Clinical trial NCT02268851
Conditions: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Mantle Cell Lymphoma
Keywords: Mantle Cell Lymphoma Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Sponsor: Dana-Farber Cancer Institute
Start date: 2014-11-01; Completion date: 2022-10-01
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This research study will be evaluating the safety and efficacy of a study drug called TGR-1202 in combination with a known drug ibrutinib, also known as Imbruvica, as a possible treatment for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Mantle Cell Lymphoma (MCL) that has come back or that has not responded to standard treatment.

Detailed description:
This research study is a Phase I and Ib combination clinical trial, which aims to both evaluate the safety of an investigational drug combination and also tries to define the appropriate dose of the investigational drug to evaluate in later clinical trials. "Investigational" means that the intervention is being studied. It also means that the FDA (U.S. Food and Drug Administration) has not approved TGR-1202 in the United States for use in MCL/CLL/SLL cancers.

TGR-1202 is a newly developed drug that may stop cancer cells from growing based on recent laboratory experiments. The results from these experiments suggest this drug may help to kill cancer cells when coupled with ibrutinib. In this research study, the safety and tolerability of TGR-1202 is being investigated to determine the highest dose that can safely be used in combination with ibrutinib. The study is also aimed to evaluate whether TGR-1202 has any effect on tumor growth (nodal response), and to determine the overall repsonse rate and duration of response in patients with CLL/SLL or MCL

Arms: arm 1: Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation.

* Each Cycle = 28 days
* TGR-1202 (oral): Starting on Day 1 administered daily.
* Ibrutinib (oral): Starting on Day 1 administered daily. arm 2: Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation.

* Each Cycle = 28 days
* TGR-1202 (oral): Starting on Day 1 administered daily.
* Ibrutinib (oral): Starting on Day 1 administered daily.
Interventions: intervention 1: TGR-1202 intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Capsules taken whole daily with water and with food intervention 2: Capsules taken whole with water- Do not consume fish oil, vitamin E, grapefruit, or Seville oranges

Protocol documents:
Prot_SAP_000.pdf: 
Phase I/Ib Study of TGR-1202 plus Ibrutinib in Patients with Select B-Cell Malignancies 
Version Date: 10.23.2019 
 
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Local Protocol #: 14-396  
NCT: NCT02268851 
 
TG Therapeutics, Inc. Protocol #: TGR-IB-105 
 
Title:  A Multi-center Phase I/Ib Study Evaluating the Efficacy and Safety of the Novel PI3k 
Delta Inhibitor TGR-1202 in Combination with Ibrutinib in Patients with Select B-Cell 
Malignancies. 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute  
 
 
 
 
 
 
 
 
 
450 Brookline Ave 
 
 
 
 
 
 
 
 
 
Boston, MA 02215 
 
*Principal Investigator (PI): 
Matthew Davids, MD 
 
Dana-Farber Cancer Institute 
 
Matthew_Davids@dfci.harvard.edu  
 
Statistician: 
 
Research Project Manager:  
 
Haesook Kim, PhD 
Alexandra Savell  
 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
 
450 Brookline Ave  
450 Brookline Ave, LG-GC    
 
Boston, MA 02215                                               Boston, MA 02215 
 
htkimc@jimmy.harvard.edu  
AlexandraE_Savell@dfci.harvard.edu 
 
 
Agents:  TGR-1202 ( umbralisib) TG Therapeutics, Inc. 
               Ibrutinib, Commercial  
 
IND #:  123439 
IND Sponsor:  Matthew Davids, MD  
 
Version #8.0 / Version Date 10.23.2019 


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SCHEMA 
 
 


Phase I/Ib Study of TGR-1202 plus Ibrutinib in Patients with Select B-Cell Malignancies 
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SYNOPSIS 
Study 
Rationale 
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.  The delta 
isoform of PI3K is highly expressed in malignant lymphocytes, where it serves 
as a key node in the B cell receptor (BCR) signaling pathway, thereby making 
this an attractive target for selective inhibition of malignant B cells. TGR-1202 
is currently in a Phase I dose escalation trial, evaluating sequentially higher 
single agent doses until a maximum tolerated dose (MTD) is determined.  
Ibrutinib is an inhibitor of Bruton’s Tyrosine Kinase (BTK), another key enzyme 
found at a different point in the BCR pathway, which has been found to be 
critical for B-cell proliferation and survival (Byrd et al., 2013).  Ibrutinib is 
approved for the treatment of patients with relapsed or refractory Mantle Cell 
Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL).  Although 
ibrutinib monotherapy is a promising therapy for relapsed CLL and MCL, not all 
patients respond to ibrutinib therapy, and among patients who initially do 
respond, complete responses have been rare, and resistance mechanisms have 
already been described, such as the C481S binding site mutations recently 
reported in CLL.  Dual inhibition of both PI3K-delta and BTK holds the promise 
of both more complete BCR pathway inhibition and also the reduced likelihood 
of developing treatment resistance. The purpose of this study is to explore the 
safety and efficacy of the PI3K-delta inhibitor TGR-1202 in combination with 
the BTK inhibitor ibrutinib, two novel, oral, once daily, targeted agents in 
patients with select B-cell lymphoid malignancies. 
Products 
TGR-1202 is a highly specific and orally available PI3K delta (δ) inhibitor 
available for this study in 200 mg tablets, supplied by TG Therapeutics, Inc. 
Ibrutinib is an orally available inhibitor of Bruton’s Tyrosine Kinase (BTK) 
commercially available in 140 mg capsules from Pharmacyclics, Inc. / Janssen 
Pharmaceuticals. 
Study 
Objectives 
Primary Objectives 
• To determine the maximum tolerated dose (MTD) of TGR-1202 when used 
in combination with ibrutinib in patients with relapsed or refractory CLL or 
MCL. 
• To evaluate the safety and determine any dose limiting toxicities (DLTs) of 
TGR-1202 in combination with ibrutinib in patients with relapsed or 
refractory CLL or MCL. 
 
Secondary Objectives 
• To preliminarily characterize the efficacy of TGR-1202 at its MTD in 
combination with ibrutinib by determining the overall response rate (ORR) 
defined as the sum of  the complete response (CR) and  partial response (PR) 
rate, as well as to determine the rate of nodal response with lymphocytosis 
(nPR), progression-free survival (PFS), and duration of response (DOR). 
 


Phase I/Ib Study of TGR-1202 plus Ibrutinib in Patients with Select B-Cell Malignancies 
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Exploratory Objectives 
• To assess whether apoptotic priming as determined by BH3 profiling and 
pharmacodynamic response as determined by phospho-flow are 
predictive of clinical response. 
 
Efficacy 
Endpoints 
 
Efficacy Endpoints: 
Overall response rate, defined as sum of CR and PR rates. Responses will be 
determined according to response criteria as follows: 
• MCL:  International Working Group (Cheson et. al 2007;  Revised Response 
Criteria for Malignant Lymphoma, [Appendix A]); 
• CLL: International Workshop for Chronic Lymphocytic Leukemia (IW-
CLL) Response Criteria (Hallek et al. 2008 [Appendix B]) as modified by 
Cheson et al., 2012. 
Safety 
Endpoints 
AEs will be evaluated during the treatment period and for 30 days following 
discontinuation from the study using CTCAE v4.0. The DLT observation period 
will be the first cycle (28 days). 
Study 
Design 
Up to 30 subjects per disease group (MCL and CLL/SLL), including a potential 
12 qualified patients who will have completed the Phase Ib dose confirmation 
part of the study, may be enrolled.   "Up to" is written because the Phase Ib can 
potentially stop early. 
 
Phase I Dose Confirmation: 
• 3 + 3 design using Cycle 1 DLTs for both CLL/SLL and MCL patients, 
conducted independently in parallel, with a minimum of 3 patients in a 
cohort, as follows: 
o MCL:  3-6 patients at cohort 1 
o CLL/SLL: 3- 6 patients at cohort 1 
• If no DLTs are reported among the initial in 3 patients in Cohort 1, the dose 
level will be considered safely cleared, and dose escalation may proceed to 
Cohort 2.  If no DLTs are reported in 3 patients in Cohort 2, the dose will be 
considered safe for Cohort 3.  If no DLT’s are reported among the initial in 3 
patients in Cohort 3, the Phase Ib part of the study will open. 
• If 1 DLT is reported in either Cohort 1, 2 or 3, an additional 3 patients will 
be enrolled.  If no additional DLTs are reported (< 1/6 pts), then dose 
escalation will continue to the next cohort or Phase Ib (if in Cohort 3 
already). 
• If at least two patients experience a DLT in either Cohort 1 (MCL or 
CLL/SLL), the combination dose will be considered above the maximum 
tolerated dose and the dose Cohort -1 will enroll 3-6 patients.  The same 
DLT rules will apply for Cohort -1 except if 2/6 patients experience a DLT 
in Cohort -1 the study will end for that respective group. If at least two 


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patients experience a DLT in Cohort 2 or 3, the next highest dose level 
which has cleared DLT evaluation will be considered the dose for the Phase 
Ib part of the study.   
Phase Ib: 
Once the dose has been confirmed separately for MCL and CLL/SLL patients, 
the Phase Ib will open and enroll up to 12 additional patients.  The efficacy 
evaluation will include the 6 patients from the Ph I cohort dose for up to 
approximately 18 total patients evaluable for efficacy in each patient group 
(MCL & CLL/SLL). 
Treatment 
Study Visits 
Each Cycle = 28 days 
Cycle 1: 
• TGR-1202 (oral): Starting on Day 1 administered daily in the morning with 
food, preferably within 30 minutes of a meal 
• Ibrutinib (oral): Starting on Day 1 administered daily in the evening  
Cycles 2 and >: 
Daily treatment with both TGR-1202 and ibrutinib should continue.  First 
efficacy assessment should be approximately 8 weeks (just prior to cycle 3) after 
Cycle 1/Day 1 (+/- 7 days) and approximately every 12 weeks thereafter (+/- 7 
days) through cycle 12 following initiation of therapy (schema below). 
 
 
 
After cycle 12, regular visits should occur every 3 cycles. After the Cycle 15 
restaging, disease assessments should occur at least every 6 cycles (+/- 14 days) 
through cycle 36, at which point assessments can be done per investigator’s 
discretion. After removal from study, patients should be followed for survival 
approximately every 3 months for up to 2 years 
Baseline Lab 
Evaluation 
(Local Lab) 
• CBC with differential 
• Serum chemistry 
• Serology to rule out active Hep B, C or HIV infection  
• Serum pregnancy test 
• FISH cytogenetic analysis 
• IGHV mutation status (CLL patients only- Test performed by Integrated 
Oncology- See correlatives section 9.1.2.3 ) 
Instrumenta
l Tests 
• Computed tomography (CT) of the chest, abdomen, pelvis (and neck if 
palpable cervical adenopathy is present) at screening. Assessments should 


Phase I/Ib Study of TGR-1202 plus Ibrutinib in Patients with Select B-Cell Malignancies 
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occur  C2D28, C5D28, C9D28, C14D28, then approximately every 6 cycles 
( +/-14 days) until Cycle 36. Disease assessments after Cycle 36 may be 
done at the investigator’s discretion. After removal from study, patients 
should be followed for survival every 3 months for up to 2 years or until 
death, lost to follow up, or initiation of a new CLL/MCL directed therapy   
• CT scan and bone marrow biopsy are mandatory for confirmation of a 
complete response. 
• Any patient who achieves a clinical response may have CT scans reviewed 
and confirmed by independent assessment. 
Dosing 
Regimen 
As of June 2014, TGR-1202 continues to enroll patients in a single agent, Phase 
I dose escalation trial, which has evaluated doses as high as 1800 mg QD.  TGR-
1202 was subsequently reformulated for greater absorption, and the 
administration state changed from a fasting state to a fed state, with a dose of 
400 mg projected to provide comparable plasma exposure to doses safely cleared 
in the single-agent study.  Ibrutinib is an approved agent for MCL and for 
CLL/SLL, and is commercially available.  TGR-1202 (TGR) and ibrutinib will 
be administered orally, once per day according to the schedule below.  A 3+3 
dose escalation design will be utilized to evaluate the dosing cohorts described 
below.  Both the CLL and MCL cohorts will start at dose level 1. 
Phase I (Dose Confirmation) – Cycle 1 Schedule 
Dose 
Level 
TGR Dose 
Ibrutinib Dose MCL 
Ibrutinib Dose CLL 
1 
400 mg 
560 mg 
420 mg 
2 
600 mg 
560 mg 
420 mg 
3 
800 mg 
560 mg 
420 mg 
If > 2 DLT’s in either Cohort 1, 3- 6 pts will enroll in Cohort -1 as follows: 
-1 
200 mg 
560 mg 
420 mg 
If > 2 DLT’s in a Cohort –1 treatment group, study will be terminated 
Cycle 2 and > 
Patients will continue daily administration of TGR-1202 + ibrutinib until 
progression or removal from study per investigator decision. 
The sponsor representative and Principal Investigator will be in charge of 
reviewing safety data (SAE’s / AE’s) after the 3rd patient of each Phase I Cohort 
(or 6th patient, in the event a DLT occurs among the first 3 patients) completes 
Cycle 1.  They will recommend whether or not it is possible to move into the 
Phase Ib portion for both the MCL and CLL disease groups independently as per 
the study design. 
 
Phase Ib: 
Once the dose in the Phase I has been confirmed for either the MCL or CLL 
patient groups, the Phase Ib part of the study will open.  All subjects will be 
treated at the established cohort dose per the same administration schedule from 


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the Phase I portion (TGR-1202 and ibrutinib administered on Day 1 of Cycle 1 
at the doses noted above and continued daily).  
For all patients at risk for tumor lysis syndrome in the opinion of the treating 
investigator, prophylaxis with allopurinol or per recommended institutional 
standards should be considered. 
Inclusion 
Criteria 
• Confirmed diagnosis of Mantle Cell Lymphoma (MCL), Chronic 
Lymphocytic Leukemia (CLL), or Small Lymphocytic Lymphoma (SLL) 
o MCL patients must have: 
 At least 1 measurable site of disease according to Revised 
Response Criteria for Malignant Lymphoma  
 Received at least one  prior standard therapy for MCL 
o CLL/SLL patients must have: 
 Indication for treatment according to the 2008 IWCLL 
Criteria 
 Received at least one prior standard treatment regimen 
• Adequate organ system function, defined as follows: 
• Absolute neutrophil count (ANC) > 500 / platelet count > 30,000. 
(Patients who have cytopenias due to significant bone marrow 
infiltration do not have to meet hematologic eligibility criteria. 
Significant bone marrow infiltration is defined as >50% involvement by 
CLL.) 
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), unless due 
to Gilbert’s disease or hemolysis, then ≤ 3.0 times ULN. 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 
2.0 x ULN if no liver involvement or ≤ 4x the ULN if known liver 
involvement 
• Creatinine ≤ 2.5 mg/dL OR calculated creatinine clearance ≥ 50 mL/min 
(as calculated by the Cockcroft-Gault method) 
• ECOG performance status ≤ 2 
• Patients must be at least 18 years of age 
In the phase I portion, patients having received prior BTK inhibitors or prior 
PI3K inhibitors are eligible 
• Ability to swallow and retain oral medication 
• Female patients who are not of child-bearing potential and female 
patients of child-bearing potential who have a negative serum pregnancy 
test at study screening.  A tubal ligation is sufficient documentation that a 
patient is not of childbearing potential. 
•  Female patients of child-bearing potential, and all male partners must 
consent to use a medically acceptable method of contraception 
throughout the study period and for 30 days after the last dose of either 
study drug.  
• Willingness and ability to comply with trial and follow-up procedures, 
and give written informed consent 
Exclusion 
Criteria 
• Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, hormonal therapy, surgery and/or 
tumor embolization) within 3 weeks of Cycle 1/Day 1, with the following 


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exceptions: 
o Patients currently taking ibrutinib do not need to undergo a 
washout period 
o Limited palliative radiation is allowed if  ≥ 2 weeks from C1D1 
o Corticosteroid therapy (prednisone or equivalent ≤ 20 mg daily) 
is allowed as clinically warranted as long as the dose is stabilized 
at least for 7 days prior to initial dosing.  Topical or inhaled 
corticosteroids are permitted. 
• Autologous hematologic stem cell transplant within 3 months of study 
entry.  Allogeneic hematologic stem cell transplant within 12 months. 
Post-allo patients must not have active graft versus-host disease and be 
off all immune suppression (other than steroids, as above) 
• Evidence of active Hepatitis B (not including patients with prior hepatitis 
B vaccination; or positive serum Hepatitis B antibody) or active Hepatitis 
C infection. Evidence of active HIV infection. 
• Active central nervous system involvement by lymphoma 
• Requires treatment with strong CYP3A4/5 inhibitors (See Appendix J) 
• Any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study such as: 
o Symptomatic, or history of documented congestive heart failure 
(NY Heart Association functional classification III-IV [see 
Appendix H]) 
o QTcF >470 msec 
o Angina not well-controlled by medication 
o Poorly controlled or clinically significant atherosclerotic vascular 
disease including cerebrovascular accident (CVA), transient 
ischemic attack (TIA), angioplasty, cardiac or vascular stenting in 
the past 6 months 
• In the phase Ib portion of the study, CLL patients who have previously 
received ibrutinib will be ineligible 
o MCL patients who have been on ibrutinib for less than 6 months 
(180 days) from the time of registration are eligible in the Ib 
portion of the trial. No washout will be required.  
• Presence of other active cancers, or history of treatment for invasive 
cancer within the past 2 years.  Patients with stage I cancer who have 
received definitive local treatment and are considered unlikely to recur 
are eligible.  All patients with previously treated in situ carcinoma (i.e. 
noninvasive) are eligible, as are patients with history of non-melanoma 
skin cancer and patients with localized prostate cancer on watch and 
wait. 
• Patients who require warfarin for anticoagulation (other anticoagulants 
are allowed) 
• Women who are pregnant or lactating 
Study 
Duration 
Approximately 18 months to accrue, plus follow-up  


