Clinical trial NCT02874404
Conditions: Recurrent Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma
Sponsor: University of Nebraska
Start date: 2016-10-07; Completion date: 2019-07-01
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase IIa trial studies the side effects and how well TGR-1202 and ibrutinib work in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement or does not respond to treatment. TGR-1202 and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of PI3K delta inhibitor TGR-1202 (TGR-1202) and ibrutinib in relapsed and refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR) defined as the sum of complete responses (CR) and partial responses (PR).

II. To determine the event-free survival (EFS), time to response (TTR), and duration of response (DOR) in patients with rel/ref DLBCL.

TERTIARY OBJECTIVES:

I. To evaluate molecular profiling of patient samples (optional lymph node biopsies) obtained at days 0 (pre-treatment; core biopsy), day 8 (fine needle aspiration) and end of treatment (progressive disease or end of study treatment-1 year; core biopsy).

II. To evaluate the baseline characteristics and dynamic shifts in mutational Landscape, transcriptional signatures and intracellular signaling cascades in primary tumor cells.

III. To define the mutational status of 384 genes that mutated in DLBCL, including cluster of differentiation (CD)79B, caspase recruitment domain family member 11 (CARD11), and myeloid differentiation primary response 88 (MYD88).

IV. To evaluate signatures of B-cell receptor signaling and the back-up pathway of oxidative phosphorylation.

V. To measure the basal and induced level of activation of components within parallel signaling pathways downstream of the B-cell receptor.

VI. To monitor changes in T-cell characteristics in response to exposure to TGR-1202 and ibrutinib.

VII. To perform quantitative response evaluation by peripheral blood cell-free deoxyribonucleic acid (DNA) sequencing at enrollment, day 8, 1 month, at every response assessment time point compared to standard radiographic response evaluation by positron emission tomography (PET)/ computed tomography (CT) or CT and end of treatment (progressive disease or end of study treatment-1 year).

VIII. To evaluate the genetic profiling for drug resistance mutations. IX. To evaluate DLBCL subtype analysis by immunohistochemistry compared to Nanostring assessment.

OUTLINE: Patients are assigned to 1 of 3 groups.

GROUP A: Patients receive PI3K delta inhibitor TGR-1202 orally (PO) once daily (QD) on days 1-28 and ibrutinib PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

GROUP B: Patients receive ibrutinib PO QD on days 1-28 and PI3K delta inhibitor TGR-1202 PO QD and days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

GROUP C: Patients then receive PI3K delta inhibitor TGR-1202 PO QD and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and after 1 year.

Arms: arm 1: Patients receive PI3K delta inhibitor TGR-1202 PO QD on days 1-28 and ibrutinib PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive ibrutinib PO QD on days 1-28 and PI3K delta inhibitor TGR-1202 PO QD and days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. arm 3: Patients then receive PI3K delta inhibitor TGR-1202 PO QD and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Ibrutinib intervention 2: Laboratory Biomarker Analysis intervention 3: PI3K-delta Inhibitor TGR-1202
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative markers intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
Protocol Title: A Single-center Phase IIa Study Evaluating the Safety and Tolerability of Umbralisib and 
Ibrutinib in Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma 
 
 
Sponsor/Principal Investigator:   
Matthew A. Lunning, D.O.  
 
 
 
 
 
 
 
 
 
Assistant Professor of Medicine  
987680 Nebraska Medical Center 
Omaha, NE 68198-7680  
Phone (402) 559-5166 
FAX (402) 559-6520 
 
 
 
 
E-mail: mlunning@unmc.edu  
 
Secondary Investigators: 
Julie M. Vose, M.D., M.B.A 
James O. Armitage, M.D. 
Philip J. Bierman, M.D. 
 
 
 
 
R. Gregory Bociek, M.D. 
 
 
 
 
Pathology/Biospecimens:  
  
Matthew A. Lunning D.O. and Michael Green Ph.D. 
Email: mlunning@unmc.edu and Mgreen@mdanderson.edu  
Phone: 402-559-5520 and  
 
Biostatistician:  
 
Jane Meza, Ph.D.  jmeza@unmc.edu  402-559-6825  
Research Coordinator(s): 
Maribeth Hohenstein / Susan Blumel 
 
Protocol Version Date: 
 
Version 1.0 
Dated 25Sep2015 
 
 
 
 
Version 2.0 
Dated 06Jun2016 
 
 
 
 
Version 3.0 
Dated 26Jan2017 
 
 
 
 
Version 4.0 
Dated 14Jul2017 
 
 
 
 
Version 4.1 
Dated 30Jul2018 
Version 4.2 
Dated 07Oct2019 
 
 
 
UNMC Investigator Initiated Project IND#130989 Janssen study Reference Number:  54179060LYM2010 
This protocol is being conducted as a translational clinical research project as part of the UNMC Fred & Pamela Buffett 
(NCI) Cancer Center Support Grant # P30 CA036727. 
DRUG REIMBURSEMENT / ACQUISITION:                                                                                   
Ibrutinib 560 mg orally daily  up to a year x 24 subjects supplied to investigators by Janssen Scientific Affairs, LLC 
(Janssen) 
Umbralisib orally daily up to a year x 24 subjects is an investigational agent supplied to investigators by TG 
Therapeutics  
Correlative Studies: Covered by Janssen Scientific LLC and TG Therapeutics external funding. (Pretreatment core 
guided biopsy of accessible lymph node: Core and FNA Fresh & FFPE;  Day 8 & at time of Progression of Disease 
(PD): US guided biopsy of accessible lymph node, FNA Fresh & FFPE   Pathology processing and Flow cytometry) 
Per Subject and Administrative Costs: Cost share between Janssen Scientific LLC and  TG Therapeutics  
 
 
 
 


UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
 
Protocol Format 
NIH designated Clinical Cancer Centers must conduct scientific peer review of clinical protocols. A standardized 
protocol format is used for the successful implementation of this process. All Fred & Pamela Buffett Cancer Center 
Investigator-initiated Institutional and Multi-Institutional protocols developed and sponsored by this institution 
involving clinical research must include the following elements or the equivalent: 
 
Title Page ………………………………………………………………………………………. 
 
Abstract (no more than 250 words) ……………………………………………………….. 
 
Schema …………………………………………………………………………………….…… 
 
Section 1.0 
Objectives ……………………………………………………………………  
 
Section 2.0 
Introduction, which includes background data and future aims ……….. 
 
Section 3.0 
Eligibility criteria …………………………………………………………….. 
 
Section 4.0 
Randomization/registration procedures ………………………………….. 
Section 5.0 
Treatment plan or research design ……………………………………..... 
 
Section 6.0 
Measurement of effect ………………………………………..……………. 
 
Section 7.0 
Study parameters …………………………………………...……………… 
 
Section 8.0 
Drug formulation and procurement ……………………………………….. 
 
Section 9.0  
Toxicity and adverse event reporting guidelines ………………………... 
 
Section 10.0 
Biostatistical considerations including stopping criteria ……..…….…… 
 
Section 11.0  
Records to be kept …………………………………………… …………… 
 
Section 12.0 
Patient consent form statement …………………………… …………….. 
 
Section 13.0 
References ……………………………………………… …………………. 
Section 14.0 
Data collection forms ……………………………………………………….  
 
 
1 
3 
4 
5 
5 
12 
14 
14 
23 
27 
28 
34 
43 
44 
45 
47 
48 
 
Appendices: 
Appendix A   Concomitant use of ibrutinib with other CYP3A inhibitors or inducers Cockroft-Gault  
49  
Appendix B Creatinine Clearance Calculation ………………………………………………………… 
 
 
49 
Appendix C  Performance Status Criteria………………………….………………………………….. 
 
 
50 
Appendix D    NEW YORK HEART ASSOCIATION (NYHA) HEART DISEASE CLASSIFICATION…..           50       
Appendix E      Eligibility checklist……………………………………….……………………………………… 
51 
Appendix F Oral, Sublingual, and/or Buccal Route Medication Adherence Standard  
Procedure (V 1.0 11-25-2013) ……………………………………………………………………….. 
56 
Appendix G  Blood and Tissue Sample Processing and Shipping …… ……………………………….  
63 
Appendix H   FDA MEDWATCH form………………………………………………………………………  
65


  
 
 
 
 
 
  
 
 
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UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
 
 
Abstract:  
Title: A Single-center Phase IIa Study Evaluating the Safety and Tolerability of Umbralisib and Ibrutinib in Patients with 
Relapsed or Refractory Diffuse Large B-cell Lymphoma: A Trial of the Lymphoma Precision Medicine Laboratory 
 
Lymphomagenesis is known to be a result of aberrant signaling through the B-cell receptor (BCR).  Several models 
have highlighted specific checkpoints that appear to be regulators of downstream signal propagation leading to 
abnormal nuclear transcription within the lymphocyte leading to either anti-apoptosis or a proliferative advantage.  A 
better understanding of the BCR signaling pathway in malignant lymphocytes has led to several small molecule 
inhibitors entering clinical practice as single agents for the treatment of non-Hodgkin lymphoma (NHL).  Two classes 
of BCR antagonists have shown strong activity in (NHL): Bruton’s Tyrosine Kinase (BTK) and phosphoinositide-3-
kinase (PI3-K) delta inhibitors.  Ibrutinib is a first generation selective and irreversible inhibitor of BTK.   umbralisib 
(formerly known as TGR-1202) is a PI3-K delta inhibitor with a novel structure unlike other PI3K inhibitors affording 
once daily dosing and to date a unique toxicity profile.  Attacking the aberrant BCR signaling pathway at separate 
nodes may be an important mechanism to overcome chemorefractory NHL.  This is a single-center Phase IIa study 
evaluating the safety and tolerability of umbralisib and Ibrutinib in patients with relapsed or refractory diffuse large B-
cell lymphoma (DLBCL). We plan to accrue 24 patients.  The primary endpoint in this phase IIa study is to consecutively 
monitor the safety and tolerability of the oral doublet and allow a preliminary assessment of the efficacy of this novel 
combination to provide background for an appropriately powered phase II or phase III study.  There will be 3 treatment 
groups given one year (12 months) of therapy, Group A (consented to optional biopsies; 6 patients):  umbralisib800 
mg PO daily on Days 1-8; then umbralisib 800 mg oral daily and Ibrutinib 560 mg oral daily; Group B (consented to 
optional biopsies; 6 patients): Ibrutinib 560 mg PO daily Days 1-8; then umbralisib 800 mg PO daily and Ibrutinib 560 
mg PO daily; and Group C (deferred consent to optional biopsies or consented to optional biopsies; 12 patients): 
umbralisib 800 mg PO daily and Ibrutinib 560 mg PO daily.  Secondary endpoints of the trial will be assessment of the 
overall response rate (ORR) defined as the sum of complete responses (CR) and partial responses (PR) and to 
determine the progression-free survival (PFS), time to response (TTR), and duration of response (DOR) in patients 
with relapsed or refractory DLBCL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
  
 
 
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UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
 
 
 
Schema:    
 
Title: A Single-center Phase IIa Study Evaluating the Safety and Tolerability of Umbralisiband Ibrutinib in Patients with 
Relapsed or Refractory Diffuse Large B-cell Lymphoma 
 
 
Group A (consented to optional biopsies; 6 patients):  umbralisib 800 mg PO daily on Days 1-8; then 
umbralisib 800 mg oral daily and Ibrutinib 560 mg oral daily 
Group B (consented to optional biopsies; 6 patients): Ibrutinib 560 mg PO daily Days 1-8; then umbralisib 
800 mg PO daily and Ibrutinib 560 mg PO daily 
Group C (deferred consent to optional biopsies or consented to optional biopsies; 12 patients): umbralisib 
800 mg PO daily and Ibrutinib 560 mg PO daily 
Duration of therapy 
In the absence of treatment delays due to adverse event(s), treatment should continue unless one of the following 
criteria applies: 
• 
Disease progression or inter-current illness that prevents further treatment, 
• 
Patient decides to withdraw from the study, or changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
• 
One year of therapy 
A cycle is 28 days of treatment with any oral agent regardless of group assignment.  The first efficacy assessment 
should be approximately 8 weeks after Cycle 1/Day 1 (+/- 7 days).  Thereafter efficacy assessment will occur 
approximately every two months until 6 months then every 3 months until completion of 12 months of treatment (+/- 7 
days).  After Month 12, efficacy assessments should occur at the investigators discretion. 


  
 
 
 
 
 
  
 
 
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UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
 
 
Section 1.0 Objectives:  
 
Primary objective:  
1. To determine the safety and tolerability of umbralisib and ibrutinib in relapsed and refractory (rel/ref) DLBCL 
Secondary objectives: 
1. 
 To determine the overall response rate (ORR) defined as the sum of complete responses (CR) and 
partial responses (PR). 
2. 
  To determine the event-free survival (EFS), time to response (TTR), and duration of response (DOR) in 
patients with rel/ref DLBCL. 
 
Exploratory objectives: 
1.  To evaluate molecular profiling of patient samples (optional lymph node biopsies) obtained at days 0 (pre-
treatment; core biopsy), day 8 (fine needle aspiration) and end of treatment (progressive disease or end of 
study treatment—1 year; core biopsy) to evaluate the baseline characteristics and dynamic shifts in mutational 
landscape, transcriptional signatures and intracellular signaling cascades in primary tumor cells. 
(i) Next generation sequencing to define the mutational status of 384 genes that mutated in DLBCL, including 
CD79B, CARD11, and MYD88; 
(ii) Transcriptional profiling to evaluate signatures of B-cell receptor signaling and the back-up pathway of 
oxidative phosphorylation. 
(iii) Phospho-specific flow cytometry to measure the basal and induced level of activation of components within 
parallel signaling pathways downstream of the B-cell receptor.  
             (iiii) Monitor changes in T- cell characteristics in response to exposure to umbralisib and ibrutinib    
2. To perform quantitative response evaluation by peripheral blood cell-free DNA sequencing at enrollment, day 
8, 1 month, at every response assessment time point compared to standard radiographic response evaluation 
by PET/CT or CT and end of treatment (progressive disease or end of study treatment—1 year). After month 
12, efficacy assessments should occur at the investigators discretion with collection of a research blood sample 
only if feasible.   
3. To evaluate the genetic profiling for drug resistance mutations 
4. To evaluate DLBCL subtype analysis by immunohistochemistry compared to Nanostring assessment 
 
Section 2.0 Introduction:  
2.1 Diffuse Large B-cell Lymphoma 
Diffuse large B-cell lymphoma (DLCBL) remains the most common non-Hodgkin lymphoma (NHL) diagnosed per 
annum 
with 
an 
increasing 
prevalence, 
now 
noted 
to 
be 
approximately 
500,000 
individuals 
(http://seer.cancer.gov/stat/facts/html/leuks.html). Nearly 40% of those individuals are older than 70 years of age.  
Patients with DLBCL presents most commonly with advanced stage disease and without treatment are nearly uniformly 
lethal.  However current multiagent immunochemotherapy regimens do provide a curative option for those able to 
receive treatment.  The most common combination chemo-immunotherapy is R-CHOP (rituximab, cyclophosphamide, 
doxorubicin, vincristine, prednisone), which now cures nearly two-thirds of patients.(1) The prognosis is dependent on 
many patient specific factors most accurately defined by the International Prognostic Index (IPI) and by recent disease 
specific characteristics defined as molecular subtyping into either Germinal Center B-cells (GCB) or Activated B-cell 
like (ABC).(2, 3)    In the current treatment era the overwhelming majority of patients will be exposed to a rituximab 
containing induction regimen.  Despite aggressive up front treatment nearly one-third of patients with DLBCL will have 
refractory disease or experience a relapse of DLBCL.  A second chance at cure is maintained with second line therapy 
in addition to high dose therapy and autologous stem cell rescue (HDT-ASCR) in those who are transplant eligible.  
However, only 1 in 4 patients who undergo transplant will achieve long-term disease control and subsequent 
chemotherapy regimens yield diminishing returns and often serve as a bridge towards allogeneic transplantation if 
eligible and/or available.(4)  Patients who are not considered transplant eligible suffer a dismal prognosis with no 


  
 
 
 
 
 
  
 
 
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UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
standard of care to help guide treatment choices.  Therefore, a substantial number of highly chemotherapy refractory 
patients remain in search of further therapy that can preserve the balance of quality and quantity of life.   
 
2.2 B-cell receptor Pathway 
The B-cell receptor pathway is a complex network of enzymatic checks and balances that regulate B-cell maturation 
and subsequent migration.(5)  Many points of divergence exist within the network creating parallel streams of potential 
reflexive regulation. Tonic stimulation of an enzymatic node by mutations within the protein can be a lymphoma 
generating event.  This has been further expounded by the molecular profiling of DLBCL.  The results have led to the 
defining of 3 different molecular subtypes of DLBCL in which the BCR pathway plays a significant role: 1) Germinal 
Center B-cell (GCB), 2) Activated B-cell like (ABC), and 3) Unclassifiable.(3)  The GCB subtype is felt to be more 
attracted to the phosphoinositol-3 kinase pathway.(6) The ABC subtype of DLBCL appears to be addicted towards the 
downstream pathway leading towards the Nfk-B stimulation and subsequent nuclear transcription.(7)  The GCB 
subtype of DLBCL represents nearly two-thirds of all DLBCL cases and has a more favorable prognosis than ABC 
DLBCL.  These downstream pathways have become clinically relevant targets with several drugs attempting to inhibit 
these processes.   
 
2.3 Targeting the B-cell receptor pathway 
Success with small molecule inhibitors that abrogate the abnormal signaling through the BCR pathway has brought 
upon an exciting paradigm shift in the management of B-cell NHL.  Several novel non-chemotherapeutic drugs now 
attack the malignant lymphocytes via mechanisms unperturbed or selected for by prior non-selective chemotherapy or 
exposure to CD20 directed monoclonal antibodies (Figure 1).  Currently these drugs are in the clinic as single agents 
or combined with a CD20 monoclonal antibody.  This 
includes but not limited to the Bruton’s tyrosine kinase 
(BTK) inhibitor ibrutinib and the PI3-K inhibitor, Idelalisib.  
Both BTK and PI3-K have several next generation 
antagonists in clinical development.  Umbralisib is a next 
generation PI3-K delta inhibitor with a novel structure 
different than other PI3-K inhibitors in development.  This 
structure may lead to differential activity and toxicity profile 
than previously seen in other PI3-K inhibitors.  Current data 
supports that BTK inhibitors may provide selective activity 
towards the ABC subtype of DLBCL whereas PI3-K 
inhibitors may provide selective activity to the GCB 
subtype of DLBCL.(8) 
 
Currently targeted agents against the BCR have been 
primarily explored as single agents or in combination with 
a CD20 monoclonal antibody.  Results have shown that as 
a single agent each may be potent enough to achieve disease control in indolent NHL, like follicular lymphoma (FL) 
and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).(9)  However, treatment of 
relapsed/refractory (rel/ref) DLBCL especially after HDT-ASCR or in transplant ineligible patients remains a difficult 
situation with a poor overall prognosis.  Combinations of novel agents that do not have cumulative toxicities are likely 
needed to overcome the clonal complexity and aggressive biology that prevents durability in the rel/ref DLBCL.  The 
novel chemo-free oral combination of umbralisib and Ibrutinib may be an attractive combination for the treatment of 
this difficult to treat population.   
2.4 Rationale for a phase IIa design 
Both BTK and PI3-K inhibitors that are in current practice have been developed under a continuous dosing scheme in 
an attempt to chronically antagonize the BCR pathway. As drugs progress through phases of clinical trials it is well 
established dogma that a maximum tolerated dose (MTD) is the objective in phase I studies.  However, this only reports 


  
 
 
 
 
 
  
 
 
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UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
dose limiting toxicities (DLT) during the initial cycle of therapy when further cumulative toxicities may be seen in 
subsequent cycles that limits the utility of a regimen.  Therefore, in paradigms were long-term safety and tolerability is 
paramount and needed to balance with objective responses phase IIa studies can be employed to not only provide this 
tolerability signal but inform future studies that lead to appropriately powered and better informed phase II or phase III 
studies.  Therefore, we must balance efficacy while limiting cumulative toxicities events (CTE).  
 
2.1 Umbralisib 
Umbralisib (formerly known as TGR-1202) is a highly specific and orally available PI3K delta inhibitor with high 
selectivity over the alpha, beta, and gamma isoforms of PI3K.  The delta isoform of PI3K is highly expressed in cells of 
hematopoietic origin, and strongly upregulated, and often mutated in NHL.  Umbralisib has demonstrated safety in an 
ongoing Phase I clinical trial in patients with NHL and chronic lymphocytic leukemia (CLL).(10)  umbralisib is 
manufactured by Alembic Pharmaceuticals and is being supplied by TG Therapeutics, Inc. 
2.1.1 
 
 
 
 
  
 
 
 
 
 
 
                  
 
 


  
 
 
 
 
 
  
 
 
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2.1.3 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
2.1.4 Clinical development of TGR 1202 in hematologic malignancies 
 
2.1.4.1 Umbralisib monotherapy 
 
Umbralisib is being evaluated in multiple studies.  The first in human phase I dose-escalation study with expansion 
cohorts in rel/ref hematologic malignancies patients has accrued approximately 55 patients. Umbralisib at doses 
ranging from 50 mg to the micronized 1800 mg QD dose has been tested. umbralisib is available as 200 mg tablets, 
as this study progressed to higher dose levels this resulted in an unfavorable number of tablets for daily administration.  
In an effort to improve the oral bioavailability of umbralisib and pill count, the particle size of the drug product was 
reduced through a micronization process. The micronization process resulted in greater absorption (approximately 3 
fold in a 24 patient healthy volunteer bioequivalence study).  
 
In this study adverse events (AEs) have been manageable, with Grade 3/4 AEs occurring in >10% of patients consisting 
of the following (March 2015) regardless of attribution to umbralisib:  neutropenia, rash, dyspnea, thrombocytopenia, 
and diarrhea.  Of note, a Grade 3 AE of rash was reported in a patient in the non-micronized 800 mg dose cohort who 
was on concomitant antibiotics.  This patient had a history of antibiotic related rash.  All medications were held until the 
rash resolved and they were re-challenged at the 800 mg dose of umbralisib with no recurrence of rash.  However, this 
event met the criteria for a DLT as stated in the protocol and subsequently 3 additional patients were treated at the 800 
mg dose, with no additional DLT’s reported.   


  
 
 
 
 
 
  
 
 
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UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
 
On this study the safety data has now been obtained on patients dosed with umbralisib daily for over a year with no 
safety concerns recognized or reported as documented by the Study Chair and Medical Monitor for the trial up through 
the micronized 1200 mg QD dose.  Dosing continues in this study using the micronized formulation of umbralisib.   
 
2.1.4.2 Umbralisib + anti-CD20 monoclonal antibody, ublituximab 
 
Umbralisib continues to be evaluated in the phase 1/1b dose escalation study with the glycoengineered anti-CD20 
monoclonal antibody ublituximab (UTX).(10)  Fifty-seven patients have been enrolled and are evaluable for safety.  
AEs (AE; all causality) include: Day 1 infusion related reactions, neutropenia, diarrhea, nausea.  To date, umbralisib 
related hepatotoxicity has not been reported in this study.  No DLTs have occurred in the NHL cohort.  A possible dose-
response relationship has been observed between “lower” and “higher” umbralisib doses.  A higher dose was defined 
as greater than 800 mg of the non-micronized umbralisib.  To date, 89% of pts (16/18) in the “high” dose cohorts remain 
on study progression free compared to 57% (8/14) in the “low” dose cohorts.  This study continues to enroll in expansion 
cohorts in NHL subtypes with umbralisib at a micronized dose of 800 and 1200 mg plus UTX.  
 
 
2.2 Ibrutinib 
Ibrutinib is indicated for the treatment of: 1) patients with chronic lymphocytic leukemia (CLL) 2) patients with chronic 
lymphocytic leukemia (CLL) with 17p deletion; 3) patients with mantle cell lymphoma (MCL) who have received at 
least one prior therapy (accelerated approval was granted for this indication based on overall response rate, 
continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials; 4) 
patients with Waldenström's macroglobulinemia (WM).  5) Chronic graft versus host disease (cGVHD) after failure of 
one or more lines of systemic therapy.  Ibrutinib is not approved in the disease state being studied here. 
 
