Clinical trial NCT03178201
Conditions: Follicular Lymphoma
Keywords: Relapsed follicular lymphoma Refractory follicular lymphoma
Sponsor: Columbia University
Start date: 2017-08-20; Completion date: 2020-06-30
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective is to determine the overall response rate (ORR) of TGR-1202 in R/R FL.

Secondary Objectives

* Determine the genetic and other novel biological markers that may be predictive of response or resistance to TGR-1202 in patients with relapsed or refractory FL.
* Describe the Progression Free Survival (PFS), Duration of Response (DoR) after treatment with TGR-1202.
* Describe the number of dose delays and dose reductions and other safety profile.

Detailed description:
This is an open label, phase II study of TGR-1202 in patients with relapsed or refractory (R/R) Grade 1, 2, or 3A follicular lymphoma (FL). FL is the most common subtype of indolent lymphoma. The prognosis of FL depends on the histologic grade, stage, treatment and age of the patient. More recently, efforts have been made to find novel regimens for the treatment of relapsed FL that do not contain non-specific cytotoxic agents.

One of the important goals of this phase II study is to discover novel genetic, biochemical, and immunological markers that are associated with the response and safety of TGR-1202 in patients with FL. TGR-1202 blocks PI3K, a signal that is required for cancer to grow.

Arms: arm 1: Patients with relapsed or refractory grade 1, 2, or 3A follicular lymphoma will receive TGR-1202.
Interventions: intervention 1: TGR-1202
Intervention descriptions: intervention 1: Treatment will be self-administered on an outpatient basis. Patients will take TGR-1202 800 mg, oral, one tablet daily on a continuous basis. Each cycle lasts 28 days.

Protocol documents:
Prot_SAP_000.pdf: 
i  
  
  
  
NCT03178201 
 
 
 
 
 
 
  
 
TITLE:     
 
PHASE II STUDY OF THE PHOSPHOINOSITIDE-3-KINASE-DELTA 
INHIBITOR TGR-1202 IN PATIENTS WITH RELAPSED OR  
REFRACTORY FOLLICULAR LYMPHOMA   
Coordinating Center:  
 
Columbia University Medical Center (CUMC)  
Participating Centers:  
Cancer Treatment Centers of America (CTCA) Philadelphia, 
PA   
 
  
  
  
 
Principal Investigator:  
Changchun Deng, M.D., Ph.D.  
 
Assistant Professor of Medicine and Experimental Therapeutics  
 
Columbia University Medical Center   
 
 
cd2448@columbia.edu  
 
  
Bin Cheng, Ph.D. (Statistician)  
  
  
  
  
Associate Professor of Professor of Biostatistics  
                                  
Columbia University Medical Center   
  
  
  
  
bc2159@cumc.columbia.edu  
  
  
CUMC Protocol #:  
AAAR1223    
 
Protocol Type / Version # / Version Date: Amendment 3/Version #1/December 12th, 2018  
 
 


ii 
  
  
  
 
 
 
 
 
 
 
 
PROTOCOL SYNOPSIS  
  
Title:  
  
Phase II Study of the Phosphoinositide-3-Kinase-Delta Inhibitor TGR-1202 in Patients with 
Relapsed or Refractory Follicular Lymphoma    
  
  
Study Design:  
  
This is an open label, phase II study of TGR-1202 in patients with relapsed or refractory Grade 1, 
2, or 3A follicular lymphoma (FL).   
  
The primary objective of the study is to determine the Overall Response Rate (ORR) 
(complete remission [CR] + partial remission [PR]) in patients with relapsed or refractory 
(R/R) FL.  
  
In addition, we will determine the genetic and other novel biological markers that may be predictive 
of response or resistance to TGR-1202.   
  
Objectives:  
  
Primary Objectives  
 Determine the ORR of TGR-1202 in R/R FL.    
  
Secondary Objectives  
  
• 
Determine the genetic and other novel biological markers that may be predictive of response or 
resistance to TGR-1202 in patients with relapsed or refractory FL.   
  
• 
Describe the Progression Free Survival (PFS), Duration of Response (DoR) after treatment with 
TGR-1202  
  
• 
Describe the number of dose delays and dose reductions and other safety profile.   
  
 
 


iii  
  
  
  
Target Population  
  
Patients with relapsed or refractory grade 1, 2, or 3A FL  
  
Inclusion Criteria   
  
  
1) Histologically proven diagnosis of grade 1, 2, or 3A FL.  
2) The diagnosis of relapsed FL must have been made within the last 6 months of screening if no other 
treatment is given for the FL in the interim; if an interim treatment is given within the last 6 month, 
re-biopsy will be required even if there is already a biopsy proven relapsed FL within the last 6 
months.  
3) Pre-treatment biopsy must establish the diagnosis AND have enough remaining tissues to satisfy 
the mandatory research studies.    
4) Relapse following first line immunotherapy or chemoimmunotherapy. There is no upper limit to 
the number of therapies received prior to study entry. Prior therapies may include high-dose therapy 
with autologous stem cell rescue.  
5) Measurable Disease according to the Lugano classification (Cheson et al., 2014a). See Appendices 
1 and 2.  
6) Lymphoma that is amenable to safe pre-treatment and post-treatment biopsy.  The safety of the 
procedures will be determined by the treating physician and the surgeon (or other proceduralist) in 
consultation with the PI, and in accordance with standard clinical practice. Acceptable sites of 
disease include, for example: (1) palpable tumor mass that is accessible under direct visualization 
or sonogram, (2) non-palpable tumor tissue that is accessible for biopsy under CT or sonogram 
guidance, (3) bone marrow.  
7) Age >18 years  
8) ECOG performance status <2 (see Appendix 3).  
9) Patients must have adequate organ and marrow function as defined below:  
a. absolute neutrophil count >1,000/microliter  
b. platelet count ≥50,000/microliter  
c. bilirubin <1.5X institutional upper limit of normal  
d. aspartate transaminase (AST, SGOT)/alanine transaminase (ALT, SGPT) <3.0X 
institutional upper limit of normal  
e. Serum creatinine <2.0X institutional upper limit of normal or creatinine clearance >50 
mL/min (according to the Cockroft and Gault equation).  
10) Negative serum pregnancy test within 7 days prior to Cycle 1/Day 1 for women of childbearing 
potential.  
11) All women of childbearing potential must agree to use an effective barrier method of contraception, 
as described in Appendix 4, during the treatment period and for at least 1 month after 
discontinuation of the study drug. Male subjects should use effective barrier method of 
contraception during the treatment period and for at least 1 month after discontinuation of the study 
drug (see Appendix 4).  
12) Ability to understand and the willingness to sign a written informed consent document.  
  


iv 
  
  
  
 
 
Exclusion Criteria  
  
1) Grade 3B FL or evidence of transformation to a more aggressive lymphoma  
  
 
2) Prior and concomitant therapy:  
  
a. Prior exposure to any PI3 Kinase inhibitor  
b. Exposure to chemotherapy, radiotherapy, or immunotherapy within 3 weeks prior to 
entering the study or lack of recovery from adverse events (AE) due to previously 
administered treatments.  
c. Ongoing chronic immunosuppressants (e.g. cyclosporine) or systemic steroids that have 
not been stabilized to the equivalent of ≤10 mg/day prednisone prior to the start of the 
study drug.  
d. Other concurrent investigational agents during the study period.  
3) Prior allogeneic stem cell transplant  
4) Central nervous system lymphoma, including lymphomatous meningitis   
5) Acute intercurrent illness including, but not limited to, active infection, unstable congestive heart 
failure, unstable angina pectoris, psychiatric illness or any social situation that would limit 
compliance with study participation requirements in the judgement of the investigator.  
6) Major surgery performed within 4 weeks of study entry  
7) Pregnant or nursing women  
8) Active concurrent malignancy (except non-invasive non-melanoma skin cancer, carcinoma in situ 
of the cervix, or prostate intraepithelial neoplasia). If there is a history of prior malignancy, the 
patient must be disease-free for ≥ 3-years at the time of study entry.  9) Documented Human 
Immunodeficiency Virus (HIV)-infection  
10) Active hepatitis A, hepatitis B, or hepatitis C infection (see Appendix 5).  
11) History of tuberculosis treatment within 2 years of study entry  
12) Administration of a live vaccine within 6 weeks of first dose of study drug  
13) Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes 
zoster (VZV) at screening  
14) Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass 
surgery, gastrectomy)  
15) Lymphoma that is not amenable for mandatory pre- and C2D15 post-treatment biopsy as described 
in item 4) of the inclusion criteria.  
16) Unstable or severe uncontrolled medical condition (e.g. unstable cardiac function, unstable 
pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal 
laboratory finding that would, in the investigator’s judgment, increase the risk to the patient 
associated with his or her participation in the study  
17) Clinically significant cardiovascular abnormalities such as:  
a. Angina not well-controlled by medication  
b. Poorly controlled or clinically significant atherosclerotic vascular disease including 
cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, 
cardiac/vascular stenting within 6 months of enrollment  
c. Symptomatic or documented congestive heart failure that meets New York Heart  
Association (NYHA) Class III to IV definitions (see Appendix 6);  
d. History of stroke within the last 6 months prior to screening  


v  
  
  
  
  
Inclusion of Women and Minorities  
  
Both men and women of all races and ethnic groups are eligible for this trial.  
  
Treatment Plan  
  
Patients will be treated with TGR-1202 at a dose of 800 mg daily from day 1 to 28 on a 28-day 
cycle.   
   
Duration of Treatment  
  
Patients will be treated until one of the following events occurs:  
  
• 
Disease progression  
• 
Unacceptable adverse event(s)   
• 
Withdrawal of consent  
• 
Changes in the patient's condition that render continuation of the study drug unacceptable in 
the judgment of the treating physician  
• 
An event that in the judgment of the treating physician warrants discontinuation of therapy.   
• 
Patient withheld study drug for >28 days  
  
Sample Size  
  
The study will accrue a total of up to approximately 20 patients.   
  
Safety  
  
Patients will be monitored carefully for the development of AE. AE will be evaluated 
according to criteria outlined in the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0.  
  
Efficacy Outcome  
  
Patients will be monitored for clinical and/or radiographic evidence of disease 
response.  Response will be evaluated using clinical parameters, CT or PET/CT scan 
(PET/CT scan is preferred), and bone marrow or other tissue biopsy, according to the  
Updated Recommendations for Evaluation, Staging, and Response Assessment for Hodgkin and Non-
Hodgkin Lymphoma: The Lugano Classification.(Cheson et al., 2014b)   
  
  
 
 
 
Figure 1: Study Plan Flow Chart  
  


vi 
  
  
  
  
   
  
  
  
  
  
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Screening:  
•  
History, Physical examination  
•  
Peripheral blood testing  
•  
Tissue biopsies  
•  
Imaging: CT scan of the neck, chest, abdomen, and pelvis (and/or PET/CT scan)  
Consent:  
•  
Informed consent for participation in the clinical study  
•  
I nformed consent for participation in the correlative studies  
Cycle 1:  
Intervention  
TGR - 
gi 
1202 ven orally at a dose of 800 mg daily on a continuous basis. Cycle duration : 28 days  
Evaluation  
•  
Visit and laboratory evaluation of safety on Days 1, 8, 15, 22  
•  
PK and PD studies pre - treatment on day 1 and post - treatment on days 1 and 15  
Subsequent Cycles:  
Intervention  
TGR - 1202 given orally at a dose of 800 mg daily on a continuous basis. Cycle  duration : 28 days  
E 
 
valuation  
•  
Visit and laboratory evaluation of safety on Day 1  
•  
CT scan of the neck, chest, abdomen, and pelvis (and/or PET/CT) at the end of Cycle  2 and  6 .  Thereafter,  
restaging CT scans will be repeated every 4 months, or every 6 months if a complete response is achieved .   
•  
Bone marrow and/or other target tissue biopsy to confirm  CR .  
•  
Mandatory and optional PD studies post - treatment on cycle 2 day 15,  cycle 4, day 15 and at the end of treatment  
and disease progression, if applicable.  
Discontinuation:  
Treatment is continued until one of the following occurs:  
•  
Unacceptable adverse events  
•  
Disease progression or initiation of new therapy  
•  
Withdrawal of cons ent  
•  
Changes in the patient’s condition that render further treatment unacceptable in the judgment of the treating  
physician.  
•  
Any event that the judgment of the treating physician warrants discontinuation of therapy  
•  
Patient withheld study drug for >28 days  


vii  
  
  
  
Figure 2. Pharmacokinetics (PK) schedule  
Pharmacokinetic studies  
  
Cycle 1, days 1 and 15; cycle 2 , day 15; cycle 4, day 15  
  
 
Pre-dose*  
0h   
4h  
 
* Only on cycle 1, day 1 only  
  
  
Figure 3. Pharmacodynamic (PD) Schedule  
  
  
 
PK sample  
pre - TGR - 1202  
PK sample  
post - TGR - 
1202  
Start of  
TGR - 1202  


viii 
  
  
  
  
Figure 4. Study schema  
  
  
 
  
1 Includes tumor cells, blood cells, and buccal fibroblasts; tumor tissue includes nodal or extranodal tumor tissue that can 
be  visualized and/or palpated + bone marrow aspiration and biopsy if bone marrow positive for lymphoma;   
2 
Optional; 3 To be performed after cycle 2 and 6, and every 3 to 6 months therea fter at the discretion of the treating 
physician. Abbreviations: PK, pharmacokinetics;  PD, pharmacodynamics; PB, peripheral blood    
  
  
  
  
  
Note: Patients who experience toxicity and require drugs to be withheld may not be 
candidates for biopsy.  Patients who miss 4 or more doses of drug prior to a planned biopsy 
should be considered ineligible for biopsy, and should be replaced. The ultimate decision will 
be at the discretion of the treating physician.  
  