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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................2 
SYNOPSIS .......................................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................9 
1. 
OBJECTIVES ....................................................................................................................12 
1.1 
Study Design ..........................................................................................................12 
1.2 
Primary Objectives .................................................................................................12 
1.3 
Secondary Objectives .............................................................................................12 
1.4 
Exploratory Objectives ..........................................................................................12 
2. 
BACKGROUND ...............................................................................................................12 
2.1 
Study Diseases .......................................................................................................12 
2.2 
B cell receptor pathway (BCR) ..............................................................................13 
2.3 
Bruton’s Tyrosine Kinase ......................................................................................14 
2.4 
Phosphatidylinositol 3-kinase (PI3K) ....................................................................14 
2.5 
IND Agents ............................................................................................................15 
2.6 
Ibrutinib..................................................................................................................20 
2.7 
Rationale ................................................................................................................20 
2.8 
Correlative Studies Background ............................................................................21 
3. 
PARTICIPANT SELECTION ...........................................................................................22 
3.1 
Eligibility Criteria ..................................................................................................22 
3.2 
Exclusion Criteria ..................................................................................................24 
3.3 
Inclusion of Women and Minorities ......................................................................25 
4. 
REGISTRATION PROCEDURES ...................................................................................25 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................25 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................25 
4.3 
General Guidelines for Other Investigative Sites ..................................................25 
4.4 
Registration Process for Other Investigative Sites .................................................26 
5. 
TREATMENT PLAN ........................................................................................................26 
5.1 
Pre-treatment Criteria .............................................................................................26 
5.2 
Treatment Regimen Phase 1 ..................................................................................26 
5.3 
Treatment Regimen Phase Ib .................................................................................29 
5.4 
Treatment Assessments ..........................................................................................29 
5.5 
Laboratory Assessments ........................................................................................32 
5.6 
Agent Administration .............................................................................................33 
5.7 
General Concomitant Medication and Supportive Care Guidelines ......................35 
5.8 
Criteria for Taking a Participant Off Protocol Therapy .........................................35 
5.9 
Duration of Follow Up ...........................................................................................37 
5.10 
Criteria for Taking a Participant Off Study ...........................................................37 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................37 


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6.1 
Critical Modifications ............................................................................................38 
6.2 
Dose Modifications of TGR-1202 .........................................................................38 
6.3 
Dose Modifications of Ibrutinib.............................................................................40 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................40 
7.1 
Expected Toxicities ................................................................................................40 
7.2 
Adverse Event Characteristics ...............................................................................43 
7.3 
Expedited Adverse Event Reporting ......................................................................44 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................44 
7.5 
Routine Adverse Event Reporting .........................................................................45 
7.6 
Expedited Reporting to Hospital Risk Management .............................................45 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................45 
8.1 
TGR-1202 ..............................................................................................................45 
8.2 
Ibrutinib..................................................................................................................47 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................49 
9.1 
Laboratory Correlative Studies ..............................................................................49 
10. 
STUDY CALENDAR .......................................................................................................53 
11. 
MEASUREMENT OF EFFECT........................................................................................55 
11.1 
Antitumor Effect ....................................................................................................55 
11.2 
Response Criteria ...................................................................................................56 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................57 
12.1 
Data Reporting .......................................................................................................57 
12.2 
Data Safety Monitoring ..........................................................................................58 
12.3 
Multicenter Guidelines ...........................................................................................58 
13. 
STATISTICAL CONSIDERATIONS...............................................................................58 
13.1 
Determining MTD .................................................................................................58 
13.2 
Phase Ib ..................................................................................................................59 
13.3 
Accrual ...................................................................................................................59 
13.4 
Analysis Plan for Secondary Objectives ................................................................59 
14. 
PUBLICATION PLAN .....................................................................................................60 
15. 
REFERENCES ..................................................................................................................61 
16. 
APPENDIX A Recommendations for Initial Evaluation, Staging, and Response 
Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification .......64 
(Cheson et. al. 2014) ......................................................................................................................64 
APPENDIX B  
Chronic Lymphocytic Leukemia Response Definition (Hallek et al. 2008)67 
Appendix C  
Contraceptive Guidelines and Pregnancy ..................................................71 


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APPENDIX D   
IWCLL Grading Scale for Hematologic Toxicity in CLL Studies ............73 
APPENDIX E: 14-396 MCL Study Participant Self-Administered Drug Diary ...........................74 
APPENDIX F: 14-396 CLL/SLL Study Participant Self-Administered Drug Diary ....................76 
APPENDIX G 
PERFORMANCE STATUS CRITERIA ..................................................78 
APPENDIX H The New York Heart Association Classification of Cardiac Disease ...................79 
APPENDIX I: Dana-farber/HARVARD Cancer Center MULTI-CENTER data SAFETY 
monitoring plan ..................................................................................................................80 
APPENDIX J: Inhibitors and Inducers of CYP3A ........................................................................94 
 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a phase I/Ib study to evaluate the maximum tolerated dose, characterize safety, and obtain 
preliminary efficacy data of TGR-1202 in combination with ibrutinib in relapsed/refractory CLL 
and MCL.  
 
1.2 
Primary Objectives 
 
• To determine the maximum tolerated dose (MTD) of TGR-1202 when used in 
combination with ibrutinib in patients with relapsed or refractory CLL or MCL. 
 
• To evaluate the safety and determine any dose limiting toxicities (DLTs) of TGR-1202 in 
combination with ibrutinib in patients with relapsed or refractory CLL or MCL. 
 
1.3 
Secondary Objectives 
 
• To preliminarily characterize the efficacy of TGR-1202 at its MTD in combination with 
ibrutinib by determining the overall response rate (ORR) defined as the sum of the 
complete response (CR) and partial response (PR) rate, as well as to determine the rate of 
nodal response with lymphocytosis (nPR), progression-free survival (PFS), and duration 
of response (DOR). 
 
1.4 
Exploratory Objectives 
 
• To assess whether apoptotic priming as determined by BH3 profiling and 
pharmacodynamic response as determined by phospho-flow are predictive of clinical 
response. 
 
2. BACKGROUND 
 
2.1 
Study Diseases 
 
Chronic lymphocytic leukemia (CLL) affects mainly older adults and is the most common 
leukemia in the Western Hemisphere.  In the US, an estimated 16,060 new cases of Chronic 
Lymphocytic Leukemia were reported in 2012, with deaths totaling 4,580 due to the disease 
according to National Cancer Institute (NCI) estimates (1).  While CLL in general is responsive 
initially to current therapies, it remains an incurable disease, and there are several higher risk 
cytogenetic abnormalities which are particularly difficult to treat.  Once such abnormality is 
deletion of a part of the short arm of chromosome 17 del(17p).  Patients with del(17p) are usually 
resistant to conventional chemotherapies and have an overall survival on the order of 2-3 years, 
even with treatment.   Thus, there is a pressing need for new, innovative, targeted therapies for 
the treatment of this heterogeneous group of diseases.  Recently, ibrutinib was approved by the 
FDA for the treatment of relapsed or refractory CLL patients, including those with del 17p, after 


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displaying high activity in this high risk patient population, with nearly 90% of patients 
achieving at least a partial response or partial response with lymphocytosis, and a progression 
free survival of 75% at 26 months (2).   
 
Mantle Cell Lymphoma (MCL) accounts for approximately 6% of all non-Hodgkin lymphoma 
(NHL), and is also more likely to affect males.  The median age of diagnosis for MCL is in the 
mid-60s.    MCL is particularly difficult to treat since it shares features of aggressive lymphomas 
often with relentless disease progression, yet more like indolent lymphomas is considered 
incurable with conventional therapies.  Rituximab (Rituxan) is used widely, generally in 
combination with chemotherapy in the front line and second line settings.  FDA-approved 
treatment options for patients with relapsed refractory MCL include the proteasome inhibitor 
bortezomib and the immunomodulatory agent lenalidomide both of which have modest response 
rates and limited durability of response.  Recently, ibrutinib was also approved for the treatment 
of relapsed and refractory MCL, based on a response rate of 68%, including 21% CR, with an 
estimated median PFS of 13.9 months (3). 
 
Despite the array of available therapies, both CLL and MCL remain incurable diseases, with 
many patients achieving no response at all, or attaining a less than optimal response to these 
therapies and often relapsing with recurrent disease.  Moreover, despite the high level of activity 
of ibrutinib, few patients achieve complete remission with this agent, and without complete 
remission it is unlikely these patients will achieve cure.  Therefore, there is a pressing need for 
new, innovative, combinations of targeted therapies for the treatment of these diseases.   
 
2.2 
B cell receptor pathway (BCR) 
 
Over the last few years, it has been recognized that the B cell receptor (BCR) pathway is a 
promising, novel target for the treatment of CLL (Figure 1).  Although not activated by somatic 
mutation, nonetheless the BCR pathway is constitutively active in CLL and further inducibly 
activated within microenvironmental niches.  Upregulation of the B cell receptor (BCR) pathway 
is now thought to be a hallmark of the pathophysiology underlying chronic lymphocytic 
leukemia (CLL). 
 


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Figure 1.  The B cell receptor (BCR) signaling pathway and molecular interactions in 
the CLL microenvironment (4) 
 
2.3 
Bruton’s Tyrosine Kinase 
 
A key protein in the BCR pathway is Bruton’s tyrosine kinase (BTK).  Loss of function 
mutations in BTK result in the human disease X-linked agammaglobulinemia (Bruton’s 
agammaglobulinemia), which leads to profound gamma globulin deficiency and increased risk of 
infection. In vitro inhibition of BTK results in abrogation of survival signaling downstream of 
the BCR, a decrease in pro-survival cytokines, and modest induction of CLL cell apoptosis (5).  
Moreover, inhibition of BTK in CLL cells in vitro with siRNA promotes apoptosis, and BTK 
inhibition in the TCL1 mouse model of CLL significantly delays the development of CLL, 
suggesting that BTK is a critical kinase for CLL development and expansion (6).   
 
2.4 
Phosphatidylinositol 3-kinase (PI3K) 
 
Phosphatidylinositol 3-kinase (PI3K) inhibitors can have a profound impact on modulating the 
CLL microenvironment (7).  For example, the delta-isoform specific PI3K inhibitor idelalisib 
(GS1101) was found in vitro to inhibit microenvironmental protection by releasing CLL cells 
from stroma, thereby leading to increased CLL cell susceptibility to cell death (8).  These 
promising preclinical results of PI3K inhibition in CLL have translated into the clinic, where a 
phase I trial of idelalisib showed that 72% of CLL patients achieved a lymph node response (9), 
and a recently published phase 3 randomized study of idelalisib plus rituximab vs. rituximab 
alone in relapsed/refractory CLL showed an 81% response rate, with a 12% absolute 
improvement in overall survival in the idelalisib arm compared to rituximab alone (5).   
 
Though promising, PI3K-δ specific inhibition has potential limitations.  For example, by 


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targeting only the δ-isoform of PI3K, CLL cells could theoretically develop resistance through 
upregulation of other PI3K isoforms.  Therefore, it is logical to explore the use of a PI3K- δ 
inhibitor in combination with an inhibitor targeting a different protein in the BCR pathway such 
as BTK. 
 
2.5 
IND Agents 
 
2.5.1 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 for the delta over the alpha, 
beta, and gamma isoforms of PI3K.  The PI3Ks are a family of enzymes involved in various 
cellular functions, including cell proliferation and survival, cell differentiation, intracellular 
trafficking and immunity.  The delta isoform of PI3K is highly expressed in cells of 
hematopoietic origin, and strongly upregulated in various hematologic malignancies (7).  TGR-
1202 has demonstrated safety and preliminary efficacy in an ongoing Phase I clinical trial in 
patients with hematologic malignancies.  TGR-1202 is manufactured by Alembic 
Pharmaceuticals and supplied by TG Therapeutics, Inc. 
 
In the summer of 2017, TG Therapeutics announced that TGR-1202 will henceforth be referred 
to as umbralisib, though the name TGR-1202 will continue to be used for the purposes of this 
trial.  
 
2.5.2 Pre-Clinical Evaluations of TGR-1202  
 
In Vitro Activity 
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) (10). Selectivity over the other three isoforms, namely, α, β, and γ was 
also determined (10, 11, 12, 13).  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. 
 
Figure 2.  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 
(14). Cells were incubated with TGR-1202 for different time-periods (72 -96 h) based on their 
PI3K isoforms 
(Human) 
IC50 
(nM) 
α 
>10,000 
β 
1,116 
γ 
1,065 
δ 
22.23 


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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 -7.5 μM 
of TGR-1202 (Figure 2). 
 
As a marker of pharmacodynamic engagement of target, the effect of TGR-1202 on AKT 
phosphorylation (15, 16, 17, 18, 19) 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 (Figure 3). 
 
Figure 3.  Reduction of pAKT by TGR-1202 in cell lines by Western blotting 
 
 
2.5.3 In Vivo Activity 
 
In vivo efficacy of TGR-1202 was confirmed in a subcutaneous mouse MOLT-4 xenograft 
model, representative of human T-cell acute lymphoblastic leukemia.  Oral administration of 150 
mg/kg/QD over a 25-day period resulted in a significant delay in tumor growth (Figure 4). 
 
Figure 4.  TGR-1202 In vivo efficacy 
 
 
Toxicology 
To assess the safety and toxicity of TGR-1202 a 28-day repeat dose study with a 14-day recovery 
period was conducted in CD-1 mice and beagle dogs, to evaluate the potential reversibility of 
findings and to support the use in humans.  TGR-1202 was administered orally in order to mimic 
the planned mode of clinical administration.       
 
Once daily oral administration of TGR-1202 was tolerated in mice at free base dose levels of 50 
and 150 mg/kg/day.  Increases in liver weights, microscopic findings in the liver and the 
increases in serum cholesterol, and female only ALT, AST, and GGT levels were observed at 


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750 mg/kg/day of free base (the highest dose tested) and were considered adverse.  The no-
observed-adverse-effect level (NOAEL) was considered to be 150 mg/kg/day in mice.  
 
Once daily oral administration by capsule of TGR-1202 was well tolerated in dogs at levels of 50 
and 150 mg/kg/day.  The gastrointestinal tract, based on clinical signs, was the target organ 
system.  Based on effects on body weight and the incidence and severity of emesis and diarrhea, 
the NOAEL was considered to be 150 mg/kg/day (114.5 mg/kg/day as free base) in this species. 
Refer to the TGR-1202 Investigator’s Brochure (IB) for detailed information on toxicology 
studies conducted to date. 
 
2.5.4 Clinical Development of TGR-1202 
 
TGR-1202 is being evaluated in an ongoing single-agent Phase I dose-escalation study in 
patients with relapsed and refractory hematologic malignancies.  As of June 1, 2014, 40 patients 
have been evaluated with single agent TGR-1202 at doses as high as 1800 mg QD.   
 
As of June 1, 2014, 21 of the 36 evaluable patients remained on TGR-1202 treatment.  No safety 
concerns have been recognized or reported as documented by the Study Chair and Medical 
Monitor for the trial for up through 1200 mg QD (the highest dose that has cleared DLT 
evaluation).  Preliminary data from this ongoing Phase I study was presented at the 2013 Annual 
Meeting of the American Society of Hematology (20) and updated at the 2014 European 
Hematology Association Annual Congress (21), as summarized below: 
 
Safety: 
One DLT event of Grade 3 rash was observed at the 800 mg dose level, which necessitated 
enrollment of an additional 3 patients.  The Grade 3 rash resolved upon suspension of TGR-1202 
and concomitant medications and did not recur upon re-challenging the patient at 800 mg QD.  
No other DLTs have been reported through 1200 mg QD dosing and adverse events have been 
manageable, with those occurring in greater than 5% of patients and deemed at least possibly 
related to TGR-1202 consisting of the following :  diarrhea (18%), nausea (16%), vomiting 
(13%), fatigue (10%), neutropenia (8%), hypokalemia (8%), and weakness (8%).   
 
Pharmacokinetics: 
TGR-1202 was rapidly absorbed (mean Tmax ~2 hours), and displayed a Cycle 1, Day 1 half-life 
of ~9 hours.  Steady state pharmacokinetics were achieved by Day 15 of dosing, with an 
estimated steady state half-life of ~50 hours observed.  Kinetics were observed to be linear 
through 1200 mg QD dosing.   
 


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Efficacy: 
A significant dose-response relationship was observed with patients treated at higher doses (400 
mg QD or greater) demonstrating marked reduction in tumor burden.  Of the 9 evaluable CLL 
patients treated at 800 mg QD or higher (including those that started at a lower dose and were 
escalated to 800 mg), 8 achieved a nodal response (>50% reduction in lymphadenopathy), while 
the ninth patient achieved a significant nodal reduction (>40%) at first scan.  Of the 8 patients 
achieving a nodal response, 4 have achieved a partial response per IW-CLL (6) criteria.   
 
 
Overall, TGR-1202 was well tolerated and displays promising signs of clinical activity.   
 
Reformulation and Change to Fed State Dosing 
The initial dosing in the Phase I single agent study for Cohorts 1 through 7 was conducted in a 
fasting state, with patients instructed to take TGR-1202 having fasted for 2 hours prior, and 1 
hour post study drug administration.  Given the formulation of TGR-1202 in 200 mg tablets, 
study drug administration at higher dose levels (i.e. 1200 mg QD or greater) resulted in an 
unfavorable number of tablets for daily administration, prompting the exploration of dosing 
alterations to improve absorption. 
 
Food Effect 
As TGR-1202 is a BCS Class 2 drug, a positive food-effect was hypothesized and tested in a 24-
subject, pharmacokinetic crossover study assessing the relative bioavailability of a single dose of 
TGR-1202 administered in either a fasting state or following consumption of a standardized 
high-fat meal.  Results indicated a positive food effect, with increased TGR-1202 exposure when 
dosing in a fed state, as detailed below.     


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Following analysis of this data, fed state dosing was implemented in select expansion cohorts 
which were opened at doses that had previously cleared DLT evaluation (800 mg and 1200 mg 
QD), both of which cleared DLT evaluation with no DLTs observed.   
 
Micronized Formulation 
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.  A 24 subject pharmacokinetic 
bioequivalence/bioavailability (BE/BA) crossover study in healthy volunteers was undertaken to 
evaluate the relative oral bioavailability of TGR-1202 and micronized TGR-1202, with all 
patients dosed in a fasting state as a control.  The results indicate markedly higher TGR-1202 
exposure with micronized TGR-1202, as illustrated below: 
 


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A 2-fold increase in AUC is projected with micronized TGR-1202 compared to TGR-1202, and 
further 1-2-fold increase in AUC is projected with fed state dosing with a non-calorically 
standardized meal in uncontrolled conditions, which, when combined results in a projected 3-4-
fold increase in TGR-1202 exposure with micronized TGR-1202 dosed in a fed state over the 
previous formulation of TGR-1202 in a fasting state.   
 
2.6 
Ibrutinib 
 
Ibrutinib is a selective and potent covalent inhibitor of Bruton’s Tyrosine Kinase (BTK), an 
enzyme found in the B-cell Receptor pathway which has been found to regulate B-cell 
proliferation and survival.  Ibrutinib has demonstrated impressive single-agent activity in a 
number of B-cell malignancies including CLL/SLL and MCL.  In a Phase Ib/II study of single 
agent ibrutinib in 85 patients with relapsed or refractory CLL/SLL, an overall response rate of 
71% (89% including nodal response with lymphocytosis) was reported with manageable toxicity 
(2).   Similarly, a 68% ORR was observed in a Phase II study of single agent ibrutinib in 111 
patients with relapsed or refractory MCL (3).  Ibrutinib is approved for the treatment of patients 
with relapsed or refractory MCL and CLL and is manufactured and supplied by Pharmacyclics, 
Inc.  For more information on the safety and efficacy profile of ibrutinib, refer to the ibrutinib 
label available at www.accessdata.fda.gov. 
 
