CD20 monoclonal 
antibody with a low fucose content, has potential 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.  Umbralisib is a highly-specific and orally 
available phosphoinositide-3-kinase (PI3K) delta (δ) inhibitor with nanomolar inhibitory potency, 
and high selectivity over the alpha, beta, and gamma Class I isoforms of PI3K.  Umbralisib is highly 
active in various B cell lymphomas. The combination of Ublituximab and Umbralisib is being 
evaluated in two signature clinical trials. The preliminary data suggests that the combination is safe 
and well tolerated.  
To improve upon the back bone of R-CHOP, we want to exlore U2-CHOP (Ublituximab with 
Umbralixib)-CHOP followed by U2 maintnenance in ASCT in eligible patients. Both the study agents 
(U2) are highly active in lymphomas. Our hypothesis is to improve rates of complete response at 
the end of induction treatment with this novel combination. We also want to explore if this novel 
combination induces more MRD negativity (as exploratory objective). 
 
4.0 OBJECTIVES AND ENDPOINTS 
 
4.1 Primary Objective 
 
Phase Ib: 
 
• 
To determine the safety of Umbralisib and Ublituximab in combination with CHOP 
chemotherapy for newly diagnosed MCL 
 
 
 
Phase II: 
 
• 
CRR: To determine the efficacy of U2-CHOP in terms of Complete Response rates (CRR) in 
patients with untreated MCL after induction phase (6 cycles of U2-CHOP) by PET/CT 
response assessment criteria by Cheson 2014 (appendix) 
 


 
 
27 
4.2 Secondary Objectives 
 
Phase II: 
 
• 
To determine Overall response rate (ORR=CR+PR) of the induction treatment with U2-CHOP 
in untreated MCL 
 
• 
To determine Overall Survival (OS) at 3 years  
 
• 
To determine Progression Free Survival (PFS) at 3 years 
 
• 
To determine the rate of disease control (CR+PR+SD) at 3 years 
 
4.3 Exploratory Objective: 
 
• 
To determine the frequency of MRD negative (MRD-) disease at the end of induction 
treatment with U2-CHOP. 
 
 
 
 
4.4 Efficacy Endpoints 
 
Primary Endpoint: 
• 
Rate of complete remission at the end of induction treatment (U2-CHOP X 6 cycles) per 
PET/CT assessment criteria for Lymphoma (Cheson et al, 2014) 
Secondary Endpoints: 
• 
Rate of Overall Response Rate (CR+PR) 
• 
Rate of PFS at 3 years 
• 
Rate of OS at 3 years 
• 
Rate of disease control rate (CR+PR+SD) at 3 years 
• 
Rate of MRD negativity at the end of induction 
• 
PFS and OS of MRD- subjects 
 
5.0 ELIGIBILITY CRITERIA 
Patients must meet all of the following inclusion criteria and none of the exclusion criteria to be 
eligible for participation in this study. 
 
 
5.1  Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation in this study: 
• 
Males or female patients >18 years of age 
• 
Diagnosis if MCL (Stage II, III, IV) as supported by histology and over expression of cyclin D1 
(in association with CD20 and CD5) or evidence of t(11;14) by FISH (fluorescent in situ 
hybridization) with indication of initiation of therapy. 
• 
At least one LN of >1.5 cm size as index/measurable site of disease 


 
 
28 
• 
No prior therapy for MCL 
• 
Not eligible for bone marrow transplantation (assessed by treating physician due to 
comorbidities) or not interested in bone marrow transplant (clear documentation of 
patient’s unwillingness to pursue transplant) 
• 
Eastern cooperative Oncology Group (ECOG): 0,1 or 2 (Appendix) 
• 
Absolute neutrophil count (ANC) >1500 (>1000 if bone marrow involvement with MCL) 
within 28 days prior to initiation of therapy 
• 
Platelets >100000 cells/µL (>75000 cells/µL if bone marrow involvement with MCL) within 
28 days prior to initiation of therapy 
• 
Hemoglobin >9.0 gm/dL (>8.0 gm/dL if bone marrow involvement with MCL) within 28 
days prior to initiation of therapy 
• 
Alanine transaminase (ALT)/Aspartate Transaminase (AST) <3.0 X Upper limit of Normal 
(ULN) within 28 days prior to initiation of therapy 
• 
Total Bilirubin <2 X ULN within 28 days prior to initiation of therapy 
• 
Calculated Creatinine Clearance >35 mL/min by Cockcroft-Gault Equation 
• 
Male patients must agree to use an acceptable method of contraception for the entire 
duration of study. 
• 
All patients (or their legal representative) must have signed an informed consent indicating 
that they are willing to participate in the study and are willing to follow the procedure 
required by the study in accordance with federal, local and institutional guidelines. 
• 
Female patients who are not of child-bearing potential (see Appendix: CONTRACEPTION 
GUIDELINES AND PREGNANCY), and female patients of child-bearing potential who have a 
negative serum pregnancy test within 72 hours prior to initial trial treatment.  Female 
patients of child-bearing potential and all 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 either study drug.  
 
5.2 Exclusion Criteria  
Patients who meet any of the following exclusion criteria are not to be enrolled to this study. 
 
• 
Any prior anti-neoplastic therapy for MCL 
• 
CNS involvement by MCL  
• 
Non-hematologic malignancy within the past 3 years with the exception of a) adequately 
treated basal cell carcinoma, squamous cell skin cancer, or localized thyroid cancer; 
b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less 
with stable prostate-specific antigen levels; or d) cancer considered cured by surgical 
resection or unlikely to impact survival during the duration of the study, such as localized 
transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas. 
• 
If patient has received prior anthracycline therapy, the cumulative anthracycline dose 
should be <150mg/m2 of doxorubicin equivalent 
• 
H/O prior Allogeneic transplantation or autologous stem cell transplantation for any other 
reason. 
• 
Use of immunosuppressive therapy (e.g. cyclosporine A, tacrolimus or high dose steroids). 
Patients receiving steroids must be at a dose of <10mg/day prednisone (or equivalent) 
within 7 days of the first day of the study treatment administration. Patients are allowed to 
use topical or inhaled corticosteroids. 


 
 
29 
• 
Concurrent any anticancer therapy for any other cancer (chemotherapy, radiation, surgery, 
immunotherapy, biologic therapy, hormonal therapy, investigational therapy or tumor 
embolization). 
• 
Use or expected use during the study of any prohibited medications including potent 
CYP3A4 inhibitors, inducers, substrates (appendix) within 14 days or 5 half-lives 
(whichever is longer) before the study treatment administration. 
• 
Significant concurrent, uncontrolled medical condition including but not limited to renal, 
hepatic, hematological, GI, endocrine, pulmonary, neurological, cerebral or psychiatric 
disease. 
• 
History of stroke or intracranial hemorrhage within 6 months of the date of study treatment 
administration (unless complete and full recovery) 
• 
Chronic or current active infections requiring systemic antibiotics, antifungal or antiviral 
treatment or exposure to live vaccines within 30 days of study treatment. 
• 
Known HIV infection. 
• 
Evidence of Hepatitis B or Hepatitis C infection or risk of reactivation. HBV DNA and HCV 
RNA Evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis 
B vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C 
infection (HCV), active cytomegalovirus (CMV), or known history of HIV.  If HBc antibody is 
positive or CMV IgM is reactive the subject must be evaluated for the presence of HBV or 
CMV DNA (by PCR) 
• 
Known history of drug-induced liver injury, alcoholic liver disease, non-alcoholic 
steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by 
stones, cirrhosis of the liver 
• 
Any severe and/or uncontrolled medical conditions or other conditions that could affect 
participation in the study such as: 
• Symptomatic, or history of documented congestive heart failure (New York 
Heart Association functional classification III-IV)[see Appendix:  NYHA 
Classifications] 
• Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, CHF, or myocardial infarction within 6 months of enrollment.  
• Concomitant use of medication known to cause QT prolongation or torsades de 
pointes should be used with caution and at investigator discretion. 
• Poorly controlled or clinically significant atherosclerotic vascular disease 
including cerebrovascular accident (CVA), transient ischemic attack (TIA), 
angioplasty, cardiac or vascular stenting within 6 months of enrollment. 
• 
Cardiac ejection fraction (EF) <45%. 
• 
Current NY heart association Class II to IV congestive heart failure or uncontrolled 
arrhythmia 
• 
Presence of an abnormal ECG that is clinically meaningful. Patients with QTc interval >450 
milliseconds are excluded (corrected by Fridericia). 
• 
Currently pregnant or breast feeding. 
• 
Unable to swallow and retain oral medication, malabsorption syndrome, disease 
significantly affecting GI function, total resection of stomach or small bowel, ulcerative 
colitis, symptomatic IBD or complete or partial obstruction. 
• 
Anaphylaxis to monoclonal antibody/Rituximab in past. 


 
 
30 
• 
Any condition that would, in investigator’s judgment, interfere with full participation in the 
study, including administration of study medication/chemotherapy, attending study visits, 
pose a risk to the patient or interfere with interpretation of study data. 
• 
Inability to comprehend or unwilling to sign the ICF. 
• 
Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis 
within 21 days prior to registration 
• 
Contraindication or intolerance to required supportive care medications (neulasta, 
acyclovir or bactim/dapson/pentamidine/atovaquone) 
• 
 Females who are pregnant or lactating. 
 