  
  
 
 


ix  
  
  
  
TABLE OF CONTENTS  
  
  
Page  
PROTOCOL SYNOPSIS............................................................................................................... i  
  
1. OBJECTIVES .......................................................................................................................... 1  
  
  
2. BACKGROUND ...................................................................................................................... 1  
  
Background on lymphoid Malignancies  ............................................................................... 1  
Background on follicular lymphoma  .................................................................................... 1  
PI3K inhibitors ........................................................................................................................ 4  
  
TGR-1202 ................................................................................................................................. 5  
  
Rationale for the study .......................................................................................................... 10  
  
  
3. PATIENT SELECTION ....................................................................................................... 13  
  Inclusion Criteria  .................................................................................................................. 13  
  
Exclusion Criteria .................................................................................................................. 14  
  
Inclusion of Women and Minorities .................................................................................... 15  
  
4. REGISTRATION PROCEDURES ..................................................................................... 15  
General Guidelines ................................................................................................................ 15  
Informed Consent .................................................................................................................. 15  
Registration ............................................................................................................................ 17  
Screening ................................................................................................................................ 17  
  
5. TREATMENT PLAN ........................................................................................................... 18  
Regimen Description ............................................................................................................. 18  
Evaluation and requirements Prior to Each Treatment Cycle ......................................... 18  
Guidelines for Administration of TGR-1202 ...................................................................... 18  
Dispensing of TGR-1202 ....................................................................................................... 19  
Supportive care ...................................................................................................................... 19  
  
Concomitant Medication Guidelines ................................................................................... 20  
  Duration of Therapy .............................................................................................................. 21  
  Duration of Follow Up ........................................................................................................... 21  
Criteria for Removal from Study ......................................................................................... 22  
  
6. DOSING DELAYS/DOSE MODIFICATIONS .................................................................. 22  
  
Dose Modifications ................................................................................................................ 22  
Summary of Dose Holds for Treatment-Related Toxicities .............................................. 23  
Ordering TGR-1202 .............................................................................................................. 24  
  
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................ 24  
  
Safety Evaluation Procedures .............................................................................................. 24  
  
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ............................. 26  
 
Adverse Event Characteristics ............................................................................................. 28  


x 
  
  
  
  
Expedited Adverse Event Reporting ................................................................................... 28  
  
Pregnancy on Study ............................................................................................................... 31  
  
Routine Adverse Event Reporting ....................................................................................... 32  
  
8. PHARMACEUTICAL INFORMATION ........................................................................... 33  
  
TGR-1202 ............................................................................................................................... 33  
  
9. PHARMACOKINETIC/DYNAMIC STUDIES ................................................................. 34  
Pharmacokinetic studies ....................................................................................................... 34  
Pharmacodynamic Studies ................................................................................................... 34  
  
10. STUDY CALENDAR ............................................................................................................ 38  
  
11. MEASUREMENT OF EFFECT .......................................................................................... 39  
Evaluation of response .......................................................................................................... 39  
Response Criteria .................................................................................................................. 41  
  
12.  DATA REPORTING / REGULATORY REQUIREMENTS .......................................... 43  
  Data Reporting ....................................................................................................................... 43  
  
Data Safety Monitoring Board ............................................................................................. 43  
  
13. STATISTICAL CONSIDERATIONS ................................................................................. 44  
  
Study Design/Primary Endpoints ........................................................................................ 44  
  
Sample Size/Accrual Rate ..................................................................................................... 44  
  
Analysis of secondary endpoints .......................................................................................... 44  
  
REFERENCES ............................................................................................................................ 45  
  
APPENDICES ............................................................................................................................. 50  
  
  


 
          
1  
1. OBJECTIVES  
  
 Primary Objective    
  
The primary objective of the study is to determine the Overall Response Rate (ORR) (complete 
remission [CR] + partial remission [PR]) in patients with relapsed or refractory (R/R) FL.  
  
Secondary Objectives  
Determine the genetic and other novel biological markers that are predictive of response and 
resistance to TGR-1202 in patients with relapsed or refractory FL.   
  
Describe the Progression Free Survival (PFS), Duration of Response (DoR) after treatment with 
TGR-1202  
  
Describe the number of dose delays and dose reductions   
  
2.    BACKGROUND  
  
Overview of Indolent Lymphomas  
The Non-Hodgkin’s lymphomas (NHL) are a heterogeneous group of lymphoproliferative 
malignancies with varying patterns of clinical behavior and responses to treatment (Armitage, 
1993). Most NHLs are of B-cell origin. Indolent NHLs (iNHL) are a group of incurable 
slowgrowing diseases and represent approximately half of NHL, and are also quite heterogeneous 
(Arcaini et al., 2012; Sousou and Friedberg, 2010; Swerdlow et al., 2008). The major types of 
iNHL include FL, marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), and 
small lymphocytic lymphomas (SLL). The most common subtype of iNHL is FL, constituting 
approximately 70% of the iNHL (Bello et al., 2012; Sousou and Friedberg, 2010). MZL accounts 
for only 5 to 17% of all NHL in adults, while SLL constitutes approximately 6% and WM 
approximately 1%.   
Overview of Follicular Lymphoma  
FL is the most common subtype of indolent lymphoma. BCL2 gene dysregulation caused by the 
t(14;18) translocation is frequently seen in FL, although it is not diagnostic of FL.(Rambaldi et al., 
2002) Mutations in histone-modifying genes have recently been described and may be variably 
involved in its pathogenesis (Morin et al., 2011; Pasqualucci et al., 2014). FL typically follows an 
indolent course with a median overall survival (OS) of 7-10 years, though this may be changing 
rapidly with the advent of many well tolerated new drugs and new immunotherapeutic agents. 
Although FL initially responds well to treatment it is characterized by recurrent relapses or 
progression with progressively shorter intervals in between (Salles, 2007). Transformation to 
diffuse large B-cell lymphoma and other aggressive lymphoma occurs at a rate of approximately 
2% to 3% per year (Bastion et al., 1997).  
The prognosis of FL depends on the histologic grade, stage, treatment and age of the patient. The 
disease is considered incurable with the exception of a small minority of patients with stage 1 FL 
who may be curable with radiation therapy.  Eventually most FL patients die of lymphoma 
regardless of the treatment. The Follicular Lymphoma International Prognostic Index (FLIPI)  


 
          
2  
(Solal-Celigny et al., 2004) and its revised version, FLIPI2 (Federico et al., 2009), have been 
developed for the assessment of newly diagnosed FL patients, but their use in relapsed FL has not 
yet been fully studied. Importantly, there is little to no information on risk stratification as a 
function of the FLIPI in this disease, though guidelines based on tumor bulk (low vs advanced) 
have been advanced and provide some clinical guidance on how to stratify patients.  
In addition to clinical demographic parameters and prognostic indices, biological (immune 
signature) prognostic factors (Dave et al., 2004; Federico et al., 2009; Gribben, 2010; SolalCeligny 
et al., 2004) and lymphoma-mediated immunosuppression (Ramsay et al., 2009) have been noted 
to be common in FL, pointing to the importance of the impaired host immune response in the 
pathogenesis of this disease.   
Treatment of Follicular Lymphoma  
There is no standard treatment for patients with relapsed/refractory FL patients and the number of 
available treatment options is rapidly expanding. These can include watch-and-wait, depending on 
the burden of the disease at diagnosis or at relapse, radiation, single-agent or combination 
chemotherapy, rituximab monotherapy or rituximab in combination with immunomodulatory 
(lenalidomide) or pathway-targeted drugs (idelalisib), obinutuzumab, with or without 
bendamustine, rituximab containing chemotherapy regimens such as BR (bendamustine, 
rituximab), fludarabine plus rituximab, R-CHOP (rituximab, cyclophosphamide, doxorubicin, 
vincristine, prednisone), R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), R-FCM 
(rituximab, 
fludarabine, 
cyclophosphamide, 
mitoxantrone), 
radioimmunotherapy 
or 
autologous/allogeneic stem cell transplant in some select patients (Dreyling M1, 2014; Ghielmini 
et al., 2013; Zelenetz et al., 2014). In addition, the repetition of a previously applied regimen is a 
valid option depending on the duration of the response obtained previously.  
Rituximab is approved in the US, Europe and other countries for treatment of relapsed or refractory 
FL as a single agent and is extensively used in the treatment of FL as monotherapy or in 
combination with chemotherapy. Several studies have demonstrated the efficacy and safety of 
rituximab monotherapy in relapsed/refractory FL or other low-grade NHL patients, and three 
multicenter single-arm studies have led to regulatory approval in the US, Europe and other 
countries. In the first study 166 relapsed/refractory FL patients were treated with 375 mg/m2 of 
rituximab weekly for 4 doses. Results demonstrated a 48% overall response rate (ORR) with 6% 
CR and median duration of response of 11.2 months (McLaughlin et al., 1998). In the second study, 
37 relapsed/refractory low-grade NHL patients received an additional 4 weekly doses of rituximab 
for a total of 8 doses, resulting in increased ORR of 57% and CR of 14% (Piro et al., 1999). The 
third study demonstrated that the retreatment of 60 relapsed/ refractory patients who had clinical 
response to prior rituximab treatment with 4 weekly doses of rituximab resulted in ORR of 38% 
and CR of 10% (Davis et al., 2000a). Thus, in some countries, the approved number of rituximab 
doses is four to eight. A recent update of the results from the SAKK 35/98 trial evaluating 
prolonged single-agent rituximab (Martinelli et al., 2010) in relapsed/refractory FL patients treated 
with 4 weekly doses of rituximab followed by additional 4 maintenance doses every 2 months 
reported a durable response with 35% of responders still in remission at 8 years.  In a Phase 2 study 
to evaluate the safety and efficacy of rituximab in patients with bulky relapsed or refractory low-
grade or FL (Davis et al., 1999), the ORR was 43% with a median TTP of 8.1 months and median 
DoR of 5.9 months. The average decrease in lesion size in patients who achieved a partial response 
was 76%, and patients with stable disease had a decrease in average lesion size of 26%.  


 
          
3  
The importance of rituximab has also been demonstrated in clinical trials that evaluated the 
addition of rituximab to combination chemotherapy and as a maintenance agent after 
chemotherapy in patients with relapsed FL. Forstpointner et al (Forstpointner et al., 2004) reported 
the results from a Phase 2 randomized study evaluating R-FCM versus FCM (fludarabine, 
cyclophosphamide, mitoxantrone) in FL (N = 93) and MCL (N = 40) patients showing improved 
response rate (79% versus 58%, respectively) and median PFS (16 months versus 13 months, 
respectively) in R-FCM group compared to FCM. Van Oers (van Oers et al., 2010) evaluated the 
role of rituximab (R) both in remission induction and maintenance treatment of relapsed/refractory 
FL; patients were randomized to induction with CHOP (cyclophosphamide, doxorubicin, 
vincristine, prednisone) or R-CHOP, and those in complete or partial remission were randomized 
to maintenance or observation. The median PFS from first randomization was 20.2 months after 
CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab 
maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months 
with observation. A randomized Phase 3 trial (RESORT) comparing two different rituximab 
dosing strategies (rituximab continuous maintenance until treatment failure RM, or rituximab re-
treatment at progression, RR) for untreated, low tumor burden (LTB) FL was not able to 
demonstrate differences in time to treatment failure (TTF) (Kahl et al., 2014a). The mean number 
of rituximab doses per patient (including the 4 induction doses) was 15.8 (range 5– 31) for MR 
and 4.5 (range 4–16) for RR. The time to initiation of cytotoxic therapy was delayed in both arms 
compared to historical watch and wait strategies. Rituximab re-treatment at progression produces 
outcomes comparable to MR in this patient population.  
The combination of rituximab and bendamustine, an alkylating agent, is approved in US, Europe 
and many other countries for the treatment of rituximab-refractory iNHL and showed a response 
rate of 90% and median PFS of 2 years in relapsed/refractory iNHL and MCL in single-arm Phase 
2 studies (Robinson et al., 2008; Rummel et al., 2005). Major reported toxicities of bendamustine 
were myelosuppression (Grade 3 or 4 neutropenia and thrombocytopenia), nausea, infection, and 
fatigue. The two anti-CD20 radioimmunotherapy agents, yttrium Y90 ibritumomab tiuxetan and 
iodine I131 tositumomab, have demonstrated high activity in patients relapsed/refractory to 
chemotherapy or rituximab. Patients achieved a response rate of 60% to 80% but with significant 
toxicities including prolonged myelosuppression with potential risk of treatment-associated 
myelodysplastic syndrome (MDS) and acute myelogenous leukemia (Cheson, 2003). A 
randomized Phase 3 trial comparing yttrium Y90 ibritumomab tiuxetan to rituximab in relapsed 
indolent NHL demonstrated significantly higher ORR (80% versus 56%) and CR rate (30% versus 
16%) but with no significant differences in median time to progression (11.2 months versus 10.1 
months) (Witzig et al., 2002).  
More recently, efforts have been made to find novel regimens for the treatment of relapsed FL that 
do not contain non-specific cytotoxic agents. Such efforts include combinations of rituximab with 
a second monoclonal antibody, such as anti-CD80 galiximab (Czuczman et al., 2012; Czuczman 
et al., 2005) and anti-CD22 epratuzumab (Leonard et al., 2005), and with targeted agents such as 
bortezomib (Baiocchi et al., 2011) interferon (Davis et al., 2000b; Sacchi et al., 2001), cytokines 
granulocyte macrophage colony stimulating factor (GM-CSF) (Cartron et al., 2008) and IL-12 
(Ansell et al., 2002), as well as lenalidomide.(Witzig et al., 2015) Of these combinations, a Phase 
3 study comparing bortezomib plus rituximab versus rituximab single agent has been reported. In 
this study 676 rituximab-naïve or rituximab-sensitive patients with relapsed Grade 1 or 2 FL were 
randomly assigned in 1:1 ratio to receive rituximab alone (weekly during first cycle x 4 doses and 


 
          
4  
then on Day 1 of cycles 2 to 5) or in combination with bortezomib (weekly x 4 doses of cycles 1 
to 5). While the difference in the PFS was statistically significant (p = 0.039), the magnitude of the 
difference in the median PFS was < 2 months (11.0 months in the rituximab-only arm and 12.8 
months in the rituximab-bortezomib arm).  
  
PI3K, PI3K-δ and PI3K-γ Inhibition  
  
There are four mammalian isoforms of class 1 PI3Ks: PI3K-α, β, (class 1a PI3Ks) and PI3K- 
(a class 1b PI3K).  These PI3Ks catalyze the synthesis of phosphatidylinositol (3,4,5)trisphosphate 
(PIP3), leading to activation of the downstream effector pathways important for cellular survival, 
differentiation, and function.  PI3K-α and PI3K-β are widely expressed, and are important 
mediators of signaling from cell surface receptors.  PI3K-α is the isoform most often found mutated 
in cancers and is known to play a role in insulin signaling and glucose homeostasis (Knight et al., 
2006; Vanhaesebroeck et al., 2010). PI3K-β is activated in cancers where phosphatase and tensin 
homolog (PTEN) is deleted.  Both isoforms are targets of small molecule therapeutics in 
development for the treatment of cancer.  PI3K- and P13K- are preferentially expressed in 
leukocytes, and are important in leukocyte function.  PI3K-δ is activated by cellular receptors (e.g., 
receptor tyrosine kinases) through interaction with the SH2 domains of the PI3K regulatory subunit 
(p85), or through direct interaction with RAS. PI3K-γ is associated with G-protein coupled 
receptors (GPCRs), is responsible for the very rapid induction of PIP3 in response to GPCRs, and 
can be also activated by RAS downstream of other receptors.  PIP3 produced by PI3K activates 
effector pathways downstream through interaction with pleckstrin homology (PH) domain 
containing enzymes (e.g., PDK-1 and AKT [PKB])(FungLeung, 2011).  
  