2.2.1 Chemical structure and description of Ibrutinib 
Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one 
and has a molecular weight of 440.50 g/mole (anhydrous basis).  Ibrutinib is a white to off-white crystalline solid. It has 
a single chiral center and is the R-enantiomer. The investigational drug product, ibrutinib, is an oral formulation 
containing micronized ibrutinib. Ibrutinib is manufactured by Pharmacyclics, Inc. and is being supplied by Janssen 
Scientific Affairs, LLC. 
      
       2.2.2 In vitro data of ibrutinib 
 
In vitro studies have shown that ibrutinib binds covalently to a cysteine residue (Cys-481) in the BTK active site, leading 
to potent and irreversible inhibition of BTK enzymatic activity.(12) In cellular signal transduction assays with a B-cell 
lymphoma cell line, ibrutinib inhibited autophosphorylation of both BTK and phosphorylation of BTK’s physiological 
substrate, phospholipase-C gamma (PLCγ).22   In DLBCL cell lines ibrutinib inhibited the proliferation at a median 
effective concentration of 1 to 2 nM.(13) 
 
2.2.3 Pharmacology/Toxicology 
 
Ibrutinib’s bioavailability is relatively low and quite variable.  A mass-balance study (PCI-32765CLL1004) demonstrated 
that ibrutinib 140 mg (admixed with 14C-ibrutinib) showed approximately 90% of radioactive ibrutinib was excreted 
within 168 hours after administration, with less than 10% accounted for in urine and the remainder in feces. A negligible 
fraction was excreted as unchanged drug.   
 
Ibrutinib is metabolized in the liver.  In a hepatic impairment study, data showed an increase in ibrutinib exposure. 
Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child 


  
 
 
 
 
 
  
 
 
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UNMC IRB#345-16 Protocol Version 4.2 Dated 07Oct2019 
 
 
-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to 
subjects with normal liver function. The safety of ibrutinib has not been evaluated in patients with hepatic impairment.  
Monitor patients for signs of ibrutinib toxicity and follow dose modification guidance as needed. It is not 
recommended to administer ibrutinib to patients with moderate or severe hepatic impairment (Child-Pugh classes B 
and C). 
 
Ibrutinib is metabolized primarily by CYP3A.  Drug-drug interaction study has demonstrated that when ibrutinib was 
administered at a 120 mg dose in combination with 40 mg of ketoconazole, a strong CYP3A inhibitor, the last 
concentration quantifiable (AUCO-last) was extended up to 29 times longer than without ketoconazole exposure.  
Terminal half-life was not increased. Therefore, use of strong CYP3A inhibitors is not allowed and guidance on 
concomitant use of ibrutinib with other CYP3A inhibitors or inducers is provided in the Appendix A. 
 
Absorption  
Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours. Ibrutinib exposure increases with 
doses up to 840 mg. The steady-state AUC (mean ± standard deviation) observed in patients at 560 mg is 953 ± 705 
ng⋅h/mL and in patients at 420 mg is 680 ± 517 ng⋅h/mL. Administration with food increased ibrutinib Cmax and AUC 
by approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after overnight fasting. 
 Distribution  
Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the 
range of 50 to 1000 ng/mL. The volume of distribution at steady state (Vd,ss) was 683 L, and the apparent volume of 
distribution at steady state (Vd,ss/F) was approximately 10000 L.  
Metabolism  
Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by 
cytochrome P450, CYP3A, and to a minoextent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol 
metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the 
mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8 
 
Ibrutinib binds covalently and irreversibly to Cys-481 near the BTK active site and inhibits the enzymatic activity with a 
half maximal inhibitory concentration (IC50) of 0.5 nM.  The binding site of Bruton's tyrosine kinase remained fully 
occupied by ibrutinib (≥90% occupancy) for at least 24 hours in subjects treated with ibrutinib doses of ≥ 2.5mg/kg/day 
(≥ 175mg/day for average weight of 70kg. Although ibrutinib is rapidly eliminated from the plasma after oral 
administration, once daily dosing with ibrutinib is adequate to sustain maximal pharmacodynamic activity for 24 hours 
post-dosing.  Therefore, 560 mg/day is adequate to achieve exposures yielding full BTK active-site occupancy in most 
patients. 
 
2.2.3 Clinical activity and Safety of ibrutinib 
 
Ibrutinib was tested in a phase I, multicenter, open-label, dose escalation study in patients with recurrent NHL.(14) The 
objectives included studying the safety profile of ibrutinib, identifying the maximum tolerated dose (MTD) and optimal 
dosing schedule, and characterizing efficacy, pharmacokinetics, and pharmacodynamics. A minimum of 6 subjects per 
cohort received 1 of 5 escalating dose levels of ibrutinib between 1.25 and 12.5 mg/kg for 28 consecutive days in a 35-
day cycle.  There was a pre-specified objective of escalating 3 dose levels above that which achieved full BTK 
occupancy based on the fluorescent probe assay.  
 
A total of 66 patients were evaluated in this study.  Two additional cohorts received a continuous ibrutinib dose of 8.3 
mg/kg without a 7-day rest and a fixed continuous dose of 560 mg/day.  Full BTK occupancy was achieved with doses 
≥2.5 mg/kg/day.  A dose of 12.5 mg/kg/day was the highest dose cohort evaluated. There were 2 dose-limiting toxicities 
(DLTs) (Grade 2 neutropenia [2.5 mg/kg/day] and Grade 3 hypersensitivity [8.3 mg/kg/day]) in separate cohorts. The 
maximum tolerated dose (MTD) of ibrutinib in subjects with B-cell malignancies was not established in this study.  Five 
of 15 subjects with DLBCL (33%) achieved objective responses, 2 CRs and 3 partial responses (PRs). The median 


  
 
 
 
 
 
  
 
 
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time on treatment was 8 weeks (range: 2 to 98 weeks). Median PFS was 2.5 months (range: 0.7 to 4.6 months) and 
the median follow-up time was 3.5 months (range: 0.8 to 22.5 months). 
 
A subsequent phase I/II, multicenter, open-label, and single-arm study in subjects with rel/ref DLBCL was performed. 
(15)In order to determine whether ibrutinib had subtype specificity subjects enrolled were retrospectively analyzed into 
cohorts by subtype, either activated B-cell like (ABC) versus germinal B-cell like (GCB).  Subtype analysis was 
performed by gene expression profiling (GEP).  In this study all subjects received a starting dose of ibrutinib at 560 
mg/day. The objectives of this study included the determining the safety of this dosing regimen and an assessment of 
efficacy of ibrutinib in DLBCL. Eighty subjects were enrolled and evaluable for response.  The overall response rate 
(ORR) was 25% (20/80 subjects). In the ABC subtype, ORR was 37% (14/38 subjects; Only 1 PR ( 5%) was observed 
in the 20 patients retrospectively determined to be of GCB subtypes. Thus, while the 2 subgroups were retrospectively 
assigned, ibrutinib may be less active in rel/ref DLBCL, GCB subtype. 
 
The most common adverse reactions (>=25%) in pts with B cell malignancies (MCL, CLL, WM) were 
thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory 
tract infection and rash. 
 
2.3 Rationale for combination of Umbralisib and Ibrutinib 
B-cell lymphomagenesis is known to be a result of aberrant signaling through the B-cell receptor (BCR).  Several 
models have highlighted specific checkpoints that appear to be regulators of downstream signal propagation leading 
to abnormal nuclear transcription within the lymphocyte leading to either anti-apoptosis or a proliferative advantage.(5)  
A better understanding of the BCR signaling pathway has led to several small molecule inhibitors entering clinical 
practice as single agents.  As described above, umbralisib and ibrutinib have shown safety and activity in DLBCL.  Also 
important is the significant lack of evidence for cumulative toxicity as single agents to date.  For umbralisib it has been 
postulated that the novel structure unlike other PI3K inhibitors has led to its lack of a significant toxicity profile making 
it a pairable novel oral agent.
 
 
.  We 
propose that attacking the aberrant BCR signaling pathway at separate nodes may 
be an important mechanism to overcome the chemorefractory DLBCL regardless 
of cell of origin.   
Alterations in single agent safety profiles can arise after an established MTD and 
often lessen the enthusiasm for such novel combinations and again question the 
durability of a continuous use paradigm.  Nevertheless, combinations of oral novel-
novel agents continue to emerge.(16)  However, an example of unforeseen 
toxicities was highlighted in a recent report with lenalidomide, idelalisib (PI3-K 
inhibitor), and rituximab in patients with relapsed/refractory CLL and indolent 
NHL.(17)  A sepsis-like syndrome was reported in 4 patients and resulted in 
stopping of these early phase studies without achieving a maximal tolerated dose 
(MTD).   
It is well established dogma that a MTD is the objective in phase I studies.  
However, this only reports dose limiting toxicities during the initial cycle of therapy 
when further cumulative toxicities may be seen in subsequent cycles that limits the 
utility of a regimen.  Therefore, in paradigms were long-term safety and tolerability is paramount and furthermore 
needed to balance with objective responses, a phase IIa study can be employed to not only provide this tolerability 
signal or cumulative toxicity events (CTEs), but be informative for future studies that lead to appropriately powered and 
better informed phase II or phase III studies. 


  
 
 
 
 
 
  
 
 
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As discussed above the phase I/Ib study (NCT #02006485) with ublituximab and umbralisib in rel/ref CLL and NHL 
continues to accrue.  An amendment to this protocol allowed for the addition of ibrutinib at 560 mg daily to UTX (fixed 
at 900 mg) in addition to increasing doses of umbralisib.  To date, safety data on umbralisib is notable for no episodes 
of hepatotoxicity reported with umbralisib as a single agent or in combination with ublituximab (doublet), or with ibrutinib 
(triplet).(10, 16, 18)  In the 12 rel/ref DLBCL patients treated with umbralisib and UTX whom were eligible for response 
5 patients had obtained a response and two had a PET/CT confirmed complete responses.   Sixteen patients have 
been enrolled into the triplet regimen without a DLT in the NHL cohorts.  The 800 mg dose level of umbralisib has been 
enrolled and completed without a DLT.  Early responses have been seen in multiple NHL subtypes.   
Given the safety of the umbralisib as a single agent, in the doublet and the triplet cohorts in combination with the early 
efficacy signal reported we propose to further explore the safety and tolerability of an all oral regimen of ibrutinib and 
umbralisib in patients with rel/ref DLBCL who have relapsed post-transplant or have been determined to be ineligible 
or unsuitable for transplant at the full doses of umbralisib (800 mg) and Ibrutinib (560 mg) in a single center open label 
phase IIa study.   
 
Section 3.0 Eligibility Criteria:  
3.1 Inclusion Criteria 
1. Histologically confirmed Diffuse Large B-cell Lymphoma (DLBCL) or transformed DLBCL 
2. Disease status defined as: 
a. Patients with relapsed or refractory DLBCL that has relapsed post-transplant or that has been 
determined to be ineligible or unsuitable for transplant.  Patients must have received at least one 
prior systemic therapy. 
3. Patients must have measurable (> 1.5 cm) or evaluable disease. Baseline measurements and evaluations 
must be obtained within 21 days of registration to the study. Abnormal PET scans will not constitute evaluable 
disease, unless verified by CT scan or other appropriate imaging. Measurable disease must have at least one 
objective measurable disease parameter. A clearly defined, bi-dimensionally measurable defect or mass 
measuring at least 1.5 cm in diameter on a CT scan will constitute measurable disease. Proof of lymphoma 
in the liver is required by a confirmation biopsy. Skin lesions can be used as measurable disease provided bi-
dimensional measurements are possible. 
4. Adequate organ system function, defined as follows: 
a. Absolute neutrophil count (ANC) ≥ 1.0  x 109/L 
i. By automated or manual review, whichever is greatest 
b. Platelets ≥100 x 109/L: 
i. Unless due to bone marrow infiltration then eligible if platelets > 50 x 109/L) 
c. Total bilirubin ≤ 1.5 x upper normal limit if documented hepatic involvement with lymphoma, or ≤ 5 
x upper normal limit if history of Gilbert’s Disease.  
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if no liver 
involvement or ≤5 x the ULN if documented liver involvement 
e. Creatinine ≤2.0 mg/dL OR calculated creatinine clearance ≥50 mL/min (as calculated by the 
Cockcroft-Gault method, Appendix B) 
5. ECOG performance status ≤2 or expected survival duration of > 2 months (Appendix C) 
6. Patients must be ≥19 years of age (the age of consent in Nebraska) 
7. Ability to swallow and retain oral medication 
8. Women must not be pregnant or breast-feeding due to teratogenic effects of therapy. 
a. All female patients of child-bearing potential must have a negative serum pregnancy test within 2 
weeks prior to treatment to rule out pregnancy  
b. Pregnancy testing is not required for post-menopausal or surgically sterilized women. 
9. Male and female patients of reproductive potential must agree to follow accepted birth control measures 
throughout the study period and for 30 days after the last dose of either study drug for females and 3 months 
after the last dose of study drug for males. 
10. Patient must be able to adhere to the study visit schedule and other protocol requirements. 


  
 
 
 
 
 
  
 
 
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11. Patient must be aware of the neoplastic nature of his/her disease and willingly sign (or their legally-acceptable 
representatives must sign) an informed consent document indicating that they understand the purpose of and 
procedures required for the study, including biomarkers, and are willing to participate in the study.  
12. No serious disease or condition that, in the opinion of the investigator, would compromise the patient’s ability 
to participate in the study 
 
3.2 Exclusion Criteria 
1. Currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, 
hormonal therapy, and surgery and/or tumor embolization) or any investigational drug within 7 days of Cycle 1/Day 
1, 14 days of Cycle 1/Day 1 for limited palliative radiation, and/or five half-live of an oral therapy. 
a. Corticosteroid therapy started at least 7 days prior to initiation of treatment (prednisone ≤10 mg daily or 
equivalent) is allowed as clinically warranted).  Topical or inhaled corticosteroids are permitted. 
2. Major surgery or a wound that has not fully healed within 4 weeks of enrollment. 
3. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
4. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon. 
5. Vaccinated with live, attenuated vaccines within 4 weeks of enrollment. 
6. Autologous hematologic stem cell transplant within 3 months of study entry.   
7. Allogeneic hematologic stem cell transplant within 12 months of study entry.  
8. Active graft versus-host disease and must not be on immunosuppression. 
9. Wide field radiotherapy within 28 days of Cycle 1/Day 1 or active side effects of such therapy 
10. Active Hepatitis B (HBV) or C (HCV) infection (negative serology required excluding those with are seropositive 
due to prior vaccination) and/or known history of human immunodeficiency virus (HIV) 
11. Primary central nervous system involvement only 
12. Require treatment with strong CYP3A inhibitors  
13. Known history of drug-induced liver injury, alcoholic liver disease, primary biliary cirrhosis, ongoing extra-hepatic 
obstruction caused by stones, cirrhosis of the liver or portal hypertension 
14. Any life-threatening illness, severe and/or uncontrolled medical condition, or organ system dysfunction, laboratory 
abnormality, psychiatric illness or other condition which, in the Investigator’s opinion,  could compromise the 
subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, put the study outcomes at undue 
risk or affect their participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure New York Heart Association (NYHA) 
functional classification III-IV (NYHA, Appendix D)  
b. QTc >470 msec (unless related to pacemaker) on EKG within 21 days of initiation of treatment 
c. Angina not well-controlled by medication 
d. Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident 
(CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting within 6 months prior to 
enrollment 
15. Prior malignancies within the past 1 years with exception of adequately treated basal cell, squamous cell skin 
cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason Grade 6 or less 
with stable PSA levels. 
16. Women who are pregnant or breastfeeding.  Women who agree to stop breastfeeding would be eligible 
17. Known hypersensitivity to either study drug (umbralisib or Ibrutinib)  
NOTE:  
All questions regarding eligibility for UNMC potential subjects should be directed to the PI at 402-559-7164.  
 
NOTE: The eligibility checklist (Appendix E) may be used as source documentation if it has been reviewed, signed, 
and dated prior to registration by the treating physician. The eligibility checklist must be accompanied by all other 
source documents that evidence the subject’s eligibility (i.e., dictation, pathology, radiology, laboratory, etc.)  


  
 
 
 
 
 
  
 
 
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Section 4.0 Registration Procedure:  
All patients, with relapsed or refractory DLBCL that has relapsed post-transplant or that has been determined to be 
ineligible or unsuitable for transplant referred to The Nebraska Medical Center (TNMC), University of Nebraska Medical 
Center (UNMC), Bellevue Medical Center (BMC), and Village Point Cancer Center may be eligible for this trial.  
Screening eligibility based on standard clinical care will be performed by the treating physician at the time of encounter. 
On initial presentation, a history and physical examination are performed, laboratory data obtained, and performance 
status is assessed. Imaging studies obtained include PET and a high-resolution multi-detector computed tomography 
(CT) of the chest, abdomen and pelvis. Further imaging studies will be obtained as clinically indicated. Pathology 
material must be reviewed, and a diagnosis of DLBCL confirmed by UNMC pathology department (retrospective). The 
patient’s primary oncologist will make the decision as to screened eligibility of the candidate based on the eligibility 
criteria listed above, prior to offering consent.  
If the patient is screened as potentially eligible, he/she will then be offered the option to participate. An informed consent 
will be signed by the patient after thorough review of the study is completed by the physician and his/her designee.  
 
Some insurance carrier’s may decline to cover the costs of usual medical care if the patient is participating in a clinical 
trial. The patient will be provided assistance by the research nurse coordinator or designated staff in determining if the 
insurance carrier will decline coverage. Insurance carriers may or may not pay for study related expenses. The patient 
can then decide if they wish to participate.  
 
4.1  
Eligibility Verification/Registration  
 
Before subjects are registered to the study, an eligibility checklist (Appendix E) must be completed to verify the subject 
meets the eligibility criteria and may be used as source documentation if it has been reviewed, signed, and dated prior 
to registration by the treating physician. The eligibility check list will be maintained in the study file. 
 
Date of Enrollment: Defined as the date of the start of study treatment / first study related intervention.  
  
Study personnel from UNMC will provide the UNMC Fred & Pamela Buffett Cancer Center PRMS office (ZIP 6805) a 
copy of the signed and dated consent form for each UNMC subject enrolled in the protocol within 24 hours that includes 
the following information: 
• 
Protocol Number 
• 
Patient Identification: Patient’s name UNMC/NMC medical record number 
• 
Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity,  
• 
New CTRP reporting requirements: Patient zip code/country (if not USA) and primary method of 
payment information 
 
4.2  
Pathology Requirements  
 
Pathological materials are to be submitted and reviewed at UNMC confirming a diagnosis of DLBCL or transformed 
DLBCL.  
 
4.3  
Instructions for Patients Who Do Not Start Assigned Protocol Treatment  
 
If a consented patient does not receive any assigned protocol treatment, baseline data will still be collected and must 
be submitted according to the instructions in the protocol. Document the reason for not starting protocol treatment on 
one of the baseline forms.  
 
Section 5.0 Treatment Plan of Research Design:  


  
 
 
 
 
 
  
 
 
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This is a single-center Phase IIa study evaluating the safety and tolerability of umbralisib and Ibrutinib as well as the 
response and event free survival of this regimen in patients with relapsed or refractory diffuse large B-cell lymphoma 
(DLBCL). There will be 3 treatment groups given a maximum of one year (12 months) of therapy. 
5.1   
Pre-treatment Evaluations Standard of Care (SOC) 
 
Within 21 days prior to the Date of Enrollment, date of the start of study treatment / first study related intervention 
(unless otherwise specified below). No tests or procedures are conducted solely for the purposes of research to 
determine subject eligibility.  
• 
History and physical 
• 
Informed Consent 
• 
CBC, diff, platelets, CMET, LDH 
• 
Hepatitis B (HBV) or C (HCV) serology 
• 
Serum pregnancy test (if applicable) within 14 days of first study-related treatment date. 
• 
Height and weight 
• 
Vital signs, including blood pressure 
• 
Performance Status 
• 
EKG  
• 
PET/CT baseline radiologic evaluation; NOTE for f/u if a Deauville 3 (CR) is achieved then CT chest, abdomen and 
pelvis with contrast may be used. Further PET/CT scans are optional at the investigators discretion.   
• 
Mandatory research peripheral blood (20 mL) for cell free DNA assessment and T-cell characterization will be 
collected in an EDTA tube pretreatment (day of biopsy or initiation of treatment), day 8, 1 month (+/- 3 days) and 10mL 
at subsequent radiographic response assessments, after cycle 2, 4, 6, 9, and 12. (+/- 7 days).  After Month 12, efficacy 
assessments should occur at the investigators discretion with collection of a research blood sample only if feasible. 
Should the patient consent any leftover peripheral blood collected for research will be stored at UNMC for future IHC 
and DNA unspecified research use. 
• 
 
• 
Optional Research Samples (Appendix G):  
o Should the patient consent, 3 additional optional lymph node biopsies for molecular profiling will be 
obtained at days 0 (pre-treatment; core biopsy), day 8 (FNA) and end of treatment (progressive disease, 
toxicity, or end of study—1 year; core biopsy) to evaluate the baseline characteristics and dynamic shifts 
in mutational landscape, transcriptional signatures and intracellular signaling cascades in primary tumor 
cells as well as assessment of comparative serologic response to radiographic assessments of response. 
   
 
Specimens submitted, by patients who consent to the additional specimen collection, will be processed to maximize 
their utility for future unspecified research projects and may include, but not limited to, extraction of plasma, serum, 
DNA and RNA.    Specimens will be archived with appropriate safeguards to ensure an efficient system for the prompt 
linkage and retrieval of the stored samples with the subject’s study records. 
 
Specimens from patients who consented to allow their specimens to be used for future IRB, TG Therapeutics, and 
Janssen Scientific LLC approved research studies, including residuals from the currently defined research studies, will 
be retained in an UNMC-designated central repository. If the patient agrees to let the samples be kept for future 
research, the samples will be kept until they are used up or destroyed. Most future research studies will focus on 
cancer, some research projects may also include other diseases, such as heart disease, diabetes or Alzheimer's 
disease. This may also include research on inherited traits. All future IRB, TG Therapeutics, and  Janssen Scientific 
LLC approved research studies will be conducted in accordance with the requirements set forth in the UNMC Human 
Tissue Use and Transfer Policy (policy #8013).  
 