5.3 Subject Enrolment 
Once a patient is identified as a candidate for the trial the investigator will contact the UAB 
CTNMO registration office (205-975-5387, Fax No: 205-975-9875) prior to obtaining informed 
consent (safety lead in cohort only). This process is intended to verify if a “slot” is available in the 
current cohort. Registration will be completed upon submission of documentation of eligibility to 
the registration office and issuance of a registration confirmation email.  
Prior to accepting the registration, the registration office will verify the following:  
 
 
- IRB approval at the registering institution. 
 
- Patient eligibility. 
 
- Existence of a signed consent form.  
 
- Existence of a signed authorization for use and disclosure of protected health  
 
  Information. 
- Pretreatment tests and procedures must be completed within the guidelines specified in the 
test schedule, including assessment of baseline symptoms. 
- Study drugs availability on site (for initial site patient only; Local site is responsible for 
assessing drug available for subsequent site enrollments).  
 
6.0 TREATMENT AND PROCEDURES: 
This is a single arm, multi-center, open label Phase II trial with safety lead in Phase Ib.Treatment will 
be administered on an outpatient basis in 3-week (21 day) cycles. 
6.1  Phase Ib: 
In phase Ib portion, 3 patients will be enrolled at the following dose levels of the induction 
treatment. These patients will be followed for 21 days to assess the Dose Limiting Toxicities. If no 
DLT occurred, the study will expand to phase II portion. If 1 DLT occurred (in 21 days), additional 3 
patients will be evaluated; if <1 DLT occurred in these three new patients, the study will expand to 
phase II portion. If >2 DLT in these three new patients, the dose will be reduced to the lower dose 
cohort: 3 patients will be evaluated at lower dose (600mg), if no DLT occurred, the study will 
expand to phase II portion; if 1 DLT occurred (in 21 days), additional 3 patients will be evaluated; if 
<1 DLT occurred  in these three new patients, the study will expand to phase II portion; if >=2 DLT 
in these three new patients, the safety monitoring committee will gather to decide lower dose and 
planning of further cohort. 
6.2 Dose Limiting Toxicities: 
v DLT will be evaluated in Phase Ib portion from the beginning of the treatment to 21 days  
v DLTs are defined as any of the following in the DLT-evaluation period, graded according to the 
National Cancer Institute’s common Terminology Criteria for Adverse Events INCI CTCAE), 
version 4.03(Appendix): 


 
 
31 
• 
Grade 3 non-hematologic lab abnormality  
• 
> Grade 4 neutropenia lasting more than 10 days 
• 
> Grade 3 Febrile Neutropenia 
• 
> Grade 4 thrombocytopenia (< 25,000/mm3) lasting for more than 10 days 
• 
> Grade 4 anemia unrelated to the disease  
• 
Delay of C#2 more than 7 days due to toxicities 
• 
> Grade 4 tumor lysis syndrome 
• 
>Grade 3 transaminitis 
• 
Any life-threatening infection (viral, bacterial or fungal) leading to death 
• 
Death related to study agent 
• 
Any non-hematologic AE > Grade 3 (fever, chills, dyspnea, rash, fatigue, flu-like syndrome, 
pain, anorexia, glucose intolerance, alkaline phosphatase elevation or hypertension) 
 
 
 
6.3  Induction treatment: (Phase I and II) 
 
 
 
 
 
 
 
 
 
*Dose adjustments are allowed on CHOP treatment based on investigators assessment for elderly 
patients. Elderly patients (>70 years) may not tolerate full dose CHOP treatment so 25% dose 
reductions on CHOP treatments are allowed. 
 
6.4 Phase II: 
• 
Once Umbralisib dose is defined in phase Ib, the study will expand to phase II portion 
after SMC/DSMB (Safety monitoring committee/Data Safety Monitoring Committee) 
agrees. 
• 
The induction treatment will be as outlined above in the table for 6, 3 weekly cycles 
 
6.5 Maintenance Treatment: 
• 
Maintenance treatment will start 8 weeks after C#6. 
• 
Ublitixumab will be given IV every 8 weeks for 24 months 
• 
Umbralisib will be given orally daily for 24 months 
• 
Throughout the study duration (both induction and maintenance phase), viral and PJP 
prophylaxis will be continued 
• 
Peg-filgrastim is allowed considered in maintenance phase in case of neutropenia 
• 
Umbralisib dose reduction may be allowed after discussing with sponsor. 
 
 
 
Treatment 
Age <70 
Age>70 
Ublituximab IV 
900mg 
900mg 
Umbralisib Orally (once a day) 800mg 
800mg 
Cyclophosphamide IV 
750mg/m2 
500-750mg/m2* 
Doxorubicin IV 
50mg/m2 
25-50mg/m2* 
Vincristine IV 
1mg/m2 (max 2mg) 1mg/m2 (max 2mg) * 
Prednisone Orally (Day 1-5) 
50-100mg 
50-100mg 


 
 
32 
Figure: 2 (Phase Ib portion outline) 
Phase IB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening and Registration 
3 patients: Umbralisib (800mg), Ublituximab (900mg) + CHOP 
<1/3 develops DLT 
>1/3 develop DLT 
Expand to Phase 2 
Enroll 3 more patients at same dose level 
<2/6 develops DLT 
>2/6 develop DLT 
Expand to Phase 2 
Dose reduced Umbralisib to 600mg 
3 patients: Umbralisib (600mg), Ublituximab (900mg) + CHOP 
<1/3 develops DLT 
>1/3 develop DLT 
Expand to Phase 2 
Enroll 3 more patients at same dose level 
<2/6 develops DLT 
>2/6 develop DLT 
Expand to Phase 2 
STOP 


 
 
33 
7.0 AGENT ADMINISTRATION AND DOSING GUIDELINES 
7.1 Guidelines for Administration of Umbralisib 
 
• 
Method of Administration: Umbralisib will be administered orally once daily with food. 
• 
Potential Drug Interactions: No drug interactions have been reported to date. 
• 
Pre-medications: Patients are required to start prophylaxis treatment for pneumocystis 
jiroveci pneumonia (PCP) as well as antiviral therapy prior to Cycle 1 Day 1. 
o Anti-viral Prophylaxis:  Valtrex 500 mg daily or Acyclovir 400 mg BID or equivalent 
o PCP Prophylaxis: Bactrim DS 1 tablet 3x per week or Dapsone 100 mg daily or 
equivalent  
• 
Final choice of PCP and anti-viral prophylaxis therapy is per investigator discretion. 
Umbralisib will be dispensed at the sites by the research coordinator or designee under the 
direction of the PI or by a pharmacist at the site.  Patients must be provided drug in its original 
container. Patients should be instructed to return all empty and partially filled bottles 
including any unused tablets when they return to the site.  Study drug compliance should be 
reviewed with the patient at the beginning of each new treatment cycle and as needed.   
 
Umbralisib should be taken at approximately the same time each day with food (within 30 minutes 
of a meal or snack). Patients should be instructed to swallow the tablets as a whole and should not 
chew or crush them. 
If a dose of umbralisib is missed, it should be taken as soon as possible on the same day. If it is missed 
for a period of greater than 12 hours, it should not be replaced. If vomiting occurs, no attempt 
should be made to replace the vomited dose. 
 
Dispensing of Umbralisib 
Before dispensing, the site pharmacist or his/her representative must check that the umbralisib is 
in accordance with the product specifications and the validity is within the re-test date.  The 
pharmacist or his/her representative should record all umbralisib drug dispensations. 
  
7.2 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: Pre-medicate approximately 30 minutes prior to each dose of ublituximab 
with an antihistamine (diphenhydramine 50 mg or equivalent), and a corticosteroid 
(dexamethasone 10-20 mg or equivalent). 
o Use of oral acetaminophen 650 mg (or equivalent) should be restricted to patients who 
experience fever or pyrexia after week 1 dose, or as clinically warranted. 
o After cycle 6, if use of a corticosteroid is of clinical concern, please contact the Principal 
Investigator. 


 
 
34 
• 
Hypersensitivity and Infusion Reaction Precautions: Medication and resuscitation equipment 
must be available per institutional guidelines prior to ublituximab administration for the 
emergency management of potential anaphylactic reactions.   
• 
Patient Care Implications:   
o Ublituximab should not be administered as an IV push or bolus. 
o Ublituximab may be administered on an outpatient basis. 
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 TG Therapeutics with any product quality concerns 
or questions. 
o It is recommended that ublituximab be administered immediately after dilution. 
o No other treatment may be co-administered with ublituximab (other than for 
immediate intervention for adverse event). 
o Concurrent glucocorticoid therapy as long as started for at least 7 days prior to study 
entry (< 10 mg per day of prednisone or equivalent) is allowed as clinically warranted.  
o Since infusion-related hypotension may occur, antihypertensive medications should 
be withheld 24 hours prior to and throughout infusion of ublituximab. 
o For patients at risk for tumor lysis syndrome in the opinion of the treating investigator, 
prophylaxis with allopurinol or per recommended institutional standards should be 
considered. 
 
 
Infusion Related Reactions and Infusion Rate Guidance – Ublituximab 
Infusion related reactions including severe reactions have been reported with ublituximab 
administration.  Guidelines are provided below for patients who experience such reactions.  
Symptomatic infusion reactions, despite premedication, may be treated at the discretion of the 
treating physician, including but not limited to: oral acetaminophen 650 mg (or equivalent), 
corticosteroids, antihistamines, oxygen, and bronchodilators.   
The following are recommended infusion rate reduction/delay guidelines for patients who 
experience severe Infusion Related Reactions (IRR’s) that result in treatment interruption.  Final 
decision for infusion rate reduction/delay or discontinuation resides with the treating investigator. 
 