PI3K- and PI3K- are expressed in hematopoietic cells, and are critical for the ability of normal 
immune cells to respond to survival and differentiation signals in their environment.  In cancer 
cells, where the pathways mediated by PI3K-δ and -γ contribute to survival, proliferation, and 
differentiation, the use of PI3K inhibitors has a stronger therapeutic rationale.  The tumor 
microenvironment plays an important role in the development and maintenance of cancer 
(Hanahan and Weinberg, 2011).  Through the expression of various cytokines, growth factors, and 
chemokines, tumor cells recruit other cell types, including myeloid cells capable of differentiating 
into tumor-associated macrophages (TAMs) which promote angiogenesis and augment tumor 
growth (Lewis and Pollard, 2006).  Therefore, agents that target TAMs as well as other types of 
infiltrating leukocytes are of potential therapeutic interest across most of oncology.  Recently, the 
work of Schmid et al. demonstrated that tumor growth, invasion of CD11b+ myeloid cells, 
angiogenesis and metastasis of tumors implanted into PI3K-γ deficient mice were substantially 
suppressed compared to wild-type controls and treatment of mice bearing Lewis Lung Carcinoma 
(LLC) allografts with the selective PI3K-γ inhibitor TG100-115, suppressed tumor inflammation, 
growth and angiogenesis despite having no effect on LLC proliferation in vitro (Schmid et al., 
2011).  
  
In hematological malignancies including acute myeloid leukemia (AML), multiple myeloma 
(MM), and chronic lymphocytic leukemia (CLL), over-expression and constitutive activation of 
PI3K-δ suggests that PI3K-δ inhibition could have therapeutic benefit (Billottet et al., 2009; 
Billottet et al., 2006; Herman et al., 2010; Herman et al., 2011; Ikeda et al., 2010; Meadows et al., 


 
          
5  
2010).  The PI3K- isoform specific inhibitor idelalisib (formerly known as CAL-101/GS1101) 
has demonstrated clinical activity in patients with hematologic malignancies (Flinn et al.,  
2014) and was approved by the FDA in 2014 for the treatment of CLL and FL (Furman et al.,  
2014a; Gopal et al., 2014a). Moreover, inhibition of PI3K-δ not only affected cancer cells directly, 
but it also affected the ability of the cancer cells to interact with their microenvironment.  Single 
agent treatment with CAL-101 has also been reported to be active in MCL and other refractory 
NHL (Flinn et al., 2014; Hoellenriegel et al., 2011; Kahl et al., 2014b; Lannutti et al., 2011; 
Meadows et al., 2010; Webb et al., 2010).  In refractory or relapsed iNHL and in CLL patients, 
CAL-101 has been combined with BR demonstrating robust clinical activity (Flinn et al., 2010; 
Sharman et al., 2011).  Subsequently, two other PI3K inhibitors, including copanlisib and 
duvelisib, demonstrated similar clinical activity in FL and were approved by the FDA in 2017 and 
2018, respectively, for the treatment of FL. However, these drugs have serious and fatal toxicities.     
   
The established roles of PI3K in cancer cells, and in the biology of the tumor microenvironment, 
support the development of PI3K-δ inhibitors in patients with hematological malignancies, in 
particular lymphoproliferative disorders, either as single agents or in combination with other drugs.  
  
TGR-1202  
  
TGR-1202 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.(Friedman et al., 2014)  TGR-1202 is currently in a Phase I dose 
escalation trial and has been administered safely at daily doses up through 1200 mg QD.  
  
Pre-clinical development of TGR-1202  
  
The potency of TGR-1202 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) (11). Selectivity over the other three isoforms, namely, α, β, and γ was also 
determined (Prasanna R, 2011) (Seeta N, AKT phosphorylation in THP-1 cells. Study Report IVT-
5264-ATP-08, 2011) (Seeta N, AKT phosphorylation in MOLT-4 cells. June Study Report IVT-
5264-APM-10, 2011).  
Data demonstrated the specificity of TGR-1202 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.  
  


 
          
6  
TGR-1202 potency against human and 
mouse PI3K isoforms  
  
  
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 (17). Cells were incubated with 
TGR-1202 for different timeperiods (72 -96 h) based on their doubling time.  Data demonstrated 
the ability of TGR-1202 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 and 7.5 μM of TGR-1202.  
Subsequent to cell viability, the effect of TGR-1202 on AKT phosphorylation (12, 13, 14, 15, 16) 
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 TGR-1202 in representative cell lines was determined by Western blotting using a 
phospho-AKT (Ser473) antibody.  
  
  
  
Reduction of pAKT by TGR-1202 in cell lines by Western blotting  
  
  
  
  
  
  
  
PI3K isoforms (Human)  
IC50 (nM)  
α  
>10,000  
β  
1,116  
γ  
1,065  
δ  
22.23  


 
          
7  
  
In-Vivo Activity  
  
In vivo efficacy of TGR-1202 was confirmed in a subcutaneous mouse MOLT-4 xenograft model.  
Oral administration of 150 mg/kg/QD over a 25-day period resulted in a significant delay in tumor 
growth.  
  
  
  
  
  
  
  
  
TGR-1202 In vivo efficacy  
  
  
  
To assess the safety and toxicity of TGR-1202 a 28-day repeat dose study with a 14-day recovery 
period was conducted in CD-1 mice and beagle dogs, to evaluate the potential reversibility of 
findings and to support the use in humans.  TGR-1202 was administered orally in order to mimic 
the planned mode of clinical administration.  
  
Once daily oral administration of TGR-1202 was tolerated in mice at free base dose levels of 50 
and 150 mg/kg/day.  Increases in liver weights, microscopic findings in the liver and the increases 
in serum cholesterol, and female only ALT, AST, and GGT levels were observed at 750 mg/kg/day 
of free base (the highest dose tested) and were considered adverse.  The noobserved-adverse-effect 
level (NOAEL) was considered to be 150 mg/kg/day in mice.   
  
Once daily oral administration by capsule of TGR-1202 was well tolerated in dogs at levels of 50 
and 150 mg/kg/day.  The gastrointestinal tract, based on clinical signs, was the target organ system.  
Based on effects on body weight and the incidence and severity of emesis and diarrhea, the 
NOAEL was considered to be 150 mg/kg/day (114.5 mg/kg/day as free base) in this species.  


 
          
8  
Refer to the TGR-1202 Investigator’s Brochure (IB) for detailed information on toxicology studies 
conducted to date.  
  
Clinical development of TGR-1202  
  
Single-agent activity in patients with relapsed or refractory hematologic malignancies.  
  
TGR-1202 is under evaluation in an ongoing single-agent Phase I dose-escalation study in patients 
with relapsed and refractory hematologic malignancies (O'Connor et al., 2015).   
  
Patients were enrolled in a 3+3 dose-escalation design starting at 50 mg QD with subsequent 
cohorts evaluating doses as high as 1800 mg QD.  In an effort to further improve the oral 
bioavailability of TGR-1202, the particle size of the drug product was reduced through a 
micronization process, resulting in greater absorption when tested in a bioequivalence crossover 
study in healthy subjects (see Section Healthy Subject Pharmacokinetics below).  This micronized 
formulation was introduced into dose escalation at 200 mg QD and dosed as high as 1200 mg QD, 
with no maximum tolerated dose (MTD) reached.  Intra-patient dose escalation rules have allowed 
patients enrolled into the study in early cohorts to increase their dose of TGR1202 as subsequent 
higher cohorts have cleared safety evaluation.  
  
As of August 2015, 75 pts were evaluable for safety including pts with CLL, FL, Hodgkin's (HL), 
DLBCL, MCL, and MZL. Patients had a median age of 65 yo (range: 22-85), 67% male, ECOG 
0/1/2: 26/47/2, median prior Tx: 3 (range: 1-14), and 49% refractory to prior Tx. No Gr≥3 AEs 
were observed in ≥10% of pts. AEs (all grades, all causality) in >20% of pts were limited to nausea 
(44%, Gr3/4 0%), diarrhea (36%, Gr3/4 1%), and fatigue (31%, Gr3/4 3%). Notably, general 
tolerability and the incidence of hepatotoxicity and colitis appear significantly less than that 
reported with other agents in this class. Expansion cohorts are open at 800 mg, 1000 mg, and 1200 
mg QD. Of 16 evaluable CLL pts, 15 (94%) achieved a nodal PR (median nodal ↓ of 76%), of 
which 10 (63%) achieved a PR per Hallek 2008 criteria. Among the 32 evaluable NHL patients, 
10 achieved an objective response, including 3/11 evaluable patients with DLBCL, while 
responses have been limited in pts with MCL (1/5) and HL (1/9). Of the 16 evaluable indolent 
NHL (FL & MZL) pts, 14 (88%) have achieved reductions in tumor burden with 6 pts on study for 
over 12 cycles (and durations upwards of 29+ cycles), with 5/12 FL and 1/4 MZL pts achieving an 
objective response to date. Notably, a strong exposure-response relationship has been observed. 
Of the 24 patients starting TGR-1202 at 800 mg or 1200 mg of the micronized formulation, 19 
(79%) remain on therapy, with 9/18 (50%) evaluable pts (6 too early to evaluate) achieving an 
objective response to date (range on study 3 - 49+ weeks).  
  
A dose-dependent response has been observed with TGR-1202, with a dose of 800 mg or higher 
of the initial formulation or any dose of the micronized formulation producing significant nodal 
reductions among CLL patients. AEs observed included diarrhea, nausea, fatigue, cough, anorexia, 
headache, vomiting, rash, neutropenia, constipation, dyspnea, and thrombocytopenia. See the 
comprehensive Adverse Events and Potential Risks Lists (CAEPRs) section for a complete 
overview of the TGR-1202 side effect profile.    
  


 
          
9  
Dosing of TGR-1202 initially occurred in the fasting state, but was transitioned mid-study to fed 
state dosing, with patients instructed to take TGR-1202 with food.  All dosing of TGR-1202 is now 
conducted using the micronized formulation and in the fed state.    
  
Overall, the available data on TGR-1202 suggest that it is considerably better tolerated that 
idelalisib and duvelisib, and does not appear to be associated with the “autoimmune-like” side 
effects of the other two agents in the class, including colitis and pneumonitis. In addition, the 
incidence of transaminitis, diarrhea and drug discontinuation is substantially lower. The clinical 
activity and favorable toxicity profile of TGR-1202 were published in April 2018 (Lancet Oncol. 
2018 Apr;19(4):486-496. PMID: 29475723).  
  
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 TGR-1202 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 TGR-1202 (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, druggender 
interaction study in 24 healthy subjects (12 males and 12 females) to assess the mean plasma TGR-
1202 concentration over time following a single oral dose of 200 mg of TGR-1202 under fasting 
and fed condition using the original formulation.  In general, administration of TGR-1202 under 
fed conditions results in a higher rate of exposure relative to when the product was given under 
fasting conditions.   
   
The statistical comparisons of TGR-1202 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 TGR-1202.  The extent (AUC0-t) and total 
extent (AUC0-inf) of exposure increased by 61% and 67%, respectively, when TGR-1202 was 
administered under fed conditions compared to fasting conditions.  The peak plasma levels of 
TGR-1202 increased by over 173% when TGR-1202 was administered with food.  
  


 
          
10  
Using these mean values, a 334 mg oral dose of TGR-1202 under fasted condition can be 
extrapolated to be equivalent to an oral dose of 200 mg of TGR-1202 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 TGR-1202.  In this study, TGR-1202 was administered under fasted conditions in 
24 healthy subjects (12 males and 12 females) to assess the mean plasma TGR-1202 concentration 
over time following a 200 mg single dose of the original drug product formulation and modified 
(micronized) drug product formulation of TGR-1202. The mean rate and extent of exposure to 
TGR-1202 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.  
  
The statistical comparison of the micronized 200 mg drug product formulation versus the original 
200 mg drug product formulation are shown below:  
  
  
  
  
Parameters  
Geometric LS Means   
%  
Geometric  
Mean Ratio  
Confidence  
Interval  
Original  
Formulation  
Micronized 
Formulation  
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 
TGR1202 under fasted conditions. The extent (AUC0-t) and total extent (AUC0-inf ) of exposure 
both increased by 60%, respectively, following administration of the modified drug product 
formulation relative to original drug product formulation. The Peak plasma (Cmax) levels of TGR-
1202 increased by over 124% following administration of the micronized drug product formulation 
relative to original drug product formulation under fasted conditions.  
  
Using these mean values, a 320 mg oral dose of TGR-1202 in the original formulation under fasted 
condition can be extrapolated to be equivalent to an oral dose of 200 mg of the original formulation 
TGR-1202 under fasted conditions in term of exposure based on AUC0-inf.   
  
The improved exposure seen with the micronized formulation of TGR-1202 was confirmed in 
patients in the Phase 1 dose escalation as well.  The chart below illustrates the pre-dose plasma 
concentrations of TGR-1202 on Day 1 of Cycle 2 in patients administered equivalent doses of 
either the initial formulation in the fasting state or the micronized formulation in the fed state:    


 
          
11  
  
  
  
  
Rationale for the Study  
PI3K- and PI3K- are expressed in hematopoietic cells, and are critical for the ability of normal 
immune cells to respond to survival and differentiation signals in their environment.  In cancer 
cells, the pathways mediated by PI3K-δ,γ are critical for cell survival and proliferation, as well as 
the inductive tumor microenvironment. PI3K inhibition with idelalisib has proven successful in 
the treatment of patients with relapsed or refractory indolent NHL, including FL (Gopal et al., 
2014a). Longer-term data of previous trials and the results of ongoing studies of idelalisib in 
patients with CLL or NHL have suggested that safety concerns may limit further clinical 
development of idelalisib in this setting. In fact, In March 2016 The U.S. Food and Drug 
Administration issued an alert to health care professionals about reports of an increased rate of 
adverse events, including deaths, in clinical trials with idelalisib in combination with other drugs. 
In addition six clinical trials in patients with CLL and iNHL were halted. The FDA label of 
idelalisib currently contains a black box warning on fatal and serious hepatitis, pneumonitis, severe 
diarrhea, colitis, and intestinal perforation.    
  
Although targeting of PI3K- has been validated as a therapeutic strategy in lymphoma, as 
demonstrated by the approval of idelalisib, this strategy has several limitations.  (a) Idelalisib does 
not have activity in aggressive lymphoma such as the most common subtype, diffuse large B cell 
lymphoma. (b) The PFS for idelalisib in CLL and FL is short, 5.5 and 11 months, respectively 
(Furman et al., 2014b; Gopal et al., 2014b). Resistance develops for essentially all patients. The 
mechanism of resistance is unknown, but could be due to genetic mutations, or activation of pro-
survival pathways. (c) Idelalisib is associated with a very high frequency of diarrhea.  Interestingly, 
TGR-1202 appears to have a number of features distinct from idelalisib.     
  