  
 
 
 
 
 
  
 
 
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5.2 Treatment Grouping and Dosing 
Medicare qualifying research related combination chemotherapy: 
Stratification will be performed on a 1:1:1 basis to Group A, B or C by willingness to consent to optional biopsies. The 
first 3 patients will be directly enrolled into cohort C regardless of decision to be included in the optional biopsy portion 
of the study.   
Group A (consented to optional biopsies; 6 patients): umbralisib 800 mg PO daily on Days 1-8; then 
umbralisib 800 mg oral daily and Ibrutinib 560 mg oral daily 
Group B (consented to optional biopsies; 6 patients): Ibrutinib 560 mg PO daily Days 1-8; then umbralisib 
800 mg PO daily and Ibrutinib 560 mg PO daily 
Group C (deferred consent to optional biopsies or consented to optional biopsies; 12 patients): umbralisib 
800 mg PO daily and Ibrutinib 560 mg PO daily 
All subjects will receive a maximum of 52 weeks of oral (self-administered) therapy. To provide a means of ensuring 
oral routes of medication adherence of patients while participating in a clinical trial Appendix F “Oral, Sublingual, 
and/or Buccal Route Medication Adherence Standard Procedure (V 1.0 11-25-2013)” will be followed. 
No routine prophylactic antiemetics or pre-medications should be given outside of protocol requirements.  However, 
these medications may be administered for symptoms when they occur, and may be given prophylactically afterwards. 
Appropriate anti-emetic regimens should be based on the recommendations made by the NCCN guidelines (SOC). 
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf  
      5.2.1 Guidelines for Administration of umbralisib 
• 
Method of Administration: Umbralisib 4 tablets each 200mg = 800mg will be administered orally once daily. 
Umbralisib should be taken in the morning.  (NOTE: After cycle 2 if no CTE have been seen then the patient 
can have the option to take umbralisib and Ibrutinib dosing together at the same time of day). 
• 
Umbralisib tablets should be swallowed whole with a full glass (approximately 8 ounces) of water.  umbralisib 
tablets should NOT be crushed or chewed.   
• 
Potential Drug Interactions:  No Drug Interactions have been reported to date. 
• 
Pre-medications: None 
Umbralisib will be self-administered (by the patient).  Tablets should be taken at approximately the same time each 
morning with food.   Patients should be instructed to swallow the tablets whole and should not chew or crush them. 
If a dose of umbralisib is missed, it should be taken as soon as possible on the same day.  If a dose is missed, 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.  (Appendix F “Oral, Sublingual, and/or Buccal Route Medication Adherence Standard Procedure (V 1.0 
11-25-2013)” 
 
      5.2.2 Guidelines for Administration of Ibrutinib 
• 
Method of Administration: Ibrutinib 4 capsules each 140mg = 560mg will be administered orally once daily. 
Ibrutinib should be taken in the evening. (NOTE: After cycle 2 if no CTE have been seen then the patient 
can have the option to take umbralisib and Ibrutinib dosing together at the same time of day). 
• 
Ibrutinib capsules should be swallowed whole with a full glass (approximately 8 ounces) of water. Ibrutinib 
capsules should not be opened, chewed or dissolved.   
• 
Potential Drug Interactions:   Avoid co-administration with strong or moderate CYP3A inhibitors and consider 
alternative agents with less CYP3A inhibition. Concomitant use of strong CYP3A inhibitors which would be 
taken chronically (e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not 
recommended. For short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals 


  
 
 
 
 
 
  
 
 
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and antibiotics) consider interrupting ibrutinib therapy until the CYP3A inhibitor is no longer needed [see Drug 
Interactions (7.1)]. Reduce ibrutinib dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., 
fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, 
imatinib, verapamil, and ciprofloxacin) [see Drug Interactions (7.1)]. Patients taking concomitant strong or 
moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity. 
• 
Also avoid grapefruit and Seville oranges during treatment, as these contain moderate inhibitors of CYP3A and 
can alter ibrutinib pharmacokinetics. 
• 
For patients with mild liver impairment (Child-Pugh class A), the recommended dose is 140 mg daily (one 
capsule). Avoid the use of ibrutinib in patients with moderate or severe hepatic impairment (Child-Pugh 
classes B and C) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)] 
• 
Pre-medications: None 
Ibrutinib will be self-administered (by the patient).  Capsules should be taken at approximately the same time each 
evening with food.  Patients should be instructed to swallow the capsules whole and should not chew, break or crush 
them.  If a scheduled dose of Ibrutinib is missed it should be taken as soon as possible on the same day with a return 
to the normal schedule the following day.  Extra capsules of ibrutinib should not be taken to make up for the missed 
dose. 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. 
(Appendix F “Oral, Sublingual, and/or Buccal Route Medication Adherence Standard Procedure (V 1.0 11-25-2013)” 
 
5.3 Supportive medications and procedures 
 
The following treatments are prohibited while on clinical trial:  other investigational drug treatments or study 
participation, radiation therapy (except as described in section 3.2 Exclusion Criteria #1), hormonal therapy for cancer, 
cancer immunotherapy or other biologic therapy excluding trial drugs. 
• 
No glucocorticoids may be administered outside of protocol requirements for premedication or AE 
management, except low doses of steroids stabilized at < 10 mg per day of prednisone or equivalent, and 
started at least 7 days prior to study entry. 
Patients should receive full supportive care while on this study. This includes blood product support, antibiotic 
treatment, and treatment of other newly diagnosed or concurrent medical conditions. All blood products and supportive 
care concomitant medications such as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical records. 
Neutropenia: Granulocyte colony stimulating factor (G-CSF; filgrastim or pegfilgrastim) may be used during the course 
of the study at the investigator discretion.  The drug(s) should be used at a dose/schedule specified in the package 
insert.   
Antiemetics: Umbralisib and ibrutinib are considered to be of low emetogenic potential that may be adequately 
prevented with prochlorperazine.  Other antiemetics may be used at the discretion of the treating physician if nausea 
and/or vomiting is not adequately controlled/prevented. Appropriate anti-emetic regimens should be based on the 
recommendations 
made 
by 
the 
NCCN 
guidelines 
(SOC). 
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf  
Tumor Lysis Syndrome:  Subjects at risk for tumor lysis syndrome in the opinion of the treating investigator, prophylaxis 
with allopurinol or institutional standards should be considered.  Patients felt to be at risk for tumor lysis syndrome 
by the treating investigator will be monitored at least for the first 3 days of cycle 1 of therapy. 
Pneumocystis Jiroveci Pneumonia (PCP) and Viral Infections:  Prophylactic treatment with pneumocystis jiroveci 
pneumonia (PCP) and antiviral therapy should be considered.  Recommended anti-viral prophylaxis is with Valtrex 500 
mg daily or Acyclovir 400 mg BID or equivalent.  Recommended PCP prophylaxis is with Dapsone 100 mg daily.  Final 
choice of PCP and anti-viral prophylactic therapy is per investigator discretion.  If PCP or anti-viral therapy is not 


  
 
 
 
 
 
  
 
 
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tolerated, alternate to a different PCP or anti-viral therapy, discontinue, or reduce dose/schedule as per investigator 
discretion.  
Blood Product Support: Blood products should be utilized as clinically warranted and following institutional policies and 
recommendations. 
5.4 Duration of therapy 
In the absence of treatment delays due to adverse event(s), treatment should continue unless one of the following 
criteria applies: 
• 
Disease progression or inter-current illness that prevents further treatment. 
• 
Patient decides to withdraw from the study, or changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
• 
One year of therapy 
5.5 Follow-up Evaluations Course Assessment Schedule 
A cycle is 28 days of treatment with any oral agent regardless of group assignment.  Response assessment will be 
done after cycles 2, 4, 6, 9, and 12 (+/- 7 days).  After Month 12, efficacy assessments should occur at the investigators 
discretion. 
We will continue to routinely monitor safety in regards to serious adverse events as well as for toxicity trends that may 
be of concern. 
The reason for study removal and the date the patient was removed must be documented in the Case Report Form.  
Patients who discontinue therapy due to an adverse event should be followed until disease progression. 
5. 6 Toxicity Assessments and Dose modifications 
5.6.1  
Definitions of Cumulative Toxicity Event (CTE) 
For this protocol, cumulative toxicity event (CTE) will be defined as follows: an adverse event attributed (definitely, 
probably or possibly related) to the study treatment and meeting following criteria within cycles 1 to 4. AE grading and 
assignment of attribution require documentation by medical personnel who are directly involved in the clinical care of 
protocol subjects. 
 
Toxicity 
Definition 
Hematologic 
Either: 
1. Grade 4 hematologic toxicities (attributed to either or both drugs) defined as: 
b. Grade 4 thrombocytopenia (platelets < 25 K/µL) 
c. Grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5) 
2. Grade 3 thrombocytopenia or neutropenia that results in a > 7 day delay in either 
drug. 
Non-hematologic 
Either: 
1. ≥ Grade 3 as per NCI Common Terminology Criteria for Adverse Events v4.03* 
(attributed to either or both study drugs). 
2. One week or greater delay in initiating any cycle day 1 due to continued drug-
related toxicity. 
 
*Grade 3 nausea, vomiting, or diarrhea with maximal supportive treatment(s) will be considered a CTE. Fatigue Grade 
>/= 3 considered to be due to treatment (definitely, probably, or possibly related) will be considered a CTE. 
 
Patients should be assessed clinically for toxicity at each visit using the NCI CTCAE v4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE) grading scale.  The study will be terminated if a cumulative toxicity event 
(CTE) occurs in: ≥2/first 4; ≥4/first 8; or if more than 12 patients when the last (24th) evaluable patient  has completed 


  
 
 
 
 
 
  
 
 
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cycle 4. If a patient has progression of disease or is removed from study not related to a CTE after completion of 2 
cycles but less than 4 cycles the patients safety evaluation will be included, but noted appropriately.  If the patient 
receives less than 2 cycles than the patient will not be included and noted, but will not be replaced. 
 
Dosing will occur only if a patient’s clinical assessment and laboratory test values are acceptable.   
Dose modification and or intervention with supportive care recommendations for umbralisib, and ibrutinib are provided 
below, however final discretion lies with the treating investigator in regards to more or less aggressive intervention, 
which specific investigational agent (or if both agents) needs to be reduced, and actual dose reductions, as well as the 
number of dose reductions. 
 
5.6.2 Treatment Initiation/Continuation: 
 
Starting a new cycle or continuing treatment after a CTE should be administered per protocol provided that: 
• 
Absolute neutrophil count ≥ 1000/uL and platelet count ≥ 50,000/uL 
• 
Recovered from grade 3-4 non-hematologic toxicity to grade 1 or baseline.  
• 
Treatment may be delayed to recover from toxicity or per investigator discretion.  
• 
No clinical or radiographic evidence of disease progression.  
 
5.7 Dose modifications of Umbralisib and Ibrutinib for Adverse Reactions 
 
If cytopenias are deemed related to the underlying disease rather than either umbralisib or ibrutinib, dose reductions 
are not required, or are per investigator discretion. 
 
 
 
Worst CTCAE Grade Toxicity 
Action to be Taken 
Grade 
Neutropenia Management 
≤ Grade 1 
No action required. 
Grade 2 
No action required; consider growth factor support. 
Grade 3  or 4 first occurrence 
 
Hold until < Grade 3.  Consider growth factor support. Recheck in at least 
1 week.  Re-challenge at same dose level. 
Grade 3 or 4 
subsequent Occurrences 
Hold until < Grade 3, or at patient’s previous baseline.  Recheck at least 
within 1 week.  Doses are reduced 1 dose level. 
Management of neutropenia is per institution guidelines and if in the opinion of treating investigator, are 
appropriate for patient care. 
 
Worst CTCAE Grade Toxicity 
Action to be Taken 
Grade 
Thrombocytopenia Management 
≤ Grade 1 
No action required. 
Grade 2 
No action required. 
Grade 3 or 4 
1st Occurrence 
Hold until < Grade 3, or at patient’s previous baseline. Recheck at least 
within 1 week.  Re-challenge at same dose level. 
Grade 3 or 4 
subsequent Occurrences 
Hold until < Grade 3, or at patient’s previous baseline.  Recheck at least 
within 1 week.  Doses are reduced 1 dose level. 
Management of thrombocytopenia are per institution guidelines and if in the opinion of treating investigator, 
are appropriate for patient care. 


  
 
 
 
 
 
  
 
 
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Patients who experience an adverse event that occurs after the CTE assessment window (cycle 1-6) will be allowed to 
delay umbralisib or ibrutinib dosing in order to recover from the toxicity.   Patients may resume umbralisib and ibrutinib, 
provided that the toxicity has resolved to Grade ≤ 1 or baseline. 
 
5.8 Non-Hematologic Toxicity 
Grade 3 or 4 Non-Hematologic Toxicity 
 
The dose reduction guidelines for other Grade 3-4 non-hematologic toxicities are shown below. 
NON-HEMATOLOGIC  
Action to be Taken 
Renal 
If serum creatinine >3 x baseline or >3 x ULN, hold dose until ≤ Grade 2.   
Hepatic 
For patients with mild liver impairment (Child-Pugh Class A) the recommended 
dose is 140mg daily (one capsule).  Avoid the use of IMBRUVICA in pts with 
moderate or severe hepatic impairment (Child-Pugh Class B and C).   
Cardiac 
If a QTcF >500 msec has been demonstrated, hold dose: 
For all patients with a new QTcF >500 msec, occurring at any time during the 
study as identified by the investigator, an immediate evaluation of that ECG 
will be obtained and confirmed.    
All cardiac events should be treated as per the local standard of care and 
referral to a specialist if clinically indicated.  Any final decisions concerning 
dose modifications or permanently discontinuing the patient from study drug 
due to QTcF prolongation will occur after discussion between the Invest\gator.  
 
Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients 
treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute 
infections, and a previous history of atrial fibrillation. Periodically monitor 
patients clinically for atrial fibrillation. Patients who develop arrhythmic 
symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should 
have an ECG performed. If atrial fibrillation persists, consider the risks and 
benefits of IMBRUVICA treatment and dose modification  
 
 
 
 
 
 
Worst CTCAE Grade Toxicity 
Action to be Taken 
                              Elevated Liver Enzymes 
Grade 
Management 
≤ Grade 1 
No action required. 
Grade 2 
No action required. 
Grade 3 or 4 
1st Occurrence 
Hold until < Grade 3, or at patient’s previous baseline. Recheck at least 
within 1 week.  Re-challenge at same dose level. 
Grade 3 or 4 
subsequent Occurrences 
Hold until < Grade 3, or at patient’s previous baseline.  Recheck at least 
within 1 week.  Doses are reduced 1 dose level. 
Management of elevated liver enzymes are at the discretion of the investigator 


  
 
 
 
 
 
  
 
 
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OTHER 
NON-
HEMATOLOGIC  
Recommended Action to be Taken   
Grade  1 or 2 
None 
Grade 3 CTCAE  
Hold dose until toxicity Grade ≤2. Reduce 1 dose level. 
If toxicity remains grade 3 
toxicity for longer than 2 weeks Reduce by one dose level or discontinue treatment 
If grade 3 toxicity lasts 2 weeks 
and resolves to ≤ Grade 2  
Hold dose until toxicity Grade ≤2.  Reduce 1 dose level 
Recurrence of Grade 3 of  
toxicity 
Consider reducing by one dose level 
Grade 4 CTCAE 
Hold dose until toxicity Grade ≤2, reduce 1 dose level. 
Recurrence of Grade 4 toxicity Reduce by one dose level or discontinue study drug 
 
5.9 Dose Reduction Guidelines of Umbralisib and Ibrutinib 
 
If a hematologic toxicity is deemed to be related to the study combination both drugs will be reduced.  If a non-
hematologic AE occurs and is felt to be related to only one of the study drug, this drug can be dose reduced alone. 
 
Dose Modifications 
Umbralisib 
Ibrutinib 
Day 
Route 
-1 
600 mg 
560mg 
Day 1-28 
orally 
-2 
400 mg 
 420mg 
Day 1-28 
orally 
-3 
200 mg 
 280mg 
Day 1-28 
orally 
 
5.10  
Assessments  
 
5.10.1  Disease Assessment Schedule  
A dedicated PET/CT Response assessment will be done after cycles 2, 4, 6, 9, and 12 (+/- 7 days).  After Month 12, 
efficacy assessments should occur at the investigators discretion. If a PET/CT CR (Deauville 3 or less) is seen then a 
CT of chest, abdomen, and pelvis with contrast can be substituted.  
 
A restaging bone marrow biopsy may be done if a staging bone marrow biopsy was previously positive or if symptoms 
suggest involvement.  
 
Patients with stable disease after 6 cycles can continue treatment if the treating investigator feels the subject is deriving 
benefit. Patients with progressive disease (PD) at any time are off study and will discontinue study treatment.  
 
Patients achieving PR/CR or stable disease that are felt by the investigator to be deriving a benefit may continue until 
disease progression or for a maximum of 12 cycles (52 weeks of any treatment).  
 
5.10.2  Post Trial Assessments  
Patients who go off study treatment at any time during the trial will be followed for 30 days after the last day of treatment. 
For all patients, drug-related SAEs and AEs will be followed until baseline or ≤ grade 1 levels. Patients who responded 
or maintained stable disease during the study will be followed for date of disease progression. Patients may refuse to 
participate in the post-trial assessments. 
 
5.11  
Biospecimens  
 
5.11.1  Mandatory Human Biologic Materials  
Pathology materials should be submitted and reviewed at UNMC confirming the diagnosis of DLBCL or transformed 
DLBCL.  


  
 
 
 
 
 
  
 
 
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Mandatory peripheral blood (20 mL) for cell free DNA assessment and peripheral mononuclear cells will be collected 
in an EDTA tube pretreatment (day of biopsy or initiation of treatment), day 8, 1 month (+/- 3 days) and 10 mL will be 
collected at subsequent radiographic response assessments, after cycle 2, 4, 6, 9, and 12. (+/- 7 days).  After Month 
12, efficacy assessments should occur at the investigators discretion with collection of a research blood sample only if 
feasible.   
 
5.11.2 Somatic Mutations Affecting B-cell Receptor Signaling 
Prior studies have identified somatic mutations in genes that regulate or modify signaling downstream from the B-cell 
receptor and toll-like receptor pathway, including CD79A, CD79B, CARD11, and MYD88. In addition, these mutations 
may be associated with the clinical response to Ibrutinib. To account for the potential influence of these mutations on 
response, they will be assessed from pre-treatment biopsy specimens by next generation sequencing. To achieve this, 
DNA will be extracted from tumor specimens, genome-wide next generation sequencing libraries constructed, and 
hybrid capture utilized to isolate 386 genes that are recurrently mutated in B-cell lymphoma, including those listed 
above.  
 
 
5.11.3 Quantitative Assessment of Kinetics and Depth of Response 
Tumor cells release DNA into the peripheral blood and it is detectable within the cell-free DNA (cfDNA) fraction isolated 
from plasma. Recent studies have shown that the burden of tumor specific cfDNA in the plasma correlates with 
metabolic tumor volume.(19, 20) In order to quantitatively assess the magnitude and kinetics of response and 
association with radiographic response we will employ cfDNA sequencing by isolating cfDNA from peripheral blood 
samples collected in a 20 ml EDTA tube pretreatment (day of biopsy or initiation of treatment), day 8, 1 month (+/- 3 
days) and 10mL EDTA tube at subsequent radiographic response assessments, after cycle 2, 4, 6, 9, and 12. (+/- 7 
days).  After Month 12, efficacy assessments should occur at the investigators discretion with 10ml EDTA peripheral 
blood samples obtained ONLY IF FEASIBLE. We will create next-generation sequencing libraries, and performing 
hybrid capture for genes with identified mutations from the tumor biopsy specimen as well as immunoglobulin genes. 
(Appendix G Blood and Tissue Sample Processing and Shipping) 
 
This will allow multiple tumor-specific genetic markers to be followed in the peripheral blood, and quantitative 
assessment of response to be calculated by the change in allelic fraction of somatic mutations.  
 
 
5.11.4 Cell Signaling Characteristics 
Malignant B-cells have unique intracellular signaling characteristics that vary between patients.(21) We will assess the 
basal level of signaling downstream from the B-cell receptor in pre-treatment biopsies using intracellular phospho-
specific flow cytometry. Therein, tumor B-cells can be identified using surface markers and fixed and permeabilized 
cells interrogated using antibodies that are specific for activating phosphorylation markers on multiple proteins. Using 
fluorescent barcoding and 10-color multiplexing, we will assess the activity of proximal B-cell receptor signaling 
components (Lyn, Syk, Btk, Blnk, Plcg2), phosphoinositol-3-kinase signaling molecules (Akt,  S6K) and downstream 
targets of casein kinase signaling (EIF4E, Myc)). This will provide a quantitative measure of the basal activation of 
these pathways within patient tumor biopsies prior to treatment. Optional lymph node biopsies will be obtained via US 
or computer tomography (CT) guided biopsy of accessible lymph nodes at day 0 (pre-treatment; core biopsy), day 8 
(FNA) and end of treatment (progressive disease, toxicity, or end of study—1 year; core biopsy) so as to assess the 
change in signaling resulting from treatment.  (Appendix G  Blood and Tissue Sample Processing and Shipping) 
 
 
5.11.5 Peripheral T-cell Characteristics 
Ibrutinib and umbralisib have been described to have secondary targets of Itk and CK1ε, respectively [PMID.(22, 23) 
These molecules play a role in T-helper cell differentiation by promoting or inhibiting Th2 polarization, respectively. 
We will therefore monitor the change in T- cell characteristics using 10mL of peripheral blood in EDTA from pre-
treatment and day 8 and 1-month. This will include the interrogation of cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, 


  
 
 
 
 
 
  
 
 
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IL10, IL-13), phenotypic markers (CD3, CD4, CD25, CD45RO, CCR6, CCR7, CD27, CD127, CXCR3, HLA-DR, 
CD38) and intracellular transcription factors (FoxP3, T-bet, GATA3). 
 
 
 
6.0 Measurement of Effect:  
 
6.1 
Response to therapy:  
 
Response to therapy will be classified as complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD), early death, or not evaluable. Response to therapy will be determined after cycle 2, 4, 6, 9, 
and 12 (+/- 7 days).  After Month 12, efficacy assessments should occur at the investigators discretion.  
 
Patients with a global deterioration of health status requiring permanent discontinuation of study treatment (taken off 
study) without objective evidence of disease progression will be counted as progressive disease unless a prior CR or 
PR has been previously documented. Every effort should be made to document the objective progression even after 
discontinuation of treatment. Deaths will be counted as treatment failure.  
 
Patients will be analyzed with respect to overall survival (OS) and progression-free survival (PFS). Overall survival is 
defined as time from the first therapy administered on trial until death from any cause. For subjects who are still alive 
at the time of the study analysis or are lost to follow-up, survival will be censored at the last recorded date that the 
subject was known to be alive. Progression-free survival is defined as time from therapy until relapse, progression, or 
death from any cause. Response will be determined by the principal investigator or the co-principal investigators.  
 
CR can be achieved at any response evaluation of umbralisib and ibrutinib. 
 
Definitions for clinical response for patients with lymphoma are from the Lugano Response Criteria for Malignant 
Lymphoma.(24) Lymph node measurements should be taken from CT or the CT portion of the PET/CT.  Measurement 
of lymphadenopathy will be determined by adding the sum of the products of the maximal perpendicular diameters of 
measured lesions (SDP).  Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease. For these recommendations, the spleen is considered nodal disease. Disease that is only assessable, such 
as diffuse infiltration of an organ such as the stomach, bone marrow, peripheral blood, liver, lungs, or bowel by 
lymphoma without a discrete mass would constitute assessable, but not measurable, disease (eg, Lymph node or 
tumor mass greater than 1.5 cm in at least one dimension by physical exam, splenic enlargement, if the spleen is 
palpable, at least 3 cm below the left costal margin) will be recorded as present or absent only, unless, while an 
abnormality is still noted by imaging studies or physical examination, it is found to be histologically negative. 
 
Response is based on PET/CT (Deauville 3 or less) or CT alone if CR is achieved by PET/CT. 
 
Response criteria, modified from the Lugano response criteria. DLBCL is considered FDG avid. 
 
Response 
Category 
Definition 
Nodal Masses 
Spleen, liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease. 
Mass of any size 
permitted if PET 
negative  
 
Not 
palpable, 
nodules 
disappeared 
Infiltrate 
cleared 
on 
repeat 
biopsy; 
if 
indeterminate 
by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression 
of 
measurable 
50% decrease in 
SPD of up to 6 
largest 
dominant 
50% decrease in 
SPD of nodules 
(for single nodule 
Irrelevant if positive prior 
to therapy; cell type 
should be specified 


  
 
 
 
 
 
  
 
 
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disease and no 
new sites 
masses; 
no 
increase in size of 
other nodes 
and 
one or more PET 
positive 
at 
previously involved 
site 
in 
greatest 
transverse 
diameter); 
no 
increase in size of 
liver or spleen 
SD 
Failure to attain 
CR/PR or PD 
PET 
positive 
at 
prior 
sites 
of 
disease and no new 
sites on CT or PET 
 
 
Relapse/ 
Progressive 
disease 
Any new lesion or 
increase by 50% 
of 
previously 
involved sites from 
nadir 
Appearance of a 
new lesion(s) > 1.5 
cm in any axis, 
50% increase from 
nadir in SPD of 
more 
than 
one 
node, 
or 
50% 
increase in longest 
diameter 
of 
a 
previously identified 
node > 1 cm in short 
axis. 
The lesions referred 
to 
above 
are 
required to be PET 
positive.  
> 50% increase 
from nadir in the 
SPD 
of 
any 
previous lesions 
New 
or 
recurrent 
involvement 
Abbreviations: CR, complete remission; FDG, [18F] fluorodeoxyglucose; PET, positron emission tomography; CT, 
computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, 
progressive disease. 
 