2.7 
Rationale 
 
TGR-1202 is a highly specific and orally available phosphoinositide-3-kinase (PI3K) delta (δ) 


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inhibitor with nanomolar inhibitory potency, and high selectivity over the alpha, beta, and 
gamma Class I isoforms of PI3K.  The delta isoform of PI3K is highly expressed in malignant 
lymphocytes, where it serves as a key node in the B cell receptor (BCR) signaling pathway, 
thereby making this an attractive target for selective inhibition of malignant B cells (4) TGR-
1202 is currently in a Phase I dose escalation trial, evaluating sequentially higher single agent 
doses until a maximum tolerated dose (MTD) is determined.     
 
Ibrutinib is an inhibitor of Bruton’s Tyrosine Kinase (BTK), another key enzyme found at a 
different point in the BCR pathway, which has been found to be critical for B-cell proliferation 
and survival.  Ibrutinib is approved for the treatment of patients with relapsed or refractory 
Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL).  Although ibrutinib 
monotherapy is a promising therapy for relapsed CLL and MCL, not all patients respond to 
ibrutinib therapy, and in patients who do respond, it is inevitable that resistance mechanisms will 
arise, such as the C481S binding site mutations recently described in CLL (22).  Notably, while 
71% of CLL patients achieved an objective response to single agent ibrutinib, only 2% of 
patients achieved a CR, with the remainder of patients achieving a PR.  Additionally, patients 
with high risk cytogenetics (deletion 17p) displayed a shorter progression free survival compared 
to those patients with normal cytogenetics (2).  Similarly, the majority of responses seen with 
ibrutinib in patients with relapsed or refractory MCL were PRs (CR rate of 21% compared to PR 
rate of 47%), with a median PFS observed to be 13.9 months, indicating room for improvement 
(23).   
 
Dual inhibition of both PI3K-delta and BTK may result in more complete BCR pathway 
blockade, and has the potential to overcome resistance mechanisms that may arise with targeting 
only one protein in this pathway.  Dual BCR pathway blockade therefore has the potential to 
drive deeper responses for longer durations and also the reduced likelihood of developing 
treatment resistance. 
 
The purpose of this study is to determine the MTD of the PI3K-delta inhibitor TGR-1202 in 
combination with the BTK inhibitor ibrutinib, and to explore the safety and efficacy of these two 
novel, oral, once daily, targeted agents in patients with relapsed refractory CLL and MCL. 
 
2.8 
Correlative Studies Background  
 
2.8.1 BH3 Profiling 
 
This study will incorporate a laboratory technique known as BH3 profiling, which is a functional 
assay we previously developed that detects the proximity of malignant cells to the threshold of 
apoptosis (what we call ‘priming’) through physiologic interrogation of BCL-2 family members.  
To perform a BH3 profile, we add individual BH3-only peptides to gently permeabilized primary 
CLL cells and use FACS to determine the amount of mitochondrial depolarization induced by 
each peptide, as measured by cytochrome c release.  
 
We previously showed using primary CLL samples co-cultured with stroma in vitro that BCR 
inhibition can release CLL cells from stroma, and thereby increase priming for apoptosis (23).  
We also found that in a small, heterogeneously treated cohort of CLL patients, increased priming 


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was associated with improved clinical response.  Building on these initial studies, we will 
incorporate BH3 profiling into this clinical trial to determine whether priming predicts degree of 
clinical response in this homogeneously treated patient population. 
 
We hypothesize that patients whose cells undergo significant depolarization to BIM BH3 peptide 
(highly primed) will have superior clinical response to TGR-1202 and ibrutinib compared to 
patients whose cells undergo minimal BIM BH3 depolarization (unprimed).  These assessments 
will be made on circulating CLL cells from the peripheral blood drawn from patients at baseline 
and correlated with our efficacy endpoints.  If we have positive bone marrow aspirates available, 
we will also perform BH3 profiling to see whether the level of priming in CLL cells from the 
marrow is a better predictor of response than the level of priming in peripheral blood CLL cells. 
 
2.8.2 Pharmacodynamic Markers 
 
Where possible, pharmacodynamic markers may be assessed to determine how effectively 
ibrutinib plus TGR-1202 are hitting their proposed targets in vivo.  Using pretreatment and week 
1 patient samples, we will use phosphoflow cytometry to determine the levels of phospho-AKT, 
phospho-BTK, and phospho-ERK compared to total AKT, BTK, and ERK, respectively.  These 
analyses may be confirmed in a subset of patients by Western Blot.  In addition, recent work has 
suggested that reduction in the cell proliferation marker Ki-67 in peripheral blood CLL cells 
occurs rapidly in patients treated with BCR pathway antagonists, and we may assess this also by 
phosphoflow cytometry. 
 
2.8.3 Genomic Markers 
 
In addition, saliva as a source of germline will be collected prior to study initiation and may be 
collected more than once if inadequate specimen is obtained.   All samples will promptly be 
delivered to the laboratory of Dr. Jennifer Brown, where DNA will be extracted and then sent to 
the Broad Institute (Cambridge, MA) for whole exome sequencing. 
 
2.8.4 Genzyme Minimal Residual Disease 
 
Blood and Bone marrow samples will be collected to confirm complete response for minimal 
residual disease analysis by Genzyme Genetics (LabCorp Specialty Testing Group/Integrated 
Oncology) by flow cytometry.  Preliminary molecular analysis will be done at baseline on 
peripheral blood.  
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Confirmed diagnosis of Mantle Cell Lymphoma (MCL), Chronic 
Lymphocytic Leukemia (CLL), or Small Lymphocytic Lymphoma (SLL) 
 
3.1.1.1 
MCL patients must have: 
• At least 1 measurable site of disease according to Revised Response 


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Criteria for Malignant Lymphoma 
• Received at least 1 prior standard therapy for MCL  
 
3.1.1.2 
CLL/SLL patients must have: 
• Indication for treatment according to the 2008 IWCLL Criteria (5) 
• Received at least one prior standard treatment regimen 
 
3.1.2 Patients must be at least 18 years of age 
 
3.1.3 ECOG performance status ≤2 (Appendix G) 
 
3.1.4 Participants must have normal organ and marrow function as defined below: 
• Absolute neutrophil count (ANC) > 500 independent of growth factor support 
and platelet count > 30,000 independent of transfusion support. (Patients who 
have cytopenias due to significant bone marrow infiltration do not have to 
meet hematologic eligibility criteria. Significant bone marrow infiltration is 
defined as >50% involvement by CLL.) 
 
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) unless due to 
Gilbert’s disease or hemolysis, then < 3.0 times ULN 
 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 
x ULN if no liver involvement or ≤ 4 x the ULN if known liver involvement 
 
• Creatinine <2.5 mg/dL OR calculated creatinine clearance >50 mL/min (as 
calculated by the Cockcroft-Gault method) 
 
3.1.5 Ability to swallow and retain oral medication 
 
3.1.6 Female patients who are not of child-bearing potential (see Appendix C), and 
female patients of child-bearing potential who have a negative serum 
pregnancy test at study screening. A tubal ligation is sufficient documentation 
that a patient is not of child bearing potential. Female patients of child-bearing 
potential (see Appendix C), and all male partners must consent to use a 
medically acceptable method of contraception throughout the study period and 
for 30 days after the last dose of either study drug. 
 
 
3.1.7 Ability to understand and the willingness to sign a written informed consent 
document. 
 
 
 
 
 


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3.2 
Exclusion Criteria 
 
3.2.1 Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor 
embolization) within 3 weeks of Cycle 1/Day 1 with the following exceptions: 
 
• Limited palliative radiation is allowed if completed ≥2 weeks of C1D1 
 
• Corticosteroid therapy (prednisone or equivalent ≤20 mg daily) is allowed as 
clinically warranted as long as the dose is stabilized at least for 7 days prior to 
initial dosing.  Topical or inhaled corticosteroids are permitted 
 
• Patients currently taking ibrutinib do not need to undergo a washout period  
 
3.2.2 Autologous hematologic stem cell transplant within 3 months of study entry.  
Allogeneic hematologic stem cell transplant within 12 months. Post allo 
patients must not have active graft versus-host disease and be off all immune 
suppression (other than steroids, as above). 
 
3.2.3 Participants who are receiving any other investigational agents.  
• 
Patients who have previously received ibrutinib will be ineligible in the 
Phase Ib portion of the study of the CLL arm 
• 
MCL patients who have been on ibrutinib for less than 6 months (180 days) 
from the time of registration are eligible in the Ib portion of the trial. No 
washout will be required.  
 
3.2.4 Evidence of active Hepatitis B (not including patients with prior hepatitis B 
vaccination; or positive serum Hepatitis B antibody) or active Hepatitis C 
infection.  Evidence of active HIV infection. 
 
3.2.5  Active central nervous system involvement by lymphoma 
 
3.2.6 Requires treatment with strong CYP3A4/5 inhibitors (See Appendix J) 
 
3.2.7 Any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 
• Symptomatic, or history of documented congestive heart failure (NY Heart 
Association functional classification III-IV [see Appendix H]) 
• QTcF >470 msec 
• Angina not well-controlled by medication 
• Poorly controlled or clinically significant atherosclerotic vascular disease 
including cerebrovascular accident (CVA), transient ischemic attack (TIA), 
angioplasty, cardiac or vascular stenting in the past 6 months 
 


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3.2.8 Presence of other active cancers, or history of treatment for invasive cancer 
within the past 2 years.  Patients with stage I cancer who have received 
definitive local treatment, and are considered unlikely to recur are eligible.  
All patients with previously treated in situ carcinoma (i.e. noninvasive) are 
eligible, as are patients with history of non-melanoma skin cancer and patients 
with localized prostate cancer on watch and wait. 
 
3.2.9 Women who are pregnant or are lactating 
 
3.2.10   Patients who require warfarin for anticoagulation (other anticoagulants are 
allowed) 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.   
 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Research Project Manager.  All sites should call the Research Project Manager at 617-632-6325 
to verify dose level availabilities.   
 


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Following registration, participants should begin protocol therapy as soon as feasible. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the research nurse or 
data manager and faxed to 617-632-5152 or e-mailed to the Research Project Manager: 
• Documentation of diagnosis, prior therapy, baseline assessments and any other 
documentation relevant to the inclusion/exclusion criteria (see section 3 for details) 
• Signed participant consent form 
• HIPAA authorization form (if appropriate) 
• DF/HCC Eligibility checklist (provided by the lead site) 
 
The participating site will then call or e-mail] the lead site to verify eligibility.  The research 
project manager will follow DF/HCC policy (REGIST-101) and register the participant on the 
protocol.  The research project manager will fax or e-mail the participant study number, and the 
dose treatment level, to the participating site.  The Study Coordinator will also contact the 
participating site and verbally confirm registration 
 
 
NOTE: Registration with the Office of Data Quality can only be conducted during the 
business hours of 8:00 AM and 5:00 PM Eastern Time Monday through Friday. Same day 
treatment registrations will only be accepted with prior notice and discussion with the DF/HCC 
Lead Institution.  
 
5. TREATMENT PLAN 
 
5.1 
Pre-treatment Criteria 
 
5.1.1 Cycle 1, Day 1 
 
Participants must have met all of the inclusion criteria and have none of the exclusion criteria at 
screening.  Participants must be registered to the protocol prior to initiating therapy. 
 
5.1.2 Subsequent Cycles 
 
Patients can receive treatment if they do not meet dose delay/dose modification criteria (see 
section 6). All toxicities must have resolved to grade 1 or less, or the patient’s baseline, prior to 
initiating subsequent cycles. 
 
5.2 
Treatment Regimen Phase 1 
 
   Cycle = 28 days 
Dose Level 
TGR-1202 Dose 
Ibrutinib Dose MCL 
Ibrutinib Dose 


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CLL 
1 
400 mg 
560 mg 
420 mg 
2 
600 mg 
560 mg 
420 mg 
3 
800 mg 
560 mg 
420 mg 
If > 2 DLT’s in either Cohort 1, 3- 6 pts will enroll in Cohort -1 as follows: 
-1 
200 mg 
560 mg 
420 mg 
If > 2 DLT’s in a Cohort –1 treatment group, study will be terminated 
 
Dose level 1 will be the starting level for patients in both the CLL and MCL arms.  Patients will 
continue daily administration of TGR-1202 + ibrutinib until progression or removal from study 
per investigator decision. 
 
5.2.1 Tumors lysis syndrome (TLS) prophylaxis 
 
For all patients at risk for tumor lysis syndrome in the opinion of the treating investigator, 
prophylaxis with allopurinol or per recommended institutional standards should be considered. 
 
5.2.2 Cohort Review 
 
The sponsor representative and Principal  Investigator will be in charge of reviewing safety data 
(SAE’s / AE’s) after the 3rd patient of Cohort 1 (or Cohort 2 and Cohort 3), per MCL and CLL 
group, is treated on Day 28 of Cycle 1.  They will recommend whether or not it is possible to 
continue to Cohort 2 and 3 or if currently in Cohort 3, move into the Phase Ib portion of the 
study for each MCL and CLL group independently as per the study design.  This decision will be 
made after a teleconference with the other investigators to obtain their input. 
 
CLL/SLL 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
TGR-
1202 
Cohort 1: 400 mg  
Cohort 2: 600 mg 
Cohort 3: 800 mg 
PO in the a.m. with 
food.* 
Days 1-28, 
continuous 
28 days  
(4 weeks) 
 
 
 
Ibrutinib 
420 mg  
PO in the p.m. 
Days 1-28, 
continuous 
* Patients should be instructed to take TGR-1202 with food, preferably within 30 minutes of a 
meal. 
MCL 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
TGR-
1202 
Cohort 1: 400 mg  
Cohort 2: 600 mg 
Cohort 3: 800 mg 
PO in the a.m. with 
food.* 
Days 1-28, 
continuous 
28 days  
(4 weeks) 
 
 
 
Ibrutinib 
560 mg  
PO in the p.m. 
Days 1-28, 
continuous 
* Patients should be instructed to take TGR-1202 with food, preferably within 30 minutes of a 
meal 


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The participant will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each cycle. See Appendices E and 
F, MCL and CLL respectively, for diary.   
 
5.2.3 Phase I Dose Confirmation 
 
The safety of TGR-1202 in combination with ibrutinib will be assessed using a standard 3 + 3 
dose-escalation design, with a starting dose of TGR-1202 at 400 mg (Cohort 1) followed by 600 
mg (Cohort 2), followed by 800 mg (Cohort 3) and the possibility of a single dose escalation or 
de-escalation based on safety in the first 3-6 patients in a given cohort.  The DLT observation 
period is the first cycle (28 days).  The ibrutinib dose will be fixed at the FDA-approved doses of 
420 mg (CLL) or 560 mg (MCL). 
 
A cohort of 3 patients will enter at each dose level. If no DLT is seen in the first 3 eligible 
patients at any dose level, then a dose escalation will take place.  
 
If 2 or more of the 3 eligible patients experience DLT at dose level 1 (400mg), dose level 2 (600 
mg), or dose level 3 (800 mg), the next cohort of 3 patients will be treated at the next lower dose 
level, unless 6 patients have already been treated at that dose level. If 2 or more of the 3 eligible 
patients experience DLT at dose level -1 (200 mg), the study will be terminated early.   
 
If 1 of the first 3 patients experiences DLT then 3 additional patients will be treated at that dose 
level. If there is no DLT in the 3 additional patients then dose escalation will take place. If this is 
does level 3 or -1, this dose is the MTD. If 1 or more of the 3 additional patients experience(s) 
DLT then the MTD is considered exceeded, and 3 more patients are treated at the next lower 
dose, unless 6 patients have already been treated at that dose level. If this is dose level -1, the 
study will be terminated early.  
 
A minimum of six patients must be evaluated at the highest tolerated dose level prior to 
proceeding to Phase Ib, and fewer than 2 patients in 6 should experience DLT. 
 
# DLT 
Dose Escalation 
0/3 
Accrue 3 new patients at next higher dose level. (if this is dose level 3 
or -1, accrue additional 3 patients at this dose level) 
1/3 
Accrue additional 3 patients at current dose level 
1/3 + 0/3 
Accrue 3 new patients at next higher dose level (if this is dose level 3 
or -1, this is the MTD) 
1/3 + ≥ 1/3 
Previous dose level is MTD if 6 treated at that level (if this is dose 
level -1, terminate the study) 
≥ 2/3 
1) Prior dose level is MTD (if 6 treated at that level)  
2) De-escalate dose, accrue additional 3 patients at prior lower level (if 
only 3 treated at the level thus far) 3) If this is dose level -1, terminate 
the study                    
 
Of note, the MCL and CLL arms of the study will be considered independently in terms of dose 


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escalation evaluation.  However, should unexpected, emergent toxicity emerge in one of the 
arms, the impact of this event will be considered for both arms. 
 
5.2.4 Stopping Rules for Phase I Dose-Escalation 
 
The Principal Investigator will be in charge of reviewing safety data following the final treatment 
dose (Day 28 of Cycle 1) of the last patient in Cohort 1, Cohort 2 and Cohort 3, and will decide 
whether or not it is possible to proceed to the next scheduled cohort or Phase Ib portion of the 
trial.  Principal Investigator will consult with a representative from TG Therapeutics before 
deciding on escalation. In order to ensure safety and limit toxicity for enrolled patients, dose 
modifications will be performed according to the schema described in Section 6.2.  These events 
will be reviewed by the sponsor representative and Principal Investigator and potentially other 
study Investigators at the end of Cycle 1 and routinely thereafter during the course of the study.  
All other serious and non-serious adverse events will be documented, managed including 
possible reductions in dose according to investigator discretion, followed until resolution or 
stabilization, and will also be reviewed by the sponsor representative and Principal Investigator 
routinely during the course of the study. 
 
5.3 
Treatment Regimen Phase Ib 
 
Once the MTD of TGR-1202 in combination with ibrutinib has been determined for either the 
MCL or CLL patient groups, independently, the Phase Ib part of the study will open.  Subjects 
will be treated per the same dosing schedule as in the Phase I, as follows: 
 
Treatment Schema for Phase Ib 
Drug 
 
TGR-1202 (PO) 
Daily Dosing – Days 1 – 28 
Ibrutinib (PO) 
Daily Dosing – Days 1 – 28 
 
5.4 
Treatment Assessments  
 
Study calendar can be found in section 10.  
 