Notably, TGR-1202 possesses a central pyrazolopyrimidine amine moiety that has been found to 
confer an ability to target a poorly understood kinase, CK1 epsilon (Blood. 2017 Jan 5;129(1):88-
99. PMID: 27784673). There is emerging evidence that targeting of CK1 epsilon by TGR-1202 
makes it uniquely active in silencing the translation of c-Myc through inhibiting phosphorylation 
of 4E-BP1 (Figure 4) in diffuse large B cell lymphoma (DLBCL) with overexpression of c-Myc. 


 
          
12  
In agreement, TGR-1202 as a single agent is reported to produce a partial response in 2 of 12 
patients with DLBCL.   
  
  
  
 TGR-1202 is active against CK1. (A) Comparison of the co-crystallization of PF-4800567 and CK1ε to in silico  
docking of TGR-1202 in the active site binding pocket.  (B) Cell-free kinase activity assay of CK1ε measuring dose  
(-X)-activity (-Y) curves of PF-4800567, TGR-1202, Idelalisib, CUX-03173, and CUX-03166. (C) Western blot  
analysis of LY7 cells treated by various singles agents and combinations for 24h. The numbers in the combinations  
 indicated the drug concentrations incells stably expressing the CK1ε targeting shRNA (shRNA+) or the parental 
untransduced control cells (shRNA M. (D) Effects of CK1ε knockdown on the combination of Ide+Cfz. LY7 -)  
were treated as indicated for 24h and assessed by Western blot.  
  
It has been shown that severe diarrhea associated with idelalisib is due to erosive colitis 
characterized by sloughing of the luminal epithelium and exudate, numerous apoptotic bodies. 
intraepithelial lymphocytes, and crypt abscesses (Louie et al., 2015; Weidner et al., 2015).  The 
pathologic findings were also observed in the kinase dead (PI3K p110dD910A/D910A) transgenic 
mice (Okkenhaug et al., 2002; Uno et al., 2010). The cytokines IL-10 and IL-12 have been shown 
to promote mucosal homeostasis and inflammation, respectively (Sartor, 2010; Uno et al., 2010).  
It was reported that mutant macrophages with an inactive PI3K (p110δKD) were associated with 
decreased IL-10 expression and increased IL-12 expression, a cytokine profile that was closely 
mirrored by the treatment of wild type macrophages with IC87114, a PI3K inhibitor structurally 
related to idelalisib (Steinbach et al., 2014). We confirmed that idelalisib caused decreased 


 
          
13  
production of IL-10 and increased production of IL-12 by macrophages stimulated with 
lipopolysaccharide (LPS) (Figure 5).  Interestingly, TGR-1202 generated an opposite pattern of 
cytokines produced by macrophages, with increased IL-10 and decreased IL12.  Collectively these 
results suggest that TGR-1202 may be equipped with a unique ability to generate a profile of IL-
10/IL-12 that is not harmful to colonic mucosal homeostasis, opposite to the effect of idelalisib.  
Furthermore, this unique feature of TGR-1202 is likely related to the activity of TGR-1202 in 
targeting CK1, as shown in Figure 4.     
  
  
Effects of PI3K inhibitors on IL-10/IL-12. PBMC cells from healthy donors were incubated with monocyte 
conditioned medium (MCM) to allow differentiation into microphages. Microphages were pretreated with the 
indicated drugs for 1h, then stimulated with lipopolysaccharide (LPS) for 24h and analyzed for IL-10 and IL-12.   
  
  
  
Hypothesis: We hypothesize that if TGR-1202 acts through targeting PI3K and CK1, then its 
response in patients may be associated with, and potentially predicted by, inhibition of key 
effectors downstream of PI3K and CK1, including 4E-BP1, p70S6K, c-Myc, E2F1, global 
mRNA translation, expression of c-Myc target genes such LDHA and E2F1, and expression of 
PD-L1 and CD47. Conversely, resistance may be associated with mutations in the PI3K and 
CK1 pathways, and loss of inhibition of the above effectors. Furthermore, TGR-1202 may 
cause increased IL-10 and decreased IL-12 produced by macrophages.   
One of the important goals of this phase II study is to discover novel genetic, biochemical, and 
immunological markers that are associated with the response and safety of TGR-1202 in patients 
with follicular lymphoma. To achieve this goal we will combine our expertise in genetics and 
genomics, molecular pathways, targeted therapy, immune therapeutics, and innovative animal 


 
          
14  
models to conduct extensive correlative studies using patient samples, including matched pre- and 
post-treatment normal and tumor tissues.  
 3.  
PATIENT SELECTION  
Inclusion Criteria   
  
  
1. Histologically proven diagnosis of grade 1, 2, or 3A FL  
2. The diagnosis of relapsed FL must have been made within the last 6 months of screening 
if no other treatment is given for the FL in the interim; if an interim treatment is given 
within the last 6 month, re-biopsy will be required even if there is already a biopsy proven 
relapsed FL within the last 6 months.  
3. Pre-treatment biopsy must establish the diagnosis AND have enough remaining tissues to 
satisfy the mandatory research studies.    
4. Relapse following first line immunotherapy or chemoimmunotherapy. There is no upper 
limit to the number of therapies received prior to study entry. Prior therapies may include 
high-dose therapy with autologous stem cell rescue.  
5. Measurable disease according to the Lugano classification (Cheson et al., 2014a). See 
Appendices 1 and 2.  
6. Lymphoma that is amenable to safe pre-treatment and post-treatment biopsy.  The safety 
of the procedures will be determined by the treating physician and the surgeon or other 
proceduralist, in consultation with the PI, and in accordance with standard clinical practice. 
Acceptable sites of disease include, for example: (1) palpable tumor mass that is accessible 
under direct visualization or sonogram, (2) non-palpable tumor tissue that is accessible for 
biopsy under CT or sonogram guidance, (3) bone marrow.  
7. Age >18 years.  
8. ECOG performance status <2 (see Appendix 3)  
9. Patients must have adequate organ and marrow function as defined below:  
a. absolute neutrophil count >1,000/microliter  
b. platelet count ≥50,000/microliter  
c. bilirubin <1.5X institutional upper limit of normal  
d. aspartate transaminase (AST, SGOT)/alanine transaminase (ALT, SGPT) <3.0X 
institutional upper limit of normal  
e. Serum creatinine <2.0X institutional upper limit of normal or creatinine clearance 
>50 mL/min (according to the Cockroft and Gault equation).  
10. Negative serum pregnancy test within 7 days prior to Cycle 1/Day 1 for women of 
childbearing potential   
11. All women of childbearing potential must agree to use an effective barrier method of 
contraception, as described in Appendix 4, during the treatment period and for at least 1 
month after discontinuation of the study drug. Male subjects should use effective barrier 
method of contraception during the treatment period and for at least 1 month after 
discontinuation of the study drug (see Appendix 4).  
12. Ability to understand and the willingness to sign a written informed consent document.  
  
Exclusion Criteria  
  
  
  
  


 
          
15  
1. Grade 3B FL or evidence of transformation of FL to a more aggressive lymphoma 2. 
Prior and concomitant therapy:  
  
a. Prior exposure to any PI3 Kinase inhibitor  
b. Exposure to chemotherapy, radiotherapy, or immunotherapy within 3 weeks prior to 
entering the study or lack of recovery from adverse events due to previously 
administered treatments.  
c. Ongoing chronic pharmacologic immunosuppression, e.g. cyclosporine, or systemic 
steroids that have not been stabilized to the equivalent of ≤10 mg/day prednisone prior 
to the start of the study drug.  
d. Other concurrent investigational agents during the study period.  
3. Prior allogeneic stem cell transplant  
4. Central nervous system lymphoma, including lymphomatous meningitis   
5. Acute intercurrent illness including, but not limited to, active infection, unstable congestive 
heart failure, unstable angina pectoris, psychiatric illness or any social situation that would 
limit compliance with study participation requirements in the judgement of the investigator  
6. Major surgery performed within 4 weeks of study entry  
7. Pregnant or nursing women  
8. Active concurrent malignancy (except non-invasive non-melanoma skin cancer, carcinoma in 
situ of the cervix, or prostate intraepithelial neoplasia). If there is a history of prior malignancy, 
the patient must be disease-free for ≥ 3-years at the time of study entry. 9. Documented Human 
Immunodeficiency Virus (HIV)-infection  
10. Active hepatitis A, hepatitis B, or hepatitis C infection (see Appendix 5).  
11. History of tuberculosis treatment within 2 years of study entry  
12. Administration of a live vaccine within 6 weeks of first dose of study drug  
13. Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or 
herpes zoster (VZV) at screening  
14. Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g., gastric 
bypass surgery, gastrectomy)  
15. Lymphoma that is not amenable for mandatory pre- and C2D15 post-treatment biopsy as 
described in item 6) of the inclusion criteria.  
16. Unstable or severe uncontrolled medical condition (e.g. unstable cardiac function, unstable 
pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal 
laboratory finding that would, in the investigator’s judgment, increase the risk to the patient 
associated with his or her participation in the study  
17. Clinically significant cardiovascular abnormalities such as:  
a. Angina not well-controlled by medication  
b. Poorly controlled or clinically significant atherosclerotic vascular disease including 
cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, 
cardiac/vascular stenting within 6 months of enrollment  
c. Symptomatic or documented congestive heart failure that meets New York Heart  
Association (NYHA) Class III to IV definitions (see Appendix 6);  
d. History of stroke within the last 6 months prior to screening    
  
Inclusion of Women and Minorities  
  


 
          
16  
Both men and women of all races and ethnic groups are eligible for this trial.  
    
  
  
 4.  
REGISTRATION PROCEDURES  
  
General Guidelines  
  
Eligible patients will be enrolled on study by the study team.    
  
Following enrollment, patients should begin the protocol treatment within 14 days.  Issues 
that could cause treatment delays should be discussed immediately with the Principal 
Investigator. If a patient does not receive protocol therapy enrollment registration, the 
patient’s enrollment on the study may be canceled.    
  
Study Informed Consent  
  
Study personnel must obtain informed consent from each potential patient prior to entering 
the clinical study.  Consent must be documented on the IRB approved consent form by 
obtaining the signature and date of both the patient and the investigator conducting the 
consent discussion.    
  
If the patient is able to understand and willing to, but unable sign the consent form, then 
oral consent, attested to by the dated signature of an impartial witness (i.e., a person not 
involved with the conduct of the study), is the required alternative.  
  
If the patient is unable to read, an impartial witness should be present during the entire 
informed consent reading and discussion. Afterward, the patient should sign and date the 
informed consent, if capable.  The impartial witness should also sign and date the informed 
consent along with the individual who read and discussed the informed consent (i.e., study 
staff personnel).  
  
  
The information from the consent form should be translated and communicated to the 
subject in a language understandable to the subject.  Consent forms will be available in 
English and Spanish. If the study participant is a non-English and non-Spanish speaker, the 
consent form must be read accurately in its entirety by a qualified professional translator. 
The translator must also translate all the questions the patient might have and all the 
answers the patient receives from the study personnel conducting the consent discussion. 
The translator will provide a written statement indicating that the consent form has been 
accurately translated from the accompanying English version, and that the study participant 
understands the information therein and consents to participate in the study.  The 
professional translator will sign the consent form as an impartial witness.  
  


 
          
17  
A copy of the consent form signed and dated should be provided to the patient before study 
entry.  
  
Tests performed within 29 days prior to the date of written informed consent may be 
accepted as study screening tests provided that these are considered part of standard care.   
  
The initial informed consent form and all subsequent revised written informed consent 
forms, as well as any amendment or additional written information regarding the study is 
contingent on the IRB approval.  The patient or his/her legally accepted representative will 
be informed in a timely manner if new information becomes available that may affect the 
patient’s willingness or ability to continue to participate in the trial. The communication of 
this information will be documented.  
  
Consent for and Use of Tissue Specimens for Correlative Studies  
  
Participation in correlative studies is mandatory for all patients. In addition to the 
mandatory correlative studies for all patients, there will also be optional correlative studies, 
which will be performed under a separate section of the informed consent procedure.   
  
Mandatory correlative studies include the following:  
 For PK studies:  
1. Collection of blood at Pre-treatment.  
2. Collection of blood at 4h post-treatment on C1D1, C1D15, C2D15 and C4D15.  
  
 For PD studies:   
1. Collection of blood at Pre-Treatment (total approx.3ml).   
Collection of blood at 4h post-treatment on C1D1, C1D15, C2D15 and C4D15 (total 
approx. 12ml).  
The studies will include T cell panel such as T-reg, expression of CD47 and PD-L1, 
cytokines such as IL-10 and IL-12, and PI3K targeting.   
2. Collection of tumor tissues, blood cells, and buccal fibroblasts pre-treatment and 4-8h 
post-treatment on C2D15.   
The studies will include whole exome sequencing, and the levels/activity of c-Myc, 4E-
BP1, CK1, and PI3K.   
  
Optional correlative studies are listed below:  
Collection of tumor tissues and buccal fibroblasts 4-8h post-treatment on C4D15, at 
Progression of Disease, and at End of Treatment.   
The studies will include whole exome sequencing, and the levels/activity of c-Myc, 4EBP1, 
CK1, and PI3K.   
  
Registration Process  
  
             The Study Coordinator will verify eligibility and complete the registration process, by:  
• 
Assigning a patient study number  


 
          
18  
• 
Registering the patient on the study  
• 
Confirming registration with the principal investigator  
  
Screening  
  
Unless otherwise specified, the following procedures and evaluations will be performed 
as noted in the study calendar (Section 10) prior to the start of study drugs (cycle 1, dose 
1):  
  
1) Obtain written informed consent and privacy authorization prior to initiating any 
protocol-required procedure that is not considered standard of care (See Section 4.3)  
  
2) Review eligibility criteria  
  
3) Review medical chart for past medical/surgical history  
  
4) Record medications and prior antineoplastic treatment regimens  
  
5) Record response to prior treatment regimens  
  
6) Document histopathology from:  
(i) 
Tumor tissue biopsy at the time of diagnosis   
(ii) 
Tissue biopsy of relapsed or refractory FL if applicable  
  
7) Document measurable disease sites by the following procedures:  
• 
CT of the neck, chest, abdomen, and pelvis (PET/CT is optional but preferred)  
• 
Other imaging studies and/or exams documenting measurable disease sites other 
than neck, chest, abdomen, and pelvis, if applicable  
  
8) Perform a comprehensive physical examination  
  
9) Assess and record ECOG Performance Status   
  
10) Local laboratory: Collect blood for complete blood count with differential; blood 
chemistry, including sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, calcium, and magnesium; liver function tests, including total 
proteins, albumin, AST, ALT, total bilirubin, direct bilirubin, alkaline phosphate; 
coagulation tests (PT,PTT,INR); serum β-human chorionic gonadotropin (β-hCG) 
pregnancy test for women of childbearing potential within 7 days of cycle 1, day 1; 
serum pregnancy test within 24 hours prior to first dose of the study drug.  
  
