Conditions: Diffuse Large B-Cell Lymphoma Unclassifiable
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
This phase II trial studies how well giving rituximab, lenalidomide, and ibrutinib with chemotherapy works in treating patients with high-risk diffuse large B-cell lymphoma. High-risk large B-cell lymphoma is a type of cancer of the immune system that is usually fast-growing in the body. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving rituximab, ibrutinib, and lenalidomide with combination chemotherapy may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the overall response rate at the end of 2 cycles of therapy with rituximab, lenalidomide, and ibrutinib in patients with high risk newly diagnosed non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL).

II. To determine the complete response rate at the end of 6 cycles of therapy with rituximab, lenalidomide, and ibrutinib combined with chemotherapy (cyclophosphamide, doxorubicin hydrochloride \[hydroxydaunorubicin hydrochloride\], vincristine sulfate \[Oncovin\], prednisone \[CHOP\] or etoposide, prednisone, vincristine sulfate \[Oncovin\], cyclophosphamide, doxorubicin hydrochloride \[hydroxydaunorubicin hydrochloride\] \[EPOCH\]) in patients with high risk newly diagnosed non-GCB DLBCL.

SECONDARY OBJECTIVES:

I. To determine the overall response rate, landmark survival outcomes (progression free and overall survival), and safety of lenalidomide and ibrutinib with chemotherapy (CHOP or EPOCH) in patients with high risk newly diagnosed non-GCB DLBCL.

II. To evaluate descriptively the complete response rate in rituximab, lenalidomide, ibrutinib (RLI)-CHOP and in RLI-EPOCH.

EXPLORATORY OBJECTIVES:

I. To evaluate the baseline and therapy induced changes in the profile of mutations, gene expression, minimal residual disease clonotype levels, immune cell subsets, and tumor protein expression in tumor biopsy and blood samples in patients with high risk newly diagnosed non-GCB DLBCL.

OUTLINE:

SMART START: Patients receive rituximab intravenously (IV) over 4-6 hours on day 1, lenalidomide orally (PO) once daily (QD) on days 1-10, and ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity.

RLI WITH EPOCH: After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive etoposide IV over 24 hours on days 1-4, prednisone PO QD on days 1-5, vincristine sulfate IV over 24 hours on days 1-4, doxorubicin hydrochloride IV over 24 hours on days 1-4, and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

RLI WITH R-CHOP: After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive prednisone PO QD on days 1-5, vincristine sulfate IV over 1 hour on day 1, doxorubicin hydrochloride IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, and then every 4 months for another year.

Arms:
arm 1: SMART START: Patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity.

After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive etoposide IV over 24 hours on days 1-4, prednisone PO QD on days 1-5, vincristine sulfate IV over 24 hours on days 1-4, doxorubicin hydrochloride IV over 24 hours on days 1-4, and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. arm 2: SMART START: Patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity.

After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive prednisone PO QD on days 1-5, vincristine sulfate IV over 1 hour on day 1, doxorubicin hydrochloride IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cyclophosphamide intervention 2: Doxorubicin Hydrochloride intervention 3: Etoposide intervention 4: Ibrutinib intervention 5: Lenalidomide intervention 6: Prednisone intervention 7: Rituximab intervention 8: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given PO intervention 5: Given PO intervention 6: Given PO intervention 7: Given IV intervention 8: Given IV

Protocol document:
Prot_SAP_000.pdf: 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2015-0147 
Protocol Title 
 A Phase II Study of Rituximab, Lenalidomide, and Ibrutinib Combined 
with Chemotherapy for Patients With High Risk Diffuse Large B-Cell 
Lymphoma 
Protocol Phase 
II 
Protocol Version 07 
Version Date 
06/21/2021 
 
Protocol PI 
Jason Westin, MD 
Department 
Lymphoma/Myeloma 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
128727 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
2 
 
THE UNIVERSITY OF TEXAS 
M.D. ANDERSON CANCER CENTER 
DIVISION OF CANCER MEDICINE 
DEPARTMENT OF LYMPHOMA AND MYELOMA 
 
 
 
 
 
 
 
 
 
Smart Start:  
A Phase II Study of Rituximab, Lenalidomide, and Ibrutinib Combined With 
Chemotherapy For Patients With High Risk Diffuse Large B-Cell Lymphoma 
 
 
 
 
 
 
 
 
Jason R. Westin, MD 
Principal Investigator 
1400 Holcombe Blvd, Unit 0429 
Houston, TX  77030 
713-792-3750 
jwestin@mdanderson.org 
 
Protocol version 7.0 
6/21/2021 MDACC protocol 2015-0147 
 
 
Janssen Scientific Affairs, LLC and Celgene are providing funding and drug support. 
 