1st or 2nd Infusion Interruption: 
• 
Hold infusion and closely monitor patient, institute symptomatic medical management until 
resolution of IRR symptoms. 
• 
Following the judgment of the Investigator, and provided the patient is stable, the infusion 
may be resumed at no more than half the previous rate. 
• 
If the patient does not experience any further IRR symptoms, infusion rate escalation may 
resume at the increments and intervals as appropriate for the treatment cycle dose (see Flow 
Rate Recommendations for Ublituximab Administration). 
 
 
 


 
 
35 
3rd Infusion Interruption (same day): 
• 
Discontinue infusion for that day – monitor patient for resolution of all symptoms.  Patient 
should have all vital signs completed as well as any other standard of care procedures 
completed as warranted by the Investigator prior to release of patient from study site. 
• 
Any remaining diluted investigational product should be discarded. 
 
If an infusion related reaction is observed, at any time during the ublituximab treatment, the treating 
investigator may reduce the infusion flow rate at their discretion. 
 
Dilutions of Ublituximab 
Ublituximab should not be mixed with other medicinal products.  Ublituximab should only be diluted 
in 0.9% NaCl before use.  No data are available for other solutions such as 5% dextrose and 5% 
mannitol. 
Ublituximab is available in 150 mg single use vials as a 25 mg/mL concentrate for dilution (6 mL 
quantity vial).   
Dosing Delays and Modifications 
Patients should be assessed clinically for toxicity at each visit using the NCI CTCAE v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE) grading scale.  Dosing should occur only if a patient’s clinical 
assessment and laboratory test values are acceptable.   
 
Dose Delay/Modifications: Umbralisib 
Supportive care should be considered for any patient who experiences Grade ≥ 2 cytopenias, or Grade 
≥ 1 non-hematologic toxicities.   A maximum 28-day (1 cycle) delay for recovery from toxicity is 
allowed for umbralisib to allow recovery of hematologic toxicities to ≤ Grade 3 or non-hematologic 
toxicities to ≤ Grade 2 or to baseline level.  If the patient withdraws consent or has documented 
progression, an end of study visit should be completed. 
 
 
TABLE 3: UMBRALISIB DOSE DELAY AND/OR MODIFICATIONS GUIDANCE 
NCI-CTCAE Grade 
Dose Delay and/or Modification 
Hematologic Adverse Event 
Neutropenia 
Grade ≤ 2 neutropenia 
Maintain current dose. Consider supportive care as warranted. 
Grade 3 neutropenia 
Maintain current dose, consider supportive care.  If recurrence or 
persistent Grade 3, resume at next lower dose level at discretion of the 
investigator. 
Grade 4 neutropenia or occurrence of 
neutropenic fever or infection 
Delay umbralisib until Grade ≤3 and/or neutropenic fever or infection is 
resolved; thereafter, resume at full dose.  Consider supportive care.  If 
delay is > 28 days discontinue study drug. 
 
If recurrence after re-challenge, resume at next lower dose level at 
discretion of the investigator. 
Thrombocytopenia 
Grade ≤3 thrombocytopenia 
Maintain current dose level and provide supportive care as clinically 
warranted. 
Grade 4 thrombocytopenia 
Delay umbralisib until Grade ≤3; thereafter, resume at full dose.  
Consider supportive care intervention as warranted.  If delay is > 28 
days, discontinue umbralisib.     
 


 
 
36 
If recurrence after re-challenge, resume at next lower dose level at 
discretion of the investigator. 
Pulmonary & Related Infections* 
Grade 2 
Stop all therapy and hold until resolution.  Restart umbralisib at 
current dose or one lower dose level per PI discretion.  Restart 
ublituximab at full dose.   
 
If recurrence after re-challenge, resume at next lower dose level at 
discretion of the investigator. 
Grade ≥3 
Stop all therapy and hold until resolution.  Restart umbralisib at one 
lower dose level per PI discretion. 
*While pneumonitis has been minimal with umbralisib, it is a reported adverse event associated with other PI3K 
delta inhibitors.  Use of anti-pneumocystis and anti-herpetic viral prophylaxis is required. 
All Other Non-Hematological Adverse Events 
Grade ≤2 
Maintain current dose level. 
 
NOTE: If persistent grade 2 diarrhea, despite supportive care, delay 
umbralisib until ≤ grade 1.  If recurrence after re-challenge, resume at 
full dose or next lower dose level at discretion of the investigator. 
Grade ≥3 
Withhold umbralisib until Grade ≤2.    
 
If recurrence after re-challenge, resume at full dose or next lower dose 
level at discretion of the investigator.  
Diarrhea and/or Colitis 
Diarrhea Grade ≤2 
Maintain current dose level if tolerable or hold and then resume at 
current dose level once has resolved. 
NOTE: If persistent grade 2 diarrhea, despite supportive care, delay 
umbralisib until ≤ grade 1.  If recurrence after rechallenge, resume at full 
dose or next lower dose level at discretion of the investigator. 
Diarrhea Grade ≥3 
Withhold umbralisib until Grade ≤2.  Resume at full dose or next lower 
dose level as per discretion of investigator   
If recurrence after rechallenge, resume at next lower dose level at 
discretion of the investigator.  
Colitis (all Grades) 
Hold umbralisib. Treat with supportive care and after resolution of 
colitis, resume umbralisib at next lower dose level 
 
STUDY DRUG DOSE REDUCTION RECOMMENDATIONS 
Study Drug 
Starting Dose 
1st Dose Reduction 
2nd Dose Reduction 
Umbralisib 
800 mg 
600 mg 
400 mg 
 
A maximum of two dose level reductions are allowed for umbralisib.   
If a patient requires a dose reduction of umbralisib due to study drug related toxicity, the dose may 
not be re-escalated.  If further evaluation of the toxicity reveals the event was not related to 
umbralisib, this must be recorded in the medical record and dose re-escalation to the next higher 
dose level may be considered at the discretion of the investigator.     
 
Dose Delay/Modifications: Ublituximab 
No reduction in the dose of ublituximab is permitted. 
Supportive care should be considered for any patient who experiences Grade ≥ 2 cytopenias, or 
Grade ≥ 1 non-hematologic toxicities.  A maximum 28 day delay of the next scheduled ublituximab 
dose is allowed for recovery of hematologic toxicities to ≤ Grade 3 or non-hematologic toxicities to 
≤ Grade 2 or to baseline level.  If the patient withdraws consent or has documented progression, an 
end of study visit should be completed. 


 
 
37 
If Grade 4 anaphylaxis is observed at any point during ublituximab treatment, permanently 
discontinue ublituximab treatment and intervene as per investigator discretion. 
 
 
TABLE 4: UBLITUXIMAB DOSE DELAY AND/OR MODIFICATIONS GUIDANCE 
NCI-CTCAE Grade 
Dose Delay and/or Modification 
Hematologic Adverse Event 
Neutropenia 
Grade ≤ 3 neutropenia 
Maintain current dose. Consider supportive care 
as warranted. 
Grade 4 neutropenia or occurrence of neutropenic 
fever or infection 
Delay ublituximab until Grade ≤ 3 and/or 
neutropenic fever or infection is resolved; 
consider growth-factor support as warranted; 
thereafter, resume at full dose.  If delay is > 28 
days, discontinue ublituximab. 
Thrombocytopenia 
Grade ≤3 thrombocytopenia 
Maintain current dose and provide supportive 
care as clinically warranted. 
Grade 4 thrombocytopenia 
Delay ublituximab until Grade ≤ 3; consider 
intervention with supportive care as warranted; 
thereafter resume at full dose.  If delay is > 28 days, 
discontinue ublituximab. 
Non-Hematological Adverse Events 
Grade ≤2 
Maintain current dose. 
Grade ≥3 
Withhold ublituximab until Grade ≤ 2 at the 
discretion of the investigator; consider supportive 
care intervention as warranted.  Resume at full 
dose or if delay > 28 days, discontinue ublituximab. 
 
 
Ordering Ublituximab and Umbralisib 
Ublituximab and TGR-1202 (umbralisib) are available from TG Therapeutics.  Please contact Hari 
Miskin at hm@tgtxinc.com and Peter Sportelli at ps@tgtxinc.com to order.  Please allow 5 to 7 
business days between drug ordering and drug arrival. 
 
Upon receipt of this shipment, the Pharmacist or the appropriate person at the site should update the 
accountability forms for both ublituximab and umbralisib.  If there is any abnormality in the supplied 
boxes (ublituximab) or bottles (umbralisib), the Pharmacist or the appropriate person must 
document it during the acknowledgement of receipt and contact TG Therapeutics. 
 