11) Calculate creatinine clearance using the glomerular filtration rate (GFR) according to 
the Cockroft-Gault equation, only if screening serum creatinine is > 1.5 mg/dL: GFR* 
= (140 – age [years]) x actual body weight (kg)72 x serum creatinine       *For female 
patients, multiply by 0.85   


 
          
19  
  
12) Obtain a 12-lead electrocardiogram (ECG) to evaluate for abnormalities.   
  
  
 5.  
TREATMENT PLAN  
  
 Regimen Description  
  
Treatment will be self-administered on an outpatient basis. Patients will take TGR-1202 800 mg, 
one tablet daily on a continuous basis. Each cycle lasts 28 days. Reported adverse events and 
potential risks for TGR-1202 are described in Section 7.  Appropriate dose modifications are 
described in Section 6.  No investigational or commercial agents or therapies other than the study 
drug may be administered with the intent to treat the patient's malignancy.  
  
Evaluation and requirements Prior to Each Treatment Cycle  
  
Before the start of each treatment cycle, patients should be reassessed and the following criteria 
must be fulfilled:  
  
• 
Absolute neutrophil count (ANC) ≥ 1,000/dL  
• 
Platelet count ≥ 50,000/dL   
• 
Serum creatinine concentration ≤ 2.0 × ULN or ≤ baseline, or creatinine clearance > 50 
ml/min  
• 
AST (SGOT) and ALT (SGPT) ≤ 3.0 × ULN   
• 
Bilirubin concentration ≤ 1.5 × ULN. Subjects with Gilbert's Syndrome may have a 
Bilirubin >1.5 × ULN if no other cause of hyperbilirubinemia is present in the judgment 
of the treating physician; aPTT and PT not to exceed 1.2 × ULN   
• 
Recovery of any drug-related non-hematological toxicity to Grade 2 or less, unless 
otherwise indicated  
  
Guidelines for Administration of TGR-1202  
  
• 
Method of Administration: TGR-1202 will be administered orally once daily with food  
Potential Drug Interactions:  No Drug Interactions have been reported to date.  
• 
Pre-medications: Patients are required to start prophylaxis treatment with pneumocystis jiroveci 
pneumonia (PCP) and antiviral therapy within 7 days prior to randomization.   
• 
Anti-viral Prophylaxis: Valtrex 500 mg daily or Acyclovir 400 mg BID or equivalent is 
recommended   
• 
PCP Prophylaxis: Bactrim DS 1 tablet 3x per week or Dapsone 100 mg daily or equivalent is 
recommended.   
  
Final choice of PCP and anti-viral prophylaxis therapy is per investigator discretion  
  


 
          
20  
TGR-1202 will be dispensed at the sites by the research coordinator or designee under the direction 
of the PI or by a pharmacist at the site.  Patients must be provided drug in its original container.  
Patients should be instructed to return any unused tablets when they return the bottle to the site. 
Study drug compliance should be reviewed with the patient at the beginning of each new treatment 
cycle and as needed.  Missed doses will be documented in the patients’ medical record.  
  
TGR-1202 will be self-administered (by the patient).  Tablets should be taken at approximately the 
same time each day with food. Patients should be instructed to swallow the tablets as a whole and 
should not chew or crush them.  
  
If a dose of TGR-1202 is missed within 12 hours of its scheduled administration, the patient should 
take the dose. If it is missed more than 12 hours after the scheduled administration time, the patient 
should omit that dose and record in the diary.   If vomiting occurs, no attempt should be made to 
replace the vomited dose.  
  
Dispensing of TGR-1202  
  
Before dispensing, the site pharmacist or his/her representative must check that the TGR-1202 is 
in accordance with the product specifications and the validity is within the re-test date.  
  
The exact dose and the date of administration of TGR-1202 must be recorded within the case report 
form (CRF), patient’s medical records.  For the purpose of drug accountability and dosing, a drug 
diary will be utilized.  Any error in drug administration should be recorded (e.g., missed dose) in 
the CRF.  
  
The Pharmacist or his/her representative should record the date dispensed and patient’s number 
and initials, as well as complete the accountability record in the electronic drug accountability 
system with information concerning the dispensation of TGR-1202.   
  
Supportive care  
  
Patients will be permitted to receive appropriate supportive care measures as deemed necessary by 
the treating physician including, but not limited to the use of anti-emetics, anti-diarrheal, 
antipyretics, anti-histaminics, analgesics, antibiotics, growth factors, blood products, and other 
drugs not prohibited during the study period.    
  
- 
Use of myeloid growth factors and erythropoiesis-stimulating agents:  
Colony stimulating factors (i.e., filgrastim, peg-filgrastim, and sargramostim) may be used 
according to the 2006 American Society of Clinical Oncology (ASCO) guidelines.(Smith 
et al., 2006) Peg-filgrastim should only be used if the time to the next dose is ≥14 days. 
Anemia may be managed with erythropoiesis stimulating agents according to the 
ASCO/ASH guidelines.(Rizzo et al., 2010) Patients with pre-existing chronic anemia 
treated with epoetin or darbepoietin, may continue to receive such agents during the study 
period, but should not start them once on study.  
  


 
          
21  
- 
Specific supportive care issues:   
Diarrhea: Diarrhea should be treated promptly with appropriate hydration and 
antidiarrheal agents such as loperamide.  Loperamide should not be taken 
prophylactically. Patients should be instructed to begin taking loperamide at the first 
sign of: 1) poorly formed or loose stool, 2) occurrence of more bowel movements than 
usual in one day or 3) unusually high volume of stool.  Loperamide should be taken in 
the following manner: 4 mg at first onset of diarrhea, then 2 mg after each non-formed 
stool. The daily dose of loperamide should not exceed 16 mg/day.  Loperamide should 
be deferred if blood or mucus is present in the stool or if diarrhea is accompanied by 
fever. In this setting, appropriate diagnostic microbiologic specimens should be 
obtained to exclude an infectious etiology.  If the treating physician diagnoses the 
diarrhea as grade 3 or 4 by CTCAE v4.0, TGR-1202 should be held.  If colitis is 
suspected colonoscopy should be considered if it can be done safely.   
  
• 
Nausea/emesis: Nausea and emesis should be treated with standard anti-emetics, 
including 
5-hydroxytryptamine 
3 
serotonin 
receptor 
(5-HT3) 
antagonists, 
prochlorperazine, metoclopramide, or benzodiazepines.  Patients should be encouraged 
to maintain adequate oral fluid intake during therapy. Dexamethasone should not be 
administered as an antiemetic.  
  
• 
Anemia: Treatment with TGR-1202 can cause anemia. Transfusions or erythropoiesis 
stimulating agents may be utilized as clinically indicated for the treatment of anemia 
and should be clearly noted as concurrent medications. Dose modifications for anemia 
are outlined in section 6.3.  
  
• 
Thrombocytopenia: Treatment with TGR-1202 can cause thrombocytopenia. 
Transfusion of platelets may be used if clinically indicated. TGR-1202 dose 
modification guidelines for thrombocytopenia are outlined in section 6.  
  
• 
Neutropenia: Neutropenia can occur during treatment with TGR-1202. Blood counts 
should be monitored regularly as outlined in the protocol and additional testing should 
be obtained when indicated, according to standard clinical practice. Colonystimulating 
factors, including G-CSF, pegylated G-CSF or GM-CSF may be utilized as clinically 
indicated. TGR-1202 dose modifications for neutropenia are outlined in section 6.  
  
• 
Infections: Serious infections, including pneumonia and febrile neutropenia have been 
reported during treatment with TGR-1202. Any suspected infection should be promptly 
managed. Hospitalization should be considered when clinically appropriate.  
  
• 
Mucositis: 
stomatitis 
has 
been 
reported 
during 
TGR-1202 
therapy. 
Lidocainecontaining oral solutions may be used as needed to ameliorate the symptoms 
thereof.   
  


 
          
22  
• 
Tumor lysis syndrome prophylaxis: Subjects should receive allopurinol and other 
treatment considered appropriate for tumor lysis prophylaxis during cycle 1 as deemed 
necessary by the treating physician.   
  
Concomitant Medication Guidelines  
  
All medications taken within 30 days of screening and medications and supportive therapies that 
are administered during the study must be recorded in the patient’s CRF and in the source 
documents. Concomitant medications for other medical conditions are permitted as clinically 
indicated. Over-the-counter and herbal products should not be taken during the study period 
without prior consultation with the PI.  
  
The following concomitant medications are prohibited during the study period:  
• 
Any antineoplastic agent other than TGR-1202  
• 
Prednisone at a stable dose of >10 mg daily  
• 
Radiation therapy; palliative radiation therapy to a pre-existing symptomatic lesion may be 
allowed on a case-by-case basis after discussion with the study PI  
  
Duration of Therapy  
  
Treatment may continue until one of the following criteria applies:  
  
• Disease progression  
• Unacceptable AE(s)  Withdrawal of consent  
• Changes in the patient's condition that render continuation of the study drug unacceptable 
in the judgment of the treating physician  
• An event that in the judgment of the treating physician warrants discontinuation of therapy  
• Study drug will be made available to responding patients for a total of three years from 
initiation of therapy. If TGR-1202 becomes commercially available during the active 
period on study, an attempt will be made to obtain this agent through commercial insurance. 
If coverage is not available, it will be provided for a period of three years as stated above.    
  
Duration of Follow Up  
  
Patients will have an end-of-study visit 4 weeks ±1 week after the last dose of the study drug to 
evaluate safety.  Patients will be further followed every three months for one year, or until they 
begin a new treatment for their disease, for evaluation of delayed toxicity. Patients removed from 
study for unacceptable AE will be followed until resolution or stabilization of the AE. Further 
follow-up should be performed according to standard clinical practice.  
  
For patients who achieve stable disease or better after 6 cycles of therapy, tumor assessment will 
be performed by medical history, physical exam, complete blood count with differential and blood 
chemistries every 3 months, and CT (PET/CT optional but encouraged) at least every 6 months, 
until progression of disease occurs.    


 
          
23  
  
Criteria for Removal from Study  
  
Patients will be removed from treatment when any of the criteria listed in Section 5.3 applies. The 
reason for and date of patient removal must be documented in the CRF.  
  
Subjects/patients may withdraw consent at any time or be dropped from the study at the discretion 
of the investigator should any untoward effects occur. In addition, a subject/patient may be 
withdrawn by the investigator if he/she violates the study plan, or due to administrative and/or 
safety reasons. The investigator or study coordinator will notify the appropriate parties within 2 
business days of becoming aware of an adverse event causing withdrawal of the subject from the 
study (Section 7).  When a subject discontinues/withdraws prior to study completion, all applicable 
activities scheduled for the final study visit should be performed at the time of discontinuation. 
Any adverse events present at the time of discontinuation/withdrawal will be followed until 
resolution.  
  
  
  
 6.  
DOSING DELAYS/DOSE MODIFICATIONS  
  
• 
For a new treatment cycle to begin, patients must meet the criteria outlined in section 5. 
Moreover, all other toxicity must have returned to grade ≤2. If either of these conditions are 
not met, the study drug will be held.  
  
• 
If interruption of study drug lasts for more than 28 days, treatment should be discontinued 
and the subject should be removed from the study (please contact the study chair to discuss 
longer interruptions).  
  
  
• 
Patients who experience toxicity and require the study drug to be withheld may not be 
candidates for biopsy.  Patients who miss 4 or more doses of drug prior to a planned biopsy 
should be considered ineligible for biopsy. The treating physician will make the ultimate 
decision in this regard.  
  
Dose Modifications  
Patients will be monitored continuously for toxicity while on study therapy.  Toxicity will be 
assessed using the NCI CTCAE v4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) grading scale.  
If a patient has an adverse event of particular severity or had an adverse event at least possibly 
related to study drug, then dose modifications will be made according to the guidelines.   
Deviations from these guidelines may occur only if agreed upon by the Principal Investigator. 
There should be no attempt to make up for doses omitted due to toxicity.    
  
A maximum four (4) week delay of treatment for recovery from toxicity is allowed to recover from 
hematologic toxicities to ≤ Grade 3 or non-hematologic toxicities to ≤ Grade 2 or to baseline level.  
If greater than a four (4) week delay is necessary, then the patient should discontinue treatment 


 
          
24  
and continue to be followed for progression.  If a patient withdraws consent or has documented 
progression, an end of study visit should be completed.  
  
Recommended treatment interruptions/holds or dose modifications are summarized below and may 
be based on the clinical judgment of the Investigator with notification to the Principal Investigator.  
For an individual patient, dose reductions and discontinuations may be more conservative than 
indicated. (i.e., to dose-reduce or discontinue for non-hematologic toxicity of lower grades) based 
on the clinical judgment of the Investigator with notification to the Medical Monitor/Sponsor.  
  
Summary of Dose Holds for Treatment-Related Toxicities  
  
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, the next lower dose level will be allowed.   
Grade 4 neutropenia or  Delay TGR-1202 until Grade ≤3 and/or neutropenic fever or infection  
occurrence of 
neutropenic fever or 
infection  
is resolved; thereafter, resume at full dose.  Consider supportive care.  If 
delay is > 4 weeks discontinue study drug.  
  
If recurrence after rechallenge, resume at the 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 TGR-1202 until Grade ≤3; thereafter, resume at full dose.  
Consider supportive care intervention as warranted.  If delay is > 4 
weeks, discontinue TGR-1202.      
  
If recurrence after rechallenge, resume at the next lower dose level.  
Pulmonary & Related Infections*  
Grade ≥2  
Withhold TGR-1202 as warranted, provide supportive care.  Resume at 
full dose.  
  
If recurrence after rechallenge, resume at the next lower dose level.  
*While pneumonitis has been minimal with TGR-1202, it is a reported adverse event associated 
with other PI3K delta inhibitors. PCP and anti-viral prophylaxis is required for any study patient.  
All Other Non-Hematological Adverse Events  
Grade ≤2  
Maintain current dose level  


 
          
25  
Grade ≥3  
Withhold TGR-1202 until Grade ≤2.  Resume at full dose.    
  
If recurrence after rechallenge, resume at the next lower dose level.  
  
  
Study Drug Dose Levels  
  
Study Drug  
Starting Dose  
1st Dose Reduction  
2nd Dose Reduction  
TGR-1202  
800 mg  
600 mg  
400 mg  
  
If a patient requires a dose reduction of TGR-1202 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 
TGR-1202, 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.      
  
Ordering TGR-1202  
  
Once the clinical study site receives regulatory approval (IRB/IEB), and the Sponsor and/or 
Sponsor designee performs the Site Initiation Visit and inspection of pharmacy, and determines 
the site to be officially open for enrollment, and once a patient is identified, a shipment of 
predetermined quantity of TGR-1202 will be shipped to the clinical study site.  
  