5.4.1 Screening (within 21 days of C1D1) 
• Informed consent 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS 
•  Serum chemistry,  hematology (within 21 days of C1D1) 
• PT/PTT/INR  
• Beta 2 microglobulin 
• Serum Protein Electrophoresis ( SPEP)   
• Urinalysis (Macroscopic only) 
• HBV, HCV, HIV assessment: HBV surface antigen, HBV surface antibody, HBV 
core antibody: if HBV core antibody is positive, must have a negative HBV viral 
load to enroll.  HCV antibody:  if positive, must have negative HCV viral load to 
enroll.  HIV 1/2 antibody:  must have negative result to enroll) 
• Correlative study sample collection 


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• Serum Pregnancy (+/- 3 days C1D1) 
• BM aspirate/biopsy (within 90 days prior to C1D1;Core, aspirate ,flow cytometry, 
cytogenetics and FISH at baseline if possible; Core, aspirate and flow cytometry 
for all marrows thereafter or at investigators discretion) 
• EKG  
• CT scan of the chest, abdomen, pelvis (and neck if palpable cervical adenopathy 
is present) within 30 days of C1D1  
• FISH analysis   ( done locally per site standard) 
 MCL patients whose cytogenetics show 11;14 translocation do not require 
FISH analysis  
• IGHV/TP53 and Zap70 status (CLL/SLL patients only unless already tested  and 
enrolled on DFCI trial i.e.: 99-224-Performed through Integrated Oncology) 
 Patients who have had prognostic assessments (TP53, FISH or Zap70) 
performed within 6 months (at the center where they are being treated 
prior to registration) do not need to have these assessments repeated. 
IGHV does not need to be repeated if ever tested previously by Integrated 
Oncology (prior testing from other laboratories only with permission from 
overall PI)   
 
5.4.2 Cycle 1, Day 1 (+/- 3 day window) 
Participants must meet all of the inclusion criteria, have none of the exclusion criteria, and must 
be registered to the protocol prior to initiating therapy.  See section 4 for more details on 
registration procedure. The laboratory tests at screening will be used to determine eligibility for 
this study.  If laboratory tests need to be repeated for clinical reasons on C1D1, these values do 
not need to meet eligibility criteria again in order for the patient to start on treatment.  
 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication 
• Serum chemistry, hematology 
• Correlative study sample collection 
  
5.4.3 Cycle 1, Day 8 (+/- 3 day window) 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication  
• Serum chemistry, hematology  
• Correlative study sample collection 
 
5.4.4 Cycle 1, Day 15 (+/- 3 day window) 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication  
• Serum chemistry, hematology 
 
5.4.5 Cycle 1, Day 22(+/- 3 day window) 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication  


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• Serum chemistry, hematology 
 
5.4.6 Cycle 2, Day 1 (+/- 3 day window) 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication 
• Serum chemistry, hematology, PT/PTT/INR  
 
5.4.7 Cycle 2, Day 15 (+/- 3 day window) 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication  
• Serum chemistry, hematology 
 
5.4.8 Cycle 3-6, Day 1 (+/- 3 day window) 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication  
• Serum chemistry, hematology 
• IgA, IgM, IgG (Only C3 Day1 and C6 Day 1 if no M- Protein detected at 
baseline)  
• SPEP (Only C3 and C6 Day 1 only if M protein is detected at baseline) 
 
5.4.9 Cycle 8-12 (every 56 days +/- 3 days)  
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication  
• Serum chemistry, hematology 
• IgA, IgM, IgG if no M-Protein detected at baseline 
• SPEP only if M-protein detected at baseline 
• Correlative samples to be collected every 6 cycles after C1D1  
• After Cycle 15 restaging, scans are required every 6 cycles (+/- 14 days) or more 
frequently until Cycle 36 
 
5.4.10 Cycles 12-36 (every 84 days +/-7 days) OR Cycle 12-Onward (every 84 days 
+/-7 days) for those not being followed by a local hematologist/oncologist 
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS, AEs, 
concomitant medication 
• Serum chemistry, hematology 
• SPEP only if M protein detected at baseline (every 6 cycles) 
• IgA, IgM, IgG if no M-Protein detected at baseline ( every 6 cycles) 
• Correlative sample collection every 6 cycles after C1D1  
• Bone marrow biopsy/aspirate and scans at investigator’s discretion after Cycle 36  
 
 


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5.4.11 After the cycle 36 visit, patients will have the option of being seen every other 
visit (approximately every 6 cycles or 168  +/- 14 days) by a 
hematologist/oncologist locally instead of  q3 month visits at the main 
research institution to reduce travel burden.  For patients who elect to do this, 
the following will should occur at their local provider’s office: 
o Standard of care comprehensive blood count with differential and 
a comprehensive chemistry panel should be completed 
o Adverse Event assessment will be done over the phone or by 
email between the patient and the main research nurse/investigator 
and documented in the EMR/study chart. 
o For the visits that occur at the main research institution, 
assessments described in 5.4.10 will apply 
 
5.4.12 Confirmation of Complete Response 
• Bone Marrow Biopsy and Aspirate (Only in patients who had positive marrow at 
baseline to confirm CR)  
• Correlative study sample collection  
 
5.4.13 End of Treatment and or Disease Progression (next visit following a cycle 
after study drug was administered)  
• Medical history, physical exam, vital signs (pulse, BP, temperature), PS,  AEs, 
concomitant medication  
• Serum chemistry, hematology 
• Correlative study sample collection  
• BM biopsy/aspirate (only in patients who had a positive BM prior to study 
initiation and if considered SOC) 
 
5.4.14 Follow-up  
 
Patient visits should occur every 3 months and efficacy assessments should occur at 
investigator’s discretion.  For patients no longer treated at the original institution, phone contact 
should occur every 3 months with documentation of disease status or date of death obtained 
whenever possible. For those removed from treatment, survival follow up should occur every 3 
months for up to 2 years, or until next CLL/MCL-directed therapy or death.  
 
For patients evaluable for hematologic toxicity as per Appendix D, the ANC must be ≥ 500 and 
the platelet count must be ≥ 30K. 
 
All non-hematologic toxicities except for alopecia must have resolved to ≤ Grade 2, or to the 
patient’s baseline condition. 
 
5.5 
Laboratory Assessments 
 
5.5.1 Hematologic 
• CBC w/ differential, hemoglobin, hematocrit, platelets  
 


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5.5.2 Serum Chemistry 
• Calcium, Sodium, Potassium, Phosphorus, Chloride, Glucose, Magnesium, 
Albumin, AST, ALT, Creatinine, BUN, Bicarbonate, Total protein, Total bilirubin 
(and direct bilirubin if total Bilirubin is abnormal), Uric acid, LDH, Alkaline 
phosphatase, lipase (only required at baseline) 
 
5.6 
Agent Administration 
 
TGR-1202 and ibrutinib will be administered orally, both on an outpatient basis.  There is no 
need for pre-treatment medications. 
 
5.6.1 TGR-1202 
 
TGR-1202 will be administered orally once daily. TGR-1202 will be self-administered (by the 
patient).  Tablets should be taken at approximately the same time each day, preferably in the 
morning.   Patients should be instructed to swallow the tablets as a whole and should not chew or 
crush them.  Patients should be instructed to take TGR-1202 with food and a full glass of 
water, preferably within 30 minutes of a meal. Patients should be instructed to take the 
dose of TGR-1202 in the morning.  
 
If a dose of TGR-1202 is missed, it should be taken as soon as possible on the same day.  If it is 
missed for more than 4 hours, it should not be replaced.  If vomiting occurs, no attempt should 
be made to replace the vomited dose. 
Study drug compliance should be reviewed with the patient at the beginning of each new 
treatment cycle.  Missed doses should be documented.  All attempts should be made by the 
patient to return any extra drug in its original container and drug diaries to the study staff to 
confirm drug accountability. 
No routine prophylactic antiemetics or premedications should be given outside of protocol 
requirements.  However, these medications may be administered for symptoms when they occur, 
and may be given prophylactically afterwards  
 
5.6.2 Ibrutinib  
 
Ibrutinib will be administered orally once daily, preferably in the evening. Ibrutinib will be self-
administered (by the patient).  Capsules should be taken at approximately the same time each 
day.   Patients should be instructed to swallow the capsules as a whole and should not chew or 
crush them.  Patients should be instructed to take the dose of the ibrutinib in the evening. 
Ibrutinib may be taken in either the fed or fasting state. 
 
If a dose of ibrutinib is missed, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should not be replaced.  If vomiting occurs, no attempt should be 
made to replace the vomited dose. 
 
No routine prophylactic antiemetics or premedications should be given outside of protocol 
requirements.  However, these medications may be administered for symptoms when they occur, 


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and may be given prophylactically afterwards. 
5.6.3 Dose-Limiting Toxicity- Cycle 1 for Phase 1 Only 
 
Toxicity will be assessed utilizing the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) v4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) with the 
exceptions recommended by the IWCLL guidelines for the diagnosis and treatment of CLL 
defined in Appendix D.   
 
Toxicity will be considered dose-limiting if it occurs during the first cycle (28 days) of treatment 
with TGR-1202 and ibrutinib, and is considered at least possibly related to either TGR-1202 
and/or ibrutinib.  Any event defined below, unless the investigator considers the event clearly 
unrelated to study drug or due to extraneous causes, will be considered a dose-limiting toxicity.   
 
Dose-limiting toxicities will be defined as the following: 
 
• Grade 4 anemia; Grade 4 neutropenia lasting >7 days (while receiving growth factor 
support); Grade 4 thrombocytopenia lasting > 7 days;  Grade ≥3 febrile neutropenia; 
and Grade ≥3 thrombocytopenia with Grade >2 hemorrhage; 
 
o For patients with CLL/SLL, hematologic toxicity will be graded according to 
the IWCLL guidelines (Appendix D) and Grade 4 toxicity lasting >7 days will 
be considered dose limiting;  this will not apply to CLL/SLL patients who are 
not evaluable for hematologic toxicity by IWCLL criteria (see Appendix D) 
 
• Grade ≥ 3 non-hematologic toxicity unresponsive to standard supportive care measure 
with the exception of:   
o Asymptomatic Grade ≥3 lab abnormalities that resolve to ≤ Grade 1 or 
baseline within 7 days; 
 
• Treatment delay of ≥14 days due to unresolved toxicity; and  
 
• Non-hematologic toxicity of Grade 2 (at any time during treatment) that, in the 
judgment of the Investigators, Study Chair, and the Medical Monitor, is 
dose-limiting. 
 
Adverse events meeting the above definitions but are clearly unrelated to study drug will not be 
considered DLTs.  In rare instances an event may fall within the definition of a DLT as defined 
above but the event may not be considered a DLT (i.e., not clinically meaningful/significant).  If 
this occurs, a discussion between the Principal Investigator, Investigator(s), a TG Therapeutics 
representative, will take place to thoroughly review the event and supporting data, and the 
reasons for not considering the event a DLT will be clearly documented with supporting 
rationale.  In addition, other events may occur which do not meet the definition of a DLT but are 
concerning to the Principal Investigator, other Investigator(s) and/or the TG Therapeutics 
representative, and may be then considered to be DLTs.  
 


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5.6.4 Determination of Dosing-Limiting Toxicity- Cycle 1 
 
The patient population used for determination of DLT will consist of patients who have met the 
minimum safety evaluation requirements of the study, and/or who have experienced a DLT.  
Minimum safety requirements will be met if, during Cycle 1 of treatment in the Phase I part of 
the study, the patient receives at least 80% of planned ibrutinib and TGR-1202 doses, completes 
the required safety evaluations, and is observed for at least 28 days following the first dose of 
TGR-1202 and ibrutinib.  Patients who experience a DLT will be considered evaluable 
regardless of the number of doses received.  
 
5.6.5 Replacement of Patients 
 
Patients who discontinue treatment early due to disease progression or withdrawal will be asked 
to have all end-of-treatment safety evaluations performed as described in the protocol.  If a 
patient withdraws from treatment during Cycle 1 due to any reason other than DLT and does not 
meet the minimum requirements for inclusion in the DLT-determining population described 
above, that patient will be replaced.  
 
5.7 
General Concomitant Medication and Supportive Care Guidelines 
 
The following treatments are prohibited while on clinical trial:  other investigational drug 
treatments or study participation, radiation therapy (except as described above), hormonal 
therapy for cancer, cancer immunotherapy or other biologic therapy.  Low dose glucocorticoids 
(< 20 mg per day of prednisone or equivalent) may be administered for premedication or AE 
management after discussion with the Principal Investigator.   
 
Neutropenia: Granulocyte colony stimulating factor (G-CSF; filgrastim, pegfilgrastim or other 
acceptable G-CSF) may be used during the course of the study at the discretion of the 
investigator. The drug(s) should be used at a dose/schedule specified in the package insert.  
 
Antiemetics: Both TGR-1202 and ibrutinib are considered to be of low emetogenic potential, and 
therefore no anti-emetics are required by protocol, but may be used as needed at the 
investigators’ discretion.  
 
Tumor Lysis Syndrome:  In subjects at risk for tumor lysis syndrome in the opinion of the 
treating investigator, prophylaxis with allopurinol or institutional standards should be considered. 
 
5.8 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. If a participant is found by the treating investigator and by the overall PI to show 
clinical benefit from study treatment, the patient may remain on treatment.  In the absence of 
treatment delays due to adverse event(s), treatment may continue until one of the following 
criteria applies: 
 
Patients will be discontinued from trial treatment for any of the following reasons: 


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• Disease progression 
• Irreversible or intolerable toxicity or abnormal laboratory values thought to be related 
to drug toxicity 
• Patient requests to withdraw consent or discontinue treatment 
• Pregnancy  
• Inability of the patient to comply with trial requirements 
• Conditions requiring therapeutic intervention not permitted by the protocol 
• Inter-current illness (this will be at the investigator’s discretion) 
• Non-compliance/lost to follow-up 
• Discontinuation of the study by the Sponsor 
 
After withdrawal from protocol treatment, patients must be followed for AEs for 30 calendar 
days after their last dose of either trial drug.  All new AEs occurring during this period must be 
reported and followed until resolution, unless, in the opinion of the investigator, these values are 
not likely to improve because of the underlying disease.  In this case the investigators must 
record his or her reasoning for this decision in the patients’ medical records and as a comment on 
the Case Report Form (CRF). 
All patients who have CTCAE grade 3 or 4 laboratory abnormalities at the time of withdrawal 
should be followed until the laboratory values have returned to grade 1 or 2, unless it is, in the 
opinion of the investigator, not likely that these values are to improve because of the underlying 
disease.  In this case, the investigator must record his or her reasoning for making this decision in 
the patients’ medical records and as a comment on the CRF. 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the QACT website or obtained from the QACT 
registration staff. External sites should submit the form to the Research Project Manager. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Matthew Davids, MD at 617-632-6331, or page through 617-632-3352.  
 
5.8.1 Pregnancy  
 
During the course of the trial, all female patients of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix C) 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 trial drug(s), 
the trial 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 trial drug(s), and must be discontinued 
from the trial.   
If an investigator suspects that a patient may be pregnant after the patient has been receiving trial 
drug(s), the trial drug(s) must immediately be withheld until the result of the pregnancy test is 
confirmed.  If a pregnancy is confirmed, the trial drug(s) must be immediately and permanently 
stopped, the patient must be discontinued from the trial, and the investigator must notify the 
Overall PI as soon as possible.  If a patient becomes pregnant while enrolled in the trial, an SAE 


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form should be completed and faxed to the Overall PI expeditiously.  For more details regarding 
handling and reporting of pregnancies that occur during treatment, see Appendix C.  
 
 
 
 
5.9 
Duration of Follow Up 
 
Participants will be followed for survival after discontinuing protocol therapy every 3 months for 
up to 2 years or until the patient receives their next CLL/MCL-directed therapy or until death, 
whichever occurs first.  Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
For patients continuing to follow up at the treating institution, regular visits should occur every 3 
months and efficacy assessments should occur at the investigator’s discretion.  For patients no 
longer treated at the original institution, phone contact should occur every 3 months with 
documentation of disease status or date of death obtained whenever possible. Patients should be 
followed for survival every three months for up to two years or until death, or next CLL/MCL 
directed therapy.  
 
5.10 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff. 
External sites should submit the form to the Research Project Manager.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Patients should be assessed clinically for toxicity at each visit using the NCI CTCAE v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) grading scale.  Hematologic toxicity for CLL 
patients will be assessed by the IWCLL defined in Appendix D.   
 
Dosing will occur only if a patient’s clinical assessment and laboratory test values are 
acceptable.   
 
It should be noted that both TGR-1202 and ibrutinib are generally well-tolerated oral agents with 
favorable adverse event profiles.  Therefore, where possible, investigators will be encouraged to 


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continue patients on the full dose of both drugs.  The dose reduction criteria on this study are 
intentionally lenient to allow investigators to continue patients on full dose given the likelihood 
that many adverse events will be related to underlying disease and co-morbidities. 
 
Dose modification and or intervention with supportive care recommendations for TGR-1202 (for 
ibrutinib follow prescribing information) are provided below, however, final discretion lies with 
the treating investigator in regard to more or less aggressive intervention. Decisions about which 
specific investigational agent (or if both agents) needs to be reduced, and actual dose reductions, 
as well as the number of dose reductions will be made after discussion between the treating 
investigator and the Principal Investigator 
 
6.1 
Critical Modifications   
 
For CLL/SLL patients, the hematologic dose modifications are per the IWCLL Grading Scale 
(see Appendix D – Grading Scale for hematologic toxicity in CLL studies).  All other dose 
modifications are graded by the CTCAE v4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE). 
 
Note:  If cytopenias are deemed related to the underlying disease rather than either TGR-
1202 or ibrutinib, dose reductions are not required and are per investigator discretion. 
Patients who experience an adverse event will be allowed to delay TGR-1202 and/or ibrutinib 
dosing by up to one month in order to recover from the toxicity.   Patients may resume TGR-
1202 and/or ibrutinib, provided that the toxicity has resolved to Grade ≤2 or baseline. 
 
6.2 
Dose Modifications of TGR-1202 
 
If toxicity, in the opinion of the investigator, is at least possibly attributable to TGR-1202, the 
following guidelines for hematologic and non-hematologic toxicities should be followed in 
patients who are evaluable for hematologic toxicity: 
 
Patients may remain on ibrutinib therapy alone if TGR-1202 has been discontinued, after 
discussion with the Overall PI.  
 
6.2.1 Hematologic Toxicity 
 
Table 1 
Dose Modifications for Hematologic Toxicity (For patients with CLL, Appendix D 
IWCLL Grading Scale should be referenced). 
 