STUDY MEDICATION OVERVIEW AND SAFETY 
Umbralisib (TGR-1202) 
Classification:    
Phosphatidylinositol-3-Kinase (PI3K) Delta Inhibitor  
Formulation: 
 
See Investigator Brochure 
 
Mode of Action: 
Irreversibly inhibits activity of the Class I Delta isoform of PI3K 
 
How Supplied:  
Umbralisib: 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 


 
 
38 
Packaging: 
Umbralisib is provided in HDPE bottles each containing 30 tablets and a silica 
gel canister as a desiccant.  
Availability: 
 
Umbralisib is available from TG Therapeutics. 
 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) 
The following adverse events were observed in patients treated with single agent umbralisib and 
were considered at least possibly related to study medication.  See the umbralisib investigator 
brochure for a complete list of all adverse events reported regardless of causality. 
Common ( >20%) 
• 
Gastrointestinal disorders: Nausea, Diarrhea 
• 
General disorders and administration site conditions: Fatigue 
 
Less Common ( ≥10% - ≤20%) 
• 
Blood and lymphatic system disorders: Neutropenia 
• 
Gastrointestinal disorders: Vomiting 
• 
Metabolism and nutrition disorders: Decreased appetite 
• 
Skin and Subcutaneous Tissue Disorders: Rash 
Uncommon  (≥1% - <10%) 
• 
Blood and lymphatic system disorders: Anaemia, Febrile neutropenia, Leukocytosis, 
Thrombocytopenia 
• 
Eye disorders: Vision blurred 
• 
Gastrointestinal disorders: Abdominal distension, Abdominal pain, Constipation, Dry 
mouth, Dyspepsia, Colitis 
• 
General disorders and administration site conditions: Asthenia, Chills, Oedema 
peripheral, Pyrexia,  
• 
Infections and infestations: Oral candidiasis, Pneumonia, Upper respiratory tract infection 
• 
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, 
Blood creatinine increased, Lymphocyte count increased, Weight decreased 
• 
Metabolism and nutrition disorders: Dehydration, Hyperglycaemia, Hypokalaemia, 
Hypophosphataemia,  
• 
Musculoskeletal and connection tissue disorders: Arthralgia, Muscle spasms, Pain in 
extremity 
• 
Nervous system disorders: Dizziness, Dysgeusia, Headache,  Neuropathy peripheral, 
Tremor 
• 
Psychiatric disorders: Insomnia  
• 
Respiratory, thoracic and mediastinal disorders: Cough  
• 
Skin and subcutaneous tissue disorders: Alopecia, Night sweats, Pruritus  
 
Events Reported in Less Than 1% of Subjects 
• 
Blood and Lymphatic System Disorders: Leukopenia, Hyperbilirubinemia, Bacteremia  
• 
Ear and Labyrinth Disorders: Tinnitus  
• 
Eye Disorders: Visual Impairment, Visual acuity reduced   
• 
Gastrointestinal Disorders: Eructation, Flatulence, Gastrooesophageal Reflux Disease, 
Abdominal Pain Upper, Mouth Ulceration, Anal Hemorrhage, Hypoaesthesia Oral, 
Paraesthesia Oral, Pancreatitis, Ileus  
• 
General Disorders and Administration Site Conditions:  Malaise, Mucosal Inflammation,  


 
 
39 
• 
Hepatobiliary Disorders: Hypocalcemia 
• 
Immune System Disorders: Allergic reaction 
• 
Infections and Infestations:  Candida infection, Fungal skin infection, Lung infection, 
Sinusitis 
• 
Investigations: International Normalized Ratio Increase, Blood lactate dehydrogenase 
increase, Blood phosphorus increased, Blood sodium increased, Blood uric acid increased, 
White blood cell count decreased 
• 
Injury, Poisoning and Procedural Complications: Contusion 
• 
Metabolism 
and 
Nutrition 
Disorders: 
Hyperlipidemia, 
Hypertriglyceridemia, 
Hyponatremia 
• 
Musculoskeletal and Connective Tissue Disorders: Muscular Weakness, Myalgia, Pain in 
Jaw  
• 
Nervous System Disorders: Somnolence, Peripheral Sensory Neuropathy, Memory 
Impairment  
• 
Psychiatric Disorders: Anxiety, Libido Decrease, Delirium, Parasomnia 
• 
Reproductive System and Breast Disorders: Erectile Dysfunction 
• 
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Epistaxis, Hypoxia, Influenza, 
Respiratory Failure, Pulmonary edema  
• 
Skin and Subcutaneous Tissue Disorders: Dermatitis, Dermatitis Acneiform 
• 
Vascular Disorders: Hot Flush 
 
 
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 (g) heavy chains and two kappa (k) 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 25mg/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 in each 
or 
• 
One vial containing 150 mg solution of ublituximab (for replacement 
if needed) 


 
 
40 
 
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 
Availability: 
 
Ublituximab is available from TG Therapeutics. 
 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LISTS (CAEPRS) 
The following adverse events were observed in patients treated with single agent ublituximab and 
were considered at least possibly related to study medication.  See the ublituximab investigator 
brochure for a complete list of all adverse events reported regardless of causality. 
Common (>20%) 
• 
Blood and lymphatic system disorders:  Neutropenia, Thrombocytopenia 
• 
General disorders and administration site conditions: Infusion-related reaction, Pyrexia, 
Chills 
• 
Nervous system disorders:  Headache 
 
Less Common (≥10 - ≤20%) 
• 
Blood and lymphatic system disorders:  Anaemia 
• 
Gastrointestinal disorders: Diarrhoea, Nausea, Abdominal pain upper 
• 
General disorders and administration site conditions:  Fatigue, Asthenia 
 
Uncommon (≥5% -  < 10%) 
• 
Blood and lymphatic system disorders:  Febrile neutropenia, Pancytopenia 
• 
General disorders and administration site conditions:  Pain 
• 
Infections and infestation:  Bronchitis 
• 
Investigations: Blood bilirubin increase, Alanine aminotransferase increased, Aspartate 
aminotransferase increased, Gamma-glutamyltransferase increased, Elevated liver enzymes 
• 
Musculoskeletal and connective tissue disorders:  Muscle weakness 
• 
Nervous system disorders: Dysgeusia 
• 
Respiratory, thoracic and mediastinal disorders:  Throat irritation/tightness, Dyspnea 
• 
Skin and subcutaneous tissue disorders: Pruritus 
• 
Vascular disorders: Hypertension 
 
Events Reported in at Least One Subject 
• 
Blood and Lymphatic System Disorders: Lymph node pain 
• 
Cardiac Disorders: Supraventricular arrhythmias 
• 
Gastrointestinal Disorders: Constipation, Gastroesophageal reflux disease, Oral pruritus 
• 
General Disorders and Administration Conditions: Edema 
• 
Hepatobiliary Disorders: Drug-induced hepatitis 
• 
Immune System Disorders: Serum sickness, Hypocomplementemia, Anaphylaxis 
• 
Infections and Infestations: Herpes zoster, Paronychia, Pneumonia, Urinary tract infection, 
Pyuria 
• 
Investigations: Blood creatinine increase, Blood potassium increase, Blood urea increase, 
Heart rate irregular, Urine output decrease, Weight increase 
• 
Metabolism and Nutrition Disorders: Hypoalbuminemia 
• 
Musculoskeletal and Connective Tissue Disorders: Arthralgia, Groin pain, Muscle spasms 


 
 
41 
• 
Nervous System Disorders: Ageusia, Dizziness, Sciatica, Cognitive disorder 
• 
Renal 
and 
Urinary 
Disorders: Hematuria, 
Proteinuria, 
Acute 
kidney 
failure, 
Tubulointerstitial nephritis 
• 
Respiratory, Thoracic and Mediastinal Disorders: Cough, Lung infiltration, Pneumonitis, 
Wheezing 
• 
Skin and Subcutaneous Tissue Disorders: Cold sweat, Hyperhidrosis, Rash 
• 
Vascular Disorders: Flushing 
 
 
UBLITUXIMAB + UMBRALISIB COMBINATION 
Adverse Events and Potential Risks 
The following adverse events were observed in patients treated with the combination of ublituximab 
+ umbralisib and were considered at least possibly related to one or both of the study medications.  
See the ublituximab and umbralisib investigator brochures for a complete list of all adverse events 
reported regardless of causality. 
Common (>20%) 
• 
Blood and Lymphatic System Disorders: Neutropenia 
• 
Gastrointestinal Disorders: Nausea, Diarrhea 
• 
General Disorders and Administration Site Conditions: Fatigue, Infusion related reaction 
 
Less Common (≥10% - ≤ 20%) 
• 
Gastrointestinal Disorders: Vomiting 
• 
Metabolism and Nutrition Disorders: Decreased appetite 
 
Uncommon (≥1 - <10%) 
• 
Blood and Lymphatic System Disorders: Anemia, Thrombocytopenia, Conjunctival pallor, 
Hyperbilirubinaemia,   
• 
Ear and Labyrinth Disorders: Ear congestion 
• 
Eye Disorders: Vision blurred, Corneal edema 
• 
Gastrointestinal Disorders: Dyspepsia, Constipation, Abdominal pain, Stomatitis, 
Abdominal distension, Abdominal discomfort, Salivary hypersecretion, Enterocolitis 
infectious, Flatulence, Dysphagia, Eructation, Gastrooesophageal reflux disease, Feces 
discolored 
• 
General Disorders and Administration Site Conditions: Oedema peripheral, Asthenia, 
Pyrexia, Chills, Cold sweat, Face Edema,  
• 
Hepatobiliary Disorders:  Hypogammaglobulinemia 
• 
Immune System Disorders: Urticaria 
• 
Infections and Infestations: Pneumonia, Sepsis, Upper respiratory tract infection, Cellulitis, 
Bronchitis, Conjunctivitis, Oral herpes, Sepsis syndrome, Urinary tract infection, Sinusitis, 
Clostridium difficile colitis, Otitis media, Rhinovirus infection, Oral candidiasis, Skin infection, 
Systemic inflammatory response syndrome, Wound 
• 
Investigations: Alanine aminotransferase increase, Aspartate aminotransferase increase, 
Blood creatinine increase, Weight decreased 
• 
Metabolism and Nutrition Disorders: Dehydration, Hyperglycemia, Hypokalemia, 
Hypophosphatasemia, Failure to thrive  