Upon receipt of drug supplies, the Pharmacist or the designee from the site should update the 
accountability forms for TGR-1202.  If any abnormality on the supplied bottles (TGR-1202) is 
observed, the Pharmacist or the appropriate person must document that on the acknowledgement 
of receipt and contact that Sponsor and/or Sponsor designee.  
  
  
  
 7.  
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS   
  
Safety Evaluation Procedures  
  
Adverse Event  
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical product; such occurrence does not necessarily have a causal relationship with this 
treatment. An adverse event is, therefore, any unfavorable and unintended change in the structure, 
function, or chemistry of the body that is temporally associated with the use of the study drugs, 
whether or not considered related to the use of the product. Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the study drugs, is also an adverse event.  
  
Adverse events may occur at any point during the study period, including pre-treatment, treatment 
and follow-up period as specified by the protocol.  


 
          
26  
  
Adverse events will be graded and recorded throughout the study period according to NCICTCAE, 
version 4.0.  Toxicities will be characterized in terms of duration, intensity, and time to onset.  
Safety endpoints will include all types of adverse events, in addition to laboratory safety 
assessments, ECOG performance status, ECGs, and vital signs.  
  
The investigator must assess all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details 
about the action taken with respect to the study drug, patient care, and outcome.  
  
The following safety evaluations will be performed during patient screening and at defined points 
during the course of the study:  
  
• 
Vital signs  
• 
Laboratory tests, including complete blood count (CBC), serum chemistry, urinalysis, 
coagulation studies (PT/PTT,INR), pregnancy test, LDH  
• 
Electrocardiograms (ECG)  
• 
Physical examinations  
• 
Performance Status Evaluation using the ECOG scale  
• 
Adverse event monitoring using the NCI CTCAE v4.0  
  
The STUDY CALENDAR (Section 10) provides specific details on collection time points.   
  
Serious Adverse Events (SAE)   
SAE as defined in the following FDA website will be reported to the FDA:   
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm  
  
Details are listed in the Appendix 8.  
  
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs)  
  
The following adverse events were observed in patients treated with single agent TGR-1202 and 
were considered at least possibly related to study medication.  See the TGR-1202 investigator 
brochure for a complete list of all adverse events reported regardless of causality.  
  
Very Common (≥ 10%) Blood and lymphatic system disorders: Neutropenia  
Gastrointestinal disorders: Nausea, Diarrhea, Vomiting  
General disorders and administration site conditions: Fatigue Metabolism and nutrition 
disorders: Decreased appetite Skin and subcutaneous tissue disorders: Rash  
Common  (≥ 1% and < 10%)  
Blood and lymphatic system disorders: Anemia, Febrile neutropenia, Leukocytosis, 
Thrombocytopenia  


 
          
27  
Ear and labyrinth disorders: Tinnitus  
Eye disorders: Vision Blurred, Visual Acuity Reduced  
Gastrointestinal disorders: Abdominal distension, Abdominal pain, Constipation, Dry 
mouth, Dyspepsia, Eructation, Hypoaesthesia oral, Mouth Ulceration, Flatulence, 
Gastroesophageal reflux disease, Paraesthesia oral, Colitis  
General disorders and administration site conditions: Asthenia, Chills, Malaise, Oedema 
peripheral, Pyrexia, Mucosal inflammation Hepatobiliary disorders: Hyperbilirubinaemia  
Infections and infestations: Candida infection, Lung infection, Oral candidiasis, Pneumonia, 
Upper respiratory tract infection, Sinusitis  
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, 
Blood creatinine increased, Blood lactate dehydrogenase increase, Blood phosphorus 
increased, Blood sodium increased, Blood uric acid increased, International normalized ratio 
increased, Lymphocyte count increased, Weight decreased  
Metabolism and nutrition disorders: Dehydration, Hyperglycaemia, Hyperlipidaemia, 
Hypertriglyceridaemia, 
Hypokalaemia, 
Hyponatraemia, 
Hypophosphataemia, 
Hypomagnesaemia  
Musculoskeletal and connection tissue disorders: Arthralgia, Muscle spasms, Muscular 
weakness, Myalgia, Pain in extremity, Pain in jaw  
Nervous system disorders: Dizziness, Dysgeusia, Headache, Memory impairment,  
Neuropathy peripheral, Somnolence, Tremor, Peripheral sensory neuropathy  
Psychiatric disorders:  Anxiety, Insomnia, Libido decreased, Delirium, Parasomnia  
Reproductive system and breast disorders: Erectile dysfunction  
Respiratory, thoracic and mediastinal disorders: Cough, Dyspnea, Epistaxis, Hypoxia, 
Respiratory failure, Sinus congestion  
Skin and subcutaneous tissue disorders: Alopecia, Dermatitis acneiform, Night sweats, 
Pruritus  
Vascular disorders:  Hot flush  
In addition to the preceding adverse events, the following adverse events occurred in patients 
administered TGR-1202 but were deemed by investigators to be unlikely related or not related to 
TGR-1202 therapy.  Due to the low number of patients evaluable for safety at this time, however, 
TG Therapeutics cannot rule out these events occurring in future studies:  
  
Liver Disorders: Elevated levels of certain liver enzymes  
Brain and nerve related disorders: Paresthesia  
Kidney disorders: Elevated blood urea nitrogen levels, Elevated phosphorus, Hyperuricemia  
Breathing and chest related disorders: Nasal congestion, Upper respiratory tract infection 
Infections and Infestations: Infection  
  
Safety analyses  
  
Safety evaluations will be based on the incidence, intensity, and type of adverse events, as well as 
on clinically significant changes in the patient’s physical examination, vital signs, and clinical 
laboratory results.  Safety analyses will be performed using the safety population.  Safety variables 
will be tabulated and presented by the dose of TGR-1202 study drug actually received.  Exposure 
to study treatment and reasons for discontinuation of study treatment will also be tabulated.  


 
          
28  
  
Adverse Event Characteristics   
  
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for AE reporting.   A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov).  
  
• ‘Expectedness’: AEs can be classified as ‘Unexpected’ or ‘Expected’ for expedited reporting 
purposes only.    
  
• Attribution of the AE:  
- Definite – The AE is clearly related to the study treatment.  
- Probable – The AE is likely related to the study treatment.  
- Possible – The AE may be related to the study treatment.  
- Unlikely – The AE is doubtfully related to the study treatment.  
- Unrelated – The AE is clearly NOT related to the study treatment.  
  
Expedited Adverse Event Reporting  
  
The Principal Investigator agrees to provide appropriate parties with copies of all serious adverse 
events within two working days.  Additionally, the Principal Investigator agrees to report any 
pregnancy occurring in association with use of TGR-1202 to the appropriate parties.   
  
It is important to distinguish between “serious” and “severe” adverse events, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke, but would be 
considered an SAE.  Severity and seriousness should be independently assessed when recording 
AEs and SAEs on the eCRF.  
  
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to the Sponsor in order to comply with regulatory requirements.  Serious adverse events 
may occur at any time from Cycle 1/Day 1 through the 30-day follow-up period after the last study 
treatment.  Sponsor or designee should be notified of all SAEs, regardless of causality, within 24 
hours of the first knowledge of the event by the treating physician or research personnel.    
  
To report an SAE, see the appropriate form.  
  
All SAEs (regardless of causality assessment) occurring on study or within 30 days of last study 
treatment should be immediately reported to the sponsor as SAEs within the CRF and followed 
until resolution (with autopsy report if applicable).  
  


 
          
29  
Progression or death due to disease progression should be reported by the investigator as a SAE 
only if it is assessed that the study drugs caused or contributed to the disease progression (i.e. by a 
means other than lack of effect).  Unrelated events of disease progression should be captured on 
the appropriate CRF.  
  
The investigator must review and sign off on the SAE data on the SAE report.  The SAE should 
be reported to the Sponsor (or Sponsor designee).  When an SAE is reported to the sponsor or 
designee, the same information should be entered on the CRF within 24 hours (1 business day).  
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the sponsor or designee as soon as it is available; these reports should be 
submitted using the appropriate SAE form.  
  
Investigators should report SAEs and follow-up information to their responsible Institutional 
Review Board (IRBs)/Independent Ethics Committee according to the policies of the responsible 
IRB (Research Ethics Committee).  
  
Sponsor SAE Reporting Requirements  
  
Sponsor is responsible for reporting relevant SAEs to the competent authority, other applicable 
regulatory authorities, and participating investigators, in accordance with ICH guidelines, FDA 
regulations, and/or local regulatory requirements.  
  
Sponsor is responsible for reporting unexpected fatal or life-threatening events associated with the 
use of the study drugs to the regulatory agencies and competent authorities within 7 calendar days 
after being notified of the event.  The Sponsor will report all related but unexpected SAEs including 
non-death/non-life-threatening related but unexpected SAEs (SUSAR) associated with the use of 
the study medications to the regulatory agencies and competent authorities by a written safety 
report within 15 calendar days of notification.  Following the submission to the regulatory agencies 
and competent authorities, Investigators and trial sites will be notified of the SUSAR.  Investigators 
must report SUSARs and follow-up information to their responsible Institutional Review Board 
(IRBs)/Independent Ethics Committee according to the policies of the responsible IRB (Research 
Ethics Committee).  
Report of Adverse Events to the Institutional Review Board (IRB)  
Reportable information should always be reported by the PI directly to the IRB within 5 working 
days since the PI’s first knowledge of the event or new information.     
Investigator Reporting to the FDA  
The investigator is responsible for reporting any SAEs to the FDA. SAEs that are 
unlisted/unexpected, at least possibly related to the drug, and that have not previously been 
reported in the Investigators brochure, or reference safety information document should be 
reported promptly to the Food and Drug Administration (FDA) by telephone (1-800-332-1088), 
fax (1-800-FDA-0178), or via MedWatch Online.  Fatal or life threatening SAEs that meet the 
criteria for reporting to the FDA must be reported to the FDA within 7 calendar days since first 


 
          
30  
awareness of the event.  All other SAEs that meet the criteria for reporting to the FDA must be 
reported to the FDA within 15 calendar days since first awareness of the event.  A clear description 
of the suspected reaction should be provided along with an assessment as to whether the event is 
drug or disease related.     
Adverse event updates/IND safety reports  
TG therapeutics shall notify the Investigator via an IND Safety Report of the following 
information:  
  
• 
Any AE associated with the use of the drug in this study or in other studies that is both 
serious and unexpected.  
• 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.  
  
The Investigator shall promptly notify his/her IRB/ethics committee of these new serious and 
unexpected AE(s) or significant risks to subjects.  
  
The Investigator must keep copies of all AE information, including correspondence with TG and 
the IRB/EC, on file.  
  
Expedited Reporting Guidelines   
  
Note:  All deaths on study require expedited reporting regardless of causality.  Attribution to 
treatment or other cause must be provided.  
  
Expedited AE reporting timelines defined:  
• 
“1 business day; 5 calendar days” – The investigator must initially report the AE within 1 
business day of learning of the event followed by a complete report within 5 calendar days 
of the initial 24-hour report.  
  
• 
“10 calendar days” - A complete report on the AE must be submitted within 10 calendar 
days of the investigator learning of the event.   
  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions.    
  
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported if the event occurs following treatment.  
  
Protocol-Specific Expedited Adverse Event Reporting Exclusions  
  


 
          
31  
For this protocol, certain AEs/grades are exceptions to the Expedited Reporting Guidelines and do 
not require expedited reporting.  The following AEs must be reported through the routine reporting 
mechanism:  
  
Table 2: CTCAE AE Reporting Exclusions  
  
  
CTCAE Category  
  
Adverse Event  
  
Grade  
Hospitalization /  
Prolongation of  
Hospitalization  
  
Attribution  
Blood/Bone 
Marrow  
Neutropenia <7 days 
without fever  
4  
No  
Yes  
Blood/ Bone 
Marrow  
Thrombocyotopenia <7 
days without bleeding  
4  
No  
Yes  
  
  
Pregnancy on Study  
  
During the course of the study, all female patients of childbearing potential (the definitions of  
“women of childbearing potential” are listed in Appendix 4) must contact the treating investigator 
immediately if they suspect that they may be pregnant (a missed or late menstrual period should 
be reported to the treating investigator).    
If an investigator suspects that a patient may be pregnant prior to administration of study drug(s), 
the study drug(s) must be withheld until the result of the pregnancy test is confirmed.  If a 
pregnancy is confirmed, the patient must not receive any study drug(s), and must be discontinued 
from the study.    
If an investigator suspects that a patient may be pregnant after the patient has been receiving study 
drug(s), the study drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed.  If a pregnancy is confirmed, the study drug(s) must be immediately and permanently 
stopped, the patient must be discontinued from the study, and the investigator must notify the Study 
Chair or Medical Monitor as soon as possible.    
If a patient becomes pregnant while enrolled in the study, an SAE form should be completed and 
submitted to the Sponsor.  Abortions (spontaneous, accidental, or therapeutic) must also be 
reported to the Sponsor.  
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  
  
Study Drug Overdose  
  
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment (TGR-1202) that is symptomatic, even if not 
fulfilling a seriousness criterion, is to be reported to the Sponsor immediately (within 24 hours) 
using the corresponding SAE form, and following the same process described for SAEs.  If a study 
drug overdose occurs, patients should stop study drug dosing and be clinically monitored as 
appropriate, managing symptoms/side effects that may occur.  


 
          
32  
  
Secondary Malignancy  
  
Any secondary malignancy event must be reported via the SAE form (in addition to the routine 
AE reporting mechanisms).  Any malignancy possibly related to cancer treatment should also be 
reported via the routine reporting mechanisms outlined in the protocol.  
  
Routine Adverse Event Reporting  
  
All Adverse Events must be reported in routine study data submissions. New onset adverse events 
occurring up to 30 days after study completion or patient withdrawal will be captured.  All new 
AEs occurring during this period must be reported and followed until resolution unless, in the 
opinion of the investigator, these values are not likely to improve because of the underlying 
disease.  In this case, the investigators must record his or her reasoning for this decision in the 
patient’s medical record and as a comment on the CRF.  Follow up of these events will be 
performed according to the same procedures as described above for AEs observed during the study 
period.  
  
After 30 days, only AEs, SAEs, or deaths assessed by the investigator as treatment related are to 
be reported.  
  
 8.  
PHARMACEUTICAL INFORMATION  
  
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.2.  
  
TGR-1202  
  
Classification:    
Phosphatidylinositol-3-Kinase (PI3K) Delta Inhibitor   
Formulation:   
See Investigator Brochure  
  
Mode of Action:  
Irreversibly inhibits activity of the Class I Delta isoform of PI3K    
How Supplied:  
TGR-1202: 200 mg tablets  
Storage:  
Store at 25°C.  Excursions permitted 15°C to 30°C.  
Stability:  
Route of   
Retest dates will be provided periodically by Sponsor.  
Administration:  
Oral  
Packaging:  
TGR-1202 is provided in HDPE bottles each containing 30 tablets and a 
silica gel canister as a desiccant.   
Availability:    
TGR-1202 is available from TG Therapeutics.  
  