Worst CTCAE Grade 
Toxicity 
Recommended Action to be Taken 
HEMATOLOGIC 
Neutropenia (ANC) 
Grade 1 
Maintain dose level 
Grade 2  
 
First incidence:          Maintain dose level 
Second incidence:     Consider growth factor support 


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Grade 3 / 4  
1st Occurrence  
Hold dose until resolved to ≤ Grade 2 or baseline, consider 
growth factor support.  
Grade 3 / 4   
Subsequent Occurrences 
Hold dose until resolved to ≤ Grade 2 or baseline, consider 
growth factor support. Consider reducing dose as per Table 3 if 
warranted. 
Thrombocytopenia 
Grades 1,2, and 3 with no 
evidence of bleeding 
Maintain dose level 
Grade ≥3 thrombocytopenia 
with Grade >2 bleeding 
Hold dose until to ≤ Grade 2 or baseline and bleeding resolves, 
consider platelet transfusion as necessary. 
 
 
Grade 4  
1st Occurrence  
Hold dose until to ≤ Grade 2 or baseline, consider platelet 
transfusion as necessary.  
Grade 4   
Subsequent Occurrences  
Hold dose until to ≤ Grade 2 or baseline, consider platelet 
transfusion as necessary. Consider reducing dose as per Table 3 
if warranted.   
  
 
 
6.2.2 Non-Hematologic Toxicities 
 
Table 2 
Dose Modifications for Non-Hematologic Toxicity 
 
NON-HEMATOLOGIC 
Recommended Action to be Taken 
Grade  1 or 2 
None 
Grade 3 CTCAE  
Hold dose until toxicity Grade ≤2  or baseline 
If toxicity remains grade 3 toxicity 
for longer than 2 weeks 
Consider reducing dose as per Table 3 if warranted or 
discontinue treatment 
If grade 3 toxicity lasts 2 weeks 
and resolves to ≤ Grade 2  
Hold dose until toxicity Grade ≤ 2 or baseline 
Recurrence of  Grade 3 toxicity 
Consider reducing dose as per Table 3 if warranted 
Grade 4 CTCAE 
Hold dose until toxicity resolves to Grade ≤2 or baseline 
Recurrence of  Grade 4 toxicity 
Consider reducing dose as per Table 3 if warranted or 
discontinue study drug 
6.2.3 Dose Modification Guidelines 
 
Table 3 
Dose Modification Guidelines 
 
Dose 
Level 
Current  
TGR-1202 Dose 
Modified TGR-1202 Dose 
(first dose reduction) 
Modified TGR-1202 Dose 
(second dose reduction) 
1 
400 mg 
200 mg 
Discontinue study drug 
2 
600 mg 
400 mg 
200 mg 
3 
800 mg 
600 mg 
400 mg 
-1 
200 mg 
Discontinue study drug 
N/A 


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6.3 
Dose Modifications of Ibrutinib  
 
If toxicity, in the opinion of the investigator is attributable to ibrutinib, the investigator and 
research team should follow recommendations per ibrutinib’s FDA approved prescribing 
information and/or per investigator discretion. 
 
Ibrutinib should be held at least 3 to7 days pre and post-surgery depending upon the type of 
surgery and the risk of bleeding. 
 
Patients may remain on TGR-1202 therapy alone if ibrutinib has been discontinued, after 
discussion with the Overall PI.  
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
The following list of reported and/or potential AEs (Section 8.1) and the characteristics of an 
observed AE (Section 8.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
7.1.1 Adverse Event List TGR-1202 
 
A Phase I clinical trial in patients with relapsed or refractory hematologic malignancies is 
ongoing evaluating escalating doses of single-agent TGR-1202.  The following adverse events 
determined to be at least possibly related to TGR-1202 have been observed as of the cutoff date 
of 1 January 2014: 
 
MedDRA system 
organ class 
Very Common 
≥10% 
Common 
≥1% and <10% 
Uncommon 
≥0.1% and <1% 
Blood and lymphatic 
system disorders 
Neutropenia  
Thrombocytopenia 
 
 
Gastrointestinal 
disorders 
Diarrhea 
Dyspepsia 
Nausea 
Vomiting 
 
General disorders 
and administration 
site conditions 
Fatigue 
Asthenia 
Chills 
Malaise 
Oedema Peripheral 
Pyrexia 
 


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Infections and 
infestations 
 
Candidiasis 
Lung Infection 
 
Investigations 
 
Blood Lactate 
Dehydrogenase 
Increased 
 
Metabolism and 
nutrition disorders 
Decrease Appetite 
Dehydration 
Hypokalaemia 
Hyponatraemia 
Hypernatraemia 
Hyperphosphataemia 
 
Musculoskeletal and 
connective tissue 
disorders 
 
Muscular Weakness 
 
Nervous system 
disorders 
Headache 
Dizziness 
 
Respiratory, thoracic 
and mediastinal 
disorders 
Cough 
Hypoxia 
 
Skin and 
subcutaneous tissue 
disorders 
Rash 
 
 
 
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: 
 
• Blood and lymphatic system disorders: anemia 
• Stomach and digestive system related disorders: constipation, abdominal 
discomfort and pain, stomatitis 
• Liver Disorders: elevated levels of certain liver enzymes 
• Brain and nerve related disorders: dizziness, paresthesia 
• Kidney disorders: elevated creatinine, elevated blood urea nitrogen levels, elevated 
phosphorus, hyperuricemia 
• Breathing and chest related disorders: nasal congestion, pneumonia, dyspnea, 
upper respiratory tract infection 
• General disorders:  arthralgia, myalgia 
• Infections and Infestations: infection 


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7.1.1.1 
Precautions and Risks Associated with TGR-1202 
 
Based on observations obtained from nonclinical toxicology studies in rodent and non-rodent 
species, the following adverse events may occur: changes in serum creatinine, changes in 
triglycerides, changes in total protein, changes in sodium, changes in chloride, reduction in 
leukocytes, reduction in lymphocytes, reduction in eosinophils, elevation in cholesterol, nausea, 
vomiting, mucoid stools, abnormal colored feces, soft stool, ocular discharge, and dehydration. 
Mild to moderate histopathological changes were noted in the liver at terminal necropsy at the 
highest doses of 750 mg/kg/day in mice and dogs.  As a result, monitoring of liver enzymes in 
subjects receiving TGR-1202 is recommended (Current TGR-1202 IB).  
 
The following adverse events have been reported to occur in patients receiving similar PI3K 
inhibitors: increased ALT/AST, skin rash, enteritis, and pneumonia.  
 
Refer to the current Investigator Brochure for details of the risks associated with the use of 
TGR-1202, and instructions on how to manage patients. 
 
 
7.1.2 Adverse Event List(s) Ibrutinib  
 
Non-Hematologic Adverse Events in >10% of Patients with Mantle Cell Lymphoma 
(N=111) 
System Organ Class 
Preferred Term 
All Grades (%) 
Grade 3 or 4 (%) 
Gastrointestinal 
disorders 
Diarrhea 
Nausea 
Constipation 
Abdominal pain 
Vomiting 
Stomatitis 
Dyspepsia 
51 
31 
25 
24 
23 
17 
11 
5 
0 
0 
5 
0 
1 
0 
Infections and 
infestations 
Upper respiratory tract 
infection 
Urinary tract infection 
Pneumonia 
Skin infections 
Sinusitis 
34 
14 
14 
14 
13 
0 
3 
7 
5 
1 
General disorders and 
administrative site 
conditions 
Fatigue 
Peripheral edema 
Pyrexia 
Asthenia 
41 
35 
18 
14 
5 
3 
1 
3 
Skin and subcutaneous 
tissue disorders 
Bruising 
Rash 
Petechiae 
30 
25 
11 
0 
3 
0 
Musculoskeletal and 
connective tissue 
Musculoskeletal pain 
Muscle spasms 
37 
14 
1 
0 


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disorders 
Arthralgia 
11 
0 
Respiratory, thoracic 
and mediastinal 
disorders 
Dyspnea 
Cough 
Epistaxis 
27 
19 
11 
4 
0 
0 
Metabolism and 
nutritional disorders 
Decreased appetite 
Dehydration 
21 
12 
2 
4 
Nervous system 
disorders 
Dizziness 
Headache 
14 
13 
0 
0 
 
Treatment-Emergent Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with 
MCL (N=111) 
 
All Grades (%) 
Grade 3 or 4 (%) 
Platelets Decreased 
57 
17 
Neutrophils Decreased 
47 
29 
Hemoglobin 
Decreased 
41 
9 
 
For more information on adverse events associated with ibrutinib, see ibrutinib prescribing 
information. 
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse 
event varies in nature, intensity or frequency from the expected toxicity 
information which is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined 
in the next section (Expedited Adverse Event Reporting) under the sub-heading 
of Protocol-Specific Expedited Adverse Event Reporting Exclusions. 
 
• 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. 
 


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7.3 
Expedited Adverse Event Reporting  
 
7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) 
that occurs after the initial dose of study treatment, during treatment, or within 
30 days of the last dose of treatment on the local institutional SAE form.  In 
addition to following the SAE reporting requirements for DFCI, other 
participating investigative sites will report SAEs to their respective IRB per the 
local IRB’s policies and procedures. 
 
7.3.2 For multi-institution studies where a DF/HCC investigator is serving as the 
Overall Principal Investigator, each participating institution must abide by the 
reporting requirements set by the DF/HCC.For Multi-Center Trials where a 
DF/HCC investigator is serving as the Sponsor, each participating institution 
must abide by the reporting requirements set by the DF/HCC.  
 
Criteria for reporting to DFCI listed in section 7.5.3. The lead site will report 
external site SAEs to the DFCI IRB on the external site’s behalf after review and 
approval by the overall PI. This applies to any medical event equivalent to an 
unexpected grade 2 or 3 with a possible, probable or definite attribution, 
unexpected grade 4 toxicities, and grade 5 (death) regardless of study phase or 
attribution. 
 
7.3.3 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
Other investigative sites will report SAEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional SAE 
form should be forwarded to the Overall PI within the timeframes detailed below.   
 
DF/HCC Reportable AEs 
 
• 
CTCAE Grade 2 and Grade 3 Events – that are Unexpected and there is a Reasonable 
Possibility that the Adverse Event is related to the study intervention.  
• 
CTCAE Grade 4 Events – Report all events that are Unexpected. Events that are Expected 
and listed within the protocol and/or current consent form do not need to be reported to the 
DFCI IRB.  
o Please note, an event that presents at a higher severity than what is currently listed 
within the protocol and/or current consent as expected would be considered 
unexpected and reportable.  
• 
ALL CTCAE Grade 5 Events.  
 
 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
Matthew Davids, MD, will be responsible for all communications with the FDA. Matthew 


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Davids, MD., will report to the FDA, regardless of the site of occurrence, any serious adverse 
event that meets the FDA’s criteria for expedited reporting following the reporting requirements 
and timelines set by the FDA. 
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
7.6 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8.1 
TGR-1202 
 
8.1.1 Description 
 
TGR-1202 is a highly specific and orally available PI3K delta inhibitor with nanomolar 
inhibitory potency, and several fold selectivity over the alpha, beta, and gamma isoforms. TGR-
1202 is manufactured by Alembic Pharmaceuticals and supplied by TG Therapeutics, Inc. For 
this trial, TGR-1202 will be supplied in 200 mg tablets. 
 
Preliminary pharmacokinetic analysis suggests TGR-1202 is rapidly absorbed (mean Tmax ~2 
hours), and displayed a Cycle 1, Day 1 half-life of ~9 hours. Steady state pharmacokinetics were 
achieved by Day 15 of dosing, with an estimated steady state half-life of ~50 hours observed. 
Kinetics were observed to be linear through 1200 mg QD dosing. 
 
8.1.2 Form 
 
TGR-1202 is available as a tablet with the following description:  
• 200 mg: Light brown to brown color, oval tablets with “L474” debossed on 
one side and plain on the other side. 
 
8.1.3 Storage and Stability 
 
The Primary packaging is HDPE bottles each containing 30 tablets of 200 mg each. The HDPE 
bottles also contain a silica gel canister as a desiccant and cotton. A revision in primary 
packaging with inclusion of cotton was made, to fill the excess void space available in the 
bottles, leading to breakages of tablets observed during transportation.  Store at 25°C.  


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Excursions permitted 15°C to 30°C. 
 
The stability data on development and clinical batch shows that the drug substance has remained stable at 
all stability conditions for a period of 12 months. 
 
8.1.4 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake handling and safe disposal of the agent in a self-contained 
and protective environment.  
 
8.1.5 Availability 
 
Drug is provided by TG Therapeutics, Inc., New York, NY 
 
8.1.6 Preparation 
 
It is an oral drug, no preparation is required.  
 
8.1.7 Administration 
 
At each visit, patients will be dispensed sufficient TGR-1202 drug supplies until the next visit. 
Study drug compliance should be reviewed with the patient at the beginning of each new 
treatment cycle.  Missed doses should be documented.   
 
TGR-1202 tablets will be self-administered by the patients.  TGR-1202 will be administered 
orally once daily.  Tablets should be taken at approximately the same time each day.  TGR-1202 
tablets should be swallowed whole with a full glass (approximately 8 ounces) of water.  TGR-
1202 tablets should NOT be crushed/opened or chewed.  Patients should be instructed to take 
TGR-1202 in the morning with food, preferably within 30 minutes of a meal. 
 
8.1.8 Ordering 
 
Once the clinical trial 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 pre-
determined quantity of TGR-1202 will be shipped to the clinical trial site. 
 
Upon receipt of treatment supplies, the Pharmacist or the appropriate person of the site should 
update the accountability forms for TGR-1202. 
 
If any abnormality on the supplied boxes is observed, the Pharmacist or the appropriate person 
must document that on the acknowledgement of receipt and contact that Sponsor and/or Sponsor 
designee. 
 
Study drug may be shipped from the investigational pharmacy to the patient’s home according to 
each institution’s policy and or SOP. 


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8.1.9 Accountability 
 
The PI (or designee) is responsible for accountability of all used and unused trial drug supplies at 
the site. 
 
The DF/HCC monitor will verify receipt of investigational product at the site during monitoring 
visit(s), and will conduct an inventory of remaining clinical trial supplies at the site close-out 
visit.  All trial drug inventories must be made available for inspection by the monitor or 
representatives of the aforementioned and regulatory agency inspectors upon request.  
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using a drug accountability form.   
 
8.1.10 Destruction and Return 
 
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed 
on site, it is the investigator’s responsibility to ensure that arrangements have been made for the 
disposal, procedures for proper disposal have been established according to applicable 
regulations, guidelines and institutional procedures, and appropriate records of the disposal have 
been documented.  
8.2 
Ibrutinib  
 
8.2.1 Description 
 
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib. All 
formulation excipients are compendial and are commonly used in oral formulations. Refer to the 
ibrutinib Investigator's Brochure for a list of excipients 
 
8.2.2 Form 
 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies. All study 
drug will be dispensed in child-resistant packaging.  Study drug labels will contain information 
to meet the applicable regulatory requirements. Each bottle will contain a study specific label 
with a unique identification number. 
 
8.2.3 Storage and Stability 
 
The recommended storage condition for ibrutinib capsules is room temperature (15 to 25°C; 59 
to 77°F). Refer to the pharmacy manual/site investigational product manual for additional 
guidance on study drug preparation and handling. 
  
8.2.4 Compatibility 
 
Not applicable 


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8.2.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agents in a self-contained and protective environment. 
 
Caution is required when handling ibrutinib. Pharmacists should follow standard procedures for 
the handling of investigational drugs, including avoidance of eye or skin contact with the drug 
product. If there is exposure to the drug product, provide treatment as necessary for physical 
exposure (skin washing) or inhalation (move to fresh air) and seek medical advice as necessary.  
 
When ibrutinib capsules are distributed for self-administration, they should only be handled by 
the study subject. After handling capsules, the subject should wash their hands thoroughly. If 
someone who is not enrolled in a clinical trial involving ibrutinib swallows a capsule or inhales 
drug powder from a broken capsule of ibrutinib, they should contact the relevant Principal 
Investigator to determine whether safety monitoring is necessary. Capsules should always be 
stored in the container provided to the study subject. 
 
8.2.6 Availability 
 
Ibrutinib will be obtained by prescription, from commercial supply. 
 
8.2.7 Preparation 
 
It is an oral drug, no preparation is required.  
 
8.2.8 Administration 
 
Patients will be prescribed a sufficient ibrutinib drug supply until their next study visit. Ibrutinib 
tablets will be self-administered by the patients. Ibrutinib will be administered orally once daily.  
Tablets should be taken at approximately the same time each day, preferably in the evening.  
Ibrutinib capsules should be swallowed whole with a full glass (approximately 8 ounces) of 
water.  Ibrutinib capsules should NOT be crushed/opened or chewed.   
 
8.2.9 Ordering 
 
See 8.2.6. 
 
8.2.10 Accountability 
 
Study drug compliance will be recorded by patients in a drug diary. 
 
8.2.11 Destruction and Return 
 
Patients should dispose of any unused ibrutinib through usual means such as returning it to 


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their local pharmacy for destruction. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
9.1.1 BH3 Profiling  
 
BH3 profiling is a functional assay we previously developed that detects the proximity of CLL 
cells to the threshold of apoptosis (what we call ‘priming’) through interrogation of BCL-2 
family members.  To perform a BH3 profile, we add individual BH3-only peptides to gently 
permeabilized malignant cells and use FACS to measure the amount of mitochondrial 
depolarization induced by each peptide, as measured by cytochrome c release.  
 
We hypothesize that patients whose cells undergo significant depolarization to BIM BH3 peptide 
(highly primed) will have superior clinical response to ibrutinib compared to patients whose cells 
undergo minimal BIM BH3 depolarization (unprimed).   
 
9.1.2 Pharmacodynamic Markers 
 
Pharmacodynamic markers will also be assessed to determine whether is hitting its proposed 
target in vivo.  Viably frozen cells will be analyzed us phosphoflow cytometry to determine the 
levels of phospho-AKT and phospho-ERK compared to total AKT and ERK, respectively.  
These analyses will be confirmed in a subset of patients by Western Blot.  In addition, current 
work has suggested that reduction in the cell proliferation marker Ki-67 in peripheral blood CLL 
cells occurs rapidly in patients treated with BCR pathway antagonists, and this may also be 
assessed in the Brown lab by phosphoflow cytometry in samples from patients on our study. 
 