6.2 
Complete Response (CR): 
 
6.2.1 
Complete disappearance of all detectable clinical evidence of disease and definitely disease-related 
symptoms if present before therapy. 
 
6.2.2 
DLBCL is a FDG-avid lymphoma:  when the PET scan was positive before therapy, a post-treatment 
residual mass of any size is permitted as long as it is PET negative. 
 
6.2.3 
The spleen and/or liver, if considered enlarged before therapy on the basis of a physical examination 
or CT scan, should not be palpable on physical examination and should be considered normal size 
by imaging studies, and nodules related to lymphoma should disappear. However, determination of 
splenic involvement is not always reliable because a spleen considered normal in size may still 
contain lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood volume, the 
use of hematopoietic growth factors, or causes other than lymphoma.  Similarly, other organs 
considered to be enlarged before therapy due to involvement by lymphoma, such as liver and 
kidneys, must have decreased in size. 
 
6.2.4 
If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on 
repeat bone marrow biopsy. The biopsy sample on which this determination is made must be 


  
 
 
 
 
 
  
 
 
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adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by morphology, it 
should be negative by immunohistochemistry. A sample that is negative by immunohistochemistry 
but that demonstrates a small population of clonal lymphocytes by flow cytometry will be considered 
a CR until data become available demonstrating a clear difference in patient outcome.  
 
6.3 
Criteria for Partial Response (PR). The designation of PR requires all of the following: 
 
 
6.3.1 
At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest 
dominant nodes or nodal masses. These nodes or masses should be selected according to all of the 
following:  
• 
they should be clearly measurable in at least 2 perpendicular dimensions 
• 
if possible they should be from disparate regions of the body 
• 
they should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 
 
 
6.3.2 
No increase should be observed in the size of other nodes, liver, or spleen. 
 
 
6.3.3 
Splenic and hepatic nodules must regress by 50% in their SPD or, for single nodules, in the greatest 
transverse diameter.  
 
6.3.4 
With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable 
and no measurable disease should be present. 
 
 
6.3.5 
Bone marrow assessment is irrelevant for determination of a PR if the sample was positive before 
treatment. However, if positive, the cell type should be specified (eg, large-cell lymphoma or small 
neoplastic B cells). Patients who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial responders.  
 
 
When the bone marrow was involved before therapy and a clinical CR was achieved, but with no 
bone marrow assessment after treatment, patients should be considered partial responders. 
 
 
6.3.6 
No new sites of disease should be observed. 
 
 
6.3.7 
For patients with PET scan was positive before therapy, the post-treatment PET should be positive 
in at least one previously involved site. 
 
6.4 
Criteria for Stable Disease (SD): 
6.4.1  
A patient is considered to have SD when he or she fails to attain the criteria needed for a CR or PR 
(see above), but does not fulfill those for progressive disease (see below).  
6.4.2  
The PET should be positive at prior sites of disease with no new areas of involvement on the post-
treatment CT or PET.  
6.5 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD):  
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of the short axis. 
If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if its short axis is more 
than 1.0. Lymph nodes 1.0 x 1.0 cm will not be considered as abnormal for relapse or progressive disease.  
 
 
6.5.1 
Appearance of any new lesion more than 1.5 cm in any axis during or after completion of therapy, 
even if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected site 


  
 
 
 
 
 
  
 
 
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should only be considered relapsed or progressive disease after confirmation with other modalities. 
In patients with no prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly 
benign. Thus, a therapeutic decision should not be made solely on the basis of the PET without 
histologic confirmation. 
 
 
6.5.2 
At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved 
node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered progressive 
disease, a lymph node with a diameter of the short axis of less than 1.0 cm must increase by 50% 
and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis. 
 
 
 
6.5.3      At least a 50% increase in the longest diameter of any single previously identified node more than 1 
cm in its short axis.  
 
6.5.4       Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive 
before therapy unless the lesion is too small to be detected with current PET systems (< 1.5 cm in its long axis by CT). 


  
 
 
 
 
 
  
 
 
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7.0  
STUDY PARAMETERS - Test Schedule for cycle 1-12 
 
1 Physical Exam, Vital Signs, ECOG PS, Hematology and Serum Chemistry visit days have +/- 3 day window in cycle 1 and +/- 
7 day window during cycles 2-12. 
2 To confirm negative HBV and HCV 
3 For women of child bearing potential completed within 14 days prior to Day 1 of Cycle 1 
4Tumor evaluation must include a PET/CT; if a Deauville 3 (CR) is achieved then CT chest, abdomen and pelvis with contrast 
may be used. Further PET/CT scans are optional at the investigators discretion.  All tumor evaluations have +/- 7 day window. 
5 Response evaluation will occur after cycle 2, 4, 6, 9, and 12 (+/- 7 days). After Month 12, efficacy assessments should occur 
at the investigators discretion. 
6 End of study will be the next visit following a cycle after study drug was administered.  If a patient has completed 12 cycles 
of treatment without evidence of PD the patient will be monitor for relapse or progression at the discretion of the treating 
investigator.  Follow up after 1 year of therapy will be per institutional guidelines.  Patient can be taken off study to proceed to 
allogeneic stem cell transplant.  Patients will be censored for EFS and DOR, but will be available for OS assessment. 
7 The study will be terminated if a cumulative toxicity event (CTE) occurs in: ≥2/first 4; ≥4/first 8; or if more than 12 patients 
when the last (24th) evaluable patients has completed cycle 4.  If a patient has progression of disease or is removed from study 
not related to a CTE after completion of 2 cycles but less than 4 cycles the patient’s safety evaluation will be included, but 
noted appropriately.  If less than 2 cycles than the patient will not be included and noted, but will not be replaced.  The stopping 
rule would be appropriately adjusted if this were to occur. 
Cycle (C) = 28 days 
Screening 
 
Cycle 1 
 
CTE Period 
Cycles 2-4 
 
Cycle 5-12 
End 
of 
Treatment6 
Procedure \ Days (D) 
21-0 
Day 1 
± 3days 
Day 8 
Day 
28 
Day 17 
Day 1 
 
Informed consent 
Х 
 
 
 
 
 
 
Pathology confirmation of 
diagnosis of DLBCL or 
transformed DLBCL. 
X 
 
 
 
 
 
 
Medical history 
Х 
 
 
 
 
 
 
Physical examination1 
Х 
X 
X 
 
X 
X 
 
Vital signs (pulse  rate, BP, 
temperature)1 
Х 
X 
 
 
X 
X 
 
ECOG performance status1 
Х 
X 
 
 
X 
X 
 
Optional lymph node biopsy8 
 
X 
X 
 
 
 
X 
Mandatory Research 
peripheral blood samples 
9 
 
 
X 
 
X 
 
X 
 
X9 
 
X9 
 
X 
EKG 
Х 
 
 
 
 
 
 
Serology: HCV, HBV2 
Х 
 
 
 
 
 
 
Umbralisib   
Defined by Grouping (A,B,C) 
 
Daily (1-28) 
Daily (1-28) 
 
Ibrutinib  
Defined by Grouping (A,B,C) 
 
Daily (1-28) 
Daily (1-28) 
 
Hematology1 
X7 
X 
X 
 
X 
X 
 
Serum Chemistry1 
X7 
X 
X 
 
X 
X 
 
Lactate dehydrogenase (LDH) 
X 
 
X 
 
X 
X 
 
Serum Pregnancy test3 
X 
 
 
 
 
 
 
Radiographic 
Tumor 
Evaluation4 
X 
 
 
 
X5 
X5 
 


  
 
 
 
 
 
  
 
 
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8 Optional biopsies obtained via US or CT guided biopsy of accessible lymph node: Day 0 (pre-treatment; core biopsy), day 8 
(fine needle aspiration) and end of treatment (progressive disease or end of study treatment—1 year; core biopsy). At the 
discretion of the treating investigator, patient on non-coumadin based anticoagulation should have anticoagulant held for 
biopsy. 
9 Mandatory research peripheral blood samples will be collected in a 20 ml EDTA tube pretreatment (day of biopsy or initiation 
of treatment; (+/- 3 days)), day 8 (+/- 3 days), 1 month (+/- 3 days) and 10 mL at subsequent radiographic response 
assessments, after cycle 2, 4, 6, 9, and 12. (+/- 7 days).  After Month 12, efficacy assessments should occur at the investigators 
discretion with 10mL EDTA peripheral blood samples obtained ONLY IF FEASIBLE.] 
 
Section 8.0 Drug Formulation and Procurement:  
 
8.1 Umbralisib 
 
Classification:    
Phosphatidylinositol-3-Kinase (PI3K) Delta Inhibitor  
Formulation: 
 
See Investigator Brochure  
Mode of Action:  
Irreversibly inhibits activity of the Class I Delta isoform of PI3K  
How Supplied: 
 
umbralisib (micronized): 200 mg tablets 
Storage: 
Store at 25°C.  Excursions permitted 15°C to 30°C. 
Stability: 
Retest dates will be provided periodically by Sponsor. 
Route:  
 
Oral 
Packaging: 
umbralisib is provided in HDPE bottles each containing 30 tablets and a silica gel canister 
as a desiccant.  
Availability: 
 
umbralisib is available from TG Therapeutics. 
 
8.2 Ibrutinib 
 
Classification:  
 
Irreversible inhibitor of Bruton’s Tyrosine Kinase 
Formulation:  
 
See Investigator Brochure 
Mode of action:  
Irreversibility inhibits activity of Bruton’s Tyrosine Kinase 
How Supplied:  
Ibrutinib: 140 mg capsules (hard gelatin capsule). Refer to the ibrutinib Investigator's 
Brochure for a list of excipients. 
Storage:  
 
Store at 20○C to 25○C 
Route:   
 
Oral 
Availability: 
 
Ibrutinib is available from Janssen Scientific Affairs, LLC.  
 
 
8.3 Administration of Umbralisib and ibrutinib 
 
At each visit, patients will be dispensed sufficient umbralisib and ibrutinib 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.   
 
Umbralisib and ibrutinib will be self-administered by the patients.  Umbralisib (4 200mg tablets = 800mg) and ibrutinib 
(4 140mg tablets = 560mg) will be administered orally once daily.  Umbralisib should be taken in the morning.  Ibrutinib 
should be taken in the evening. (NOTE: After cycle 2 if no CTE have been seen then the patient can have the option 
to take umbralisib and Ibrutinib dosing together at the same time of day.) 
 
Umbralisib and ibrutinib tablets should be swallowed whole with a full glass (approximately 8 ounces) of water.  
Umbralisib tablets should NOT be crushed/opened or chewed.  Ibrutinib capsules should not be opened, broken or 
chewed.   


  
 
 
 
 
 
  
 
 
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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 umbralisib, and instructions 
on how to manage patients. 
 
Prohibitions and restrictions for ibrutinib:  
The following guidance should be applied during the perioperative period for subjects who require surgical intervention 
or an invasive procedure while receiving ibrutinib: 
• 
For any planned surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be held 
at least 7 days prior to the intervention and should be held at least 7 days after the procedure, and restarted at 
the discretion of the investigator when the surgical site is reasonably healed without serosanguineous drainage 
or the need for drainage tubes.   
• 
For planned minor procedures (such as a central line placement, needle biopsy, thoracentesis, or paracentesis) 
ibrutinib should be held for at least 3 days prior to the procedure and should not be restarted for at least 3 days 
after the procedure. For bone marrow biopsies that are performed while the subject is on ibrutinib, it is not 
necessary to hold ibrutinib for these procedures. 
• 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is reasonably 
healed, for at least 7 days after the urgent surgical procedure, or at the discretion of the investigator. 
 


  
 
 
 
 
 
  
 
 
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8.5 Ibrutinib Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
The most common side effects, occurring in at least 1 of every 5 patients ( 20%), have been:  
 
• 
Increase in frequency of loose or watery stools (Diarrhea)  
• 
Muscle and bone pain (Musculoskeletal pain) 
• 
Nausea 
• 
Low white blood cell count (cells that help fight infection) (Neutropenia) 
• 
Rash 
• 
Bruises  
 
Side effects that have been seen in at least 1 of every 10 ( 10%) patients include:  
 
• 
Fever (Pyrexia) 
• 
Low platelet count (cells that help blood to clot) (Thrombocytopenia) 
• 
Common cold (Upper Respiratory Tract Infection) 
• 
Pneumonia 
• 
Constipation 
• 
Swelling of the hands or feet (Oedema peripheral)  
• 
Muscle spasms  
• 
Vomiting 
• 
Joint aches (Arthralgia) 
• 
Sores in mouth (Stomatitis) 
• 
Headache 
• 
High Blood pressure (Hypertension) 
• 
Skin infection 
• 
Sinus infection (Sinusitis) 
 
Side effects that have been seen in at least 1 of every 100 ( 1%) patients include:  
 
• 
Dizziness 
• 
Urinary tract infection 
• 
Noses bleed (Epistaxis) 
• 
Increased level of uric acid in the blood (Hyperuricemia) 
• 
Small red or purple spots caused by bleeding under the skin (Petechiae) 
• 
Abnormal heart rhythm (Atrial fibrillation) 
• 
Non-melanoma skin cancer 
                       Type of non melanoma skin cancer (Basal cell carcinoma) 
                       Type of non melanoma skin cancer (Squamous cell carcinoma) 
• 
Blurry vision (Vision blurred) 
• 
Low white blood cell counts with fever (Febrile neutropenia) 
• 
Severe infection throughout the body (Sepsis) 
• 
Redness of the skin (Erythema) 
• 
Increase in white blood cell counts (Leukocytosis) 
• 
Breaking of the nails (Onychoclasis)  
• 
Inflammation within the lungs that may lead to permanent damage (Interstitial lung disease)  
• 
Increase in lymphocyte count (Lymphocytosis) 


  
 
 
 
 
 
  
 
 
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Side effects that have been seen in at least 1 of every 1000 (<1%) patients include: 
 
• 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells, which may lead to 
changes in kidney function, abnormal heartbeat, or seizures. (Tumor lysis syndrome) 
• 
Itchy rash (Urticaria)  
• 
Bleeding around the brain (Subdural hematoma) 
• 
Swollen face, lip, mouth, tongue or throat (Angioedema)  
• 
High WBC count with abnormal clumping that can lead to bleeding (Leukostasis syndrome) 
• 
Severe rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-
Johnson syndrome)  
• 
Liver failure (Hepatic failure) 
 
Hemorrhage 
Fatal bleeding events have occurred in patients treated with ibrutinib.  Grade 3 or higher bleeding events (subdural 
hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of 
patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients 
treated with ibrutinib.  
The mechanism for the bleeding events is not well understood.  
Ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.  
Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the 
type of surgery and the risk of bleeding.   
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. Grade 3 or greater infections occurred in 14% to 
26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with 
ibrutinib. Monitor patients for fever and infections and evaluate promptly.  
 
A rare and usually fatal viral disease in the brain, Progressive Multifocal Leukoencephalopathy (PML), has been 
reported in patients treated with ibrutinib in combination with rituximab and in patients who were previously treated 
with rituximab. 
 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 
to 17%), and anemia (range, 0 to 9%) occurred in patients treated with ibrutinib. Monitor complete blood counts 
monthly.  
Atrial Fibrillation 
Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with ibrutinib, particularly in 
patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor 
patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) 
or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of 
ibrutinib treatment and dose modification.  
Hypertension 
Hypertension (range, 6 to 17%) has occurred in patients treated with ibrutinib with a median time to onset of 4.5 
months (rang, 0.03 to 18.40 months). Monitor patients for new onset hypertension or hypertension that is not 


  
 
 
 
 
 
  
 
 
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adequately controlled after starting ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-
hypertensive treatments as appropriate. 
Second Primary Malignancies 
Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients 
treated with ibrutinib. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to11 
%).  
Tumor Lysis Syndrome  
Tumor lysis syndrome has been reported with ibrutinib therapy. Monitor patients closely and take appropriate 
precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden).  
Embryo-Fetal Toxicity  
Based on findings in animals, ibrutinib can cause fetal harm when administered to a pregnant woman. Ibrutinib 
caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported 
in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. 
Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking 
ibrutinib. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient 
should be apprised of the potential hazard to a fetus. 
 
Allergic reactions  
 
Serious allergic reactions to ibrutinib, including rash, difficulty breathing, wheezing, sudden low blood pressure with 
light-headedness, swelling around the mouth, throat or eyes, a racing heartbeat, and/or sweating may occur.   
 
Rash 
 
A maculopapular rash (flat, red areas on the skin with small bumps) has been commonly reported in patients treated 
with ibrutinib alone or in combination with other drugs. Most rashes are mild to moderate in severity and begin 2 to 3 
weeks or longer after starting ibrutinib.  
 
There have been rare reports of severe skin reactions (known as severe cutaneous adverse reaction or “SCAR”, 
involving more than 50% of the body) or rash with blisters and peeling skin, which may include open ulcers or sores 
in the mouth and other areas of the body (Stevens - Johnson syndrome). These skin rashes could be life-threatening. 
 
Lymphocytosis and leukostasis 
 
Lymphocytosis is an increase in the number of lymphocytes, a type of white blood cell, in your blood. This may occur 
in the first few weeks of treatment and one should not assume that this increase in white blood cells means that the 
disease is worsening. This increase may last for several weeks to months. Increased number of white blood cells in 
the bloodstream may alter blood flow resulting in bleeding or clotting (leukostasis). Isolated cases of these events have 
been reported in patients treated with ibrutinib.  
 
Liver Failure 
 


  
 
 
 
 
 
  
 
 
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Rare cases of liver failure have been reported in patients treated with ibrutinib.  
 
Interstitial lung disease 
 
Lung abnormalities not associated with infections (e.g, bacteria, viruses, fungi) have been reported in patients treated 
with ibrutinib 
 
Interference with other drugs  
 
Some foods like grapefruit juice and Seville oranges, as well as some medications, may interfere with the way the body 
processes ibrutinib. This interference could cause the amount of ibrutinib in the body to be higher or lower than 
expected. It is also possible that taking the study drug with regular medications or supplements, including fish oil, 
Vitamin E, or other vitamins, may change how the regular medications, or regular supplements, work. It is very 
important that grapefruit juice and Seville oranges be avoided.  
 
9.0  
Toxicity and Adverse Event Reporting Guidelines 
 
The reporting is only for TGR 1202 and Ibrutinib “study medications,” until 30 days after last administration of study 
medication.  
 
NOTE: Problems related to insurance coverage for UNMC potential subjects or enrolled subjects will be reported to 
the IRB as they are encountered.  
 
This protocol will comply with monitoring and adverse event reporting requirements of the UNMC Fred & Pamela Buffett 
Cancer Center Data Monitoring plan. The protocol will adhere to the institutional and FDA guidelines for the toxicity 
reporting. 
 
All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration 
of study medication. Adverse event and serious adverse events will be followed until baseline or ≤ grade 1 levels. 
Toxicity will be assessed using the revised NCI CTCAE version 4.02.  
 
All adverse events will be followed to a satisfactory conclusion. Serious adverse events should be followed until 
resolution, death, or until no further improvement is reasonably expected. Deaths occurring within 30 days of study 
treatment regardless of relationship will be reported to the UNMC DSMC. 
 
In addition to complying with all applicable regulatory reporting laws and regulations, all serious adverse events and 
toxicities will be reported to the University of Nebraska Medical Center, Institutional Review Board (IRB), participating 
sites own IRB and Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee (DSMC). 
 
Definitions:  
 
Adverse Event  
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the 
event is considered causally related to the use of the product.  
 
An elective surgery or procedure that is scheduled to occur during a study will not be considered an adverse event if 
the surgery or procedure is being performed for a pre-existing condition and the surgery or procedure has been planned 
before study entry. However, if the pre-existing condition deteriorates unexpectedly during the study (e.g., the surgery 


  
 
 
 
 
 
  
 
 
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is performed earlier than planned), then the deterioration of the condition for which the elective surgery or procedure 
is being done will be considered an adverse event.  
 
An adverse event can result from use of the drug as stipulated in the protocol or labeling, as well as from accidental or 
intentional overdose, drug abuse, or drug withdrawal. Any worsening of a pre-existing condition or illness is considered 
an adverse event. Laboratory abnormalities and changes in vital signs are considered to be adverse events if they 
result in discontinuation from the study, necessitate therapeutic medical intervention, meet protocol specific criteria 
(see Section 5.0, Treatment Plan) and/or if the investigator considers them to be adverse events. In general, if a 
laboratory abnormality or change in vital sign is associated with a specific diagnosis that is being reported concurrently 
as an adverse event (e.g. elevated creatinine with renal failure or sinus tachycardia in febrile neutropenia) the findings 
that support the diagnosis do not need to be reported as separate adverse events unless the investigator feels it is 
appropriate.  
 
Treatment-emergent Adverse Event  
 
Treatment-emergent adverse event is defined as any adverse event with onset or worsening from the time that the first 
dose of study drug is administered until 30 days after the final dose of study drug is administered.  
 
Unexpected Adverse Event  
 
An unexpected adverse event is any adverse drug event that is not listed in the current labeling/Investigator’s Brochure. 
This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, 
but differ from the labeled event because of greater severity or specificity. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the labeling only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an 
adverse drug experience that has not been previously observed (i.e., included in the labeling) rather than from the 
perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical 
product.  
 
Serious Adverse Event  
 
A serious adverse event is one that at any dose (including overdose) and regardless of causality that:  
• 
Results in death  
• 
Is life-threatening1  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity2  
• 
Is a congenital anomaly or birth defect  
• 
Is an important medical event3  
• 
Pregnancy  
1 “Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse 
event; it does not refer to a serious adverse event that hypothetically might have caused death if it were more 
severe.  
2 “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s 
ability to carry out normal life functions.  
3 Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate 
in situations where none of the outcomes listed above occurred. Important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above should also usually be 
considered serious. Examples of such events include allergic bronchospasm requiring intensive treatment in 


  
 
 
 
 
 
  
 
 
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an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. A new diagnosis of cancer during the course of a 
treatment should be considered as medically important. 
 
9.1  
Adverse Event Reporting and Definitions Per University of Nebraska Medical Center, IRB and Fred & 
Pamela Buffett Cancer Center Data and Safety Monitoring Committee (DSMC) 
 
 
 
This protocol will adhere to all institutional guidelines for adverse event reporting. Adverse events will be 
evaluated using the NCI Common Terminology Criteria for Adverse Events (CTC-AE) version 4.02.  
 
9.1.1  
IRB REPORTING  
All internal serious adverse events (AE) must be reported to the local IRB promptly per institutional policy 
[UNMC – through the electronic Research Support System(s) (RSS) mechanism] and in no case later than 
two (2) business days following PI notification that the event occurred if the principal investigator determines 
that conditions A, B, and C are met:  
 
a. The AE is unexpected, AND  
b. The AE is related to, or possibly related to, the drug, biologic, device, or other research intervention, AND  
c. The AE is more than minor in nature which is defined as requiring treatment from a health professional.  
 
All unexpected, internal, fatal AEs must be reported promptly to the local IRB per institutional policy [UNMC - 
through the electronic RSS mechanism], but no later than 24 hours following PI notification that the event 
occurred. If documentation is still pending, the IRB office must be notified by a telephone call or e-mail.  
 
All expected, internal, fatal AEs (i.e., due to progressive disease or which reflect a risk currently found in the 
consent form) must be reported to the local IRB per institutional policy [UNMC - through the electronic RSS 
system] no later than ten (10) business days following PI notification that the event occurred.  
The UNMC RSS is accessed through a link on the UNMC IRB website (http://unmc.edu/irb). 
 