  
  


 
          
33  
 9.  
PHARMACOKYNETIC/PHARMACODYNAMIC STUDIES  
  
Pharmacokinetic (PK) Studies  
  
Up to 5 ml of blood will be collected in Lithium Heparin tubes for isolation of plasma at 
PreTreatment on C1D1, and 4h post-treatment on C1D1, C1D15, C2D15 and C4D15 (Figure 2).   
  
Figure 2. PK schedule  
  
Pharmacokinetic studies  
  
 
Cycle 1, days 1 and 15; cycle 2 , day 15; cycle 4, day 15  
  
 
Pre-dose*  
0h   
4h  
 
  
* Only on cycle 1, day 1 only  
  
Blood samples will be stored on ice until centrifuged.  After centrifuge, plasma will be stored in 
polypropylene screw top tube at -70ºC until evaluation by liquid chromatography.   
  
  
Pharmacodynamics Studies  
  
Collection of specimens  
  
Participation in correlative studies is mandatory for all patients. In addition to the mandatory 
correlative studies for all patients, there will also be optional correlative studies, which will be 
performed under a separate section of the informed consent form.   
  
Missing 4 doses or more 1 week prior to the planned biopsy on Cycle 2 Day 15 could render that 
patient ineligible for biopsy, but that decision will be made at the discretion of the treating 
physisican and Study PI.  
  
Mandatory correlative studies include the following:  
For PK studies:  
1. Collection of blood at Pre-treatment (approx. 3 ml).  
PK sample  
pre - TGR - 1202  
PK sample  
post - TGR - 
1202  
Start of  
TGR - 1202  


 
          
34  
2. Collection of blood at 4h post-treatment on C1D1, C1D15, C2D15, and C4D15 (total approx. 
12 ml).  
  
For PD studies:   
1. Collection of blood at Pre-Treatment.   
Collection of blood at 4h post-treatment on C1D1, C1D15, C2D15 and C4D15.   The 
studies will include T cell panel such as T-reg, expression of CD47 and PD-L1, 
cytokines such as IL-10 and IL-12, and PI3K targeting.   
2. Collection of tumor tissues, blood cells, and buccal fibroblasts pre-treatment and 4-8h 
posttreatment on C2D15.   
The studies will include whole exome sequencing, and the levels/activity of c-Myc, 4E-BP1, 
CK1, and PI3K.  
  
Missing 4 doses or more 1 week prior to the planned biopsy on C2D15 could render that patient 
ineligible for biopsy, but that decision will be made at the discretion of the treating physician and 
Study PI.  
  
Optional correlative studies are listed below:  
Collection of tumor tissues and buccal fibroblasts 4-8h post-treatment on C4D15, at Progression 
of Disease, and at End of Treatment.   
The studies will include whole exome sequencing, and the levels/activity of c-Myc, 4E-BP1, CK1, 
and PI3K.  
  
Figure 3. PD schedule  
 


 
          
35  
  
  
The patient will have the option of checking off boxes within the main consent form for this study 
to indicate consent or denial for the optional studies as explained above.    
  
Fine Needle Aspirations (FNA): A series of FNAs will be performed on palpable tumors in 
consenting patients as a function of drug exposure.  
  
Tumor Tissue Biopsies: The biopsies will be performed by a surgeon or an interventional 
radiologist, as appropriate. If multiple lymph nodes are available, the safest lymph node will be 
selected. A cytopathologist will evaluate the biopsy for tumor cells microscopically at the time of 
the biopsy. Correlative studies will be performed on de-identified tissue samples. Tissue will be 
labeled only with the protocol-specific unique identifier.  
  
Bone Marrow Biopsy: a bone marrow aspirate and biopsy will be performed pre-treatment if 
necessary to determine the stage of the disease.  
  
Handling of Specimens  
Specimens required for clinical diagnosis will be submitted to Pathology per standard patient care 
practice.   


 
          
36  
  
Research specimens will be handled as explained below:   
  
• 
Blood will be processed to isolate the serum and mononuclear cells.  The specimens may then 
be used immediately for correlative studies such as flow cytometry or stored for future studies 
in bulk with all patient samples. Stored samples will be either frozen at -80 degrees or 
refrigerated at 4 degrees Celsius.    
  
• 
Bone marrow and other tissue aspirate samples will be processed to isolate the mononuclear 
cells enriched for viable lymphoma cells.  The specimens may then be used for correlative 
studies such as flow cytometry immediately or stored for future studies in bulk with all patient 
samples.   
  
• 
Samples from core biopsy (e.g. bone marrow, skin, lymph nodes or other lymphoid tissue) may 
be snap frozen in a dry ice/alcohol bath or liquid nitrogen, or processed for the isolation of 
viable lymphoma cells.   
  
• 
Fibroblasts will be isolated from buccal swabs, and frozen or refrigerated as above.    
  
• 
Cellular samples will be used immediately or snap frozen, depending on the type of correlative 
studies.  For example, ex vivo pharmacological studies require fresh isolated lymphoma. 
mRNA and DNA may be extracted from frozen or fixed cellular or tissue specimens.     
  
  
Biomarker studies  
  
A major goal of this study is to determine the genetic, and biochemical heterogeneity in the 
follicular lymphoma cells, and discover the effects of distinct cellular and molecular alterations 
on patient response to TGR-1202. To this end, we will perform the following studies using 
patient samples:   
  
• 
Conduct DNA and RNA sequencing and gene expression studies on samples before and after 
treatment with TGR-1202.   
  
• 
Compare and contrast the effects of TGR-1202 on mRNA translation in normal fibroblasts and 
lymphocytes versus lymphoma cells from the same patient, using the state of the art technology 
of ribosome profiling.  
  
• 
Compare and contrast the effects of TGR-1202 on the mTOR signaling in normal fibroblasts 
and lymphocytes versus lymphoma cells from the same patient, using Western blot and IHC 
staining.   
  
• 
Develop an in vitro system to test responsiveness to TGR-1202 in primary lymphoma cells 
isolated fresh from patients.  
  


 
          
37  
• 
Test synergy of TGR-1202 with drugs targeting pathways that interact with PI3K, using 
lymphoma cell lines and primary FL cells from patients on study  
  
• 
Determine the effects of TGR-1202 on cytokine production in the blood of patients treated on 
study   
  
• 
Develop an in vivo model of FL by directly implanting FL cells from patient biopsies into mice 
patient derived xenograft (PDX) model.  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 10.  
STUDY CALENDAR  
  
Baseline evaluations are to be conducted as indicated in the table below, prior to start of protocol 
therapy.  In the event that the patient’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of the next cycle of therapy.  
  
(All study assessments allow a +/- 3 day window)  
  
Cycle  
  
  
1       
2+  
  
  
  
  
Screening  
D1  
D8  
D15  D22n  
D1  
D15  
End of 
treatmentk  
End of Study  
(4 weeks after 
last dose)  
Follow -
upm  
Eligibility, 
safety 
monitoring, 
efficacy  
  
  
  
  
  
  
  
  
  
  
Informed 
Consent  
Xa  
  
  
  
  
  
  
  
  
  
Demographics  
Xa  
  
  
  
  
  
  
  
  
  
Medical History  
Xa  
  
  
  
  
  
  
  
  
  


 
          
38  
EKG  
Xa  
  
  
  
  
  
  
  
  
  
Concurrent 
Medications  
Xb   
Xe  
X  
X  
X  
X  
  
X  
X  
  
Physical exam  
Xb   
Xe  
X  
X  
X  
X  
  
X  
X  
X  
Vital Signs, 
weight  
Xb  
X  
X  
X  
X  
X  
  
X  
X  
X  
Performance  
Status   
Xb  
X  
X  
X  
X  
X  
  
X  
X  
X  
CBC w/  
differential  
Xb  
Xe  
X  
X  
X  
X  
  
X  
X  
X  
Chemistriesc,g  
Xb  
Xe  
X  
X  
X  
X  
  
X  
X  
X  
Coagulation  
tests  
Xb  
  
  
  
  
  
  
  
  
  
Creatinine 
clearance  
Xb  
  
  
  
  
  
  
  
  
  
Serum -hCGd  
Xb  
X  
  
  
  
  
  
  
  
  
CT (or PET/CT)  
Xa  
  
  
  
  
Xf  
  
  
  
Xf  
Bone Marrow 
Biopsy  
Xa  
  
  
  
  
Xo  
  
Xp  
  
  
Drug  
Administration  
  
  
  
  
  
  
  
  
  
  
TGR-1202 800 mg 
  
X  
  
  
  
  
  
  
  
  
Toxicity  
Assessment  
  
X  
X  
X  
X  
X  
  
X  
X  
  
Correlative 
Studies  
 
  
  
 
  
 
 
  
  
 
Blood for PK  
 
Xi  
  
Xi    
 
Xi  
  
  
 
Blood for PD  
 
Xh  
  
Xh  
  
 
Xh  
  
  
 
Buccal swab  
Xl  
  
  
  
  
 
Xl,p  
Xp  
  
 
Lymph  
Node/Bone  
Marrow Biopsy  
Xa  
  
  
  
  
 
Xl,p  
Xp  
  
 
a. 
To be done within 4 weeks of treatment start date.  
b. To be done within 1 week of treatment start date. Nurse practitioner can perform exams after cycle 1.  
c. 
Chemistries include: Chem *, Mg, K, Hepatic Function Panel, and LDH.    
d. To be done within 1 week of treatment start date for patients of childbearing age.  
e. 
Not necessary if conducted within 72 hours of screening assessment.  
f. 
CT scan of the neck, chest, abdomen, and pelvis (and/or PET/CT) at the end of Cycle 2 and 6. Thereafter, 
restaging CT scans will be repeated every 4 months, or every 6 months if a complete response is achieved. To 
be performed on every cycle.  
g. Sodium, potassium, chloride, calcium, and glucose are part of the electrolyte assessment at every time point.  
h. Pre-treatment on C1D1, and 4 hours post-treatment on C1D1, C1D15, C2D15 and C4D15   
i. 
Pre-treatment on C1D1, and 4 hours post-treatment on C1D1, C1D15, C2D15 andC4D15  
j. 
To be done within 4 weeks of treatment stop date.  
k. To be performed pre-treatment and 4-8 hours post-treatment on C2D15 (mandatory), and C4D15, end of 
treatment and progression of disease, if applicable (optional).  
l. 
May be done +/- 7 days.  
m. May be done +/- 3 days.  
n. To be performed after cycle 2 to confirm response if positive at baseline.  


 
          
39  
o. If positive at baseline and hasn’t been performed to confirm CR  
p. Optional collection of buccal fibroblasts, bone marrow, and Lymph Node Biopsy will be allowed post-treatment 
on C4D15, at Progression of Disease, and at End of Treatment.  
  
(All study assessments allow a +/- 3 day window)  
  
  
 11.  
MEASUREMENT OF EFFECT  
  
The primary objective of this study is to evaluate the ORR of the study drug. Patients with 
measurable disease will be assessed by standard criteria.  Patients will be re-evaluated at the end 
of cycle 2 and cycle 6, thereafter every 4 months, or every 6 months if a CR is achieved. Response 
will be evaluated with physical exam, computerized tomography (CT) and tissue biopsies as 
defined in the 2014 Lugano classification.(Cheson et al., 2014b)  PET/CT is optional, but strongly 
encouraged.    
  
Evaluation of response:  
  
Definitions  
  
Evaluable for toxicity: All patients will be evaluable for toxicity starting from Day 1 of Cycle 1.  
  
Evaluable for objective response: Patients who have received at least 1 cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response.  These patients will have 
their response classified according to the definitions stated below (Table 3).  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered.  
  
Disease Parameters   
  
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
two dimensions (longest diameter to be recorded) as >20 mm with conventional techniques 
(PET/CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements will be 
recorded in millimeters (or decimal fractions of centimeters).  Tumor volume will be recorded as 
the sum of the product of the diameters (SPD) of the largest predominant target lesions (for sites 
of measurable disease, see Appendix 7).  
  
FDG avidity is based on comparison with background tissues.  There is no specific SUV cut-off 
value that is considered indicative of response.  
  
Non-measurable disease (evaluable disease).  All other lesions (or sites of disease), including small 
lesions (<10 mm using spiral CT scan), are considered non-measurable disease.  Bone lesions, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all nonmeasurable.  
  


 
          
40  
Target lesions.  All measurable lesions, up to a maximum of 6, that are representative of all 
involved organs, should be identified as target lesions and measured and recorded at baseline.  If 
PET/CT is performed, target lesions should be selected on the basis of their FDG avidity (High 
SUV lesions will be prioritized, even if not the largest lesions), size (lesions with the largest SPD 
diameter) and their suitability for accurate repeated measurements (either by imaging techniques 
or clinically).  An SPD for all target lesions will be calculated and reported as the baseline sum 
SPD.  The baseline sum SPD will be used as reference by which to characterize the objective tumor 
response based on CT criteria.  
  
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be recorded 
at baseline.  Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up.   
  
Methods for Evaluation of Measurable Disease in NHL  
  
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.  
  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. As a general rule imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been used 
to assess the antitumor effect of a treatment.  
  
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by color 
medical photography that includes a ruler to measure the size of the lesion, is recommended.   
  
CT, PET/CT and MRI. These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Imaging of head and neck 
tumors and those of the extremities will be performed according to institutional specific protocols.  
  
Ultrasound (US) Will not be used for disease assessment  
Response Criteria  
  
Response assessment in NHL   
  
Responses will be evaluated using clinical parameters, CT scan (PET scan is optional) and bone 
marrow biopsy according to the 2014 Lugano Classification (Cheson et al., 2014a) as outlined in 
Table 3.   
  