9.1.2.1 
Collection of Specimen(s) 
 
These assessments will be made on circulating CLL and MCL, when possible, cells from the 
peripheral blood drawn from patients at baseline.  These samples will be drawn either at 
screening or prior to study drug dosing on Cycle 1, Day 1,  If we have bone marrow aspirates 
available, we will also perform BH3 profiling to see whether the level of priming in CLL cells 
from these tissues is a better predictor of response than peripheral blood CLL cells. Bone marrow 
aspirate sample is requested if bone marrow procedure is performed as standard of care or as part 
of protocol schedule. In addition, saliva as a source of germline DNA will be collected prior to 
study initiation and may be collected more than once if inadequate specimen is obtained.   All 
samples will promptly be delivered to the laboratory of Dr. Jennifer Brown  (CLL patients )or  
Dr. Anthony Letai ( MCL patients), where DNA will be extracted and then sent to the Broad 
Institute (Cambridge, MA) for whole exome sequencing. 
 
After 1 week of treatment on Cycle 1, Day 8 (pre-dose), we will obtain another blood sample. 
We will compare the BH3 profile of this steady-state sample to a baseline sample, which will 
allow us to assess in vivo the short term change in apoptotic priming induced by these agents.  


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Finally, a peripheral blood will be collected from subjects at the time of disease progression, and 
the BH3 profile of these samples will be compared to subjects’ baseline samples to help identify 
whether a change in anti-apoptotic protein dependence is observed as a possible mechanism of 
resistance. A bone marrow sample at confirmation of complete response will be obtained and 
sent to Integrated Oncology for minimal residual disease assessment, while blood from the same 
time point is analyzed at the laboratory of Jennifer Brown (CLL or SLL patients) or Antony 
Letai ( MCL patients). For the patients that have obtained a complete response, we request that 
peripheral blood samples be obtained every 6 cycles thereafter until disease progression, removal 
from study, or death.  
 
9.1.2.2 
Handling of Specimens(s) 
 
All peripheral blood and bone marrow samples obtained at DFCI will promptly be refrigerated 
and delivered the same day as soon as possible to the laboratory of Dr. Jennifer Brown  or Dr. 
Anthony Letai  at room temperature, where they will undergo Ficoll purification and then be 
viably frozen in FBS with 10% DMSO.  The viably-frozen samples will be used for BH3 
profiling assays (for detailed methods see (24). 
 
Samples obtained from other institutions may either undergo Ficoll purification locally and then 
be viably frozen in FBS with 10% DMSO prior to shipment, or may be kept as whole blood and 
shipped on ice as soon as possible to Dr. Brown’s or Dr. Letai’s lab. 
 
9.1.2.3 
Shipping of Specimen(s) 
 
CLL/SLL patient samples obtained from sites other than DFCI should be shipped directly to Dr. 
Brown’s lab at the following address: 
 
Stacey Fernandes, Principal Research Technician 
CLL Center, J. Brown lab 
Dana Farber Cancer Institute 
1 Jimmy Fund Way, JFB 426  
Boston, MA 02115, U.S.A. 
617-632-5828 (phone) 
Email: Stacey_Fernandes@dfci.harvard.edu.   
 
 
MCL patient samples obtained from sites other than DFCI should be shipped directly to Dr. 
Letai’s lab at the following address: 
 
Tim Lehmberg, Research Technician 
Dana Farber Cancer Institute 
1 Jimmy Fund Way, Mayer 545  
Boston, MA 02115, U.S.A. 
Email: TimothyZ_Lehmberg@dfci.harvard.edu 
 
 


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The study sample requisition form provided to the site should be included in every shipment and 
an email notification with the package tracking number emailed the Research Project Manager.  
 
The blood and bone marrow samples that are requested to confirm complete response for 
minimal residual disease will be sent to Genzyme Genetics (LabCorp Specialty Testing 
Group/Integrated Oncology) for analysis by flow cytometry. These samples will be shipped 
alongside the Integrated Oncology/LabCorp requisition form (to be provided) ambient priority 
overnight to:   
        
Genzyme/LabCorp Specialty Testing Group 
521 West 57th Street  
  
New York, NY 10000 
 
9.1.2.4 
Site(s) Performing Correlative Study 
 
All sites will be encouraged to provide the correlative samples for analysis, as feasible. While the 
goal of the biomarkers is to provide supportive data for the clinical study, there may be 
circumstances when a decision is made to stop a collection, not perform, or discontinue an 
analysis due to either practical or strategic reasons (e.g., inadequate sample number, issues 
related to the quality of the sample or issues related to the assay that preclude analysis, 
impossibility to perform correlative analyses, etc). Therefore, depending on the results obtained 
during the study, sample collection/analysis may be omitted at the discretion of the PI.


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9.1.2.5 
Sample Collection  
 
Sample Time 
Point 
Container 3 
Sample 
Type 
Shipping 
Method1,2 
Recipient4,7 
Baseline or 
C1D1 Predose 
6x6mL Green 
1x6ml Red 
Peripheral 
Blood 
Fridge pack same 
day 
Brown/Letai Lab 
1x6ml Green 
Bone 
Marrow 
Aspirate 
Fridge pack same 
day 
Brown/Letai Lab 
Oragene Kit 
Saliva 
Ambient same day 
Brown/Letai Lab 
2x10ml Purple* 
1x6ml Green* 
Peripheral 
Blood 
Fridge pack same 
day 
Integrated 
Oncology 
C1D8 Predose 
6x6mL Green 
1x6ml Red 
Peripheral 
Blood 
Fridge pack same 
day 
Brown/Letai Lab 
Disease 
Progression/End 
of Treatment 
6x6mL Green 
1x6ml Red 
Peripheral 
Blood 
Fridge pack same 
day 
Brown/Letai Lab 
1x6ml Green6 
Bone 
marrow 
Aspirate 
Confirmation of 
Complete 
Response 
6x 6mL Green 
1x6ml Red 
Peripheral 
Blood 
Fridge pack same 
day 
Brown/Letai Lab 
1x6ml Green6 
Bone 
Marrow 
Aspirate 
Fridge pack same 
day 
Brown/Letai Lab 
1x6mL 
Green5,6** 
Bone 
Marrow 
Aspirate 
Fridge pack same 
day 
Integrated 
Oncology 
Every 6 Cycles8 
from C1D1 
6x6mL Green 
1x6ml Red 
Peripheral 
Blood 
Fridge pack same 
day 
Brown/Letai Lab 
1For outside sites, local lab may also Ficoll purify sample then viably freeze in Fetal Bovine Serum with 10% 
DMSO prior to shipment on dry ice. 
2For DFCI sites: refrigerate and deliver as soon as possible same day to Jennifer Brown lab 
3Green=Sodium Heparin Tube; Red= No additive; Purple = K2EDTA; Oragene kit provided by DFCI 
4 Requisition form and shipping instructions for Integrated Oncology provided by lead site 
5 Only required to confirm CR in patients who had a positive marrow at baseline   
6 Only for patients who had a positive marrow at baseline 
7 CLL/SLL patient correlatives are sent to Dr. Jennifer Brown’s Lab; MCL patient correlative samples are sent to Dr. 
Anthony Letai’s Lab, except for Oragene kits, all of which go to the CLL lab of Dr. Brown 
8 Requested for all patients who remain on study; ie: stable disease to morphologic/radiographic CR eg: Cycles 6, 
12, 18, 24, 30, 36 etc. 
*Not required for MCL patients, or patients who have already enrolled on DFCI Trial 99-224 
** Not required for MCL patients 


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10. STUDY CALENDAR 
Baseline evaluations / laboratory tests should be conducted within 21 days prior to C1D1. Scans 
used to identify measurable/evaluable disease are required to be done within 30 days prior to 
C1D1.  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.  During cycles 12 and 
beyond, patients will be seen every 3 cycles (84 days +/- 7 days). After Cycle 36, participant 
have the option to return to the main research institution every 6 cycles (168 days +/-14 days) for 
full evaluation only if they are being followed every 3 cycles by a local oncologist. For full list 
of required assessments, please refer to section 5.4.10. After Cycle 15, scans will be performed 
approximately every 6 cycles (168 +/- 14 days) or more frequently, until C36 at which point they 
may be performed at the investigator’s discretion until removal from treatment. Survival follow 
up should occur approximately every 3 cycles for up to 2 years, until death or next CLL/MCL-
directed therapy, whichever occurs first.  
 
 
Cycle = 28 days 
Screeni
ng 
Cycle 1  
 (+-3 Days) 
Cycle 2  
(+-3 Days) 
   
Cycles 
–3-6 
(+-3 
Days) 
Cycles 8+  
(Every 2 cycles 
until C12, then 
every 3 cycles 
until C36 or 
beyond 11 
Disease 
Progression/E
nd of 
Treatment9,10 
Follow Up 
(every 3 cycles for up 
to 2 years until new 
therapy, death, or 
withdrawal) 
Procedure \ Days 
-21-0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
15 
Day 1 
Day 1 
 
 
TGR-1202 Dose 
 
Daily Dosing - Days 1 – 28 
 
 
Ibrutinib Dose 
 
Daily Dosing - Days 1 – 28 
 
 
Survival Status12  
 
 
 
X12 
Informed consent 
Х 
 
 
 
 
 
 
 
 
 
 
Medical history 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Pregnancy test 
 Х* 
 
 
 
 
 
 
 
 
 
Physical examination 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (pulse  
rate, BP, temperature) 
Х 
X 
X 
X 
Х 
X 
X 
X 
X 
X 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
BM aspirate /biopsy 1, 
2, 3 
Х3 
 
 
 
 
 
 
X2,3 
 
    X2,3 
X2,3 
SPEP + 
Immunoglobulins 4  
X 
 
 
 
 
 
 
X 
 
 
 
ECOG performance 
status 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EKG 
Х 
 
 
 
 
 
 
 
 
 
 
Serology: HIV, HCV, 
HBV 
Х 
 
 
 
 
 
 
 
 
 
 
CT scan (+/- 7 days) 
X 
 
 
 
 
 
 
X5 
   X5,6 
X 
X5,6 
Hematology 
X 
X 
Х 
X 
Х 
X 
X 
X 
X 
X 
 
Serum Chemistry 
X 
X 
Х 
X 
Х 
X 
X 
X 
X 
X 
 
PT/PTT/INR 
X 
 
 
 
 
X 
 
 
 
 
 
FISH Analysis / 
IGHV 
status/TP53/Zap70 7 
X 
 
 
 
 
 
 
 
 
 
 
Correlative studies 
   X8,3 
X 
X 
 
 
 
 
 
 
X3 
 


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Cycle = 28 days 
Screeni
ng 
Cycle 1  
 (+-3 Days) 
Cycle 2  
(+-3 Days) 
   
Cycles 
–3-6 
(+-3 
Days) 
Cycles 8+  
(Every 2 cycles 
until C12, then 
every 3 cycles 
until C36 or 
beyond 11 
Disease 
Progression/E
nd of 
Treatment9,10 
Follow Up 
(every 3 cycles for up 
to 2 years until new 
therapy, death, or 
withdrawal) 
Procedure \ Days 
-21-0 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
15 
Day 1 
Day 1 
 
 
Adverse Event 
Evaluation  
      X 
X 
X 
X 
X 
X 
X 
X 
X 
          X 
 
Concomitant 
Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 Unilateral bone marrow aspirate and/or biopsy required within 90 days prior to Day 1 of Cycle 1
 
2 Only in patients who had a positive bone marrow prior to study initiation who achieve a radiographic CR, to confirm CR.  
3 Marrow sample requested for correlative studies if bone marrow biopsy is done as standard of care, or as part of protocol schedule  
 4 SPEP required at baseline and then at Cycle 3 and 6, 8, 10, 12, then every 3 cycles until Cycle 36, and every 6  cycles thereafter only if 
M protein detected at  baseline; If no M protein detected at baseline, IgG, IgA, IgM to be checked Cycle 3 and 6, 8, 10, 12, then every 3 
cycles until Cycle 36, and every 6  cycles thereafter (B2M only at baseline) 
5 Just prior to cycle 3, then just prior to cycles 6, 10 and 15 (eg: C2D28, C5D28, C9D28, C14D28 +/- 7 days)  
6 After C14D28 scans, CT scans should occur approximately every 6 cycles until C36 (+/- 14 days), then per investigator discretion 
thereafter 
7 FISH for both CLL/SLL and MCL are to be done locally- IGHV, TP53 and Zap70 for CLL/SLL patients only (Integrated Onc.) 
 8 Baseline correlative studies may be obtained either at the screening visit or prior to study drug administration on C1D1. 
9 End of treatment should be the next visit following a cycle after study drug was administered (within 3 days). 
10 Patients are to be followed for survival and response every 3 months for up to two years or until death or other CLL/MCL directed 
therapy 
* Within 3 days of Day 1 / Cycle 1 
11 After cycle 36, participants may return to the main study site every 6 cycles (168 days+/-14 days) if they are being followed by a local 
hematologist/oncologist in the interim q3 cycles (84 +/-14 days). No study specific assessments need occur at the interim visits. Please see 
section 5.4.10 for additional information . Those who remain at the main research institution for all visits will continue to be seen every 3 
cycles.  
12 Survival data may be collected by phone if necessary 
* Within 3 days of Day 1 / Cycle 1 


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11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, participants with measurable disease 
will be assessed by standard criteria.  For the purposes of this study, the first efficacy 
assessment should be approximately 8 weeks after Cycle 1/Day 1 (+/- 7 days) and then just 
prior to cycles 6, 10 and 15. After cycle 15, efficacy assessments should occur at least every 6 
cycles (168 +/- 14 days) until Cycle 36, where scans may be performed per investigator 
discretion. 
 
 
 
11.1 
Antitumor Effect  
 
Assessment of lymphoma response (CR, PR or SD) and disease progression will be evaluated as 
outlined in the schedule of events, according to the Revised Response Criteria for Malignant 
Lymphoma for MCL and SLL patients (26) and for CLL patients, the IWCLL Response Criteria 
(27) as modified by (28).   
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment on Cycle 1/Day 1. 
 
Evaluable for objective response.  Only those patients who have had a pre-treatment baseline 
efficacy evaluation and at least one post-treatment efficacy evaluation will be considered 
evaluable for response.  These patients will have their response classified according to the 
definitions stated below. 
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least two dimensions as >1 cm with spiral CT scan.  All tumor measurements should be 
recorded in centimeters.  For CLL, patients without measurable lymph node disease will have 
measureable disease include lymphocytosis > 5,000/µL and/or bone marrow involvement. 
 
Non-measurable disease.  All other lesions (or sites of disease) including small lesions, (<1 cm 
using spiral CT scan) are considered non-measurable disease.  Bone lesions, ascites, 
pleural/pericardial effusions, lymphangitis, and cystic lesions are all non-measurable.   
 
Target lesions.  All measurable lesions up to a maximum of 6 lesions total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with the longest SPD 


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56 
diameter), and their suitability for accurate repeated measurements (either by imaging techniques 
or clinically).  A baseline sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters.  
The baseline sum of the diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
 
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, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool.  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. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT thickness is 0.5cm or less. If CT scans have slice thickness greater 
than 0.5 cm, the minimum size of a measurable lesion should be twice the slice thickness.  
 
11.2 
Response Criteria 
 
See Appendix A for SLL and MCL. See Appendix B for CLL.  
 
11.2.1 Radiographic Response Review 
 
Radiology will be centrally reviewed by the DF/HCC Tumor Imaging Metrics Core (TIMC). 
 
Each participating site will be responsible for assuring review and confirmation of response as 
per standard review guidelines at that center.   Patients who achieve an objective response may 
have scans collected and reviewed by independent radiology set up by the Sponsor. 
 
11.2.2 Nodal Partial Response (nPR) 
 
It is anticipated that many patients on this study, particularly in the CLL arm, will experience 
increased lymphocytosis after starting on the study drugs.  This is a well-known phenomenon 
that is a class effect of the BCR inhibitor drugs.  In clinical experience, these patients appear to 
derive a similar clinical benefit from BCR inhibitors as patients who achieve a traditional PR. 
Therefore, a revision to the IWCLL criteria was proposed and is now widely recognized.  As per 
Cheson et al., 2012, patients who achieve a radiographic PR but continue to have a 


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57 
lymphocytosis with >5,000 B-lymphocytes per µL where the absolute lymphocyte count has not 
decreased by 50% or more compared to baseline are considered to have a nodal partial response, 
also known as PR with lymphocytosis. 
 
11.2.3 Evaluation of Best Overall Response  
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria as per the MCL and 
CLL established criteria used in this study (See Appendix A and B). 
 
11.2.4 Duration of Response 
 
Duration of response is defined as the time from documentation of a response to treatment to the 
first documentation of documentation of tumor progression or death due to any cause whichever 
comes first.  Duration of the response will be summarized using n (sample size), mean, standard 
deviation, median, minimum, and maximum for the responders. 
 
 
11.2.5 Progression-Free Survival 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
registration to the earlier of progression or death due to any cause. Participants alive without 
disease progression are censored at date of last disease evaluation. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0  
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ)  will collect, manage, and perform quality checks on the data 
for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the QACT according to the schedule set by the QACT. Data should be entered within 
14 business days of the corresponding visit and within 14 business days of the end of a cycle for 
any forms to be completed per cycle. 
 


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12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
12.3 
Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing. 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports to all participating institutions for submission to their 
individual IRBs for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the 
study agent(s) directly from supplier.  A participating site may order the agent(s) only 
after the initial IRB approval for the site has been forwarded to the Coordinating 
Center. 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a multi-center Phase I/Ib study evaluating the safety of the novel PI3k delta inhibitor 
TGR-1202 in combination with ibrutinib in patients with relapsed or refractory CLL or MCL. 
The primary endpoint of this study is to determine the maximum tolerated dose (MTD) in each 
disease group separately.  
 
13.1 
Determining MTD 
 
This is a 3+3 design with four doses of TGR-1202 to be considered to determine MTD: 200mg 
(dose level -1), 400 mg (dose level 1, starting dose), 600 mg (dose level 2), and 800 mg (dose 


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59 
level 3). Dose limiting toxicities (DLTs) were defined in section 5.6.3.  
 
A cohort of 3 patients will enter at each dose level. If no DLT is seen in the first 3 eligible 
patients at dose level 1 or 2, a dose escalation will take place. If no DLT is seen in the first 3 
eligible patients at dose level 3 or -1, 3 additional patients will be treated at that dose level. If 2 
or more of the 3 eligible patients experience a DLT at dose level 1, 2, or 3, the next cohort of 3 
patients will be treated at the next lower dose level, unless 6 patients have already been treated at 
that dose level. If 2 or more of the first 3 eligible patients experience a DLT at dose level -1, the 
study will be terminated early.  If 1 of the first 3 patients experiences a DLT then 3 additional 
patients will be treated at that dose level. If there is no DLT in the 3 additional patients then dose 
escalation will take place. If this is dose level 3 or -1, then this dose is the MTD. If 1 or more of 
the 3 additional patients experience(s) DLT then the MTD is considered exceeded, and 3 more 
patients are treated at the next lower dose, unless 6 patients have already been treated at that dose 
level. If this is dose level -1, the study will be terminated early.  
 