9.1.2  
FRED & PAMELA BUFFETT CANCER CENTER DATA AND SAFETY MONITORING 
COMMITTEE (DSMC) REPORTING  
 
Per UNMC DSMC guidelines, the following must be reported: 
• 
All adverse events ≥ grade 3 (expected or unexpected, regardless of attribution) will be reported to 
the University of Nebraska Medical Center, Fred & Pamela Buffett Cancer Center Data and Safety 
Monitoring Committee (DSMC).  
• 
All serious adverse events will be fully reported and reviewed by the University of Nebraska Medical 
Center, Fred & Pamela Buffett Cancer Center Data and Safety Monitoring Committee (DSMC).  
o The principal investigator is responsible for submitting a copy of the UNMC SAE 
Assessment Form along with a blinded copy of any related patient source documents 
o If additional information about the SAE is still being collected a preliminary report should 
be filed to the DSMC within seven (7) business days with final reporting when additional 
information is available. 
 
Attribution of AE: The likelihood of relationship of the AE to the study drugs will be determined by the 
investigator based on the following definitions:  
 
Not related: The subject was not exposed to the study treatment or another cause is obvious.  
 
Probably not related: The AE is most likely explained by another cause, and the time of occurrence of the 
AE is not reasonably related to the study treatment. 


  
 
 
 
 
 
  
 
 
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Possibly related: Study treatment administration and AE occurrence reasonably related in time, and the AE 
is explained equally well by causes other than study treatment, or treatment administration and AE occurrence 
are not reasonably related in time, but the AE is not obviously a result of other causes.  
 
Probably related: Study treatment administration and AE occurrence are reasonably related in time, and the 
AE is more likely explained by study treatment than by other mechanisms.  
 
Definitely related: There occurrence and timing of the AE are clearly attributable to the study treatment.  
 
Severity Grade of AE. The severity of events reported on the AE case report form will be determined by the 
principal investigator according the NCI Common Toxicity Criteria (CTC version 4.02).  
 
AEs will be collected from the time the subject signs the consent form and ending 30 days following the final 
chemotherapy. All AEs will be followed until resolution or a cause is identified. Prescription medication taken 
to relieve symptoms of the AE will be recorded in addition to the outcome.  
 
AEs judged by the investigator as not related or probably not related to the treatment will NOT be followed 
beyond the 30 days after the final chemotherapy.  
 
Copies of the SAE report will be submitted to the IRB as indicated in Section 9.1.1.  
 
Detailed 
policy 
and 
procedures 
for 
this 
section 
may 
be 
reviewed 
at: 
http://www.unmc.edu/cancercenter/clinical/prms.html 
9.1.3  
FOOD AND DRUG ADMINISTRATION (FDA) REPORTING  
 
It is the responsibility of the UNMC sponsor-investigator, Matthew Lunning, D.O., to submit to the FDA 
IND Safety Reports in accordance with 21 CFR 312.32. The SAE will be submitted to FDA if the PI 
determines 21CRF312.32 criteria are met. 
 
SAEs not meeting expedited criteria will be made available to FDA by the sponsor-investigator via the annual 
report.  
 
The investigator will utilize the FDA MedWatch Form (Appendix H) for the reporting of serious adverse events 
and follow up information to those events. The form can be found at the following URL:  
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf  
 
Additionally, serious adverse events will be reported to the IRB, SRC, Audit Committee and the Data Safety 
Monitoring Committee by the Investigator as described further within Section 9.0.  
 
9.1.4 Janssen Interventional Investigator Initiated Study Requirements for  Safety Data Collection and Reporting 
   
Overview 
As the sponsor of the Study, PRINCIPAL INVESTIGATOR shall be solely responsible for complying, within the 
required timelines, any safety reporting obligation to competent Health Authorities, IRB/ECs and any 
participating (co or sub) investigators, as defined in applicable laws and regulations.  For the purposes of this 
section, safety data includes adverse events, product quality complaints (PQCs), and special situations including 
pregnancies. 
 
UNMC and PRINCIPAL INVESTIGATOR will provide safety information to the Janssen on adverse events, 
special situations including pregnancies and product quality complaints as defined within this Section. 


  
 
 
 
 
 
  
 
 
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Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events regardless of causality 
and special situations excluding those from subjects not exposed to a Janssen Medicinal Product and product 
quality complaints with or without an adverse event as described in this section will be reported from the time a 
subject has signed and dated an Informed Consent Form (ICF) until completion of the subject’s last study-related 
procedure (which may include contact for follow-up safety).  Serious adverse events will be reported for 30 days 
after the last dose of study drug. 
 
For the purposes of this study, the Janssen medicinal product is: Ibrutinib (Imbruvica)  
 
Definitions 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An adverse event does not necessarily have a causal 
relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational or non- investigational) product, whether or not related to that medicinal (investigational or non-
investigational) product.  
This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities. 
 
Adverse Events of Special Interest  
Adverse events of special interest are events that the Janssen Scientific Affairs, LLC is actively monitoring 
as a result of a previously identified signal (even if non-serious). These adverse events are: 
• 
Major Hemorrhage 
Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or greater in severity or that 
results in 1 of the following: intraocular bleeding causing loss of vision, the need for a transfusion of 
2 or more units of red cells or an equivalent amount of whole blood, hospitalization, or prolongation 
of hospitalization. 
• 
Intracranial Hemorrhage 
Any intracranial hemorrhage adverse event, including subdural hematoma/hemorrhage, epidural 
hematoma/hemorrhage and intracerebral hemorrhage, of any grade severity, will be captured as 
an event of special interest. 
• 
Other Malignancies  
In addition to all routine AE reporting, all new malignant tumors, including solid tumors, skin 
malignancies and hematologic malignancies, are to be reported for the duration of study treatment 
and during any protocol-specified follow-up periods including post-progression follow-up for overall 
survival. 
 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting requirements. 
• 
an identifiable subject (but not disclosing personal information such as the subject’s name, initials or 
address) 
• 
an identifiable reporter (investigational site) 
• 
a Janssen medicinal product 
• 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• 
suspected Janssen medicinal product (doses, indication) 


  
 
 
 
 
 
  
 
 
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• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
age at AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, action taken, outcome, 
(if available) 
• 
Janssen protocol ID 
 
Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a potential quality 
issue during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage or 
distribution of the product, or delivery system.  Not all PQCs involve a subject.  Lot and batch numbers are 
of high significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 
• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Potential Dosing Device Malfunction: e.g., auto injector button not working, needle detaching from 
syringe 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
 
Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose: 
 
• 
Results in death 
• 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is also 
appropriate in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. These should usually be considered 
serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE EVENT. 
 
Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the hospitalization that is the 
serious event for which details must be provided. 


  
 
 
 
 
 
  
 
 
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Any event requiring hospitalization or prolongation of hospitalization that occurs during the study must be 
reported as a serious adverse event, except hospitalizations for the following: 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons such as 
pending placement in long-term care facility) 
• 
Surgery or procedure planned before entry into the study. [Note: Hospitalizations that were planned 
before the start of data collection and where the underlying condition for which the hospitalization 
was planned has not worsened will not be considered serious adverse events. Any adverse event 
that results in a prolongation of the originally planned hospitalization is to be reported as a new 
serious adverse event.] 
 
 
Life-Threatening Conditions 
Disease progression should not be recorded as an adverse event or serious adverse event term; instead, 
signs and symptoms of clinical sequelae resulting from disease progression/lack of efficacy will be reported 
if they fulfill the serious adverse event definition. 
 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information. For a medicinal product(s) with a marketing authorization, the expectedness of an 
adverse event will be determined by whether or not it is listed in the applicable product information. 
  
http://www.imbruvica.com/hcp/?utm_source=google&utm_medium=cpc&utm_campaign=Imbruvica&utm_term=imbru
vica&utm_content=ibrutinib-+Exact|mkwid|ssjPpM0Gh_dc|pcrid|39412243694 
 
Special Reporting Situations  
Safety events of interest for a Janssen medicinal product that require expediting reporting and/or safety 
evaluation include, but are not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a Janssen medicinal product  
• 
Exposure to a Janssen medicinal product from breastfeeding  
• 
Suspected abuse/misuse of a Janssen medicinal product 
• 
Inadvertent or accidental exposure to a Janssen medicinal product  
• 
Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen medicinal product 
• 
Medication error involving a Janssen medicinal product (with or without patient exposure to the Janssen 
medicinal product, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a medicinal product 
• 
Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from Janssen Scientific 
Affairs, LLC and TG Therapeutics perspective, they are treated in the same manner as adverse events. 
Special situations should be recorded on the Adverse Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be recorded on a Serious 
Adverse Event Report Form and be reported to the Janssen Scientific Affairs LLC and TG Therapeutics 
within 24 hours of becoming aware of the event. 
 
Pregnancy  
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC and TG Therapeutics by the 
PRINCIPAL INVESTIGATOR within 24 hours of their knowledge of the event using the Serious Adverse 


  
 
 
 
 
 
  
 
 
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Event Form. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomaly, ectopic pregnancy) are considered serious adverse events and must be reported using the Serious 
Adverse Event Form.  
 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study and discontinue 
further study treatment. 
 
Because the effect of the Janssen medicinal product on sperm is unknown, pregnancies in partners of male 
subjects exposed to a Janssen medicinal product will be reported by the PRINCIPAL INVESTIGATOR within 
24 hours of their knowledge of the event using the Serious Adverse Event Form.  Depending on local 
legislation this may require prior consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required. 
 
Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. The PRINCIPAL 
INVESTIGATOR shall provide all adverse events, both serious and non-serious, in report format. However, in 
certain circumstances more frequent provision of safety data may be necessary, e.g. to fulfill a regulatory 
request, and as such the data shall be made available within a reasonable timeframe at the Janssen’s request. 
 
Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Janssen Medicinal 
Products to Janssen  
All adverse events and special situations whether serious or non-serious, related or not related, following exposure 
to a Janssen medicinal product are to be documented by the investigator and recorded in the CRF and in the 
subject’s source records. Investigators must record in the CRF their opinion concerning the relationship of the 
adverse event to a Janssen medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product should be followed-up in 
accordance with clinical practice. 
 
SAEs and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health care practitioner 
refusal to provide additional information, lost to follow-up after demonstration of due diligence with follow-
up efforts) 
 
The PRINCIPAL INVESTIGATOR) will transmit all SAEs and special situations following exposure to a 
Janssen product under study in a form provided by Janssen Scientific Affairs and TG Therapeutics in 
accordance with Transmission Methods, in English within 24-hours of becoming aware of the event(s). 
 
 
All follow-up information for serious adverse events that are not resolved at the end of the study or by the 
time of patient withdrawal must be reported directly by the PRINCIPAL INVESTIGATOR, within 24 hours 
becoming aware, to Janssen Scientific Affairs, LLC using Janssen’s Serious Adverse Event Report  


  
 
 
 
 
 
  
 
 
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All available clinical information relevant to the evaluation of a related SAE or special situation is required. 
• 
The  PRINCIPAL INVESTIGATOR is responsible for ensuring that these cases are complete and if not 
are promptly followed-up. A safety report is not considered complete until all clinical details needed to 
interpret the case are received. Reporting of follow-up information should follow the same timeline as 
initial reports. 
 
• 
Copies of any and all relevant correspondences with regulatory authorities and ethics committees 
regarding any and all serious adverse events, irrespective of association with the Janssen Product under 
study, are to be provided to Janssen Scientific Affairs, LLC using a transmission method listed below 
within 24 hours of such report or correspondence being sent to applicable health authorities. 
 
Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC and TG Therapeutics Y 
according to the timeframe outlined in the Research Funding Agreement section entitled Reporting of Data. 
 
PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of patients, 
investigators, and Janssen, and are mandated by regulatory agencies worldwide. Janssen Scientific Affairs 
has established procedures in conformity with regulatory requirements worldwide to ensure appropriate 
reporting of PQC information. Lot and/or Batch #s shall be collected or any reports failure of expected 
pharmacological action (i.e., lack of effect). The product should be quarantined immediately and if possible, 
take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to Janssen Scientific 
Affairs, LLC by the PRINCIPAL INVESTIGATOR within 24 hours after being made aware of the event. 
The Janssen contact will provide additional information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a serious adverse event or 
non-serious adverse event, the PRINCIPAL INVESTIGATOR must report the PQC to Janssen according to 
the serious adverse event reporting timelines.  A sample of the suspected product should be maintained for 
further investigation if requested by Janssen. 
 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Non-Janssen 
Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen medicinal product under 
study, the PRINCIPAL INVESTIGATOR should notify the appropriate regulatory/competent authority or the 
manufacturer of that medicinal product (in the absence of appropriate local legislation) as soon as possible. 
 
Transmission Methods 
The following methods are acceptable for transmission of safety information to Janssen Scientific Affairs, LLC: 
• 
Electronically via Janssen SECURE Email service (preferred) 
• 
For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission report 
• 
Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen Scientific Affairs. 
 
9.2 Auditing  


  
 
 
 
 
 
  
 
 
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The UNMC Fred & Pamela Buffett Cancer Center Scientific Review Committee (SRC) will review this protocol on at 
least an annual basis.  
 
This study will undergo audit on at least a quarterly basis by the UNMC Fred & Pamela Buffett Cancer Center Audit 
Committee.  
 
 
Detailed policy and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html.  
 
 
Section 10.0 Statistical Considerations 
 
The phase IIa portion will further assess the safety and tolerability and allow a preliminary assessment of the efficacy 
of the novel combination to provide background for an appropriately powered phase II study.  We plan to accrue 24 
patients into the phase IIa portion at a micronized dose of 800 mg of umbralisib and 560 mg of ibrutinib.  The 
assessment of toxicity and efficacy will be performed within the entire cohort. To consecutively monitor the safety 
primary endpoint in the phase IIa portion, we will employ a sequential probability stopping rule for the predefined portion 
of cycles 1-4. This stopping rule specifies that the study will be terminated if a cumulative toxicity event (CTE) occurs 
in: ≥2/first 4; ≥4/first 8; or if more than 12 patients when the last (24th) evaluable patient has completed the trial have 
any CTE. This rule has the following stopping probability: 
 
 
 
 
 
 
 
A CTE is defined as: 
• 
Grade ≥ 3 non-hematologic (attributed to either or both study drugs)  
• 
Grade 4 hematologic toxicities (attributed to either or both drugs) defined as: 
o Grade 4 thrombocytopenia (platelets < 25 K/µL) 
o Grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5) 
• 
Grade 3 thrombocytopenia or neutropenia that results in a > 7 day delay in either drug. 
• 
One week or greater delay in initiating any cycle day 1 due to continued drug-related toxicity.  
 
 
If a patient has progression of disease or is removed from study not related to a CTE after completion of 2 cycles but 
less than 4 cycles the patient’s safety evaluation will be included, but noted appropriately.  If less than 2 cycles than 
the patient will not be included and noted, but will not be replaced.  The stopping rule would be appropriately adjusted 
if this were to occur. 
 
An efficacy-stopping rule is also in place for the combination.   After testing the combination on 12 patients, the trial will 
be terminated if </= 1 patients respond.  If the trial goes on to the second stage and not discontinued due to the CTE 
stopping rules prior to, a total of 24 patients will be studied. If the total number responding is less than or equal to five, 
the regimen will be rejected.  This follows a Simon two-stage design for efficacy following a minimax design with the 
following parameters:  overall response rate for a poor regimen of 0.01, overall response rate for a good regimen of 
0.31, a type I error of 0.20 and power of 80%. 
True 
toxicity 
rate 
5% 
10% 
15% 
20% 
25% 
30% 
35% 
40% 
50% 
Stopping 
prob. 
0.000 0.000 0.001 0.004 0.016 0.056 0.118 0.243 0.632 


  
 
 
 
 
 
  
 
 
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Efficacy measures which will be determined include ORR, TTR, DOR, and PFS.   ORR is defined as the percentage 
of patients achieving a best response of CR/CR, PR at any disease assessment time point.  TTR is defined as the time 
or number of cycles between study registration and documentation of first response (CR/Cru, or PR).  DOR is defined 
as the time or number of cycles between documentation of first response and progression, change of therapy, death, 
or date of last contact (if still alive without progression).  PFS is defined as the time between study registration and 
documented progression or death if no progression was observed. 
 
 
11.0  
RECORDS TO BE KEPT 
 
Information regarding the actual treatments, adverse effects, radiographic and laboratory information, and pathology 
are to be recorded on appropriate forms. See attached Data forms. Source documents which support data entered 
must be provided for centralized compliance monitoring. Serious adverse events, when noted, will be recorded on site 
via the standard serious adverse effects form.  
 
11.1 Quality assurance  
Complete records must be maintained in a research chart on each patient treated on the protocol. These records 
should include primary documentation (e.g., lab. report slips, X-ray reports, scan reports, pathology reports, physician 
notes, etc.) which confirm that:  
- The patient met the eligibility criteria.  
- Signed informed consent was obtained prior to treatment.  
- Treatment was given according to protocol (dated notes about doses given & reasons for any dose modifications).  
- Toxicity was assessed according to protocol (laboratory report slips, etc.).  
- Response was assessed according to protocol (x-ray, scan, lab reports, dated notes on measurements & clinical 
assessment, as appropriate).  
 
11.2 Medidata Rave 5.6 Electronic Data Capturing (EDC) System 
 
The UNMC Fred & Pamela Buffett Cancer Center (NCI-designated cancer center) is a participant in the National Cancer 
Institute Cancer Biomedical Informatics Grid (CaBIG™) initiative.   
 
The NCI purchased software license for cancer centers use of Medidata Rave 5.6 a web-based EDC application for 
managing clinical trial data across multiple cancer clinical trials.  Data will be stored electronically for this study on the 
Rave secure server.  Data forms will not differ from the paper versions with the exception of an electronic format 
containing the UNMC Fred & Pamela Buffett Cancer Center and Rave logo. 
 
Medidata Rave 5.6 provides for remote data collection that meets FDA 21 CFR Part 11 requirements as well as HIPAA 
and other regulatory requirements designed to enhance data security and protect patient confidentiality. Authorized 
users log into Medidata Rave 5.6 through a secure connection and must provide a valid username, password, and 
database ID.  De-identified research data will be shared with the NCI and the CaBIG community.  This data may be 
made available to the public at large. 
 
RAVE Builder Contact Information 
University of Nebraska Medical Center 
Fred & Pamela Buffett Cancer Center 
Att: Eugene “Gene” Sehi, M.S., CCRP 
986805 Nebraska Medical Center 
Omaha, NE 68198-6805 
FAX: (402) 559-5669 Ph: (402) 559-8514 
Email: esehi@unmc.edu 


  
 
 
 
 
 
  
 
 
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12.0  
PATIENT CONSENT  
 
12.1  
Human Subjects Research Protection Training  
All personnel involved in this research project will have completed the OHRP-approved computer based 
training course on the Protection of Human Research Subjects. All clinical and correlative research included 
in this application will have approval by the institutional review board.  
 
12.2  
Study Population  
Patients are from all socio-economic groups and will be entered into the study without bias with respect to 
gender or race. Attempts will be made to recruit minorities. No vulnerable subjects will be included in the 
study.  
 
12.3  
Sources of Material  
Pathology material (as stated in Section 5) must be reviewed, and the diagnosis confirmed by University of 
Nebraska Medical Center pathology department (retrospectively) as outlined in the protocol. 
 
12.4  
Recruitment and Informed Consent  
Patients with a history of relapsed or refractory DLBCL for whom this therapy would be appropriate will be 
available for recruitment. These patients will be informed of the nature of this study, and will be asked to 
participate on a voluntary basis after informing them of the possible risks and benefits of the study. A number 
of public registries may be accessible to health care providers and prospective subjects as listed below.  
National Library of Medicine - http://clinicaltrials.gov (NCT02874404) 
National Cancer Institute - http://www.cancer.gov (NCI-2016-01082)  
 
12.5  
Subject Competency  
Subjects will be eligible to participate in the study only if they are competent to give informed consent. A 
subject that the investigators judges to be incompetent will not be enrolled.  
 
12.6  
Process of Informed Consent  
If the patient chooses to be a participant in this study, informed consent will be obtained by the investigators. 
The study and procedures involved including the risks will be explained in detail to each subject. It will be 
clearly explained to the subject that this is a research study and that participation is entirely on a voluntary 
basis. Subjects will be given the option to discuss the study with a family member, friend, counselor or, another 
physician. The participating investigators will be available to discuss the study with them.  
 
12.7  
Subject/Representative Comprehension  
When the process of informed consent is completed, the subject will be asked to state in his/her own words, 
the purpose of the study, the procedures that will be carried out, potential risk, potential benefits to the subject, 
the alternatives and the right to withdraw from the study. If there is any indication that a given subject's 
comprehension is anything less than accurate, the points of confusion will be discussed and clarified.  
 
12.8  
Information Purposely Withheld.  
The results of the tests done solely for research purposes will not be disclosed to the subject. No other 
information will be purposely withheld from the subject.  
 


  
 
 
 
 
 
  
 
 
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12.9  
Potential Benefits of the Proposed Research to the Subjects  
It is hoped that the use of protocol therapy in this patient population may result in tumor shrinkage or 
stabilization of disease.  
 
12.10  Potential Benefits to Society.  
Information obtained from this study may help patients by Identifying safety and tolerability of umbralisib and 
ibrutinib.  
 
12.11  Potential Risks  
Use of umbralisib and ibrutinib is associated with numerous potential risks. Combinations of novel targeted 
therapies are considered to be a valid treatment option for patients with advanced malignancies. It is believed 
the treatment option outlined in the study will not pose significant additional risks compared to conventional 
treatment that might consist of other chemotherapy drugs given alone or in combination.  
 
12.12  Therapeutic Alternatives  
If patients choose not to participate in this study they may elect to receive standard salvage therapy as per 
their primary oncologist, which may include other chemotherapy drugs given alone or in combination.  
 
 
12.13  Risk/Benefit Relationship  
Although there are inherent risks involved because of the use of chemotherapy agents, the risk is considered 
to be acceptable in the setting of cancer.  
 
12.14  Consent Form Documents  
No information will be purposely withheld from the patients. The consent document used in this study will 
include the adult consent document. (See attached consent form) 
 
 


  
 
 
 
 
 
  
 
 
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Section 13.0 References 
 
1. 
Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP 
versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 2006 Jul 1;24(19):3121-7. 
2. 
A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma 
Prognostic Factors Project. The New England journal of medicine. 1993 Sep 30;329(14):987-94. 
3. 
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to 
predict survival after chemotherapy for diffuse large-B-cell lymphoma. The New England journal of medicine. 2002 
Jun 20;346(25):1937-47. 
4. 
Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, et al. Autologous bone marrow 
transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's 
lymphoma.[see comment]. New England Journal of Medicine. 1995;333(23):1540-5. 
5. 
Young RM, Shaffer AL, 3rd, Phelan JD, Staudt LM. B-cell receptor signaling in diffuse large B-cell 
lymphoma. Seminars in hematology. 2015 Apr;52(2):77-85. 
6. 
Chen L, Monti S, Juszczynski P, Ouyang J, Chapuy B, Neuberg D, et al. SYK inhibition modulates distinct 
PI3K/AKT- dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas. Cancer cell. 
2013 Jun 10;23(6):826-38. 
7. 
Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for 
survival of activated B cell-like diffuse large B cell lymphoma cells. The Journal of experimental medicine. 2001 Dec 
17;194(12):1861-74. 
8. 
The ABC Subtype of Diffuse Large B-Cell Lymphoma Is Responsive to Ibrutinib. Cancer discovery. 2015 Jul 
30. 
9. 
Sanford DS, Wierda WG, Burger JA, Keating MJ, O'Brien SM. Three newly approved drugs for chronic 
lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice. Clinical lymphoma, 
myeloma & leukemia. 2015 Jul;15(7):385-91. 
10. 
Burris HA PM, Fenske et al. A novel once daily PI3-K delta inhibitor demonstrates clinical actiivity and lack 
of hepatotoxicity in patients with CLL and B-cell NHL. Hematology/oncology clinics of North America. 2015;33:119. 
11. 
Prasanna R, Viswanadha S. PI3K delta enzyme assay.  Shamerrpet, India: Incozen therapeutics PVT LTD; 
2011 April Protocol IVT-5264-EAG-19 Sponsored by Rhizen Pharmaceutical S.A. Switzerland. 
12. 
Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, et al. Discovery of selective irreversible 
inhibitors for Bruton's tyrosine kinase. ChemMedChem. 2007 Jan;2(1):58-61. 
13. 
Inc. IBIP-VJP. 
14. 
Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor 
ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2013 Jan 1;31(1):88-94. 
15. 
Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling 
with ibrutinib in diffuse large B cell lymphoma. Nature medicine. 2015 Aug;21(8):922-6. 
16. 
Lunning MA VJ, Folwler NH et a. Ublituximab plus TGR-1202 activity and safety profile in 
relapsed/refractory B-cell NHL and high-risk CLL. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology. 2015;33; Abstr 8548. 
17. 
Cheah CY, Nastoupil LJ, Neelapu SS, Forbes SG, Oki Y, Fowler NH. Lenalidomide, idelalisib, and rituximab 
are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood. 2015 May 21;125(21):3357-9. 
18. 
Fowler NH NL, Lunning MA et al. Safety and activity of the chemotherapy-free triplet of ublituximab, TGR-
1202, and ibrutinib in relapsed B-cell malignancies. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2015;33; Abstr 8501. 
19. 
Roschewski M, Dunleavy K, Pittaluga S, Moorhead M, Pepin F, Kong K, et al. Circulating tumour DNA and 
CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. The lancet 
oncology. 2015 May;16(5):541-9. 
20. 
Kurtz DM, Green MR, Bratman SV, Scherer F, Liu CL, Kunder CA, et al. Noninvasive monitoring of diffuse 
large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood. 2015 Jun 11;125(24):3679-87. 