 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
3 
1 
OBJECTIVES AND HYPOTHESES .............................................................................................5 
1.1 
OBJECTIVES: ............................................................................................................................. 5 
1.2 
HYPOTHESES: ............................................................................................................................ 5 
2 
BACKGROUND .....................................................................................................................6 
2.1 
DIFFUSE LARGE B-CELL LYMPHOMA: ............................................................................................. 6 
2.2 
STANDARD TREATMENT OF DLBCL: .............................................................................................. 7 
2.3 
DOSE ADJUSTED RITUXIMAB EPOCH ............................................................................................ 7 
2.4 
CELL OF ORIGIN SUBTYPES: .......................................................................................................... 8 
2.5 
PET/CT SCANS IN LYMPHOMA .................................................................................................... 9 
2.6 
NON-IMAGING BASED DISEASE MONITORING .................................................................................. 9 
2.7 
TARGETED THERAPY OPPORTUNITIES IN THE ABC DLBCL SUBTYPE: ................................................. 10 
2.8 
LENALIDOMIDE ........................................................................................................................ 12 
2.9 
IBRUTINIB ............................................................................................................................... 17 
2.10 
BACKGROUND DRUG INFORMATION OF R-DA-EPOCH .................................................................. 23 
2.11 
OVERALL RATIONALE FOR THE STUDY .......................................................................................... 24 
3 
STUDY DESIGN AND RATIONALE ......................................................................................... 28 
3.1 
STUDY DESIGN: ....................................................................................................................... 28 
3.2 
RATIONALE OF STUDY DESIGN: .................................................................................................. 28 
4 
PATIENT ELIGIBILITY ........................................................................................................... 29 
4.1 
INCLUSION CRITERIA: ................................................................................................................ 29 
4.2 
EXCLUSION CRITERIA: ........................................................................................................... 3130 
5 
DOSAGE AND ADMINISTRATION SCHEDULE: ....................................................................... 32 
5.1 
SMART START: ........................................................................................................................ 32 
5.2 
EPOCH CHEMOTHERAPY: ......................................................................................................... 33 
5.3 
LENALIDOMIDE AND IBRUTINIB DOSING: ...................................................................................... 34 
5.4 
PROPHYLACTIC MEDICATIONS: ................................................................................................... 37 
5.5 
RADIATION THERAPY: ............................................................................................................... 39 
5.6 
TREATMENT FOR SUBJECTS WHO DEVELOP CNS DISEASE WHILE ON STUDY: ..................................... 40 
5.7 
DOSE MODIFICATIONS OF DA-EPOCH DRUGS FOR ADVERSE EVENTS:............................................... 40 
5.8 
MANAGEMENT OF RASH: .......................................................................................................... 42 
6 
STUDY EVALUATIONS ......................................................................................................... 43 
6.1 
SCREENING EVALUATIONS ......................................................................................................... 43 
6.2 
PRETREATMENT EVALUATION .................................................................................................... 43 
6.3 
EVALUATION DURING THERAPY .................................................................................................. 45 
6.4 
EVALUATION AFTER CONCLUSION OF THERAPY .............................................................................. 46 
6.5 
POST-TREATMENT FOLLOW UP .................................................................................................. 47 
7 
CRITERIA FOR RESPONSE .................................................................................................... 49 
7.1 
RESPONSE CRITERIA: ................................................................................................................ 49 
8 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................... 50 
8.1 
COMPLETION .......................................................................................................................... 50 
8.2 
DISCONTINUATION OF STUDY TREATMENT ................................................................................... 50 
8.3 
WITHDRAWAL FROM THE STUDY ................................................................................................ 50 
9 
STATISTICAL CONSIDERATIONS........................................................................................... 52 
9.1 
STUDY DESIGN ........................................................................................................................ 52 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
4 
9.2 
PHASE 2 CLINICAL TRIAL DOSING AND SAMPLE SIZE ........................................................................ 52 
9.3 
ANALYSIS PLAN ....................................................................................................................... 55 
9.4 
CORRELATIVE STUDY ENDPOINTS ................................................................................................ 55 
10 
REPORT OF ADVERSE EVENTS ............................................................................................. 59 
10.1 
REPORTING REQUIREMENTS ............................................................................................... 59 
10.2 
ADVERSE EVENT CLASSIFICATIONS ............................................................................................... 59 
10.3 
ADVERSE EVENT RELATIONSHIP TO STUDY DRUG ............................................................................ 62 
10.4 
ADVERSE EVENTS OF SPECIAL INTEREST ....................................................................................... 63 
10.5 
PREGNANCY ............................................................................................................................ 64 
10.6 
SPECIAL REPORTING SITUATIONS ................................................................................................ 64 
10.7 
ADVERSE EVENT REPORTING ...................................................................................................... 65 
10.8 
MAINTENANCE OF SAFETY INFORMATION .................................................................................... 66 
10.9 
RECONCILIATION OF SAES ......................................................................................................... 67 
11 
STUDY CALENDAR .............................................................................................................. 70 
12 
APPENDIX A: CHEMOTHERAPY INFORMATION .................................................................... 72 
12.1 
RITUXIMAB ............................................................................................................................. 72 
12.2 
CYCLOPHOSPHAMIDE: .............................................................................................................. 77 
12.3 
VINCRISTINE: .......................................................................................................................... 77 
12.4 
DOXORUBICIN ......................................................................................................................... 78 
12.5 
ETOPOSIDE ............................................................................................................................. 79 
12.6 
PREDNISONE ........................................................................................................................... 79 
13 
APPENDIX B. REVISED IPI .................................................................................................... 81 
14 
APPENDIX C. DECISION TREE FOR IMMUNOHISTOCHEMISTRY CLASSIFICATION OF DLBCL .... 82 
15 
APPENDIX D  EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS SCALE ... 83 
16 
APPENDIX E. INHIBITORS AND INDUCERS OF CYP3A ............................................................ 84 
17 
APPENDIX F. UNITED STATES PRODUCT INSERT FOR IBRUTINIB ........................................... 85 
18 
APPENDIX G. UNITED STATES PRODUCE INSERT FOR LENALIDOMIDE .................................. 85 
20 
REFERENCES: ..................................................................................................................... 86 
 