 
 
42 
• 
Musculoskeletal and Connective Tissue Disorders: Muscle spasms, Muscular weakness 
Myalgia, Pain in extremity 
• 
Nervous System Disorders: Dizziness, Dysgeusia, Headache, Somnolence  
• 
Psychiatric Disorders: Anxiety, Nervousness, Agitation, Insomnia  
• 
Renal and Urinary Disorders: Micturition urgency, Renal failure, Acute kidney injury  
• 
Reproductive System and Breast Disorders:  Scrotal cyst, Semen discoloration 
• 
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Cough, Hypoxia, Dysphonia, 
Lung infiltration, Productive cough, Pneumonitis, Choking, Oropharyngeal pain  
• 
Skin and Subcutaneous Tissue Disorders: Alopecia, Rash, Dry skin, Ecchymosis, Pruritus 
• 
Vascular Disorders: Hypertension, Epistaxis, Flushing  
 
Events Reported in Less Than 1% of Subjects 
• 
Infections and Infestations: Progressive multifocal leukoencephalopathy 
• 
Metabolism and Nutrition Disorders: Tumor lysis syndrome 
• 
Neoplasms Benign, Malignant and Unspecified:  Malignant melanoma 
• 
Skin and Subcutaneous Tissue Disorders: Erythrodermic eczematous rash 
 
 
7.3 CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) dosing  and 
administration guidelines 
CHOP chemotherapy and premedications will be administered per institutional guidelines. 
Patients will receive standard CHOP regimen as follows: 
Cyclophosphamide 750mg/m2 intravenously (IV), Doxorubicin 50mg/m2 IV,  Vincristine 
1.4mg/m2 (maximum total dose of 2mg) IV will be administered on Day 1. Prednisone 100mg 
daily from Day 1-5 days orally will be administered. 
 
The administration schedule is provided in the table (Table).  The amount of drug (in mg) of all 
the chemotherapy medications will be adminstered based on body surface area (BSA). BSA will 
be calculated on Day 1 of each cycle. If a patient has >5% change in weight from the previous 
BSA calculation, then BSA and dose should be recalculated. Full doses of all study medications 
should be given based on the patient’s actual BSA measured on Day 1 of every cycle except for 
Vincrsitine (dose is capped at 2 mg). 
 
 
 
 
 
 
 
Cyclophosphamide Administration Guidelines: 
• 
Cyclophosphamide will be administered IV over 30 minutes on Day 1 
• 
Refer to approved package insert (PI) for cyclophosphamide storage and preparation 
• 
IV hydration on the day of cyclophosphamide administration is highly recommedned 
based on institutional guidelines 


 
 
43 
• 
Patients who develop hematological toxicities must have their dose adjusted 
accordingly as follows: 
 
WBC count (µL) 
Platelets count(µL) 
Dose 
>4000 
>100000 
100% dose 
2500-4000 
50,000-100,000 
50% of dose 
<2500 
<50,000 
Postpone/per 
instituitional guidelines 
 
Doxorubicine Adminstration Guidelines: 
• 
The recommended life time cummulative doxorubicin dose is 450-550mg/m2 
• 
The maximum dose given on the study will be 300mg/m2 
• 
Before Doxorubicin adminstration, EF of left ventricle MUST be evaluated by 
Echocardiogram or MUGA scan per institutional standard 
• 
IF EF is <50%, do not adminster doxorubicin 
• 
Doxorubicin is vesicant and should be administered through central line (Mediport or 
any central venous access) 
• 
Doxorubicin will be adminstered through IV push on Day 1 through central venous 
access. 
• 
 Refer to approved package insert (PI) for Doxorubicin storage and preparation 
• 
Doxorubicin dose must be adjusted based on liver function/bilirubin as follows: 
 
 
Serum Bilirubin levels 
Dose 
1.2-3.0 mg/dl 
50% dose 
>3.0 mg/dl 
25% dose 
 
Vincristine Administration Guidelines: 
• 
Vincristine will be administered IV on Day 1 as IV push  
• 
Refer to approved package insert (PI) for vincristine storage and preparation 
• 
In case of severe preipheral neuropathy vincristine should not be administered 
• 
For grade I/II peripheral neuropathy, the dose of vincristine should be decreased per 
instituitional guidelines or investigator’s judgement. 
 
Serum Bilirubin levels 
Dose 
1.2-3.0 mg/dl 
50% dose 
>3.0 mg/dl 
25% dose 
 
Prednisone Administration and Guidelines: 
• 
Prednisone will be administered orally 100mg daily from Day 1-Day 5 of chemotherapy 
• 
Close monitoring of blood sugars are recommended for those who are diabetics. 
 


 
 
44 
7.4 CHOP Chemotherapy Dose adjustments for Elderly (>70 years old): 
• 
Due to the fact that many elderly patients (>70 years old) may not be able to handle full 
dose of CHOP chemotherapy, dose adjustments on Cyclophosphamide, Doxorubicin and 
Vincristine may be allowed. 
• 
If the investigator feels that dose of CHOP chemotherapy needs to be reduced, he MUST 
discuss with sponsor.  
• 
Typically, 25% dose reduction of the standard dose should be considered after 
discussing with sponsor. 
 
8.0 CONCOMITANT THERAPY: 
All therapies other than from study treatments must be reocrded in the concomitant therapy 
section of CRF. 
 
8.1 Permitted Medications and Supportive Treatment: 
• 
All supportive therapies for medical conditions other than MCL are allowed as clinically 
indicated. 
• 
Anti-Emetics: Anti-emetics are permitted per institutional standard. Any anti-emetic 
with potential to prolong, QTc should be use with caution. Frequent monitoring with 
EKG is highly recommended. 
• 
Anti-Diarrheal: Loperamide is recommended for Grade I diarrhea. For Grade >2 
diarrhea, high suspicion for immune colitis should be practiced and treated 
accordingly. 
• 
Growth Factor: All patients will receive growth factor during the induction chemotherapy. 
Peg-filgrastim will be administered either on same day or day#2 of chemotherapy per 
center’s standards. Short acting growth factors are also allowed (starting on Day2-10 of every 
induction treatment). 
• 
Prophylaxis: Viral and Pneumocystis Jirovecii prophylaxis will be given all through the 
treatment (both induction and maintenance phase) 
 
o Viral Prophylaxis: All patients will receive Ayclovir (400 BID orally daily) or 
famciclovir (250mg orally twice a day) or Valacyclovir (500mg orally twice or thrice 
a day) for prophylaxis.  
 
o PJP Prophylaxis: Bactrim DS Monday, Wednesday and Friday every week or Dapsone 
(100mg daily orally)/Atovaquone (1500mg orally daily)/Pentamidine (300mg NEB 
every 4 weeks) per institution standard. G6PD testing should be done in patients 
going on Bactrim/Dapsone. 
 
8.2 Excluded Medications: 
• 
Any other systemic anti-neoplastic agent other than U2-CHOP is prohibited on study 
(e.g. megace, methotraxate, Cox-2 inhibitors and biophosphonates) 
 
8.3 Subsequent Therapies: 
• 
Administration of any other neoplastic therapy apart from U2-CHOP (induction) and U2 
(maintenance) is NOT allowed on study unless confirmed progression according to 
Lugano Lymphoma assessment criteria (Appendix).  


 
 
45 
• 
After Progressive disease is established, the patient will be taken off the study and can 
be treated per investigator’s chocie.  
 
 
9.0 Discontinuation of study, treatment and participation: 
9.1 Study Discontinuation: 
Patients will be discontinued from study if there is safety concerns indicated by investigator, data 
safety monitoring board or request to discontinue trial by regulatory or health authroity/IRB or 
manufacturing difficulties/concerns. 
 
9.2 Treatment Discontinuation: 
Phase Ib: 
• 
If patient meets DLT criteria 
Phase II: 
• 
Patient experiences treatment related intolerable toxicities that persist despite following the 
guidelines for dose modifications and dose reductions, including supportive care measures. 
o Treatment may be delayed to recover from toxicity for a maximum of four weeks. 
• 
Confimred Progression of disease based on the response assessment criteria (Appendix) 
After withdrawal from protocol treatment, patients should be followed for AEs for 30 calendar days 
after their last dose of either study drug.  All new AEs occurring during this period must be reported 
and followed until resolution, unless, in the opinion of the investigator, these values are not likely 
to improve because of the underlying disease. 
 
9.3 Study Participation Discontinuation: 
• 
Patient withdraws consent to participate.  
• 
Any reason that in opinion of investigator DSMB or IRB makes subject paarticipation in the 
study is unsafe or unfeasible. 
 
 


 
 
46 
 
10.1  Table: 1: Study Assessments and Treatment Schedule (Induction phase) 
The table below lists all of the required assessments that should be performed at each study visit. 
 