Table 3. Revised Criteria for Response Assessment (Cheson et al., JCO 2014)  
Complete   
Complete metabolic response   
Complete radiologic response (all of the 
following):  


 
          
41  
Lymph 
nodes 
and 
extralymphatic sites  
Score 1, 2, or 3* with or without a residual mass on  
5PS†  
It is recognized that in Waldeyer’s ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (eg, with chemotherapy or 
myeloid colony-stimulating factors), uptake may be  
Target nodes/nodal masses must regress to 
≤ 1.5 cm in LDi. No extralymphatic sites of 
disease  
 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the tissue 
has high physiologic uptake  
 
Nonmeasured lesion   
Not applicable   
Absent  
Organ enlargement  
Not applicable  
Regress to normal  
New lesions  
None  
None  
Bone marrow  
No evidence of FDG-avid disease in marrow  
Normal by morphology; if indeterminate, 
IHC negative  
Partial  
Partial metabolic response  
Partial remission (all of the following):  
Lymph 
nodes 
and 
extralymphatic sites  
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size  
 ≥50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites  
Non-measured lesion   
At interim, these findings suggest responding disease  
When a lesion is too small to measure on 
CT, assign 5 mm x 5 mm as the default 
value  
Organ enlargement  
At end of treatment, these findings indicate residual 
disease  
When no longer visible, 0 x 0 mm. For a 
node >5 mm x 5 mm, but smaller than 
normal, use actual measurement for 
calculation  
New lesions  
None  
None  
Bone marrow  
Residual uptake higher than uptake in normal marrow 
but reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response,  
consideration should be given to further evaluation with  
MRI or biopsy or an interval scan  
Not applicable  
No response or stable 
disease  
No metabolic response  
Stable disease:  
Target nodes/nodal 
masses, extranodal 
lesions  
Score 4 or 5 with no significant change in FDG uptake 
from baseline at interim or end of treatment  
- 
≤50% decrease from baseline in 
SPD of up to 6 dominant, measurable nodes 
and extranodal sites;  
- 
no criteria for progressive disease 
are met  
Non-measured lesion   
Not applicable  
No increase consistent with progression  
Organ enlargement  
Not applicable  
No increase consistent with progression  
New lesions  
None  
None   
Bone marrow  
No change from baseline  
Not applicable  
Progressive disease  
Progressive metabolic disease  
Progressive disease requires at least 1 of 
the following:  
Individual target 
nodes/nodal 
Masses  
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or  
PPD progression  


 
          
42  
Extranodal lesions  
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment  
An individual node/lesion must 
be abnormal with: - LDi >1.5 cm 
and  
- 
Increase by ≥50% from PPD nadir 
and  
- 
An increase in LDi or SDi from 
nadir  
- 
0.5 cm for lesions ≤2 cm - 1.0 cm 
for lesions >2 cm  
In the setting of splenomegaly, the splenic 
length must increase by >50% of the extent 
of its prior increase beyond baseline (eg, a  
15-cm spleen must increase to  
>16 cm). If no prior splenomegaly, must 
increase by at least 2 cm from baseline. New 
or recurrent splenomegaly  
Non-measured lesion  
None   
New or clear progression of preexisting non 
measured lesions  
New lesions  
New FDG-avid foci consistent with lymphoma rather 
than another etiology (eg, infection, inflammation). If  
- Regrowth of previously resolved lesions  
- A new node >1.5 cm in any axis  
 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered  
- 
A new extranodal site >1.0 cm in 
any axis; if >1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to  
lymphoma  
- 
Assessable disease of any size 
unequivocally attributable to lymphoma  
Bone marrow  
New or recurrent FDG-avid foci  
New or recurrent involvement  
  
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, 
longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product 
of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular 
diameters for multiple lesions.  
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. 
However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid under treatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and 
extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the 
body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs 
(eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any 
disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites 
include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements 
for measurability but are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that 
would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal 
sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid 
growth factors).  
†PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > 
liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.  
  
Overall Response Rate  
  
Overall Response Rate (ORR) will be defined as the sum of CR rate and PR rate based on 
evaluation of best response in each patient.  
  
Evaluation of Best Response  
  


 
          
43  
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria. The best overall response will be used as the reference 
to define progression of disease, should this occur.    
  
  
  
 12.   
DATA REPORTING / REGULATORY REQUIREMENTS  
  
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).  
  
Data Reporting  
  
Monitoring  
  
The Institutional Review Board (IRB) at Columbia University Medical Center will monitor this 
study.  
  
Responsibility for Data Submission  
  
The Study Coordinator is responsible for compiling data for all participants and for providing the 
data to the Principal Investigator for review.    
  
Data Safety Monitoring Board   
  
The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center’s Data 
Safety Monitoring Board (DSMB) will oversee conduct of the study, patient safety and all interim 
analyses as specified in the data analysis plan.  Detailed guidelines regarding the structure, function 
and decision-making mechanisms for the Data Safety Monitoring Board are provided in the DSMB 
charter.  
Investigator Reporting Responsibilities  
The conduct of the study will comply with all FDA safety reporting requirements.    
  
Study auditing  
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and 
in the US Code of Federal Regulations.  
  
Investigators must enter study data onto CRFs or other data collection system.  The Investigator 
will permit study-related audits by TG Therapeutics or its representatives, IRB/EC review, and 
regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where 
the study took place, to source documents, to CRFs, and to all other study documents.  
  


 
          
44  
Protocol amendments  
  
Any amendment to this protocol must be agreed to by the Principal Investigator.Amendments 
should only be submitted to IRB/EC after consideration of TG Therapeutics review.  Written 
verification of IRB/EC approval will be obtained before any amendment is implemented.    
  
Protocol deviations  
  
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation 
will be made only for that specific subject.  A decision will be made as soon as possible to 
determine whether or not the subject (for whom the deviation from protocol was effected) is to 
continue in the study.  The subject’s medical records will thoroughly and completely describe the 
deviation from the protocol and state the reasons for such deviation.  In addition, the Investigator 
will notify the IRB/EC in writing of such deviation from protocol and when possible deviation will 
not be implemented until IRB approval is obtained..  
  
Non-emergency minor deviations from the protocol will be permitted after approval of the 
Principal Investigator.   
  
  
  
 13.   
STATISTICAL CONSIDERATIONS  
  
Study Design/ Primary Endpoints  
  
This is a phase 2 study of oral TGR-1202 in patients with relapsed or refractory follicular 
lymphoma.  (See figure 1 for study plan flow chart)  
  
Sample Size/Accrual Rate  
  
The phase II will allow for a total accrual of 20 patients.   
  
We estimate accrual of an average of 1-3 patients per month, with a goal of completing accrual 
within 12 months.  
  
Based on the phase I study of TGR-1202, the ORR for TGR-1202 will be 60%. The ORR is 33% 
based on historical control drugs,  such as lenalidomide. We estimate that 20 patients will be 
needed to have a power of 87% to reject the null hypothesis that ORR=0.33 in favour of alternative 
hypothesis ORR=0.6 with one side type I error rate of 0.10.   
  
Analysis of Primary and Secondary Endpoints   
  
Disease and patient characteristics at baseline will be summarized using descriptive statistics. For 
qualitative variables, frequency distributions and proportions will be provided; for quantitative 
variables, summary statistics (e.g., mean, median, quartiles, standard deviations, etc) and graphical 


 
          
45  
displays (e.g., box plots) will be used.  Overall response rates will be measured upon completion 
of the study with exact 95% confidence intervals.   
 
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APPENDICES:  
  
  
Appendix 1. Ann Arbor Classification  
  
Stage  Description  
I  
Involvement of a single lymph node region or lymphoid structure (eg, spleen, thymus,  
Waldeyer’s ring)  
II  
Involvement of two or more lymph node regions on the same side of the diaphragm  
III  
Involvement of lymph regions or structures on both sides of the diaphragm  
IV  
Involvement of extranodal site(s) beyond that designated E  
NOTES:   
1. For each stage, A= no symptoms; B= Fever (>38C), drenching sweats, 10% body weight loss over 6 months 2. 
For Stages I to III: E = Involvement of a single, extranodal site contiguous or proximal to known noda site 
Adapted from: Armitage JO. CA Cancer J Clin.2005;55:368-376.  
  
  
  
Appendix 2. Revised Staging System for Primary Nodal Lymphoma  
  
Stage  
Involvement   
Extranodal (E) Status  
 
Limited  
 
I  
One node or a group of adjacent nodes  
Single extranodal lesions without 
nodal involvement  
II  
Two or more nodal groups on the same 
side of the diaphragm  
Stage I or II by nodal extent with 
limited contiguous extranodal 
involvement  
II bulky*  II as above with “bulky” disease  
Not applicable  
 
Advanced  
 
III  
Nodes on both sides of the diaphragm; 
nodes above the diaphragm with spleen 
involvement  
Not applicable  
  
IV  
Additional noncontiguous 
extralymphatic involvement  
Not applicable  
  
* A variety of sizes have been suggested for the definition of bulky disease in NHL. However, none of the proposed 
sizes have been validated in the current therapeutic era. Therefore, it is recommended to record the longest 
measurement by CT scan. Whether stage II bulky disease is treated as limited or advanced disease may be 
determined by histology and a number of prognostic factors.  
  
NOTE. Extent of disease is determined by positron emission tomography–computed tomography for avid 
lymphomas and computed tomography for nonavid histologies. Tonsils, Waldeyer’s ring, and spleen are considered 
nodal tissue.  
Adapted from: Cheson BD, Fisher RI, Barrington SF, et al. J Clin Oncol. 2014;32:3059-3067  
  


 
          
51  
  
  
  
  
Appendix 3. Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status  
  
Grade  Description  
0  
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction  
1  
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work)  
2  
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours.  
3  
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.  
4  
Bedridden 100% of the time. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair  
5  
Dead  
Ref: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6): 649-55  
  
  
  
Appendix 4. Contraceptive Guidelines and Pregnancy  
  
Women Not of Childbearing Potential are Defined as Follows:  
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical 
bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential.  
  
Contraceptive Guidelines for Women of Child-Bearing Potential:  
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 30 days after stopping 
treatment. The highly effective contraception is defined as either:  
• 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.  
• 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 


 
          
52  
reproductive status of the woman has been confirmed by follow up hormone level 
assessment.  
• 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.  
• Oral contraception, injected or implanted hormonal methods.  
• Use of a combination of any two of the following (a+b):  
o Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
o Barrier methods of contraception: Condom or Occlusive cap (diaphragm or   
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.  
The following are unacceptable forms of contraception for women of childbearing potential:   
1. Female condom   
2. Natural family planning (rhythm method) or breastfeeding   
3. Fertility awareness   
4. Withdrawal   
5. Cervical shield  
  
Women of child-bearing potential must have a negative serum pregnancy test within 5 days of 
initiating treatment.  
  
Fertile Males:  
Fertile males, defined as all males physiologically capable of conceiving offspring must use 
condom during treatment, for five half-lives (8 days) after stopping treatment and for additional 
12 weeks (3 months in total after study drug discontinuation) and should not father a child in this 
period.    
  
Pregnancies  
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to TG 
Therapeutics Inc. within 24 hours of learning of its occurrence. The pregnancy should be 
followed up for 3 months after the termination of the pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy 
should be recorded on a Clinical Study Pregnancy Form and reported by the investigator to TG 
Therapeutics Inc.  Pregnancy follow-up should be recorded on the same form and should include 
an assessment of the possible relationship to the study drug and reported by the investigator to 
TG Therapeutics Inc.  Any SAE experienced during pregnancy must be reported on the SAE 
Report Form.  
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother  
  
 
  


 
          
53  
Appendix 5. Interpretation of Hepatitis B serologic test results  
  
  
  
  
  
  
  
  
  
  


 
          
54  
  
Appendix 6. New York Heart Association Functional Classification  
  
Class  Functional capacity: how a patient with cardiac disease feels during physical 
activity  
I  
 Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitations, dyspnea, or anginal pain  
II  
 Patients with cardiac disease resulting in slight limitation physical activity. They’re 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.  
III  
 Patient with cardiac disease resulting in marked limitation of physical activity. They’re 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain  
IV  
 Patients with cardiac disease resulting and inability to carry on any physical activity 
without discomfort. Intense of heart failure or the angina syndrome maybe present even 
at rest. If any physical activity undertaken, discomfort increases.  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
          
55  
Appendix 7. Measurable Lymph Node Locations  
  
  
 
Appendix 8. Groupe d'Etude des Lymphomas Folliculaires (GELF) Criteria  
   
Presence of one or more of the following:  
Involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3 cm  
Any nodal or extranodal tumor mass with a diameter of ≥ 7 cm  
B symptoms*  
Splenomegaly (enlarged spleen)  
Pleural effusions or peritoneal ascites  
Cytopenias (leukocytes < 1.0 x 109/L and/or platelets < 100 x 109/L)  
Leukemia (> 5.0 x 109/L circulating malignant cells)  
* include unexplained and persistent: Fever and chills, drenching night sweats, fatigue, pruritus/skin 
itchiness, weight loss   
  
NOTE: These criteria provide general guidance. The need for treatment can vary in individual patients 
Adapted from: Brice P, Bastion Y, Lepage E, et al. J Clin Oncol 1997;15(3):1110-7  
  
  
  
 
 
 
 
 
 
 
Ref: Solal - Celigny P, et  
al.  Blood.  
2004;104:1258 - 1265  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
          
56  
  
  
Appendix 9. Follicular Lymphoma International Prognostic Index (FLIPI)  
  
Factor  
Criterion  
Age  
≥ 60 years  
Ann Arbor stage  
III-IV  
Hemoglobin level  
<12 g/dL  
Serum LDH level  
>upper limit of normal  
Number of nodal sites  
≥5  
  
Number of factors  
Risk   
0-1  
Low   
2  
Intermediate   
≥3  
High  
Adapted from: Solal-Celigny P, et al. Blood. 2004;104:1258-1265   
  
  
Appendix 10: SAE  
The FDA website classify the following as SAE:  
An adverse event is any undesirable experience associated with the use of a medical product in a 
patient. The event is serious and should be reported to FDA when the patient outcome is:  
 
Death  
Report if you suspect that the death was an outcome of the adverse event, and include the 
date if known.   
Life-threatening  
Report if suspected that the patient was at substantial risk of dying at the time of the 
adverse event, or use or continued use of the device or other medical product might have 
resulted in the death of the patient.  
Hospitalization (initial or prolonged)  
Report if admission to the hospital or prolongation of hospitalization was a result of the 
adverse event.  
Emergency room visits that do not result in admission to the hospital should be evaluated 
for one of the other serious outcomes (e.g., life-threatening; required intervention to 
prevent permanent impairment or damage; other serious medically important event).  
Disability or Permanent Damage  


 
          
57  
Report if the adverse event resulted in a substantial disruption of a person's ability to 
conduct normal life functions, i.e., the adverse event resulted in a significant, persistent or  
permanent change, impairment, damage or disruption in the patient's body 
function/structure, physical activities and/or quality of life.  
Congenital Anomaly/Birth Defect  
Report if you suspect that exposure to a medical product prior to conception or during 
pregnancy may have resulted in an adverse outcome in the child.  
Required Intervention to Prevent Permanent Impairment or Damage (Devices)  
Report if you believe that medical or surgical intervention was necessary to preclude 
permanent impairment of a body function, or prevent permanent damage to a body 
structure, either situation suspected to be due to the use of a medical product.  
Other Serious (Important Medical Events)  
Report when the event does not fit the other outcomes, but the event may jeopardize the 
patient and may require medical or surgical intervention (treatment) to prevent one of the 
other outcomes. Examples include allergic brochospasm (a serious problem with breathing) 
requiring treatment in an emergency room, serious blood dyscrasias (blood disorders) or 
seizures/convulsions that do not result in hospitalization. The development of drug 
dependence or drug abuse would also be examples of important medical events.