A minimum of six patients must be evaluated at the highest tolerated dose level, and fewer than 2 
patients in 6 should experience DLT. 
 
Table 5 shows the probability of escalation under various true DLT rates. With this design, there 
is 91% probability of dose escalation if the true rate of DLT is 10% and 17% probability of 
escalation if the true DLT rate is 50%. 
 
Table 5: probability of dose escalation 
True Rate of DLT 
Prob. of Escalation 
10% 
0.91 
20% 
0.71 
30% 
0.49 
40% 
0.31 
50% 
0.17 
60% 
0.08 
 
13.2 
Phase Ib 
 
Once the MTD is established, an additional 12 eligible patients in each disease group will be 
treated at the MTD level to further evaluate the safety of TGR-1202 in combination of ibrutinib. 
The estimation of toxicity rate will be based on these 12 additional patients. With 12 patients, the 
90% confidence interval of the toxicity rate will be within ±25%.  
 
13.3 
Accrual 
 
The sample size will approximately range from 4-30 eligible patients in each disease, depending 
on the observance of DLTs and the number of dose levels tested. Based on the current practice, 
we anticipate that the accrual rate will be approximately 2-3 patients per month per disease.  
 
13.4 
 Analysis Plan for Secondary Objectives 
 


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60 
The secondary objectives include assessment of the overall response rate, nodal partial response 
rate, progression-free survival, and duration of response. Due to the exploratory nature, the 
analysis for secondary endpoints will largely be descriptive. Response rate and duration of 
response will be summarized descriptively and the Kaplan Meier method will be used to estimate 
the median progression-free survival time and progression-free survival. A similar descriptive 
analysis will be performed for laboratory correlative studies of BH3 profiling and 
pharmacodynamic markers such as phosphorylated levels of AKT, BTK, and ERK, as well as 
Ki-67 level. If feasible, association between clinical response and laboratory endpoints will be 
explored.   
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 


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61 
 
 
15. REFERENCES 
 
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62 
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Therapeuticis PVT Ltd; 2011 June Study Report IVT-5264-APM-10 Sponsored by Rhizen 
Pharmaceutical S.A Switzerland 
17. Seeta N, Viswanadha S. AKT phosphorylation in DB cells. Shameerpet, India: Incozen 
Therapeuticis PVT Ltd; 2011 June Study Report IVT-5264-APD-11 Sponsored by Rhizen 
Pharmaceutical S.A Switzerland 
18. Seeta N, Viswanadha S. AKT phosphorylation in JURKAT cells. Shameerpet, India: Incozen 
Therapeuticis PVT Ltd; 2011 August Study Report IVT-5264-APG-12 Sponsored by Rhizen 
Pharmaceutical S.A Switzerland 
19. Seeta N, Viswanadha S. AKT phosphorylation in HL-60 cells. Shameerpet, India: Incozen 
Therapeuticis PVT Ltd; 2011 August Study Report IVT-5264-APH-09 Sponsored by Rhizen 
Pharmaceutical S.A Switzerland  
20.  Savona, M, Lanasa, M, O'Connor, O, Changchun, D, Gutierrez, M, et al.  A Phase I Dose 
Escalation Study of TGR-1202, a Novel PI3k-d Inhibitor for Patients with Relapsed or 
Refractory Hematologic Malignancies.  2013 ASH Annual Meeting, Abstract 4373. 
21. Burris, HA., Patel, MR., Lanasa, MC., Brander, D., O'Connor, OA., Deng, C., Gutierrez, M., 
Jones, SF., Kuhn, JG., Muskin, HP., Sportelli, P., Vakkalanka, S. Flinn, I. Activity of TGR-1202, 
a Novel Once-Daily PI3Kδ Inhibitor, in Patients with Relapsed or Refractory Hematologic 
Malignancies. 2014 EHA Annual Meeting, Abstract P250.  


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63 
22.  Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Xue L, Li DH, 
Steggerda SM, Versele M, Dave SS, Zhang J, Yilmaz AS, Jaglowski SM, Blum KA, Lozanski 
A, Lozanski G, James DF, Barrientos JC, Lichter P, Stilgenbauer S, Buggy JJ, Chang BY, 
Johnson AJ, Byrd JC.  Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor 
Ibrutinib.  N Engl J Med 2014 Jun 12;370(24):2286-2294. 
23.  Davids MS, Deng J, Wiestner A, Lannutti BJ, Wang L, Wu CJ, Wilson WH, Brown 
JR, Letai A.  Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment 
resistance in chronic lymphocytic leukemia.  Blood. 2012 Oct 25;120(17):3501-9. 
24.  Ryan J and Letai A.  BH3 profiling in whole cells by fluorimeter or FACS.  Methods. 2013 
Jun 1;61(2):156-64. 
25. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. 
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the 
International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-56. PMCID: 2972576. 
26.  Cheson BD, Fisher, RI, Barrington SF, Cavali F, Schwartz LH, Zucca E, and Lister TA. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification.  J. Clin Oncol 2014 Sep 20;32(27):3059-
3067. 
27.  Cheson BD, Byrd, JC, Rai, KR, Kay, NE, O'Brien, SM, Flinn, IW, Wiestner, A, Kipps, TJ.  
Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia.  
J. Clin Oncol. 2012 Aug 10;30(23):2820-2 
 


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16. APPENDIX A 
RECOMMENDATIONS FOR INITIAL EVALUATION, STAGING, 
AND RESPONSE ASSESSMENT OF HODGKIN AND NON-HODGKIN 
LYMPHOMA: THE LUGANO CLASSIFICATION 
 (CHESON ET. AL. 2014)  
 
Revised Criteria for Response Assessment 
 
Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all 
of the following) 
Lymph nodes 
and 
extralymphatic 
sites 
Score 1, 2, or 3* with or without a 
residual mass on 5PS† 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
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 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 
No extralymphatic sites of disease 
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 
 
At interim, these findings suggest 
responding disease 
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value 
 
At end of treatment, these findings 
indicate residual disease 
When no longer visible, 0 × 0 mm 


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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
 
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 
50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given to further evaluation with MRI or 
biopsy or an interval scan 
Not applicable 
No response or 
stable disease 
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 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression 
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive 
disease 
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: 
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 


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Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
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 
Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy 
or interval scan may be considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new 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 undertreatment). 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 


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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. 
 
 
 
APPENDIX B  
CHRONIC LYMPHOCYTIC LEUKEMIA RESPONSE 
DEFINITION (HALLEK ET AL. 2008) 
 
Assessment of response should include a careful physical examination and evaluation of the 
blood and marrow. 
Complete 
Response: 
(CR) 
CR requires all of the following criteria as assessed at least 2 months after completion 
of therapy: 
1. Peripheral blood lymphocytes (evaluated by blood and differential count) below 
4 x 109/L (4000/µL). 
2. Absence of significant lymphadenopathy (e.g., lymph nodes >1.5 cm in diameter) 
by physical examination. 
3. No hepatomegaly or splenomegaly by physical examination and CT. 
4. Absence of constitutional symptoms. 
5. Blood counts above the following values: 
• Neutrophils >1.5 x 109/L (1500/µL) without need for exogenous growth 
factors. 
• Platelets >100 x 109/L (100 000/µL) without need for exogenous growth 
factors. 
• Hemoglobin >110 g/L (11.0 g/dL) without red blood cell transfusion or 
need for exogenous erythropoietin. 
 
For patients in clinical trials, a marrow aspirate and biopsy should be performed at 
least 2 months after the last treatment and if clinical and laboratory results listed 
above a-e demonstrate that a CR has been achieved.  To define a CR, the marrow 
sample must be at least normocellular for age, with less than 30% of nucleated cells 
being lymphocytes.  Lymphoid nodules should be absent.  In some cases, lymphoid 
nodules can be found, which often reflect residual disease.  These nodules should be 
recorded as "nodular PR."  Moreover, immunohistochemistry should be performed to 
define whether these nodules are composed primarily of T cells or lymphocytes other 
than CLL cells or of CLL cells.  If the marrow is hypocellular, a repeat determination 
should be performed after 4 weeks, or until peripheral blood counts have recovered.  
However, this time interval should not exceed 6 months after the last treatment.  A 
marrow biopsy should be compared with that of pretreatment marrow. In general 
practice, the use of a marrow biopsy for evaluating a CR is at the discretion of the 
physician.  


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In clinical trials aiming at maximizing the CR rate, the quality of the CR should be 
assessed for MRD by flow cytometry or by immunohistochemistry. 
 
A controversial issue is how best to categorize the response of patients who fulfill all 
the criteria for a CR (including the marrow examinations described above) but who 
have a persistent anemia or thrombocytopenia or neutropenia apparently unrelated 
to CLL but related to drug toxicity.  We recommend that these patients be considered 
as a different category of remission:  CR with incomplete marrow recovery (CRi).  For 
the definition of this category, CRi, the marrow evaluation (described above) should be 
performed with scrutiny and not show any clonal infiltrate.  In clinical trials, CRi 
patients should be monitored prospectively to determine whether their outcome differs 
from that of patients with detectable residual or with noncytopenic CR. 
 
 
 
 
Partial 
Response: 
(PR) 
To define a PR (partial remission): at least two of the criteria of Group A plus one of 
the criteria of Group B have to be met. The parameters below should be documented 
for no less than 2 months.  Constitutional symptoms persisting for >1 month should 
be recorded. 
Group A 
a. Decrease in the number of blood lymphocytes by 50% or more from the value 
before therapy. 
b. Reduction in lymphadenopathy (by PE and CT scans) as defined by the 
following: 
• A decrease in lymph node size by 50% or more either in the sum 
products of up to 6 lymph nodes, or in the largest diameter of the 
enlarged lymph node(s) detected prior to therapy. 
• No increase in any lymph node, and no new enlarged lymph node. In 
small lymph nodes (<2 cm), an increase of less than 25% is not 
considered to be significant. 
c. Reduction in the noted pretreatment enlargement of the spleen or liver by 50% 
or more, as detected by CT scan. 
Group B 
d. Blood count should show one of the following: 
• Neutrophils >1.5 x 109/L (1500/µL) without need for exogenous growth 
factors. 
• Platelet count >100 x 109/L (100 000/µL) or 50% improvement over 
baseline without need for exogenous growth factors. 
• Hemoglobin >110 g/L (11.0 g/dL), or 50% improvement over baseline 
without requiring red blood cell transfusions or exogenous 
erythropoietin. 
 
 
 


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 Chronic Lymphocytic Leukemia Response Definition (Hallek et al. 2008) (continued) 
 
Progressive 
Disease: 
(PD) 
Progressive disease during or after therapy is characterized by at least one of the 
following: 
a. Lymphadenopathy:  Progression of lymphadenopathy is often 
discovered by physical examination and should be recorded. In 
CLL, the use of CT scans usually does not add much information 
for the detection of progression or relapse.  Therefore, the use of 
imaging methods to follow CLL progression is at the discretion of 
the treating physician. Disease progression occurs if one of the 
following events is observed: 
• Appearance of any new lesion, such as enlarged lymph 
nodes (>1.5 cm), splenomegaly, hepatomegaly, or other 
organ infiltrates. 
• An increase by 50% or more in greatest determined 
diameter of any previous site. 
b. An increase in the previously noted enlargement of the liver or 
spleen by 50% or more, or the de novo appearance of hepatomegaly 
or splenomegaly. 
c. An increase in the number of blood lymphocytes by 50% or more, 
with at least 5000 B-lymphocytes per µL. 
d. Transformation to a more aggressive histology (e.g., Richter 
syndrome).  Whenever possible, this diagnosis should be 
established by lymph node biopsy. 
e. Occurrence of cytopenia (neutropenia, anemia, or 
thrombocytopenia) attributable to CLL  
• During therapy:  Cytopenias may occur as a side effect of 
many therapies.  During therapy, cytopenias cannot be used 
to define disease progression. 
• After treatment:  The progression of any cytopenia 
(unrelated to autoimmune cytopenia), as documented by a 
decrease of Hb levels by >20 g/L (2 g/dL) or to <100 g/L 
(10 g/dL), or by a decrease of platelet counts by >50% or to 
<100 x 109/L (100,000/µL), which occurs at least 3 months 
after treatment, defines disease progression, if the marrow 
biopsy demonstrates an infiltrate of clonal CLL cells. 
 
Stable 
Disease:  
(SD) 
Patients who have not achieved a CR, PR, or nPR and who have not exhibited 
progressive disease, will be considered to have stable disease (which is equivalent 
to a non-response). 
Nodular 
Partial 
Response 
(nPR) 
As per Cheson et al., 2012, patients who achieve a radiographic PR but continue to 
have a lymphocytosis with >5,000 B-lymphocytes per µL are considered to have a 
nodular partial response, also known as PR with lymphocytosis, due to the fact that 
they appear to derive a similar clinical benefit from BCR inhibitors as patients who 
achieve a traditional PR. 


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


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APPENDIX C  
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. A tubal 
ligation is  also sufficient documentation that a patient is not of child bearing potential for this 
trial. 
 
 
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 additional 4 weeks 
after study drug discontinuation.  The highly effective contraception is defined as either: 
 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
 
2. Sterilization:  have had surgical bilateral oophorectomy (with or without hysterectomy) 
or tubal ligation at least six weeks ago.  In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment. 
 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female subjects on the study, the vasectomised 
male partner should be the sole partner for that patient. 
 
4. Use of a combination of any two of the following (a+b): 
a.  Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or   
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
 
The following are unacceptable forms of contraception for women of childbearing potential:  
• Oral contraception, injected or implanted hormonal methods are not allowed as ibrutinib 
potentially decreases the effectiveness of hormonal contraceptives. 
• IUD progesterone T  
• Female condom  
• Natural family planning (rhythm method) or breastfeeding  
• Fertility awareness  
• Withdrawal  


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• Cervical shield 
 
Women of child-bearing potential must have a negative serum or urine pregnancy test ≤ 72 hours 
prior to initiating treatment. 
 
Fertile Males: 
Fertile males, defined as all males physiologically capable of conceiving offspring must use 
condom during treatment, for additional 4 weeks after study drug discontinuation, and should not 
father a child in this period.   
 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to TG 
Therapeutics Inc. within 24 hours of learning of its occurrence. The pregnancy should be 
followed up for 3 months after the termination of the pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to TG Therapeutics Inc.  Pregnancy follow-up should be recorded on the same form 
and should include an assessment of the possible relationship to the study drug and reported by 
the investigator to TG Therapeutics Inc.  Any SAE experienced during pregnancy must be 
reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D   
IWCLL GRADING SCALE FOR HEMATOLOGIC TOXICITY IN 
CLL STUDIES 
  
Grade 
Decrease in Platelets¢ or 
Hb‡ (nadir) from 
Pretreatment Value, % 
Absolute neutrophil 
count/µL (nadir)§ 
0 
No change to 10% 
≥2000 
1 
11% - 24% 
≥1500 and <2000 
2 
25% - 49% 
≥1000 and <1500 
3 
50% - 74% 
≥ 500 and <1000 
4 
≥75% 
<500 
 
Grades:  1, mild; 2, moderate; 3 severe; 4 life-threatening; 5 fatal.  Death occurring as a result of 
toxicity at any level of decrease from pretreatment will be recorded as grade 5. 
 
¢Platelet decrease, must be below normal levels for grades 1 to 4 at any level of decrease, the 
platelet count is <20X 109/L (20,000/µL), this will be considered grade 4 toxicity, unless a 
severe or life-threatening decrease in the initial platelet count (eg, 20 X 109/L [20 000/µL]) was 
present pretreatment, in which case the patient is not evaluable for toxicity referable to platelet 
counts. 
 
‡ Hb levels must be below normal levels for grades 1 to 4.  Baseline and subsequent Hb 
determinations must be performed before any given transfusions. The use of erythropoietin is 
irrelevant for the grading of toxicity but should be documented. 
 
§ If the absolute neutrophil count (ANC) reaches <1X 109/L (1000/µL), it should be judged to be 
grade 3 toxicity. Other decreases in the white blood cell count, or in circulating neutrophils, are 
not to be considered because a decrease in the white blood cell count is a desired therapeutic 
endpoint. A gradual decrease in granulocytes is not a reliable index in CLL for stepwise grading 
of toxicity.  If the ANC was< 1X 109/L (1000/µL) before therapy, the patient is not evaluable for 
toxicity referable to the ANC. The use of growth factors such as G-CSF is not relevant to the 
grading of toxicity, but should be documented.


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APPENDIX E: 14-396 MCL STUDY PARTICIPANT SELF-ADMINISTERED DRUG DIARY 
PATIENT INSTRUCTIONS:  Take your medications exactly as prescribed by your doctor.  See the next page for specific doses for each 
medication that you are taking. 
Both TRG-1202 and ibrutinib should be kept in the provided bottles. Store drugs at room temperature.  
TGR-1202:  
• TGR-1202 should be taken by mouth once per day, preferably in the morning. TGR-1202 should be taken with food, preferably within 30 
minutes of a meal and with a full glass of water (approximately 8 ounces). 
• Do not split or crush tablets or empty into any food or drink for oral ingestion. Tablets must be swallowed whole.  
• If you vomit after taking TGR-1202, do NOT take another dose. Please note any vomiting in the Comments section of the diary on the next 
page.  
• If a dose is missed and it is less than 4 hours from usual time of dosing, then you may take that dose. Otherwise that dose should be skipped 
and NOT taken. You should resume regular dosing the following day.  If you miss a dose, record “0” for Number Taken on the next page.  
• If you accidentally take an extra dose during a day skip the next day’s dose and record the extra dose on the next page.   
• Please bring any unused TGR-1202 tablets, all empty TGR-1202 containers and diary to your next visit.  
Ibrutinib: 
• Ibrutinib should be taken by mouth once per day, preferably in the evening and can be taken with or without food. Capsules should be 
swallowed intact with 8 ounces of water (approximately 8 ounces). 
• Do not consume grapefruit, grapefruit juice or Seville oranges. Do not take fish oil or vitamin E supplements.  Consult your doctor before 
making any changes to medications or supplements.  
• If a dose is missed, it can take it as soon as possible on the same day and you should take dose at the normally scheduled time the next day.  
• If you vomit drug, please record this in diary as a missed dose and do not take another dose of drug that day. 
 