U2-CHOP-U2 
Screening 
(-28 day to -1 day) 
Induction Treatment Phase 
End of Treatment 
Procedures 
Cycle#1 
Cycle#2-6 
 
 
D#1 
D#8 
D#15 
D#1 
D#11 
(+3 days) 
5-6 weeks post C#6 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demography/Medical History 
X 
 
 
 
 
 
 
ECOG Performance status 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant Medications 
X 
X 
 
 
X 
X 
X 
Comprehensive Physical Exam1 
X 
X 
 
X 
X 
X 
X 
Adverse Event assessment 
 
 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
 
 
 
X 
 
 
PET/CT 
X 
 
 
 
 
 
X 
Bone Marrow Biopsy 
X 
 
 
 
 
 
X2 
Biopsy-FFPE 15 slides 
X 
 
 
 
 
 
 
ClonoSEQ (Adoptive)3 
 
 
 
 
 
 
X3 
Laboratory 
 
 
 
 
 
 
 
Serum Chemistry (CMP, LDH, Uric 
Acid)4 
X 
 
X 
X 
X 
 
X 
Hematology (CBC with diff) 
X 
 
X 
X 
X 
 
X 
Serology (Hep B, C, HIV, CMV)5 
X 
 
 
 
 
 
 
Beta 2 microglobulin and 
Immunoglobulins 
X 
 
 
 
 
 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
Ublituximab 
 
X 
X 
X 
X 
 
 
Umbralisib 
 
X 
X 
X 
X 
X 
X 
PJP Prophylaxis 
 
X 
X 
X 
X 
X 
X 
Viral Prophylaxis 
 
X 
X 
X 
X 
X 
X 
Neulasta 
 
X 
 
 
X 
 
 


 
 
47 
 
1: Comprehensive physical exam: Includes height, weight, vitals, full history and physical 
2: Bone marrow biopsy at the end of treatment will be performed only if BMBx was positive at the time of diagnosis. Bone marrow aspiration 
and biopsy MUST include flowcytometry. Histopathological staining must also include cyclin D1. If needed, Fluorescent in situ hybridization 
(FISH) testing should be done for t(11;14) on biopsy. 
3:ClonoSEQ (Adoptive) MRD Assay: For MRD assay, 15 FFPE slides from the diagnostic biopsy and peripheral blood sample from end of 
treatment (5-6 weeks post C#6) will be sent to Adoptive for MRD assay. For details please refer to MRD section. 
4: Serum chemistry includes CMP (Na, K, bicarb, creatinine, Chloride, BUN, Calcium, phosphorus) Liver function tests (AST, ALT, T.Bili, 
Alkaline Phosphatase), LDH, Uric Acid 
5: Hepatitis Serologies include: Hepatitis B (IgM core antibody, IgG core antibody, Surface antigen, Surface antibody), Hepatitis C (Hepatitis 
C antibody). CMV includes IgG and IgM antibody, HIV: HIV antibody 
 
 
 
 


 
 
48 
10.2 Table: 2: Study Assessments and Treatment Schedule (Maintenance phase) 
The table below lists all of the required assessments that should be performed at each study visit. 
 
 
 
1: Comprehensive physical exam: Includes height, weight, vitals, full history and physical 
2: Serum chemistry includes CMP (Na, K, bicarb, creatinine, Chloride, BUN, Calcium, phosphorus) Liver function tests (AST, ALT, T.Bili, 
Alkaline Phosphatase), LDH, Uric Acid
U2-CHOP-U2 
U2 Maintenance Phase 
End of Treatment 
Procedures 
D#1 
Every 3 month Follow up 
(3,9,12,15,18,21 and 24 months follow up) 
30 days post last 
treatment 
ECOG Performance status 
X 
X 
X 
Prior/concomitant 
Medications 
X 
X 
X 
Comprehensive Physical 
Exam1 
X 
X 
X 
Adverse Event assessment 
 
X 
X 
12 Lead ECG 
X 
X 
 
CT of Neck, Chest, Abd and 
Pelvis 
X 
Every 6 months (6,12,18 and 24) 
 
Laboratory 
 
 
 
Serum Chemistry 2 
X 
X 
X 
Hematology (CBC with diff) 
X 
X 
X 
Beta 2 microglobulin and 
Immunoglobulins 
X 
Every 6 months (6,12,18 and 24) 
 
Treatment 
 
 
 
Ublituximab 
X 
X 
 
Umbralisib 
X 
X 
X 
PJP Prophylaxis 
X 
X 
X 
Viral Prophylaxis 
X 
X 
X 


 
 
49 
 
 
11. STATISTICAL ANALYSIS 
This is a Phase Ib/II open label, single arm clinical trial. The primary of objective is to determine the 
safety and tolerability (Phase Ib), and complete response rate of Umbralisib in combination with 
Ublituximab-CHOP in Mantle Cell lymphoma (Phase II). The secondar endpoints are to explore PFS, 
OS at 3 years, disease control rate, rate of MRD negative disease and PFS/OS in MRD negative 
patients. 
 
11.1 Study design 
In the proposed study, the primary endpoint is to estimate the biological response rate of the 
combination of Umbralisib at dose 800 mg with Ublituximab (900mg)-CHOP, but a phase Ib portion 
with dose de-escalation at two does level (800 and 600 mg) will be built in to further confirm its 
safety and tolerability.  
 
Assuming the DLT is no more than  (<) 33% in the combination, the dose de-escalation rule is as 
following: 3 patients will be evaluated at the first dose cohort, if no DLT occurred, the study will 
expand to phase II portion; if 1 DLT occurred (in 20 days), additional 3 patients will be evaluated; if 
<=1 DLT occurred  in these three new patients, the study will expand to phase II portion; if >=2 DLT 
in these three new patients, the dose will be reduced to the lower dose cphort: 3 patients will be 
evaluated at lower dose (600mg), if no DLT occurred, the study will expand to phase II portion; if 1 
DLT occurred (in 3 weeks), additional 3 patients will be evaluated; if <=1 DLT occurred  in these three 
new patients, the study will expand to phase II portion; if >=2 DLT in these three new patients, the 
study will be terminated. 
 
 
11.2 Sample size and power justification 
 
Phase Ib safety study will use 3+3 dose de-escalation design at two dose cohorts assuming the DLT 
is no more than (<=) 33% in the combination. The sample size in this portion will range from 3-12.  
 
We expect that Umbralisib in combination with  Ublituximab-CHOP will improve the CRR to 70%  
comparing to the standard treatment with R-CHOP alone at 40% response rate. Using Single-Stage 
Phase II design for Testing H0: P < P0 versus H1: P > P1, A sample size of 25 achieves 90% power to 
detect a difference (P1-P0) of 0.3 using a one-sided binomial test. If the number of responses is 15 or 
more, the hypothesis that P <= 0.4 is rejected with a target error rate of 0.050 and an actual error 
rate of 0.034. If the number of responses is 14 or less, the hypothesis that P >= 0.7 is rejected with a 
target error rate of 0.1 and an actual error rate of 0.098.  
 
Thus, a total of 28-35 of patients will be required to both portions of the study. 
 
11.3 Statistical analysis plan 
 
The primary endpoint of response rate will be estimated with binomial distribution along with 2-
sided 95% exact confidence intervals with the method of Clopper-Pearson intervals. Frequency and 
percentage will be presented. KM method will be used to estimate medium PFS, overall survival (OS) 
and time to response. Analysis of safety data will be descriptive. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled for classification of 
qualitative safety data. Adverse event and serious adverse event (AE/SAE) reporting during the study 


 
 
50 
will be summarized by relationship to study drug and intensity by dose cohorts. Number and 
proportion of adverse event, serious adverse event and grade 3 or 4 lab toxicity will be reported by 
body system.  Patient’s baseline lab data and its change during treatment at each visit will be 
presented. Graphic statistics tool such as  
box plot will be used when it is appropriate. 
 
 
 
12. DEFINITIONS OF TUMOR RESPONSE AND PROGRESSION: 
• 
Tumor and efficacy assessment will be based on Positron Emission Tomography 
(PET)/Computed Tomography (CT) Scans criteria based on cheson 2014 (appendix) at 
indicated times (table). 
• 
Positron Emission Tomography (PET)/Computed Tomography (CT) Scans will be peformed 
at screening (within 28 days of beginning of treatment) and 5-6 weeks post C#6. 
• 
The criteria for response assessment are listed in appendix. 
• 
Bone marrow apsiration and biopsy will be peformed at the screening. If positive, it will be 
repeated at end of treatmnet (EOT, 5-6 weeks post C#6) 
• 
Minimal residual disease assessment will be done 5-6 weeks post C#6 (End of treatment-
EOT). Both FFPE sample from diagnostic biopsy (lymphnode/extranodal tissue, 15 slides) 
with peripheral blood sample MUST be provided. The shipping box and label will be 
provided by Adoptive Biotechnologies (South San Francisco, CA) directly to the site upon 
request. 
• 
During the maintenance period, patients will be followed by CT/MRI of Neck, chest, 
abdomen and pelvis with contrast every 6 months. If renals function is not permitting, 
without contrast scans (CR/MRI) are allowed.  
 
13. MINIMAL RESIDUAL DISEASE ASSESSMENT: 
The ClonoSEQ® assay by Adaptive Biotechologies (South San Francisco, CA), developed by 
Sequenta and previously called ClonoSIGHT®, will be used to identify clonal immunoglobulin DNA 
sequences unique to a patient’s lymphoma, which will then be used to determine the existence of 
minimal residual disease (MRD) in the peripheral blood of patients following induction. ClonoSEQ® 
is a novel, deep sequencing-based method to identify cells with specific molecular signatures. This 
will be used to determine the patients’ response to therapy and to determine eligibility for this 
clinical trial. The patient-specific rearrangement can be determined from a sample with high 
disease load, e.g., the diagnostic sample. The level of the specific clone can then be determined with 
high sensitivity and specificity in different samples in the patient. Detection of minimal residual 
disease can help inform the patient’s response as well as detection of relapse.  The details of the 
assay can be found at https://www.adaptivebiotech.com/clonoseq/clonoseq-assay 
 
MRD status is an exploratory endpoint for this trial. Peripheral blood samples are required at the end 
of induction treatment (within 4-6 weeks post induction treatment).  
 