  
 
 
 
 
 
  
 
 
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21. 
Krutzik PO, Nolan GP. Intracellular phospho-protein staining techniques for flow cytometry: monitoring 
single cell signaling events. Cytometry Part A : the journal of the International Society for Analytical Cytology. 2003 
Oct;55(2):61-70. 
22. 
Deng C, Lipstein MR, Scotto L, Jirau Serrano XO, Mangone MA, Li S, et al. Silencing c-Myc translation as a 
therapeutic strategy through targeting PI3K delta and CK1 epsilon in hematological malignancies. Blood. 2016 Oct 
26. 
23. 
Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible 
molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013 Oct 10;122(15):2539-49. 
24. 
Cheson BD. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification.  J Clin Oncol 2014 Sep; 32(27); 3059-3067. 
 
 
Section 14.0 Data Collection Forms  
Attached.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
  
 
 
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Appendix A:  
Use of ibrutinib with other CYP3A inhibitors or inducers (per ibrutinib USPI) 
 
CYP3A Inhibitors:  
In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of 
ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual 
doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng⋅ hr/mL which is 
approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).  
 
Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A 
inhibition. Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, 
nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For strong CYP3A inhibitors used 
short-term (e.g., antifungals and antibiotics treatment for 7 days or less  e.g., ketoconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin)) consider interrupting ibrutinib therapy until the CYP3A 
inhibitor is no longer needed. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A 
inhibitor must be used, reduce ibrutinib dose to 140 mg (e.g., fluconazole, darunavir, erythromycin, diltiazem, 
atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, and ciprofloxacin).  Patients taking 
concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity. 
 
Avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain moderate  
inhibitors of CYP3A.  
 
CYP3A Inducers:  
Administration of ibrutinib with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by 
approximately 13- and 10-fold, respectively.  
 
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). 
Consider alternative agents with less CYP3A induction.  
 
 
 
 
Appendix B:  
Cockroft-Gault Creatinine Clearance Calculation 
 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
 
CrCl (ml/min) = (140-age) (actual wt in kg) divided by 72 x serum creatinine (mg/dl) 
 
For females use 85% of calculated CrCl value.  
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
  
 
 
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Appendix C 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead. 
 
 
Appendix D      
NEW YORK HEART ASSOCIATION (NYHA) HEART DISEASE CLASSIFICATION 
 
Class 
 
Definition 
 
I. 
 
No limitation of physical activity.   Ordinary physical activity does not cause undue fatigue, 
or dyspnea. 
 
II. 
 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, or dyspnea. 
 
III. 
 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary activity 
causes fatigue, or dyspnea. 
 
IV. 
 
Unable to carry on any physical activity without symptoms.  Symptoms are present even 
at rest.  If any physical activity is undertaken, symptoms are increased. 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
  
 
 
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Appendix E 
Eligibility Checklist 
 
Date Completed: 
 
Institution:  
Patient ID#:  
Checklist Version #3.0 
 Dated: 14Jul2017 
 
IRB# 345-15   Title: : A Single-center Phase IIa Study 
Evaluating the Safety and Tolerability of umbralisib and 
Ibrutinib in Patients with Relapsed or Refractory Diffuse 
Large B-cell Lymphoma: A Trial of the Lymphoma 
Precision Medicine Laboratory  
Reference #:  
 
PI: Mathew Lunning, MD 
Waiver #: 
Gender:  [  ] M  [  ] F 
Race:  [  ] White [  ] Black        [  ] Hispanic 
[  ] Asian 
[  ] Native American [  ] Other 
[  ] Unknown 
Zip Code/country (if not 
USA):  
 
Primary method of payment information:  
Inclusion Criteria:  Response should be YES 
Yes    No      N/A 
1. Histologically confirmed Diffuse Large B-cell Lymphoma (DLBCL) or 
transformed DLBCL 
[  ]     [  ]  
1. 
2.  
 
2. Disease status defined as Patients with relapsed or refractory DLBCL that 
has relapsed post-transplant or that has been determined to be ineligible or 
unsuitable for transplant.  Patients must have received at least one prior 
systemic therapy. 
[  ]     [  ] 
[  ] 
3. Patients must have measurable (> 1.5 cm) or evaluable disease. Baseline 
measurements and evaluations must be obtained within 21 days of 
registration to the study. Abnormal PET scans will not constitute evaluable 
disease, unless verified by CT scan or other appropriate imaging. 
Measurable disease must have at least one objective measurable disease 
parameter. A clearly defined, bi-dimensionally measurable defect or mass 
measuring at least 1.5 cm in diameter on a CT scan will constitute 
measurable disease. Proof of lymphoma in the liver is required by a 
confirmation biopsy. Skin lesions can be used as measurable disease 
provided bi-dimensional measurements are possible 
[  ]     [  ]  


  
 
 
 
 
 
  
 
 
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4. Adequate organ system function, defined as follows: 
a. Absolute neutrophil count (ANC) ≥ 1.0  x 109/L 
i. By automated or manual review, whichever is greatest 
b. Platelets ≥100 x 109/L: 
i. Unless due to bone marrow infiltration then eligible if 
platelets > 50 x 109/L) 
c. Total bilirubin ≤ 1.5 x upper normal limit if documented hepatic 
involvement with lymphoma, or ≤ 5 x upper normal limit if history of 
Gilbert’s Disease.  
d. Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤2.5 x ULN if no liver involvement or ≤5 x the ULN if 
documented liver involvement 
e. Creatinine ≤2.0 mg/dL OR calculated creatinine clearance ≥50 
mL/min (as calculated by the Cockcroft-Gault method, Appendix B) 
 
[  ]     [  ]  
5. ECOG performance status ≤2 or expected survival duration of > 2 months  
(Appendix C) 
 
[  ]     [  ]  
6. Patients must be ≥19 years of age (the age of consent in Nebraska) 
 
[  ]     [  ]    
7. Ability to swallow and retain oral medication  
[  ]     [  ]    
8.  Women must not be pregnant or breast-feeding due to teratogenic 
effects of therapy 
All female patients of child-bearing potential must have a negative 
serum pregnancy test within 2 weeks prior to treatment to rule out 
pregnancy  
Pregnancy testing is not required for post-menopausal or surgically sterilized 
women 
[  ]     [  ]        [  ] 
9. Male and female patients of reproductive potential must agree to follow 
accepted birth control measures throughout the study period and for 30 days 
after the last dose of either study drug for females and 3 months after the 
last dose of study drug for males 
[  ]     [  ]    
 
10. Patient must be able to adhere to the study visit schedule and other protocol 
requirements 
 
[  ]     [  ]   [  ] 
11. Patient must be aware of the neoplastic nature of his/her disease and 
willingly sign (or their legally-acceptable representatives must sign) an 
informed consent document indicating that they understand the purpose of 
and procedures required for the study, including biomarkers, and are willing 
to participate in the study 
[  ]     [  ]   


  
 
 
 
 
 
  
 
 
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12. No serious disease or condition that, in the opinion of the investigator, would 
compromise the patient’s ability to participate in the study 
 
[  ]     [  ]   
Exclusion Criteria: Response should be NO 
Yes    No      N/A 
1.  Currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, hormonal therapy, and surgery and/or 
tumor embolization) or any investigational drug within 7 days of Cycle 1/Day 
1, 14 days of Cycle 1/Day 1 for limited palliative radiation, and/or five half-
live of an oral therapy 
Corticosteroid therapy started at least 7 days prior to initiation of treatment 
(prednisone ≤10 mg daily or equivalent) is allowed as clinically warranted).  
Topical or inhaled corticosteroids are permitted 
[  ]     [  ]    
2.      Major surgery or a wound that has not fully healed within 4 weeks of 
enrollment 
 
[  ]     [  ]    
3.    History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment 
[  ]     [  ]    
4.    Requires anticoagulation with warfarin or equivalent vitamin K antagonists 
(eg, phenprocoumon) 
[  ]     [  ]    
5.    Vaccinated with live, attenuated vaccines within 4 weeks of enrollment 
[  ]     [  ]    
6.    Autologous hematologic stem cell transplant within 3 months of study entry 
[  ]     [  ]    
7.    Allogeneic hematologic stem cell transplant within 12 months of study entry 
[  ]     [  ]    
8.     Active graft versus-host disease and must not be on immunosuppression 
[  ]     [  ]   
9.    Wide field radiotherapy within 28 days of Cycle 1/Day 1 or active side effects 
of such therapy 
[  ]     [  ]   


  
 
 
 
 
 
  
 
 
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10. Active Hepatitis B (HBV) or C (HCV) infection (negative serology required 
excluding those with are seropositive due to prior vaccination) and/or known history 
of human immunodeficiency virus (HIV) 
 
[  ]     [  ]      
11. Primary central nervous system  involvement only 
[  ]     [  ]      
12. Require treatment with strong CYP3A inhibitors  
 
[  ]     [  ]      
13.Known history of drug-induced liver injury, alcoholic liver disease, primary biliary 
cirrhosis, ongoing extra-hepatic obstruction caused by stones, cirrhosis of the liver or 
portal hypertension 
[  ]     [  ]      
14. Any life-threatening illness, severe and/or uncontrolled medical condition, or 
organ system dysfunction, laboratory abnormality, psychiatric illness or other 
condition which, in the Investigator’s opinion,  could compromise the 
subject’s safety, interfere with the absorption or metabolism of ibrutinib 
capsules, put the study outcomes at undue risk or affect their participation 
in the study such as: 
a. Symptomatic, or history of documented congestive heart failure 
New York Heart Association (NYHA) functional classification III-IV 
(NYHA, Appendix D)  
b. QTc >470 msec (unless related to pacemaker) on EKG within 21 
days of initiation of treatment 
c. Angina not well-controlled by medication 
d. Poorly controlled or clinically significant atherosclerotic vascular 
disease including cerebrovascular accident (CVA), transient 
ischemic attack (TIA), angioplasty, cardiac or vascular stenting 
within 6 months prior to enrollment 
 
[  ]     [  ]      
15. Prior malignancies within the past 1 years with exception of adequately treated 
basal cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix 
or breast; prostate cancer of Gleason Grade 6 or less with stable PSA levels 
[  ]     [  ]      
16. Women who are pregnant or breastfeeding.  Women who agree to stop 
breastfeeding would be eligible 
[  ]     [  ]      
17. Known hypersensitivity to either study drug (umbralisib or Ibrutinib)  
[  ]     [  ]      


  
 
 
 
 
 
  
 
 
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NOTE: All questions regarding eligibility for potential subjects should be directed to the PI at 402-559-5166.   
 
Eligibility: [  ] Patient satisfies all criteria    
                     [  ] Patient not formally eligible, but admitted to this study because (state reason): 
 
 
 
 
Patient Initials:  __________MR or Study ID#______________DOB ________ 
 
ELIGIBILITY reviewed and confirmed.  
Consenting/Treating Investigator Signature _______________________Date_____________   
          Printed Name of Consenting/Treating Investigator:  __________________________ 
 
 
 
 
 


  
 
 
 
 
 
  
 
 
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Appendix F 
Oral, Sublingual, and/or Buccal Route  
Medication Adherence Standard Procedure 
(V 1.0 11-25-2013) 
PURPOSE 
To provide a means of ensuring oral, sublingual and/or buccal routes of medication adherence to patients while 
participating in a clinical trial. 
1. A physician’s order will be completed by study patients or representative for oral, sublingual and/or buccal 
administration per IRB approved protocol. 
2. To ensure the consistent and safe administration of medications not given under the direct supervision of 
study staff (at home), there will be a “Medication Information Sheet” and a calendar to document times of drug 
administration. 
3. To record medication adherence Study staff will document results of medication reconciliation and or 
medication return in the patient’s chart. 
4. Maintain documentation of medications returned or sent to investigational pharmacy for destruction (if 
applicable).  
PROCEDURE 
1. Protocol specific information regarding the individual medication(s) should be listed on the form “Medication 
Information Sheet” and given to the patient at the start of the study and throughout treatment if necessary to 
help ensure adherence. (See Form A) 
2. Name, dose and route of each medication should be listed under ‘How to take your Medication’ on the 
“Medication Information Sheet”. 
3. Patients will be given a monthly “Medication Calendar”.  The calendar will have a place for the patient to 
record the time that the medication(s) were taken. (See Form B for example) 
4. The research nurse will review the patient’s “Medication Calendar” for adherence to the study regimen for oral 
medication administration. Adherence will be noted in the patient’s chart.  Medication reconciliation will be 
done and if there is medication to be returned/destroyed it will be sent to the Nebraska Medical Center 
Investigational Pharmacist for return/destruction in accordance to the Nebraska Medical Center Destruction 
of Investigational product, Policy #4.860.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
  
 
 
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Medication Information Sheet (Form A)  
 
IRB# 345-16    Title of protocol: A Single-center Phase IIa Study Evaluating the Safety and 
Tolerability of umbralisib (formerly known as TGR-1202) and Ibrutinib in Patients with Relapsed 
or Refractory Diffuse Large B-cell Lymphoma: A Trial of the Lymphoma Precision Medicine 
Laboratory 
  
 
You have been enrolled into the following Dosing Group _______________. 
How to take your medication:   
Group A:  You will take umbralisib 800mg (4 tablets) Day 1-8  
Starting day 9, you will take both umbralisib 800mg (4 tablets) and Ibrutinib 560mg (4 capsules) by mouth 
once a day with a full 8 ounce glass of water until your treating physician tells you to stop.  Follow your 
Medication Calendar that is provided to record your dosing. 
 
Group B:  You will take Ibrutinib 560mg (4 capsules) Day 1-8  
Starting day 9, you will take both umbralisib 800mg (4 tablets) and Ibrutinib 560 mg (4 capsules) by mouth 
once a day with a full 8ounce glass of water until your treating physician tells you to stop.  Follow your 
Medication Calendar that is provided to record your dosing. 
 
Group C:  You will take both umbralisib 800mg (4 tablets) and Ibrutinib 560 mg (4 capsules) by mouth once 
a day with a full 8ounce glass of water until your treating physician tells you to stop.  Follow your Medication 
Calendar that is provided to record your dosing. 
 
• 
Umbralisib should be taken in the AM.  (NOTE: After cycle 2 if no side effects have been seen you 
can have the option to take umbralisib and Ibrutinib dosing together at the same time of day.) 
• Ibrutinib should be taken in the evening. (NOTE: After cycle 2 if no side effects have been seen 
you can have the option to take umbralisib and Ibrutinib dosing together at the same time of day.) 
 
Things to know about your medication:  
1. The dose of the study medications will remain the same during your entire treatment, unless your 
doctor informs you of a change.   
2. If your doctor modifies the dose of either medication for any reason, please record the change on 
your Medication Calendar (Form B).  
3. You should take your medications at the same time each day with food.  
4. You should avoid grapefruit and Seville oranges (Known as “Chinese Bitter Orange”, bitter orange, 
sour orange, bigarade orange, or marmalade orange. The Seville orange variety is used in the 
production of marmalade/cooking) during treatment, as these can alter the absorption of the 
medications. 
5. You should swallow the tablets and capsules as a whole, do not chew or crush them. 
6. If you miss a dose of your medications, it should be taken as soon as possible on the same day.  If 
it is missed for the entire day, it should not be made up.  If a dose is missed make sure to mark it on 
your Medication Calendar (Form B). 
7. If vomiting occurs, no attempt should be made to replace the vomited doses. 


  
 
 
 
 
 
  
 
 
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Your Doctor is:  ___________________________Contact Phone # _______________  
Your Research Nurse is:  ___________________________Contact Phone # _______________  
After hours, nights, weekends and holidays please call 402-559-5600 and ask for the Oncologist on call. 
 
 
 
Medication Diary (Form B)  Template 
 


  
 
 
 
 
 
  
 
 
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Appendix G 
Blood and Tissue Sample Processing and Shipping  
Description of Sample Collection:  
No therapeutic intervention will be undertaken and the results of these studies will not have any influence on the medical 
management of the subjects.  
 
Lymph Node Biopsy Guidelines: 
Day 1 – pretreatment and END OF TREATMENT or Progression 
CORE NEEDLE BIOPSY 
 
STANDARD path review 
               Plus  2 cores requested for research.   
Per Dr McBride, it is standard for them to use an 18 gauge. Sample size is approx. 2cm per each core. 
 
Day 8 – cycle 1 of treatment 
FINE NEEDLE ASPIRATE  
 
Sample ONLY FOR RESEARCH.   
No path review needed.   
              Collect sample per the IR standard.     Per Dr. McBride, it is standard to use a 22g or 25g needle.  They 
determine what size is best, based on the patient.  They will provide aspirate per their standard process.  Typically, 
four passes for collection of FNA.    
 
 
Facility 
Sample 
Contact Person(s) 
Date and Time Points 
 
 
 
 
UNMC 
Designated 
Repository  
Laboratory  
 
Optional 
Lymph 
Node 
Pathology material:  
Lymph 
node 
biopsies 
obtained via US guided 
biopsy of accessible lymph 
node at day 0 (pre-
treatment; core biopsy ), 
day 
8 
(fine 
needle 
aspiration) and end of 
treatment 
(progressive 
disease or end of study 
treatment—1 year; core 
biopsy) 
Keenan Hartert Phone: 402-
559 7921Email: 
keenan.hartert@unmc.edu  
 Baseline day 0 (pre-
treatment; core biopsy )  
Date: ___/___/____ 
 
 Day 8 (fine needle 
aspiration)  
Date: ___/___/____ 
 
 End of treatment 
(progressive disease or 
end of study treatment—1 
year; core biopsy)  
Date: ___/___/____ 
 
UNMC 
Designated 
Repository  
Laboratory  
 
Mandatory Research blood 
specimen: 
20 
ml 
EDTA 
tube 
pretreatment 
(day 
of 
biopsy or initiation of 
treatment), day 8, 1 month 
(+/- 3 days) and 10ml 
EDTA 
at 
subsequent 
radiographic 
response 
assessments, after cycle 
2, 4, 6, 9, and 12. (+/- 7 
Keenan HartertPhone: 402-
559-7921 
Email:  
keenan.hartert@unmc.edu  
 
Location: 
UNMC Designated Repository  
Laboratory   
F&PBCC, 4th floor, Room 379 
 
 
 Baseline Blood 
      Sample 
 (pretreatment = day of 
biopsy or initiation of 
treatment) 
Date: ___/___/____ 
 
 Day 8 Blood 
      Sample  
Date: ___/___/____ 
 


  
 
 
 
 
 
  
 
 
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days).  After Month 12, 
efficacy 
assessments 
should 
occur 
at 
the 
investigators 
discretion 
with 
10ml 
EDTA 
peripheral blood samples 
obtained 
ONLY 
IF 
FEASIBLE. 
Additional 
  Optional: Please  
Check the box if patient 
consented to the storing of 
any 
leftover 
peripheral 
blood for future unspecified 
research use) 
 
 
 1 month (+/- 3 days)  
Blood Sample  
Date: ___/___/____ 
 
 
                     Page 1 of 2 
  Re-staging  Blood 
Sample after cycle 2 
(+/- 7 days).   
Date: ___/___/____ 
 
  Re-staging  Blood 
Sample after cycle 4 
(+/- 7 days).   
Date: ___/___/____ 
  Re-staging  Blood 
Sample after cycle 6 
(+/- 7 days).   
Date: ___/___/____ 
  Re-staging  Blood 
Sample after cycle 9 
(+/- 7 days).   
Date: ___/___/____ 
  Re-staging  Blood 
Sample after cycle 12 
(+/- 7 days)   
Date: ___/___/____ 
 
After Month 12, efficacy 
assessments 
should 
occur 
at 
the 
investigators discretion 
peripheral 
blood 
samples obtained ONLY 
IF FEASIBLE. 
  Re-staging  Blood 
Sample  
Date: ___/___/____ 
 
  Re-staging  Blood 
Sample 
Date: ___/___/____ 
 
  Re-staging  Blood 
Sample 
Date: ___/___/____ 


  
 
 
 
 
 
  
 
 
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  Re-staging  Blood 
Sample 
Date: ___/___/____ 
 
 
 
 
 
Appendix H  
FDA MEDWATCH form 
 
Available on-line at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf  
 
 