 
 
FOR CLINIC USE ONLY:  
• Give patient all 2 pages of Drug Diary stapled together.  
Provide one diary per cycle (28 days). 
• Complete patient identifiers and medical team contact 
information on page 2.  
• Complete correct dose levels for TGR-1202 and Ibrutinib 
therapy on page 2.  
• When patient returns pill bottles and diary perform a TGR-
1202 pill count and record adherence information in the box 
to the right.  
Staff Initials: 
  
Date Dispensed: 
  
Date Returned: 
  
#  TGR-1202 tablets dispensed:  
#   TGR-1202 tablets returned: 
#   TGR-1202 tablets that should have been taken: 
Discrepancy Notes: 
  


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APPENDIX E: MCL 14-396 STUDY PARTICIPANT 
 
 SELF-ADMINISTERED DIARY  
 
Participant Identifier: _________   Cycle #: ______ 
Your MD ____________________  
Phone ____________________  
Your RN _____________________  
Phone ____________________ 
 
STUDY DRUG INSTRUCTIONS:  
Take the following medications as indicated below.  
Record the dose of each medication on the chart to  
the right after taking each day. 
 
TGR-1202 dose:  
 1 x 200 mg tablets by mouth on Days 1-28 (200 mg) 
 2 x 200 mg tablets by mouth on Days 1-28 (400 mg) 
 3 x 200 mg tablets by mouth on Days 1-28 (600 mg) 
 4 x 200 mg tablets by mouth on Days 1-28 (800 mg) 
 
Ibrutinib:   
 4 x 140 mg capsules by mouth on Days 1-28 (560 mg) 
 
Patient 
Signature:___________________________Date:_______ 
 
Study Staff 
Signature:______________________Date:_______ 
 
 
Date 
TGR- 1202 
Ibrutinib 
 
Comments 
Number 
Taken 
Time 
Taken 
Number 
Taken 
Time 
Taken 
Ex.  
11/2/14 
1 
8:00 AM 
1 
 8:00 PM 
 
Day 1 
 
 
 
 
 
 
Day 2 
 
 
 
 
 
 
Day 3 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
Day 5 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
Day 8 
 
 
 
 
 
 
Day 9 
 
 
 
 
 
 
Day 10  
 
 
 
 
 
Day 11  
 
 
 
 
 
Day 12  
 
 
 
 
 
Day 13  
 
 
 
 
 
Day 14  
 
 
 
 
 
Day 15  
 
 
 
 
 
Day 16  
 
 
 
 
 
Day 17  
 
 
 
 
 
Day 18  
 
 
 
 
 
Day 19  
 
 
 
 
 
Day 20  
 
 
 
 
 
Day 21  
 
 
 
 
 
Day 22  
 
 
 
 
 
Day 23  
 
 
 
 
 
Day 24  
 
 
 
 
 
Day 25  
 
 
 
 
 
Day 26   
 
 
 
 
 
Day 27  
 
 
 
 
 
Day 28  
 
 
 
 
 


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CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
76 
APPENDIX F: 14-396 CLL/SLL STUDY PARTICIPANT SELF-ADMINISTERED DRUG DIARY 
PATIENT INSTRUCTIONS:  Take your medications exactly as prescribed by your doctor.  See the next page for specific doses for each 
medication that you are taking. 
Both TRG-1202 and ibrutinib should be kept in the provided bottles. Store drugs at room temperature.  
TGR-1202:  
• TGR-1202 should be taken by mouth once per day, preferably in the morning. TGR-1202 should be taken with food, preferably within 30 
minutes of a meal and with a full glass of water (approximately 8 ounces). 
• Do not split or crush tablets or empty into any food or drink for oral ingestion. Tablets must be swallowed whole.  
• If you vomit after taking TGR-1202, do NOT take another dose. Please note any vomiting in the Comments section of the diary on the next 
page.  
• If a dose is missed and it is less than 4 hours from usual time of dosing, then you may take that dose. Otherwise that dose should be skipped 
and NOT taken. You should resume regular dosing the following day.  If you miss a dose record “0” for Number Taken on the next page.  
• If you accidentally take an extra dose during a day skip the next day’s dose and record the extra dose on the next page.   
• Please bring any unused TGR-1202 tablets, all empty TGR-1202 containers and diary to your next visit.  
Ibrutinib: 
• Ibrutinib should be taken by mouth once per day, preferably in the evening and can be taken with or without food.  Capsules should be 
swallowed intact with 8 ounces of water (approximately 8 ounces). 
• Do not consume grapefruit, grapefruit juice or Seville oranges while taking ibrutinib. Do not take fish oil or vitamin E supplements.  Consult 
your doctor before making any changes to medications or supplements. 
• If a dose is missed, it can take it as soon as possible on the same day and you should take dose at the normally scheduled time the next day.  
• If you vomit drug, please record this in diary as a missed dose and do not take another dose of drug that day. 
 
 
 
FOR CLINIC USE ONLY:  
• Give patient all 2 pages of Drug Diary stapled together.  
Provide one diary per cycle (28 days). 
• Complete patient identifiers and medical team contact 
information on page 2.  
• Complete correct dose levels for TGR-1202 and Ibrutinib 
therapy on page 2.  
• When patient returns pill bottles and diary perform a TGR-
1202 pill count and record adherence information in the box 
to the right.  
Staff Initials: 
  
Date Dispensed: 
  
Date Returned: 
  
#  TGR-1202 capsules 
dispensed:  
#   TGR-1202 capsules returned: 
#   TGR-1202 capsules that should have been taken: 
  
Discrepancy Notes: 
   


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CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
APPENDIX F: 14-396 CLL/SLL STUDY 
PARTICIPANT  
 SELF-ADMINISTERED DIARY  
 
 
Participant Identifier: _________   Cycle #: ______ 
Your MD ____________________  
Phone ____________________  
Your RN _____________________  
Phone ____________________ 
 
STUDY DRUG INSTRUCTIONS:  
Take the following medications as indicated below.  
Record the dose of each medication on the chart to  
the right after taking each day. 
 
TGR-1202 dose:  
 1 x 200 mg tablets by mouth on Days 1-28 (200 mg) 
 2 x 200 mg tablets by mouth on Days 1-28 (400 mg) 
 3 x 200 mg tablets by mouth on Days 1-28 (600 mg) 
 4 x 200 mg tablets by mouth on Days 1-28 (800 mg) 
 
Ibrutinib:   
 3 x 140 mg capsules by mouth on Days 1-28 (420 
mg) 
 
Patient 
Signature:___________________________Date:_____ 
 
Study Staff Signature:__________________________Date:_______ 
 
 
Date 
TGR- 1202 
Ibrutinib 
 
Comments 
Number 
Taken 
Time 
Taken 
Number 
Taken 
Time 
Taken 
Ex.  
11/2/2014 1 
8:00 AM 
1 
 8:00PM 
 
Day 1 
 
 
 
 
 
 
Day 2 
 
 
 
 
 
 
Day 3 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
Day 5 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
Day 8 
 
 
 
 
 
 
Day 9 
 
 
 
 
 
 
Day 10 
 
 
 
 
 
 
Day 11 
 
 
 
 
 
 
Day 12 
 
 
 
 
 
 
Day 13 
 
 
 
 
 
 
Day 14 
 
 
 
 
 
 
Day 15 
 
 
 
 
 
 
Day 16 
 
 
 
 
 
 
Day 17 
 
 
 
 
 
 
Day 18 
 
 
 
 
 
 
Day 19 
 
 
 
 
 
 
Day 20 
 
 
 
 
 
 
Day 21 
 
 
 
 
 
 
Day 22 
 
 
 
 
 
 
Day 23 
 
 
 
 
 
 
Day 24 
 
 
 
 
 
 
Day 25 
 
 
 
 
 
 
Day 26 
 
 
 
 
 
 
Day 27  
 
 
 
 
 
 
Day 28 
 
 
 
 
 
 


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CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
APPENDIX G 
PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 


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CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
APPENDIX H THE NEW YORK HEART ASSOCIATION CLASSIFICATION OF 
CARDIAC DISEASE 
 
The following table presents the NYHA classification of cardiac disease: 
 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
No objective 
evidence of 
cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence 
of minimal 
cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence 
of moderately severe 
cardiovascular 
disease. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort is increased. 
Objective evidence 
of severe 
cardiovascular 
disease. 


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DFCI IRB Protocol #: 14-396 
 
 
APPENDIX I: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER 
DATA SAFETY MONITORING PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION .............................................................................................................82 
1.1 
Purpose ...................................................................................................................82 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ..................................82 
2. 
GENERAL ROLES AND RESPONSIBILITIES .............................................................83 
2.1 
DF/HCC Sponsor ...................................................................................................83 
2.2 
Coordinating Center ...............................................................................................84 
2.3 
Participating Institution ..........................................................................................84 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................85 
3.1 
Protocol Distribution ..............................................................................................85 
3.2 
Protocol Revisions and Closures ...........................................................................85 
3.3 
Informed Consent Requirements ...........................................................................86 
3.4 
IRB Documentation ...............................................................................................86 
3.5 
IRB Re-Approval ...................................................................................................86 
3.6 
Participant Confidentiality and Authorization Statement ......................................86 
3.7 
DF/HCC Multi-Center Protocol Registration Policy .............................................87 
3.8 
DF/HCC Protocol Case Number ............................................................................87 
3.9 
Safety Assessments and Toxicity Monitoring .......................................................89 
3.10 
Data Management ..................................................................................................90 
4. 
REQUISITIONING INVESTIGATIONAL DRUG..........................................................90 
5. 
MONITORING: QUALITY CONTROL ..........................................................................90 
5.1 
Ongoing Monitoring of Protocol Compliance .......................................................91 
5.2 
Monitoring Reports ................................................................................................92 
5.3 
Accrual Monitoring ................................................................................................92 
6. 
AUDITING: QUALITY ASSURANCE ...........................................................................92 
6.1 
Audit Plan: NCI Sponsored Trials ......................... Error! Bookmark not defined. 
6.2 
Audit Plan: DF/HCC Sponsored Trials..................................................................92 
6.3 
Audit Notification ..................................................................................................92 
6.4 
Audit Reports .........................................................................................................92 
6.5 
Participating Institution Performance ....................................................................93 
 


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1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol. 
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures..        
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth 
Israel Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham 
and Women’s Hospital (BWH)) responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the 
DFCI IRB and applicable regulatory guidelines. The Lead Institution is typically the home 
of the DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating 
Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies. The DF/HCC Sponsor has ultimate authority over the protocol and is responsible 
for the conduct of the study at DF/HCC and all Participating Institutions. In most cases the 
DF/HCC Sponsor is the same person as the DF/HCC Overall Principal Investigator; 
however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor 
as having the ultimate authority and responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc) that provides administrative support to the DF/HCC 


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Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines. In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. 
Should the DF/HCC Sponsor decide to use a CRO, the CRO will be deemed the 
Coordinating Center.   
 
DF/HCC Quality Assurance Office for Clinical Trials: A group within DF/HCC 
responsible for registering human subjects for trials, ensuring high-quality standards are 
used for data collection and the ongoing management of clinical trials, auditing, and data 
and safety monitoring. QACT also coordinates quality assurance efforts related to multi-
center clinical research. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities:  
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Matthew Davids, MD will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol 
as well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives 
adequate protocol training and/or a Site Initiation Visit prior to enrolling 
participants and throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments 
prior to extending the protocol to that site. 


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• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 
2.2 Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Review registration materials for eligibility and register participants from 
Participating Institutions with DF/HCC QACT. 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review.   
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all 
sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites. 
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
2.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not 
limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents 
as requested. 
• Participate in protocol training prior to enrolling participants and throughout the 
trial as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 


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• Register participants through the Coordinating Center prior to beginning research 
related activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements.  
• Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA 
standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 
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about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that only attending physicians obtain informed consent and re-consent to interventional 
trials (i.e. drug and/or device trials).   
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date.   
 
 
3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 


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information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an authorization statement.  This 
authorization statement may or may not be separate from the informed consent document.  
The Coordinating Center, with the approval from the DFCI IRB, will provide a consent 
template, with information regarding authorization for the disclosure of protected health 
information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health 
information must be collected. DF/HCC has chosen to use authorizations, signed by the 
participant in the trial, rather than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center 
should be de-identified. It is recommended that the assigned DF/HCC QACT case number 
(as described below) be used for all participant specific documents. Participant initials 
may be included or retained for cross verification of identification.  
 
3.7 DF/HCC Multi-Center Protocol Registration Policy 
  
3.7.1 Participant Registration and Randomization  
 
See Sections 4.3 and 4.4 of the protocol.  
 
3.7.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC QACT before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives confirmation of 
the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. 
 
3.7.3  Eligibility Exceptions 
 
The DF/HCC QACT will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC QACT requires each institution to fully 
comply with this requirement. 
 
3.8 DF/HCC Protocol Case Number 
 


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At the time of registration, QACT requires the following identifiers for all subjects: 
initials, date of birth, gender, race and ethnicity. Once eligibility has been established and 
the participant successfully registered, the participant is assigned a unique protocol case 
number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.   
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB. 
 
3.8.2  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation.  
 
 
3.8.3  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all 
protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original 
submission.  


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All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will 
forward all violation reports to CTEP via an internal DF/HCC process, as applicable. 
 
3.9 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in Section 7 of the protocol.  
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures 
 
3.9.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review and submit to their IRB according to their institutional policies and procedures. 
 
 


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3.10 Data Management 
 
The DF/HCC QACT develops case report forms (CRF/eCRFs), for use with the protocol.  
These forms are designed to collect data for each study. The DF/HCC QACT provides a 
web based training for eCRF users. 
   
3.10.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in accordance 
with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution 
will receive a written or electronic query from the DF/HCC QACT Data Analyst, 
Coordinating Center or designee.  Responses to all queries should be completed and 
submitted within 14 calendar days.  Responses may be returned on the written query or on 
an amended paper case report form, or in the case of electronic queries, within the 
electronic data capture (eDC) system. In the case of a written query for data submitted on 
a paper case report form, the query must be attached to the specific data being re-
submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  These 
reports are compiled by the DF/HCC QACT and distributed on a monthly basis.  
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
The ordering of investigational agent is specified in Section 8 of the protocol.  
 
Participating Institutions should order their own agent regardless of the supplier. 
   
If the agent is commercially available, check with the local Director of Pharmacy and/or 
the Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, 
ensure that the agent can be ordered once the protocol is approved by the local IRB.  
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed 
of who will supply the agent so that any regulatory responsibilities can be met in a timely 
fashion.  
 
5. MONITORING: QUALITY CONTROL 
 


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The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the QACT provides quality 
control oversight for the protocol. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions will be required to submit subject source documents to the 
DF/HCC Lead Institution or designee for monitoring. Also, the Participating Institution 
may be subject to on-site monitoring conducted by the DF/HCC Lead Institution. 
 
The DF/HCC Lead Institution will implement on-site as well as virtual monitoring 
activities to ensure that Participating Institutions are complying with regulatory and 
protocol requirements, data quality, and subject safety. At a minimum, the DF/HCC Lead 
Institute, or designee, will monitor each participating site twice a year while patients are 
receiving treatment. Should a Participating Institution be monitored once and then not 
accrue any additional patients or participant visits, then a second monitoring visit may not 
be necessary.  
 
Monitoring practices may include but are not limited to; source verification, review and 
analysis of the following: eligibility requirements of all participants, informed consent 
procedures, adverse events and all associated documentation, study drug administration / 
treatment, regulatory records and site trial master files, protocol deviations,  pharmacy 
records, response assessments, and data management.  Additionally, regular and ongoing 
communication with Participating Institutions will be accomplished by holding all site 
teleconferences at least monthly. The Lead Institution will keep in close touch with the 
Participating Institutions via email and phone. Source documents from Participating 
Institutions, will be collected at specific data points that support the primary and or 
secondary endpoints. 
 
On-Site Monitoring: On-site monitoring will occur ideally once per year while the site is 
actively enrolling patients, budget permitting. Participating Institutions will be required to 
provide access to participants’ complete medical record and source documents for source 
documentation verification during the on-site visit. In addition, upon request from a 
monitor or auditor, Participating Institutions should provide access to regulatory 
documents, pharmacy records, local policies related to the conduct of research, and any 
other trial-related documentation maintained by the participating site. If there are concerns 
for protocol compliance, issues that impact subject safety or the integrity of the study are 
found, or trends identified based on areas of need, additional monitoring visits may be 
scheduled. On site monitoring visits can be supplemented with virtual monitoring 
assessments, provided that the minimum monitoring frequencies are adhered to. 
 
Virtual Monitoring: The Coordinating Center will request source documentation from 
Participating Institutions as needed to complete monitoring activities. Participating 
Institutions will be asked to forward de-identified copies of participants’ medical record 
and source documents to the Coordinating Center to aid in source documentation 
verification. 
 


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5.2 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and remote 
monitoring of Participating Institutions to ensure protocol compliance. The DF/HCC 
Sponsor may increase the monitoring activities at Participating Institutions that are unable 
to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. Participating Institutions may also be subject to an audit as determined by the 
DF/HCC Sponsor. 
 
5.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination.  Due to the small patient 
population, the accrual minimum requirement is at least 1 patient per site annually. 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1 Audit Plan: DF/HCC Sponsored Trials 
 
One on-site audit will be scheduled by the QACT, assuming at least three participants 
have been treated on protocol at the site, or at the discretion of the DF/HCC Sponsor. 
Approximately 3-4 participants would be audited at the site over a 2 day period.  If 
violations which impact participant safety or the integrity of the study are found, more 
participant records may be audited.  
 
6.2 Audit Notification 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve 
this protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after 
the audit date.  
 
6.3 Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC QACT 


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per DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up.  For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4 Participating Institution Performance 
 
The DF/HCC Sponsor and DFCI IRB is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
6.4.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. 
A DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above. 
 
 
 
 
 


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APPENDIX J: INHIBITORS AND INDUCERS OF CYP3A  
 
Inhibitors and inducers of CYP3A are defined as follows. A comprehensive list of inhibitors can 
be found at the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The 
general categorization into strong, moderate, and weak inhibitors according to the website is 
displayed below.  
 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors:  
INDINAVIR  
NELFINAVIR RITONAVIR  
CLARITHROMYCIN  
ITRACONAZOLE KETOCONAZOLE  
NEFAZODONE  
SAQUINAVIR  
TELITHROMYCIN  
 
Moderate inhibitors:  
Aprepitant 
Erythromycin  
diltiazem  
Fluconazole  
grapefruit juice 
Seville orange juice 
Verapamil 
 
Weak inhibitors: 
Cimetidine 
 
All other inhibitors: 
Amiodarone 
NOT azithromycin 
Chloramphenicol 
Boceprevir 
Delavirdine 
diethyl-dithiocarbamate 
Fluvoxamine 
Gestodene 
Imatinib 
Mibefradil 
Mifepristone 
Norfloxacin 
Norfluoxetine 
star fruit 
Telaprevir 
Troleandomycin 
Carbamazepine 
Efavirenz 
Nevirapine 
Barbiturates 
Carbamazepine 
Glucocorticoids 
Modafinil 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s Wort 
Troglitazone