 
 
 
 


 
 
51 
 
 
 
14.0 SAFETY REPORTING 
Reporting Serious Adverse Events to TG Therapeutics and FDA  
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 any of the following:  
• 
Death, 
• 
Life-threatening adverse event,  
• 
Inpatient hospitalization of at least 24 hours, or prolongation of existing hospitalization,  
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions,  
• 
Congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
SAE Reporting to TG Therapeutics  
SAEs require expeditious handling and reporting to TG Therapeutics in order to comply with 
regulatory requirements.  All SAEs (regardless of causality assessment) occurring on study or within 
30 days of last study treatment should be immediately reported to TG Therapeutics at 
safety@tgtxinc.com within 24 hours of the first knowledge of the event by the treating physician or 
research personnel on an SAE Form (MedWatch FORM FDA 3500 or equivalent) and followed until 
resolution (with autopsy report if applicable). 
 
SAE Reporting to the FDA and IRB   
Investigator is responsible for reporting relevant SAEs to the FDA.  Investigator is responsible for 
reporting unexpected fatal or life-threatening events associated with the use of the study drugs to 
the FDA within 7 calendar days after being notified of the event.  Investigator will report all related 
but unexpected SAEs including non-death/non-life-threatening related but unexpected SAEs 
(SUSAR) associated with the use of the study medications to the FDA by a written safety report within 
15 calendar days of notification.  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).  
 
The following are events of special interest, and will need to be reported expeditiously: 
Pregnancy 
During the course of the study, all female patients of childbearing potential must contact the treating 
investigator immediately if they suspect that they may be pregnant (a missed or late menstrual 
period should be reported to the treating investigator).   
If an investigator suspects that a patient may be pregnant prior to administration of study drug(s), 
the study drug(s) must be withheld until the result of the pregnancy test is confirmed.  If a pregnancy 


 
 
52 
is confirmed, the patient must not receive any study drug(s), and must be discontinued from the 
study.   
If an investigator suspects that a patient may be pregnant after the patient has been receiving study 
drug(s), the study drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed.  If a pregnancy is confirmed, the study drug(s) must be immediately and permanently 
stopped, the patient must be discontinued from the study, and the investigator must submit an SAE 
form to TG Therapeutics at safety@tgtxinc.com within 24 hours of the first knowledge of the event 
by the treating physician or research personnel.  Abortions (spontaneous, accidental, or therapeutic) 
must also be reported to TG Therapeutics at safety@tgtxinc.com within 24 hours of awareness. 
Study Drug Overdose 
Any accidental or intentional overdose with the study treatment (either umbralisib or ublituximab) 
that is symptomatic, even if not fulfilling a seriousness criterion, is to be reported to TG Therapeutics 
at safety@tgtxinc.com immediately (within 24 hours of awareness) on an SAE form.  If a study drug 
overdose occurs, patients should stop study drug dosing and be clinically monitored as appropriate, 
managing symptoms/side effects that may occur. 
Secondary / Second Malignancy 
Any secondary or second malignancy event must be reported to TG Therapeutics at 
safety@tgtxinc.com via the SAE form within 24 hours of awareness.   
 
15. REGULATORY, ADMINISTRATIVE AND LEGAL OBLIGATIONS 
 
15.1 Prestudy Document Requirements: 
Participating study sites cannot begin enrollment until an initiation letter has been issued from 
the UAB CTNMO. Each center is required to participate in an initiation conference call. Before the 
start of this study and the shipment of study drug to a participating study site, the following 
documents must be on file at UAB CTNMO. Participating sites will be responsible for forwarding 
the initiation documents toUAB CTNMO. All start-up documents can be submitted via electronic 
mail to pamdixon@uab.edu or via fax at (205) 975-9875. Please ensure that the fax cover page 
clearly identifies the site, study identifier and is addressed to ATTN: UAB CTNMO.  
 
 
These documents are required to be submitted by each participating center:   
1. U.S. Food and Drug Administration (FDA) Form 1572, signed by the Principal 
Investigator at the participating center. 
2. The names of any sub-investigators at the participating center must appear on e 
1572.  Investigators must also complete all regulatory documentation as required by 
local regulations. This includes any required human subjects training required by the 
site’s local IRB. 
3. Current curricula vitae and documentation of professional licensure of the Principal 
Investigator and sub-investigators listed on the 1572. 


 
 
53 
4. Resumes and human subject protections documentation (e.g. NIH, CITI) for all 
research personnel (e.g. study coordinators, data managers and other research 
personnel) and documentation of ICH-GCP training.  
5. A signed and dated investigator brochure acceptance form.  
6. Written documentation of IRB approval of protocol (identified by title, protocol 
version and date of approval) for each site. 
7. IRB approved study informed consent and HIPAA consent form. HIPAA consent 
language can be included within the study informed consent. Please note that all 
informed consent forms should be reviewed and approved by the UAB CTNMO prior 
to submission to the site’s designated IRB. 
8. A signed Confidentiality Agreement.  
9. A signed Clinical Trial Agreement for each site.  
10. Laboratory certifications (CAP, CLIAs) and laboratory reference value ranges for each 
laboratory listed on the site’s 1572. 
11. The UAB CTNMO site specific forms as specified in the investigator-initiated 
multicenter manual.  
 
 
15.2 Compliance with Law and Regulation 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), the 
Declaration of Helsinki, Health Canada, any applicable local health authority, and Institutional 
Review Board (IRB) or Ethics Committee requirements.  This study must have the approval of a 
properly constituted IRB or Ethics Committee.  Before the investigational drug is shipped to the 
Investigator, the Investigator or designee will provide TG Therapeutics with a copy of the IRB or 
Ethics Committee approval letter stating that the study protocol and any subsequent amendments 
and informed consent form have been reviewed and approved. 
 
 
 
The Investigator or designee will be responsible for obtaining annual IRB or Ethics Committee 
reapproval throughout the duration of the study.  Copies of the Investigator’s annual report to the 
IRB or Ethics Committee and copies of the IRB or Ethics Committee continuance of approval must 
be provided to TG Therapeutics, with copy to UAB CTNMO  


 
 
54 
 
Name: Pamela Dixon 
Address: 1802 6th Avenue South; NP 2515; Birmingham, AL 35294 
Phone No: 205- 975-5387  
Fax No: 205-975-9875   
Email Address: pamdixon@uab.edu  
 
The Investigator is also responsible for notifying their IRB or Ethics Committee of any significant 
adverse events that are serious and/or unexpected. TG Therapeutics will provide study sites with 
any expedited safety reports generated from any ongoing studies with carfilzomib, changes to the 
Investigator’s Brochure, and any other safety information which changes the risk/benefit profile 
of carfilzomib during the conduct of the study, to allow him/her to fulfill his/her obligation for 
timely reporting to the IRB/ECs and other Investigators participating in the study. Upon 
completion of the trial, the Investigator must provide the IRB or Ethics Committee, TG 
Therapeutics with a summary of the trial’s outcome. 
 
 
15.3 Protocol Amendments  
Proposed amendments to the protocol require review and approval by TG Therapeutics prior to 
implementation.  The amendment will be submitted formally to the FDA by the Principal Investigator.  
If an amendment to the protocol substantially alters the study design or the potential risks to 
patients, patients’ consent to continue participation in the study should be obtained per institutional 
policies. 
 
15.4 Ethical, Financial, and Regulatory Considerations 
This study will be conducted according to the standards of Good Clinical Practice outlined in the ICH 
E6 Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, institutional 
research policies and procedures and any other local applicable regulatory requirement(s).  
 
15.5 IRB Approval 
The study protocol, the informed consent form and other necessary study documents must be 
submitted to the IRB for ethical review and approval prior to the study start.  Principal Investigator 
is also responsible for insuring IRB renewals, and IRB approval for all subsequent protocol 
amendments and changes to the informed consent document.  Copies of the initial IRB approval letter 
and IRB approved ICF must be provided to TG Therapeutics prior to the study start.  Copies of any 
subsequent IRB approval letters and IRB approved ICFs must also be provided to TG Therapeutics as 
they become available. 
 
15.6 Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form. 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 copy of the 


 
 
55 
informed consent form, to include the patient’s signature, will be provided by the investigator to the 
patient.  If an amendment to the protocol substantially alters the study design or the potential risks 
to patients, patients’ consent to continue participation in the study must be obtained. 
 
 
 
15.7 Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), and national data protection laws. HIPAA 
regulations require that, in order to participate in the study, a patient must sign an authorization 
from the study that he or she has been informed of following: 
• 
What protected health information (PHI) will be collected from patients in this study; 
• 
Who will have access to that information and why; 
• 
Who will use or disclose that information;  
• 
That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal or 
state privacy laws;  
• 
The information collected about the research study will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the 
conclusion of the study; 
• 
Whether the authorization contains an expiration date; and 
• 
The rights of a research patient to revoke his or her authorization.  
 
15.8 Data Recording: 
The Clinical Research Coordinator and Investigator will be responsible for the recording of all data 
on the electronic Case Report Forms (eCRFs) on OnCore system. The Investigator will provide 
access to his/her original records to permit a representative from the funding or auditing 
institution(s) to verify the proper transcription of data.  Data submission will be electronically via 
Fax or email.  
 