ICF_001.pdf: 
PT NAME:   
MR#: 
CONSENT FORM
IRB PROTOCOL # 345-16-FB
  Page 1 of 29
ADULT CONSENT - CLINICAL BIOMEDICAL
Title of this Research Study
A Single-center Phase IIa Study Evaluating the Safety and Tolerability of Umbralisib
and Ibrutinib in Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma
Invitation
You are invited to take part in this research study. You have a copy of the following,
which is meant to help you decide whether or not to take part:
Informed consent form
"What Do I need to Know Before Being in a Research Study?"
The Rights of Research Subjects
Why are you being asked to be in this research study?
You are being asked to be in this study because you are an adult and have a
diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
If you are pregnant, nursing an infant, or plan to become pregnant during this study,
you may not be in this study.
What is the reason for doing this research study?
This research study will test a combination of two oral drugs, unbralisib (formerly
known as TGR-1202) and ibrutinib. This study will try to determine what the safest
and most effective dose is for these chemotherapy pills.
Umbralisib is an investigational drug not approved for marketing by the FDA. It is
available from TG Therapeutics for use this research study.
Ibrutinib used in this research study is an FDA approved medication for patients with
Mantle Cell Lymphoma who have received at least one prior therapy, for patients with
Chronic Lymphocytic Leukemia (CLL) for CLL patients with 17p deletion, for patients
with Waldenstroms Macroglobulinema, Marginal zone lymphoma (MZL) who require
a medicine by mouth or injection (systemic therapy) and have received a certain type
of prior treatment and Chronic graft versus host disease (cGVHD) after failure of one
or more lines of systemic therapy. Ibrutinib is not approved for the treatment of
patients with DLBCL.
It is planned that 24 patients total will be enrolled to this study at the University of
Nebraska Medical Center.
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PT NAME:   
MR#: 
CONSENT FORM
IRB PROTOCOL # 345-16-FB
  Page 2 of 29
What will be done during this research study?
There will be 3 treatment groups given one year (12 months) of therapy, you will be
assigned to one of the 3 groups, to see what effects (good and bad) it has on you
and your cancer and to find the doses that can be given safely.
All subjects will be assigned to only one group and receive a maximum of 52 weeks
(1 year) of self-administered oral therapy. The first 3 subject to consent will be
directly enrolled into Group C regardless of their decision to be included in the
optional biopsy. Then the next subjects will be assigned in order to group A, B or C
based on date of consent and those willing to consent to the optional biopsies. You
will be informed as to which group of this research you are enrolled into. You will also
be made aware of what dose of umbralisib and ibrutinib you are to receive.
Group A will receive umbralisib 800 mg (four-200mg tablets) orally every day
on days 1-8; then umbralisib 800 mg (four-200mg tablets) and ibrutinib 560
mg (four-140mg tablets) orally every day for one year (12 months). Group A
(6 patients) will have the option to consent to 3 additional lymph node
biopsies.
Group B will receive ibrutinib 560 mg (four-140mg tablets) orally every day
on days 1-8; then ibrutinib 560 mg (four-140mg tablets) and umbralisib 800
mg (four-200mg tablets) orally every day or one year (12 months). Group B (6
patients) will have the option to consent to 3 additional lymph node biopsies.
Group C will receive umbralisib 800 mg (four-200mg tablets) and ibrutinib
560 mg (four-140mg tablets) orally every day or one year (12 months). Group
C (12 patients) will have the option to consent to 3 additional lymph node
biopsies.
The investigator will review your medical history and current medications to
determine if you might qualify to participate in the study. If you choose to sign this
informed consent form, you will continue with the screening process. Many of the
tests may be the same as those you have already completed for the diagnosis of
your lymphoma.
The screening process may take place over a period of up to 21 days before you
start your study medication. These may take more than one visit and will include the
following:
A physical examination will be performed.
Your actual health status and your well-being will be assessed. This is called
a performance status assessment.
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PT NAME:   
MR#: 
CONSENT FORM
IRB PROTOCOL # 345-16-FB
  Page 3 of 29
A little less than 3 teaspoons (15 mL) of blood will be taken for specific
standard laboratory (lab) tests.
If you are female and are able to have children, a pregnancy test will be done
on your blood or urine. This test must be done within 14 days before receiving
study medication. The test must be negative for you to be in the study.
You will have tests completed to check the function of your heart. These tests
include an Electrocardiogram.
A PET/CT is mandatory pre-treatment (as part of your screening process).
In addition, we will draw a blood sample for research testing, a little less than
4 teaspoons (20 mL), being completed for this project. (See mandatory
sample collection below).
Diagnosis of DLBC or transformed DLBC lymphoma will be confirmed by the
pathologists at UNMC.
Up to 4 teaspoons (20 ml) of blood will be taken for research samples (See
mandatory sample collection below).
An optional core biopsy will be obtained via US or CT guided biopsy of
accessible lymph node before you begin treatment. ((See decision for
optional biopsies at the end of this consent form)).
Study Medication: (umbralisib is a tablet. Ibrutinib is a capsule.)
The doses of umbralisib and ibrutinib will be determined by the group you are
enrolled into the study.
You will receive up to 12 cycles of oral study medication, umbralisib and
ibrutinib.
Each cycle will last for 28 days.
Follow your medication calendar that is provided to you by the research
nurse.
During the first cycle you will be asked to take your assigned study
medication by mouth once a day for 8 days and starting on day 9 and every
day thereafter until the investigator tells you to stop, you will be asked to take
your assigned study medication combination.
Umbralisib should be taken in the morning and ibrutinib should be
taken in the evening. (NOTE: After cycle 2 if no side effects have been seen
you have the option to take umbralisib and ibrutinib dosing together at the
same time of day.)
You will be given a monthly Medication Diary. The diary will have a place for
you to record the time you took your prescribed doses of umbralisib and
ibrutinib.
Things to know about taking your study medication:
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PT NAME:   
MR#: 
CONSENT FORM
IRB PROTOCOL # 345-16-FB
  Page 4 of 29
1. You should take your study medication each day with a full 8 ounce glass of
water and food.
2. You should avoid grapefruit and Seville oranges (Known as Chinese Bitter
Orange, bitter orange, sour orange, bigarade orange, or marmalade orange.
The Seville orange variety is used in the production of marmalade/cooking)
during treatment, as these can alter the absorption of the study medication.
3. You should swallow the tablets and capsules as a whole, do not chew or
crush them.
4. If you miss a dose of your study medication, it should be taken as soon as
possible on the same day. If it is missed for the entire day, it should not be
made up. If a dose is missed make sure to mark it on your Medication
Calendar.
5. If vomiting occurs, no attempt should be made to replace the vomited doses.
If the investigator thinks you are at risk for tumor lysis syndrome (complications
caused by the breakdown products of dying cancer cells) you will receive
pre-medication with allopurinol or a suitable alternative 12-24 hours prior to the first
dose of chemotherapy. No routine pre-medications for nausea and vomiting should
be needed, however, medications may be administered for symptoms or side effects
when they occur, and the investigator may order other pre-medications if needed.
Follow-Up Process and Procedures
During the study, you will be followed closely to find out the effects of umbralisib and
ibrutinib. If there are any safety concerns, additional blood tests may be required. If
you experience any bad side effects, the investigator may delay treatment or re-start
the study medications at a lower dose.
On day 8 of the first cycle before you begin treatment you will have the following:
A physical examination will be performed.
A little less than 3 teaspoons (15 mL) of blood will be taken for specific
standard laboratory (lab) tests.
In addition, we will draw a blood sample for research testing a little less than 4
teaspoons (20 mL) being completed for this project. (See mandatory sample
collection below).
An optional core biopsy will be obtained via US or CT guided biopsy of
accessible lymph node before you begin treatment (See decision for optional
biopsies at the end of this consent form).
Before each 28 day cycle of your treatment you will have the following:
A physical examination will be performed. Any side effects and other
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PT NAME:   
MR#: 
CONSENT FORM
IRB PROTOCOL # 345-16-FB
  Page 5 of 29
medication use will be reviewed.
Your actual health status and your well-being will be assessed. This is called
a performance status assessment.
Umbralisib and ibrutinib medication diaries will be reviewed and drug returns
will be counted and additional umbralisib and ibrutinib will be ordered.
A little less than 3 teaspoons (15 mL) of blood will be taken for specific
standard laboratory (lab) tests (complete blood count, chemistry panel, as
indicated).
In addition, before the 2nd cycle, we will draw a blood sample for research
testing a little less than 4 teaspoons (20mL) being completed for this project.
(See mandatory sample collection below).
At the completion of the 2nd, 4th, 6th, and 9th, and 12th cycles (+/- 7 days) (before
you begin the following cycles) you will have the following:
The investigator will do a restaging assessment of your lymphoma, a PET/CT
or a CT chest, abdomen and pelvis with contrast may be used at the
investigators discretion. If your disease is improving or staying the same, you
will continue to receive more cycles (a total of 12 cycles) of this combination
therapy.
In addition, we will draw a blood sample for research testing a little less than 2
teaspoon (10 mL) being completed for this project. (See mandatory sample
collection below).
At the end of treatment (disease progression) or end of cycle 12 (+/- 7 days) of your
treatment you will have the following:
A little less than 3 teaspoons (15mL) of blood will be taken for specific
standard laboratory (lab) tests (complete blood count, chemistry panel, as
indicated).
In addition, we will draw a blood sample for research testing a little less than 2
teaspoons (10 mL) being completed for this project. (See mandatory sample
collection below).
After Month 12, restaging assessments of your lymphoma should occur at the
investigators discretion with collection of a blood sample for research testing a little
less than 2 teaspoons (10 mL) being completed for this project only if feasible.
MANDATORY SAMPLE COLLECTION
The researchers doing this study need to do tests on blood (described below) to see
how the cancer cells respond to the study drug combination. These tests will look for
ways to help predict which patients are most likely to be helped by the combination
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PT NAME:   
MR#: 
CONSENT FORM
IRB PROTOCOL # 345-16-FB
  Page 6 of 29
treatment, including looking for DNA/tumor markers, peripheral mononuclear cells
and cytokine profiles (proteins released by cells that have a specific effect on the
interactions between cells, on communications between cells or on the behavior of
cells).
The collection of these samples (research blood only) before you begin treatment (+/-
3 days) and at day 8 (+/- 3 days), 1 month (+/- 3 days) and the end of your cycle 2, 4,
6, 9, and 12 cycles (+/- 7 days) is a necessary part of this study and will be used only
for these purposes. After Month 12, research blood samples obtained ONLY IF
FEASIBLE during scheduled restaging assessments of your lymphoma that occur at
the investigators discretion. The samples will not be sold.
At the end of this consent form, we will ask for your permission to store any left-over
samples for future research.
What are the possible risks of being in this research study?
You may need to be admitted to the hospital for treatment for the side effects. Every
effort will be taken to lessen side effects, but there is no way to tell which side effects
may happen or how bad they may be. Unless otherwise stated, the side effects are
reversible.
You will be closely monitored for any side effects you experience on the study. The
investigator can give you other medications to treat the side effects or can decrease
the doses of medications to stop or reduce the severity of the side effect and allow
you to continue in the study.
As with any medication, allergic reactions are a possibility.
Umbralisib
The following side effects are common (greater than 20% of people):
Stomach and digestive disorders: nausea, diarrhea
General disorders and administration site conditions: tiredness
Less Common (greater than or equal to 10% to less than or equal to 20% of
people)
Blood and lymphatic system disorders: decrease in number of white blood
cells
Stomach disorders: vomiting
Metabolism and nutrition disorders: decreased appetite
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Skin Disorders: rash
Uncommon (greater than or equal to 1% to less than 10% of people)
Blood and Lymphatic System Disorders: decrease in number of red blood
cells, fever with decrease in white blood cells, white blood cells above normal
range, decreased number of platelets
Eye Disorders: vision blurred
Gastrointestinal 
Disorders: 
abdominal 
bloating, 
abdominal 
pain,
constipation, dry mouth, indigestion, inflammation of the bowel that can cause
severe diarrhea which may require hospitalization
General Disorders and Administration Site Conditions: fever, weakness,
chills, swelling of hands, arms, legs, ankles, and/or feet
Infections and Infestations: yeast infection in the mouth, pneumonia,
infection of the mouth or throat
Investigations: increase in liver enzymes, increase in levels of creatinine in
blood which can indicate decreased kidney function, increase in lymphocyte
count (type of white blood cell), weight loss
Metabolism and Nutrition Disorders: dehydration, increase in blood sugar
levels, decrease in levels of potassium in blood, decrease in levels of
phosphate in blood which can lead to bone weakness
Musculoskeletal and Connective Tissue Disorders: pain in joints, muscle
spasms, pain in arms and/or legs
Nervous System Disorders: dizziness, change in taste, headache,
numbness and/or tingling of the hands and/or feet, involuntary shaking or
trembling
Psychiatric Disorders: difficulty sleeping
Respiratory, Thoracic and Mediastinal Disorders: cough
Skin and Subcutaneous Tissue Disorders: hair loss, night sweats, itching
Events Reported In Less Than 1% of Subjects
Blood and Lymphatic System Disorders: Leukopenia, Hyperbilirubinemia,
Bacteremia
Ear and Labyrinth Disorders: Tinnitus
Eye Disorders: Visual Impairment, Visual acuity reduced
Gastrointestinal Disorders: Eructation, Flatulence, Gastrooesophageal
Reflux Disease, Abdominal Pain Upper, Mouth Ulceration, Anal Hemorrhage,
Hypoaesthesia Oral, Paraesthesia Oral, Pancreatitis, Ileus
General Disorders and Administration Site Conditions: Malaise, Mucosal
Inflammation,
Hepatobiliary Disorders: Hypocalcemia
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Immune System Disorders: Allergic reaction
Infections and Infestations: Candida infection, Fungal skin infection, Lung
infection, Sinusitis
Investigations: International Normalized Ratio Increase, Blood lactate
dehydrogenase increase, Blood phosphorus increased, Blood sodium
increased, Blood uric acid increased, White blood cell count decreased
Injury, Poisoning and Procedural Complications: Contusion
Metabolism and Nutrition Disorders: Hyperlipidemia, Hypertriglyceridemia,
Hyponatremia
Musculoskeletal and Connective Tissue Disorders: Muscular Weakness,
Myalgia, Pain in Jaw
Nervous System Disorders: Somnolence, Peripheral Sensory Neuropathy,
Memory Impairment
Psychiatric Disorders: Anxiety, Libido Decrease, Delirium, Parasomnia
Reproductive System and Breast Disorders: Erectile Dysfunction
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Epistaxis,
Hypoxia, Influenza, Respiratory Failure, Pulmonary edema
Skin and Subcutaneous Tissue Disorders: Dermatitis, Dermatitis
Acneiform
Vascular Disorders: Hot Flush
In addition to the preceding adverse events, the following adverse events occurred in
patients administered umbralisib but were deemed by investigators to be unlikely
related or not related to umbralisib therapy. Due to the low number of patients
evaluable for safety at this time, however we cannot rule out these events occurring
in future:
Liver Disorders: Elevated levels of certain liver enzymes
Brain and nerve related disorders: Paresthesia
Kidney disorders: Elevated blood urea nitrogen levels, elevated phosphorus,
hyperuricemia
Breathing and chest related disorders: Nasal congestion, upper respiratory
tract infection
General disorders: Arthralgia, myalgia
Ibrutinib
You may develop side effects while participating in this study. You should tell the
study doctor about any side effects that you develop.
The side effects listed below have been reported by patients who have received
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Redness of the skin (Erythema)
Increase in white blood cell counts (Leukocytosis)
Breaking of the nails (Onychoclasis)
Inflammation within the lungs that may lead to permanent damage (Interstitial
lung disease)
Increase in lymphocyte count (Lymphocytosis)
Side effects that have been seen in less than 1 of every 100 (< 1%) patients include:
Unusual levels of chemicals in the blood caused by the fast breakdown of
cancer cells, which may lead to changes in kidney function, abnormal
heartbeat, or seizures. (Tumor lysis syndrome)
Itchy rash (Urticaria)
Bleeding around the brain (Subdural hematoma)
Inflammation of the fatty tissue underneath the skin (Panniculitis)
Swollen face, lip, mouth, tongue or throat (Angioedema)
High WBC count with abnormal clumping that can lead to bleeding
(Leukostasis syndrome)
Severe rash with blisters and peeling skin, particularly around the mouth,
nose, eyes and genitals (Stevens-Johnson syndrome)
Liver failure (Hepatic failure)
The combination of the study drugs ibrutinib and umbralisib:
The following side effects were observed in patients treated with the combination of
ibrutinib and umbralisib in another study and were considered at least possibly
related to one or both study medications.
Common (greater than 20% of people)
Blood and lymphatic system disorders: decreased number of white blood
cells
General Disorders: infusion related reaction, tiredness
Stomach disorders: nausea, diarrhea
Less Common (greater than or equal to 10% to less than or equal to 20% of
people)
Stomach Disorders: vomiting
Nutrition Disorders: decreased appetite
Uncommon (greater than or equal to 1% to less than 10% of people)
Blood and Lymphatic System Disorders: decreased number of red blood
cells, decreased number of platelets, paleness of membrane that lines the
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inside of the eyelids (which may indicate low levels of red blood cells),
increase in bilirubin in blood
Ear and Labyrinth Disorders: ear congestion
Eye Disorders: vision blurred, swelling of the eye
Gastrointestinal Disorders: indigestion, constipation, abdominal pain, sores
in mouth, abdominal discomfort, swollen abdomen, passing gas, gastric
reflux, excessive saliva, infection and swelling of the small and large intestine,
burping, difficulty swallowing, discolored feces
General Disorders and Administration Site Conditions: swelling of hands
and/or feet, weakness, fever, chills, cold sweat, swelling of the face
Hepatobiliary Disorders: decreased number of globulins (type of protein that
helps fight infections)
Immune System Disorders: hives
Infections and Infestations: pneumonia, infection in the bloodstream that
may cause organ failure, infection of the upper respiratory tract, skin infection,
inflammation of the lungs (bronchitis), pink eye, herpes in the mouth, infection
of the urinary tract, sinus infection, severe diarrhea caused by a bacteria, ear
infection, fungal infection in or around the mouth, inflammatory response
throughout the body that can cause organs to fail, wound
Investigations: elevated liver enzymes, weight loss, increase in blood
creatinine level which may indicate kidney damage
Metabolism and Nutrition Disorders: dehydration, high levels of sugar in
blood, low levels of potassium in blood, low levels of phosphate in blood
which can indicate bone weakness, failure to thrive
Musculoskeletal and Connective Tissue Disorders: muscle spasms,
muscle weakness, pain or tenderness in the muscles, pain in extremity
Nervous System Disorders: dizziness, altered taste, headache, drowsiness
Psychiatric Disorders: anxiety, nervousness, agitation, difficulty with sleep
Renal and Urinary Disorders: feeling of urgency to urinate, decreased
kidney function, kidney damage
Reproductive System and Breast Disorders: cysts on the scrotum,
discolored semen
Respiratory, Thoracic and Mediastinal Disorders: shortness of breath,
infiltrated lungs, inflammation of the lungs with or without infection, choking,
cough, low levels of oxygen in blood, hoarseness or strained voice, cough
that expels mucus, persistent sore throat
Skin and Subcutaneous Tissue Disorders: hair loss, bruising, rash, dry
skin, itching
Vascular Disorders: flushing, high blood pressure, nose bleeds
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Although rare, the events listed below have been reported in subjects treated with
ublituximab and/or umbralisib
erythrodermic eczematous rash (itchy, red and peeling rash that can be fatal)
malignant melanoma (skin cancer)
tumor lysis syndrome (a serious metabolic disorder caused by the breakdown
of cancer cells and their release in the bloodstream)
progressive multifocal leukoencephalopathy (a serious brain infection that can
lead to severe disability and death)
drug-induced hepatitis (inflammation of the liver due to toxic exposure to
medication)
pulmonary edema (excess fluid in the lungs)
ileus (blockage in the intestines)
allergic reaction
Most of these side effects listed above have been mild to moderate in severity;
however severe side effects have occurred. Some side effects have been severe
enough to lead to study drug discontinuation, dose modification or reduction,
hospitalization, disability, and sometimes death.
You should tell your study doctor or medical team about any side effects you are
having. Your study doctor may be able to give you medications to help treat the side
effects and prevent them from becoming worse. Your study doctor may also choose
to stop ibrutinib for a short time or reduce its dose to allow you to recover from any
side effects.
Bleeding
You may experience bruising or nosebleeds during treatment with ibrutinib. Rarely,
serious internal bleeding, such as bleeding in your stomach, intestine, or brain may
occur, sometimes resulting in death. If you take other medicines or supplements that
increase the risk of bleeding, such as aspirin, non-steroidal anti-inflammatory drugs
(NSAIDs) or medicines used to prevent or treat blood clots or stroke, ibrutinib may
increase this risk. Blood thinners such as warfarin or other vitamin K antagonists
should not be taken together with ibrutinib. Supplements such as fish oil and vitamin
E preparations should be avoided while taking ibrutinib. Call your study doctor if you
have signs or symptoms of serious bleeding, such as blood in your stools or urine or
bleeding that lasts for a long time or that you cannot control.
Effects on the heart
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Abnormal heartbeats (atrial fibrillation and/or atrial flutter) have been reported in
patients treated with ibrutinib, especially when they also have heart conditions,
increased blood pressure, acute infections, or had abnormal heartbeat in the past.
Atrial fibrillation/flutter is a common type of abnormal heartbeat. The heartbeat may
be fast or irregular causing symptoms such as a pounding or racing heart, dizziness,
weakness, feeling light-headed or shortness of breath. If you develop any of these
symptoms wile on the study drug, you should tell your study doctor immediately.
Infections
You may experience viral, bacterial, or fungal infections during treatment with
ibrutinib. Some of these infections have led to hospitalization and death. Contact your
study doctor immediately if you have fever, chills, weakness, confusion, body aches,
cold or flu symptoms, vomiting, jaundice, feel tired or feel short of breath - these
could be signs of an infection.
A rare and usually fatal viral disease in the brain, Progressive Multifocal
Leukoencephalopathy (PML), has been reported in patients treated with ibrutinib in
combination with rituximab and in patients who were previously treated with
rituximab. If you experience symptoms such as weakness, paralysis, vision loss
and/or impaired speech, you should tell your study doctor immediately.
Lymphocytosis and leukostasis
You may experience an increase in the number of lymphocytes, which is a type of
white blood cell, in your blood (lymphocytosis). This may occur in the first few weeks
of treatment and you should not assume that this increase in white blood cells means
that your disease is worsening. This increase may last for several weeks to months.
Increased number of white blood cells in your bloodstream may change the blood
flow, resulting in bleeding or clotting (leukostasis). Isolated cases of these events
have been reported in patients treated with ibrutinib. Your study doctor will monitor
your blood counts and may administer additional therapy as needed. Talk to your
study doctor about what your test results mean.
Decreased blood counts
Severe decreases in white blood cells, red blood cells, and platelets (neutropenia,
anemia, and thrombocytopenia) were reported in subjects treated with ibrutinib. If you
experience symptoms such as fever, weakness, or easy bruising and/or bleeding,
you should tell your study doctor immediately.
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Allergic reactions
Sometimes people have allergic reactions to drugs. Serious allergic reactions can be
life-threatening. If you have an allergic reaction to ibrutinib, you might develop a rash,
difficulty breathing, wheezing when you breathe, sudden low blood pressure with
light-headedness, swelling around the mouth, throat or eyes, a racing heartbeat,
and/or sweating.
Before starting the study drug, you must tell your study doctor about any drug
allergies. You should tell the study doctor right away if you have any allergy
symptoms listed above.
Rash
A maculopapular rash (flat, red areas on the skin with small bumps) has been
commonly reported in patients treated with ibrutinib alone or in combination with
other drugs. Most rashes are mild to moderate in severity and begin 2 to 3 weeks or
longer after starting ibrutinib.
There have been rare reports of severe skin reactions (known as severe cutaneous
adverse reaction or SCAR, involving more than 50% of the body) or rash with blisters
and peeling skin, which may include open ulcers or sores in the mouth and other
areas of the body (Stevens - Johnson syndrome). These skin rashes could be
life-threatening. You should notify your study doctor immediately if you develop a
rash that spreads quickly, or if you notice peeling of your skin, with or without ulcers
or sores in your mouth.
Non Melanoma Skin Cancer and Other Cancers
Non melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of
the skin) have been reported with more frequency and maybe related to the use of
ibrutinib. Other cancers have been reported such as solid tumors and blood cancers
the relationship to the use of ibrutinib is unknown. You should tell your study doctor if
you develop a new cancer while in the study.
Tumor Lysis Syndrome (TLS)
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer
cells have happened during treatment of cancer and sometimes even without
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treatment. This may lead to changes in kidney function, abnormal heartbeat, or
seizures. Your study doctor may do blood tests to check for TLS.
Hypertension
Hypertension is also called high blood pressure, and has been commonly reported in
subjects treated with ibrutinib. Sometimes, people with high blood pressure may have
headaches, dizziness, nervousness, sweating, difficulty in sleeping, facial flushing or
nosebleeds, but in some cases, there may be no symptoms and it may go
undetected. After starting ibrutinib, your doctor may measure your blood pressure
regularly. You should let your study doctor know if you have any of the symptoms of
high blood pressure which may mean that you have developed hypertension or that
your hypertension is getting worse. Your study doctor may adjust existing
anti-hypertensive medications and/or initiate anti-hypertensive treatment as
appropriate.
Liver Failure
Rare cases of liver failure have been reported in patients treated with ibrutinib.
Symptoms of liver failure include yellowing of the eyes and skin (Jaundice), itching of
the skin, dark colored urine, gray or clay-colored stools, confusion, nausea, loss of
appetite, fatigue or diarrhea,. You should tell your study doctor immediately if you
have any of these symptoms which may suggest liver disease. Your study doctor
may be able to diagnose and provide you required medical care.
Interstitial lung disease
Interstitial lung disease is a group of lung disorders in which the tissues become
inflamed and may become damaged. Interstitial lung disease is not associated with
infections (e.g., bacteria, viruses, fungi) and has been reported in patients treated
with ibrutinib. You should report to your physician if you have cough, any signs of
new or worsening respiratory symptoms such as shortness of breath or difficulty
breathing.
Interference with other drugs
Some foods like grapefruit juice and Seville oranges, as well as some medications,
may interfere with the way your body processes ibrutinib. This interference could
cause the amount of ibrutinib in your body to be higher or lower than expected. It is
also possible that taking the study drug with your regular medications or
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supplements, including fish oil, Vitamin E, or other vitamins, may change how your
regular medications, or your regular supplements, work. It is very important that you
avoid grapefruit juice and Seville oranges and tell the study doctor about all
medications, supplements, or herbal medicine like St. John's wort that you are taking
during the study. You should notify your study doctor immediately about any side
effects to avoid possible harm
Drug interruption for any surgical procedures
Ibrutinib may increase the risk of bleeding with any surgical procedure. Ibrutinib
should be held at least 3 to 7 days before and after surgery depending upon the type
of surgery and the risk of bleeding. The ibrutinib will not be held for optional biopsies.
Please contact your study doctor if you have any planned surgical procedures. For
emergency surgical procedures, ibrutinib should be discontinued (stopped) after the
procedure until the surgical site is reasonably healed (not oozing fluid).
Please contact your study doctor as soon as possible and your study doctor will tell
you when to stop ibrutinib and when to restart it following a surgical procedure.
Breastfeeding
It is not known whether ibrutinib or its metabolites are excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from ibrutinib, breast-feeding should be
discontinued during ibrutinib treatment.
In addition to the risks listed above, there could be unknown or unexpected side
effects associated with the use of ibrutinib. You will be told in a timely manner,
verbally and in writing, of any new information, findings, or changes to the way the
research will be done that might influence your willingness to continue your
participation in this study.
You may have all, some, or none of the listed side effects of ibrutinib. Your study
doctors and nurses will check you closely for side effects. You may receive
medicines or other treatments to prevent or reduce some of these effects. Please tell
the study doctor or study staff right away if you have any side effects. Please tell
them if you have any other problems with your health or the way you feel during the
study, whether or not you think they are related to the study drug.
You should get medical help and contact the study doctor or study staff if you have
any of these or any other side effects during the study.
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Risks of Study Procedures/Tests
Echocardiogram: The echocardiogram uses sound waves to measure the pumping
function of the heart and does not pose any additional risk.
X-RAY/ PET CT, CAT Scans: X-rays, PET CT, and CT Scans involve exposure to
radiation. The risk of harmful effects from a single exam is very small. The dye that is
injected into a vein for the CT scan is usually well tolerated. Some people feel dizzy
or queasy or get a headache with it or notice a cold feeling near the injection site.
There is a chance of having an allergic reaction to the dye that rarely can be serious
and life threatening. The radiologist will obtain a separate informed consent
explaining this procedure in specific detail.
Drug Administration/Blood Drawing: Some known risks, although rare, are
associated with placing a needle into a vein or under the skin (when the study drug is
given or when blood samples are taken). These include the possibility of infections,
inflammation, a hole poked through the other side of the vein by the needle, bleeding,
discomfort, pain, bruising, and a change in skin color at the site. Fainting may occur
shortly after having blood collected.
Venous Access Device (Central Line): In order to undergo this therapy you
may need a central line. You may already have one from prior therapy. These
are the risks associated with these central lines:
Placement of Vascular Access Device: The surgeon or radiologist who
puts this catheter in will explain the risks in detail before he/she
performs the procedure. These risks include the risks associated with
anesthesia as for any operation, infection and bleeding. There may
also be pain at the site where the device is inserted. Although it is
rare, occasionally the lung is punctured during placement of a device
and a tube must be placed in the chest to re-inflate the lung. It is also
possible that there may be injury to a major blood vessel, which could
lead to severe bleeding.
Use of Venous Access Device: These devices can become infected
and these infections may require antibiotics, or occasionally removal
of the device. It is possible for a blood clot to develop at the end of the
catheter in the vein. This might prevent the catheter from working or
rarely lead to swelling of the arm or neck and face, or to pain.
Sometimes the device would need to be removed and replaced.
Trial Risks:
A trial of a new combination of drugs may involve increasing risk, to a small number
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of participants. In studies of small numbers of subjects, toxicity may more readily
become apparent through close monitoring of individual subjects. This new
combination of drugs may be less effective than standard of care treatments.
Other and Unknown Risks:
It is possible that other rare side effects could occur which are not described in this
protocol. It is also possible that you could have a side effect that has not occurred
before.
Pregnancy Risks:
It is possible that the medicines used in this study could injure a fetus if you, or your
partner, becomes pregnant while taking them. You have already been told what is
known about this possibility, and you are encouraged to ask further questions.
You may want to discuss this with others before you agree to take part in this study.
If you wish, we will arrange for a doctor, nurse, or counselor who is not part of this
study to discuss the potential risks and benefits with you and anyone else you want
to have present.
Because of the potential risks, you, or your partner, must not become pregnant while
you are participating in this study. Women must have a negative pregnancy test
before entering the study.
If you are sexually active and can get pregnant, or can get your partner pregnant, you
must use TWO appropriate methods of birth control every time you have sex, or you
must not have sex.
Because of the nature of this research, methods of natural family planning are not, by
themselves, sufficiently reliable to avoid pregnancy.
You can get additional information about methods to avoid pregnancy by calling the
UNMC Research Subject Advocate's Office at (402) 559-6941.
The effects of ibrutinib on a developing baby are unknown; therefore, women who
are pregnant or nursing are not allowed to be in this study. Nobody knows what these
risks are right now. Some drugs cause women to have their babies prematurely
(early) or to have babies with birth defects.
Women: If you are able to have children, you must use a highly effective method of
birth control and a barrier method while taking study treatment, as well as for 1 month
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after you stop taking study treatment, to prevent pregnancy in either you or your
partner. A highly effective method of birth control is defined as a method that has a
low failure rate (i.e., less than 1% per year) when used consistently and correctly and
includes implants, injectables, birth control pills with 2 hormones, some intrauterine
devices (IUDs), sexual abstinence (which is defined as refraining from all aspects of
sexual activity) or a sterilized partner. If you are using hormonal contraceptives such
as birth control pills or devices, a second barrier method of contraception (e.g.,
condoms) must be used.
Men: You must use a barrier method while on treatment with ibrutinib and for 3
months after the last dose of treatment to prevent pregnancy of your partner.
Note: Some birth control pills may not work when you are taking certain drugs. If you
have any questions about this, please discuss this with the study doctor.
Be aware that you can still become pregnant even if you use a highly effective
method of birth control.
Men: If your partner becomes pregnant while you are on study treatment, or within 3
months of your last dose of ibrutinib, you must notify the study staff. The study staff
will discuss this with you further. You should not donate sperm while you are taking
the study drug and for 3 months after you stop taking the study drug.
Women: If you become pregnant while you are on study treatment or within 1 month
of your last dose of ibrutinib you must notify the study staff. If you become pregnant
on the study, you must immediately stop taking the study treatment. The Investigator
will ask if information may be collected about the pregnancy and the birth of the baby
even after study treatment is stopped. You may refuse to provide this information.
What are the possible benefits to you?
It is hoped that the use of protocol therapy may result in tumor shrinkage or
stabilization of your disease.
You may not get any benefit from being in this research study.
What are the possible benefits to other people?
Information obtained from this study may help subjects in the future with the same
disease by contributing to the knowledge of whether this therapy offers advantages
over other therapies available.
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What are the alternatives to being in this research study?
Instead of being in this research study, you can choose not to participate.
If you choose not to participate in this study you may elect to receive standard
salvage therapy as per your primary oncologist, which may include other
chemotherapy drugs given alone or in combination. You may also have the option of
receiving palliative therapy or hospital care.
What will being in this research study cost you?
You and/or your health plan/insurance company will need to pay for some or all of
the costs of treating your cancer in this study. Some health plans will not pay these
costs for people taking part in studies. Check with your health plan or insurance
company to find out what they will pay for. Taking part in this study may or may not
cost your insurance company more than the cost of getting regular cancer treatment.
The study will pay for the handling of the optional research biopsy, sample collection
and storage. While you are participating in the study, the drug supply for ibrutinib
orally daily for up to a year of treatment will be supplied to you free of charge by
Janssen Scientific Affairs LLC. The drug supply for umbralisib orally daily for up to a
year of treatment will be supplied to you free of charge by TG Therapeutics.
All other clinically indicated tests and procedures (laboratory tests, radiology tests,
chest CT, physical examinations) will be your responsibility or your health insurance
company's responsibility as these are considered standard cancer treatment. You or
your health insurance company might also have to pay for other drugs or treatments
that are given to help you control side effects.
You will be responsible for any applicable insurance deductibles and co-payments. If
you wish to speak with a financial counselor about your insurance coverage and
benefits, let the investigator or other study personnel know. A contact for personal
assistance will be made available for you.
For more information on clinical trials and insurance coverage, you can visit the
National 
Cancer 
Institutes 
Web 
site 
at:
http://cancer.gov/clinicaltrials/understanding/insurance-coverage
You can print a copy of the Clinical Trials and Insurance Coverage information from
this Website.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and
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ask them to send you a free copy.
Will you be paid for being in this research study?
You will not be paid to be in this research study.
Who is paying for this research?
Janssen Scientific Affairs LLC and TG Therapeutics are providing monetary support
and study drug. The Institution receives money from these companies to conduct this
study.
Dr. Matthew Lunning, the Principal Investigator on this study, provides consulting
services to Janssen Pharmaceuticals, the sponsor of this study, in which he receives
money
Dr. Lunning also receives money for participating on the Advisory Board for TG
Therapeutics.
This research is being paid for by the Fred & Pamela Buffett Cancer Center at the
University of Nebraska Medical Center.
What should you do if you are injured or have a medical problem during this
research study?
Your welfare is the main concern of every member of the research team. If you are
injured or have a medical problem as a direct result of being in this study, you should
immediately contact one of the people listed at the end of this consent form.
Emergency medical treatment for this injury or problem will be available at the
Nebraska Medical Center. If there is not sufficient time, you should seek care from a
local health care provider.
The Institution has no plans to pay for any required treatment or provide other
compensation. If you have insurance, your insurance company may or may not pay
the costs of medical treatment. If you do not have insurance, or if your insurance
company refuses to pay, you will be expected to pay for the medical treatment.
Agreeing to this does not mean you have given up any of your legal rights.
How will information about you be protected?
You have rights regarding the protection and privacy of your medical information
collected before and during this research. This medical information is called
"protected health information" (PHI). PHI used in this study may include your medical
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record number, address, birth date, medical history, the results of physical exams,
blood tests, x-rays as well as the results of other diagnostic medical or research
procedures. Only the minimum amount of PHI will be collected for this research. Your
research and medical records will be maintained in a secure manner.
Who will have access to information about you?
By signing this consent form, you are allowing the research team to have access to
your PHI. The research team includes the investigators listed on this consent form
and other personnel involved in this specific study at the Institution.
Your PHI will be used only for the purpose(s) described in the section What is the
reason for doing this research study?
You are also allowing the research team to share your PHI, as necessary, with other
people or groups listed below:
The UNMC Institutional Review Board (IRB)
Institutional officials designated by the UNMC IRB
Federal law requires that your information may be shared with these groups:
The HHS Office of Human Research Protections (OHRP)
The Food and Drug Administration (FDA)
The HIPAA Privacy Rule requires the following groups to protect your PHI:
Your health insurance company
The Fred & Pamela Buffett Cancer Center Scientific Review
Committee (SRC)
Your PHI may also be shared with the following groups. However, these
organization(s) do not have the same obligation to protect your PHI:
Janssen Scientific Affairs and TG Therapeutics, these companies provide the
study drugs and funds to the Institution to conduct this research
Data and Safety Monitoring Committee (DSMC)
The National Cancer Institute's (NCI) Clinical Trial Reporting Program
You are authorizing us to use and disclose your PHI for as long as the research
study is being conducted.
You may cancel your authorization for further collection of PHI for use in this
research at any time by contacting the principal investigator in writing. However, the
PHI which is included in the research data obtained to date may still be used. If you
cancel this authorization, you will no longer be able to participate in this research.
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How will results of the research be made available to you during and after the
study is finished?
In most cases, the results of the research can be made available to you when the
study is completed, and all the results are analyzed by the investigator/sponsor of the
research. The information from this study may be published in scientific journals or
presented at scientific meetings, but your identity will be kept strictly confidential.
If you want the results of the study, contact the Principal Investigator at the phone
number given at the end of this form or by writing to the Principal Investigator at the
following address:
Matthew A. Lunning, D.O
Assistant Professor of Medicine
986840 Nebraska Medical Center
Omaha, NE 68198-6840
A description of this clinical trial will be available on www.ClinicalTrials.gov, as
required by U.S. law. This website will not include information that can identify you. At
most, the website will include a summary of the results. You can search this website
at any time.
What will happen if you decide not to be in this research study?
You can decide not to be in this research study. Deciding not to be in this research
will not affect your medical care or your relationship with the investigator or the
Institution. Your doctor will still take care of you and you will not lose any benefits to
which you are entitled.
What will happen if you decide to stop participating once you start?
You can stop participating in this research (withdraw) at any time by contacting the
Principal Investigator or any of the research staff.
Deciding to withdraw will otherwise not affect your care or your relationship with the
investigator or this institution. You will not lose any benefits to which you are entitled.
For your safety, please talk to the research team before you stop taking any study
drugs or stop other related procedures. They will advise you how to withdraw safely.
If you withdraw you may be asked to undergo some additional tests. You do NOT
have to agree to do these tests.
You may be taken off the study if you do not follow instructions of the investigator or
the research team.
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Any research data obtained to date may still be used in the research.
Any tissue (e.g., blood sample) obtained to date may also be used in the research.
Should you wish to have any leftover tissue samples withdrawn from use in future
research, a request must be made in writing to the Principal Investigator at the
address indicated above.
Will you be given any important information during the study?
You will be informed promptly if the research team gets any new information during
this research study that may affect whether you would want to continue being in the
study.
What should you do if you have any questions about the study?
You have been given a copy of "What Do I Need to Know Before Being in a
Research Study?" If you have any questions at any time about this study, you should
contact the Principal Investigator or any of the study personnel listed on this consent
form or any other documents that you have been given.
What are your rights as a research participant?
You have rights as a research subject. These rights have been explained in this
consent form and in The Rights of Research Subjects that you have been given. If
you have any questions concerning your rights, or want to discuss problems,
concerns, obtain information or offer input, or make a complaint about the research,
you can contact any of the following:
The investigator or other study personnel
Institutional Review Board (IRB)
Telephone: (402) 559-6463.
Email: IRBORA@unmc.edu
Mail: UNMC Institutional Review Board, 987830 Nebraska Medical
Center, Omaha, NE 68198-7830
Research Subject Advocate
Telephone: (402) 559-6941
Email: unmcrsa@unmc.edu
OPTIONAL SAMPLE COLLECTIONS
Sample Collections for Biobanking for Possible Future Studies
This research study also involves the collection and storage of blood and tissue for
future studies that are not a part of the study in which you are participating. The
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process of collecting and storing blood or tissue for future research is referred to as
tissue banking. A collection of blood or tissue available for use by researchers is
referred to as a tissue bank or bio-repository.
A UNMC designated Laboratory manages the bio-repository for the samples
collected in this study. The purpose of storing the samples is to make them available
to researchers including those from TG Therapeutics, and Janssen Scientific LLC
who have approved new ideas for research that require studying human tumors or
blood. As part of this study, your samples and health information collected from your
medical records (after removal of your name, date of birth and medical record
number and identified only by a code) may be shared with other investigators who
are conducting research regarding the causes, prevention, diagnosis, and treatment
of cancer.
The samples will be kept until they are used up or destroyed.
Most future research studies will focus on cancer, some research projects may also
include other diseases, such as heart disease, diabetes or Alzheimer's disease. This
may also include research on inherited traits also known as hereditary genetic testing
(to find out if cancer runs in your family). The research that may be done is unknown
at this time.
Reports about any research tests done with your samples will not be given to you or
your oncologist, or family doctor. These reports will not be put in your medical
records.
This research may not benefit you, but may help people in the future who have the
same kind of cancer as you have. You can indicate your wish to participate in this
additional research, and have your samples stored by the UNMC designated central
repository for future extended research purposes when signing this consent form.
You may decide not to participate in the "optional" study and still participate in this
main study
Optional US or CT Image Guided Lymph Node Biopsies for Research:
The researchers doing this study are interested in doing additional research now in
tumor cell signaling ( a complex system of a communication that activates basic
cellular activities and coordinates cell actions) or in the future on the optional
ultrasound (US) or computer tomography (CT) guided lymph node biopsy samples
collected from you to better understand the nature of cancer and how patients
respond to treatment. Errors in cellular information processing are responsible for
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diseases such as cancer and diabetes for example. By understanding cell signaling,
diseases may be treated effectively. Rapid advances in technology make it
impossible to predict what new tests or studies may be possible in the future.
The collection of these 3 optional lymph node biopsies will be obtained via US or CT
guided biopsy of accessible lymph nodes at day 0 (pre-treatment; core biopsy), day 8
(fine needle aspirate) and end of treatment (progressive disease, toxicity, or end of 1
year of study drug; core biopsy) so as to assess the change in signaling resulting
from treatment. The samples will not be sold. Once these tests have been completed,
and with your permission any leftover samples will be saved and stored for future
use. Again, your samples and health information collected from our medical records
will have your name, date of birth and medical record number removed and samples
will be identified only by a code.
During an image guided (US or CT scan) biopsy, a small amount of tissue is removed
from the abnormal area (lymph node) with a needle. Radiologists or the investigator
will use image guidance (ultrasound) in performing the biopsies to obtain tissue from
the right spot and to avoid injuring important nearby body parts. This can be
performed on an outpatient basis using local anesthetic. Conscious sedation can also
be used when necessary.
Reasons for choosing an image guided biopsy rather than a surgical biopsy include:
Smaller incision
No stitches
No scar
Shorter procedure
Minimal bruising
No or minimal cosmetic disfigurement
Less expensive
Types of Image Guided Biopsies:
Following is information on two types of image guided biopsies performed by
radiologists or the investigator in this optional biopsy for research.
Fine Needle Aspiration Biopsy (Radiologist or Investigator): Ultrasound or CT guided
for accurate placement of the needle. Uses a tiny needle, smaller than the needle
used to draw blood. Commonly used on the thyroid gland, salivary glands, breasts,
and lymph nodes. CT guidance will only be used by the radiologist.
Needle Core Biopsy (Radiologist only): Ultrasound guided for accurate placement of
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the needle. Uses a larger needle than a fine needle aspiration biopsy. Used to
remove tissue from many organs and body structures.
The risks involved in an image guided biopsy include the following:
Bleeding and infection at the puncture site
A hematoma or collection of blood may form at the biopsy site
Infection or abscess
MAKING YOUR CHOICE:
_____ I agree to up to three US or CT guided biopsies of accessible lymph nodes
samples taken from me for extended research (optional).
_____ I do not agree to the three possible US or CT guided biopsies of accessible
lymph nodes samples taken from me for extended research (optional).
MAKING YOUR CHOICE:
_____ I agree to allow storage and use of the optional lymph node tissue samples
taken from me for extended research (optional).
_____ I do not agree to allow optional lymph node tissue samples taken from me to
be stored for extended research (optional).
Optional extended research on your blood samples collected during the
research
The researchers doing this study are interested in doing additional research now or in
the future on the samples collected from you to better understand the nature of
cancer and how patients respond to treatment. Rapid advances in technology make it
impossible to predict what new tests or studies may be possible in the future.
The collection of the research blood samples before you began treatment and before
the 2nd cycle and at the end the 2nd, 4th, 6th, and 9th, and 12th cycles (+/- 7 days)
cycle (research blood only), as well as after month 12, restaging assessments of your
lymphoma when they occur and only if feasible (research blood only) is a necessary
part of this study and will be used only for these purposes. The samples will not be
sold. Once these tests have been completed, and with your permission any leftover
samples will be saved and stored for future use.
MAKING YOUR CHOICE:
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_____ I agree to allow storage and use of blood samples taken from me for
extended research (optional).
_____ I do not agree to allow blood taken from me to be stored for extended
research (optional).
Confidentiality of ALL Samples
To protect your identity, the information that will be on your research samples will be
limited to your pathology identification number (if applicable), and your participant
code, which may include your initials.
Withdrawal of ANY Samples
If you no longer want your samples to be used in this research, you should tell the
study doctor. The study doctor will notify the sponsor-investigator who will ensure the
samples are returned to the hospital from which they were obtained if needed, or
destroyed. If tests have already been done on your sample(s) it will not be possible to
withdraw those results. However, no further testing will be done.
Documentation of informed consent
You are freely making a decision whether to be in this research study. Signing this
form means that:
You have read and understood this consent form.
You have had the consent form explained to you.
You have been given a copy of The Rights of Research Subjects
You have had your questions answered.
You have decided to be in the research study.
If you have any questions during the study, you have been directed to talk to
one of the investigators listed below on this consent form.
You will be given a signed and dated copy of this consent form to keep.
Signature of Subject ___________________________
Date ___________
My signature certifies that all the elements of informed consent described on this
consent form have been explained fully to the subject. In my judgment, the subject
possesses the legal capacity to give informed consent to participate in this research
and is voluntarily and knowingly giving informed consent to participate.
Signature of Person obtaining consent ___________________________
Date ___________
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Authorized Study Personnel
Secondary
* Armitage, James
phone: 402-559-7290
alt #: 402-888-7290
degree: M.D.
* Bierman, Philip
phone: 402-559-5520
alt #: 402-888-1004
degree: MD
 