15.9 Study Monitoring: 
CTNMO will be responsible for the monitoring of study patient data and records. Monitoring will be 
performed centrally. All monitoring reports will be kept by the UAB CTNMO to ensure that all 
reports are contained in a central study file. The CTNMO manager or UAB internal auditor will be 
responsible for conducting the review of monitoring packets. A final monitoring report will be 
generated and issued to the site and will be kept in the central study file by the UAB CTNMO. 
 
15.10 Frequency of Reviews: 
The each patient at each participating center will have their eligibility criteria reviewed prior to 
enrollment by the UAB CTNMO. During the course of the study, each site will be selected for an 
audit by the UAB Quality Assurance Committee approximately once a year. Audit will include 10% 
of the subjects enrolled at the site. In addition to the once yearly QA audit, monitoring for each 
patient entered into this trial will be 100%. Sites are to send source information on each patient to 
the UAB CTNMO office where a shadow chart will be maintained on each subject for this trial.  
Source will be verified to data entered into the OnCore database.  
 


 
 
56 
15.11 Protocol Deviation and Safety reporting: 
The University of Alabama Comprehensive Cancer Center Data Safety Monitoring Board will have 
oversight of the protocol. The UAB CCC DSMB will meet at a minimum on a monthly basis to discuss 
hematology related trials. In addition, all protocol deviations and SAEs as defined above will be 
reviewed by the UAB CCC DSMB for review during the DSMB monthly meetings. The coordinating 
center will review protocol deviation and SAE events for form completion and provide assistance in 
communicating to the subsite if more information is warranted. The UAB CTNMO will report the 
event report to the UAB CCC DSMB so that the information can be reviewed at the next available 
DSMB meeting. During the DSMB review, the DSMB can make recommendations for any further 
study action.  
 
 
15.12 Data Collection: 
Data collection will be managed by the UAB CTNMO staff via the study database which is housed and 
maintained at UAB Cancer Center. Time sensitive information such as patient registration, serious 
adverse events reporting, and protocol deviation reporting will be collected via completed hard copy 
form. These forms are available from the UAB CTNMO. . Information collected will be reviewed and 
processed by the UAB CTNMO. 
 
The data will be initially reviewed for quality assurance purposes to identify any discrepancies or 
missing data. The staff of the UAB CTNMO will notify the participating site of any data queries and 
manage the overall data quality of the study. If data received relates to a serious adverse event or 
protocol deviation, the information will be processed for report to the UAB CCC DSMB for review. 
The sponsor- investigator, Luciano Costa, MD and the assigned statistician, will also have access to 
study data for quality assurance and analysis purposes. During the course of the study, data quality 
will be monitored by random inspection of the completed forms by a designated monitor.  Any 
problems detected will be discussed with the PI. If necessary, re-training of data collectors will be 
conducted. 
 
All data should be substantiated by clinical source documents organized within a patient research 
record. ICH Good Clinical Practices are to be followed.  The study will be subject to a yearly internal 
audit via the UAB CCC Quality Assurance Committee at a minimum and audits may occur more 
frequently at the request of the QA Committee.  
 
 


 
 
57 
 
 
 
15.13 Study Completion: 
 
The following data and materials are required by UAB CTNMO , TG Therapeutics before a study can 
be considered complete or terminated: 
1. Copies of protocol amendments and IRB approval/notification, if appropriate. 
2. Copies of the IRB final report, documentation of submission to the IRB.  
3. A summary of the study prepared by the Principal Investigator (Study report, 
manuscript and/or abstract). 
4. All regulatory documents (e.g., updated curriculum vitae for each Principal 
Investigator, updated U.S. FDA Form 1572 for each site). 
 
 
15.14 Record Retention: 
Federal law requires that an Investigator maintain all study records for two years after the 
investigation is discontinued. 
 
 
 
15.15 Publication 
All manuscripts, abstracts, or other presentation materials generated by site investigators must be 
reviewed and approved by TG Therapeutics prior to submission. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
58 
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kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 
2011;117:591-4. 
37. 
Meadows SA, Vega F, Kashishian A, et al. PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway 
signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of 
Hodgkin lymphoma. Blood 2012;119:1897-900. 
38. 
Liu N, Rowley BR, Bull CO, et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with 
potent p110alpha and p110delta activities in tumor cell lines and xenograft models. Mol Cancer Ther 
2013;12:2319-30. 
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Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in 
patients with relapsed/refractory mantle cell lymphoma (MCL). Blood 2014;123:3398-405. 
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Preliminary results of a phase II study of single agent Bay 80-6946, a Novel PI3K inhibitor, in patients 
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Additional 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. (2015). American Cancer Society. Retrieved June 5, 2015, 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. 
Cheson, B. D., Pfistner, B., Juweid, M. E., Gascoyne, R. D., Specht, L., Horning, S. J., . . . Diehl, V. (2007). 
Revised response criteria for malignant lymphoma. Journal of Clinical Oncology, 25(5), 579-
586. doi: 10.1200/JCO.2006.09.2403 
 
Cheson, B.C., Fisher, R.I., Barrington, S.F., Cavalli, F., Schwartz, L.H., Zucca, E., Lister, T.A. (2014). 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and 
Non-hodgkin lymphoma: The Lugano classification. Journal of Clinical Oncology, 32, (1-10). 
doi: 10.1200/JCO.2013.54.8900 
 
de Romeuf C, D. C.-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. 
Lunning M, Vose J, Fowler N, Nastoupil L…..O'Brien S. (2015). Ublituximab + TGR-1202 demonstrates 
activity and a favorable safety profile in relapsed/refractory B-cell NHL and high-risk CLL: Phase I 
Results. ASCO Annual Meeting and Exposition, Orlando, FL.  
 
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. 
Prasanna R, V. S. (2011). PI3Kgamma enzyme assay. Shameerpet, India: Incozen Therapeutics. 
Seeta N, V. S. (2011). AKT phosphorylation in MOLT-4 cells. June Study Report IVT-5264-APM-10. 
Shameerpet, India: Incozen Therapeuticis PVT Ltd. 
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India: Incozen Therapeuticis PVT Ltd. 
Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, Au WY, et al. Follicular Lymphoma 
International Prognostic Index. Blood. 2004; (104)5: 1258-65.Therapeutics, T. (2017). Ublituximab 
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APPENDIX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
62 
 
APPENDIX: A 
CONTRACEPTION GUIDELINES AND PREGNANCY 
Females Not of Childbearing Potential are Defined as Follows: 
Females are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum 
FSH levels > 40 mIU/mL and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy 
(with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
 
Contraceptive Guidelines for Females of Child-Bearing Potential: 
Females of child-bearing potential, defined as all females physiologically capable of becoming 
pregnant, must use effective contraception during the study and for 4 months after the last dose 
of either study treatment.  Effective contraception is defined as either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
2. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) 
or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment. 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate).  For female patients on the study, the vasectomised 
male partner should be the sole partner for that patient. 
4. Oral contraception, injected or implanted hormonal methods. 
5. Use of a combination of any two of the following (a+b): 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository. 
The following are unacceptable forms of contraception for females of childbearing potential: 
• 
Female condom 
• 
Natural family planning (rhythm method) or breastfeeding 
• 
Fertility awareness 
• 
Withdrawal 
• 
Cervical shield 
 
Females of child-bearing potential must have a negative serum pregnancy test ≤ 72 hours 


 
 
63 
prior to initiating treatment. 
 
Fertile Males 
Fertile males, defined as all males physiologically capable of conceiving offspring must use condom 
during treatment and for 4 months after the last dose of either study treatment. They should also 
not father a child during this period. 
 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to TG 
Therapeutics within 24 hours of learning of its occurrence as outlined in the Safety Reporting section 
of this protocol.  The pregnancy 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 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. 
 


 
 
64 
APPENDIX B:  NEW YORK HEART ASSOCIATION CLASSIFICATION 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at 
rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may 
be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 
1994:253-256. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
65 
APPENDIX: C  Hepatitis B Serologic Test Results 
 
 


 
 
66 
 
APPENDIX D: Mantle Cell Lymphoma IPI (MIPI) 
 
 
 
• 
For each prognostic factor, 0-3 ponts are given. The ponts are summed up to total of max 11. 
• 
Total score: 0-3 is considered low risk, 4-5 is considered intermediate risk and patients with 
6-11 points are considered ar high risk 
 
EASTERN COOPERATIVE GROUP PERFORMANCE STATUS 
 
 
 
 
 


 
 
67 
APPENDIX E: CHESON ET AL, RESPONSE ASSESSMENT FOR LYMPHOMA (2014) 
 
 
 
 
 
 
 


 
 
68 
 
 
ANN ARBOR STAGING FOR LYMPHOMA 
 
 
 
 
 


 
 
69 
APPENDIX E: CTAE. 
 
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf 
 
 
 
 


Date: 6/28/23 
 
Subject: Final Report on NCT04692155 (Phase I/II trial of Ublituximab with CHOP followed by U2 
maintenance in previously untreated MCL. 
 
IRB#300006404 
 
This was an investigator initiated trial in Untreated Mantle Cell lymphoma patients who are 
ineligible for consolidative Autologus stem cell Transplant. This trial was terminated in 
September 2022 due to toxicity concerns. The umbralisib was associated with high risk of 
COVID related mortality as shown in other trials. Therefore, this trial was initially on hold by 
FDA but then was terminated. 
 
We enrolled only 1 patient who had advanced Mantle Cell Lymhoma. He completed 3 cycles of 
U2-CHOP but then developed grade 5 event with COVID PNA and passed away.  
 
 
Ref: https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-
announces-voluntary-withdrawal-blasnda-u2-treat