* Bociek, Robert (Greg)
phone: 402-559-5388
alt #: 402-888-2630
degree: MD
* Vose, Julie
phone: 402-559-3848
alt #: 402-305-0790
degree: M.D.
 
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Institutional Review Board (IRB)
What Do I Need To Know
Before Being In A Research Study?
You have been invited to be in a research study. Research studies are also called
"clinical trials" or "protocols." Research is an organized plan designed to get new
knowledge about a disease or the normal function of the body. The people who are in
the research are called research subjects. The investigator is the person who is
running the research study. You will get information from the investigator and the
research team, and then you will be asked to give your consent to be in the
research.
This sheet will help you think of questions to ask the investigator or his/her
staff. You should know all these answers before you decide about being in the
research.
What is the purpose of the research? Why is the investigator doing the research?
What are the risks of the research? What bad things could happen?
What are the possible benefits of the research? How might this help me?
How is this research different than the care or treatment I would get if I wasnˆt in
the research? Are there other treatments I could get?
Does everyone in this research study get the same treatment?
Will being in the research cost me anything extra?
Do I have to be in this research study? Will the doctor still take care of me if I say no?
Can I stop being in the research once Iˆve started? How?
Who will look at my records?
How do I reach the investigator if I have more questions?
Who do I call if I have questions about being a research subject?
Make sure all your questions are answered before you decide whether or not to
be in this research.
Academic Research & Services Building 3000  /  987830 Nebraska Medical Center  /  Omaha NE  68198-7830
402-559-6463  /  FAX 402-559-3300 / Email: irbora@unmc.edu  /   http://www.unmc.edu/irb


Institutional Review Board (IRB)
THE RIGHTS OF RESEARCH SUBJECTS
AS A RESEARCH SUBJECT YOU HAVE THE RIGHT ˆ
ˆ to be told everything you need to know about the research before you are
asked to decide whether or not to take part in the research study. The research
will be explained to you in a way that assures you understand enough to decide
whether or not to take part.
ˆ to freely decide whether or not to take part in the research.
ˆ to decide not to be in the research, or to stop participating in the research at
any time. This will not affect your medical care or your relationship with the
investigator or the Nebraska Medical Center. Your doctor will still take care of you.
ˆ to ask questions about the research at any time. The investigator will answer
your questions honestly and completely.
ˆ to know that your safety and welfare will always come first. The investigator will
display the highest possible degree of skill and care throughout this research. Any
risks or discomforts will be minimized as much as possible.
ˆ to privacy and confidentiality. The investigator will treat information about you
carefully, and will respect your privacy.
... to keep all the legal rights you have now. You are not giving up any of your
legal rights by taking part in this research study.
ˆ to be treated with dignity and respect at all times
The Institutional Review Board is responsible for assuring that your rights and
welfare are protected. If you have any questions about your rights, contact the
Institutional Review Board at (402) 559-6463.
Academic Research & Services Building 3000  /  987830 Nebraska Medical Center  /  Omaha NE  68198-7830
402-559-6463  /  FAX 402-559-3300 / Email: irbora@unmc.edu  /   http://www.unmc.edu/irb
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