 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
5 
1 
Objectives and Hypotheses 
 
1.1 Objectives: 
1.1.1 Primary Endpoint 1: To determine the overall response rate at the end of 2 
cycles of therapy with rituximab, lenalidomide, and ibrutinib in patients with 
high risk newly diagnosed non-GCB DLBCL 
1.1.2 Primary Endpoint 2: To determine the complete response rate at the end of 6 
cycles of therapy with rituximab, lenalidomide, and ibrutinib combined with 
chemotherapy (CHOP or EPOCH) in patients with high risk newly diagnosed 
non-GCB DLBCL 
1.1.3 Secondary Endpoint 1: To determine the overall response rate, landmark 
survival outcomes (progression free and overall survival), and safety of 
lenalidomide and ibrutinib with chemotherapy (CHOP or EPOCH) in patients 
with high risk newly diagnosed non-GCB DLBCL. 
1.1.4 Secondary Endpoint 2: To evaluate descriptively the complete response rate 
in RLI-CHOP and in RLI-EPOCH. 
1.1.5 Exploratory objectives: To evaluate the baseline and therapy induced 
changes in the profile of mutations, gene expression, minimal residual 
disease clonotype levels, immune cell subsets, and tumor protein expression 
in tumor biopsy and blood samples in patients with high risk newly diagnosed 
non-GCB DLBCL. 
 
1.2 Hypotheses: 
1.2.1 The combination of rituximab, lenalidomide, and ibrutinib alone will show a 
high overall response rate in newly diagnosed non-GCB DLBCL, higher than 
single-agent ibrutinib, lenalidomide, or rituximab ORR in patients with 
relapsed DLBCL  
1.2.2 Response-associated characteristics will be identified from analysis of biopsy 
material and peripheral blood from baseline and on-therapy time points, for 
future validation and potential patient selection. 
 
 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
6 
2 
Background 
2.1 Diffuse large B-cell lymphoma: 
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy 
with ~30,000 new cases in the US annually, is uniformly treated with a combination 
(CHOP) which remains essentially unchanged over the past 30+ years.(1-3) 
Knowledge of DLBCL biology has made significant advances, including the definition 
of two distinct subtypes with unique gene expression programs,(4-6) genomic 
abnormalities,(7) microRNA profiles,(8-10) signaling pathways,(11-13) and response 
to targeted therapies.(14, 15)  
 
In 1976, McKelvey et al demonstrated a 67% complete response (CR) rate and 
~70% 
1-year 
overall 
survival 
(OS) 
in 
“diffuse 
lymphoma” 
with 
CHOP 
chemotherapy.(1) Multiple attempts to improve upon the CHOP regimen have 
yielded disappointing results, including the American Intergroup Trial which 
evaluated three more aggressive regimens (m-BACOD, ProMACE-CytaBOM, and 
MACOP-B) versus CHOP.(16) The trial found that the four regimens were 
essentially equivalent in efficacy, with CHOP achieving a 54% 3-year disease-free 
survival (DFS). The CHOP regimen had moderately lower toxicity rates than the 
other regimens, and has thus remained the standard of care. 
 
In 1998, rituximab, a chimeric immunoglobulin G1 monoclonal antibody targeting 
surface CD20, was reported to have efficacy in relapsing or refractory aggressive 
lymphomas. Coiffier et al. reported a 37% overall response rate (ORR) with single-
agent rituximab, but the duration of clinical benefit was brief.(17) With significant 
activity in relapsed or refractory patients, rituximab was moved to clinical trials in 
frontline therapy. In a phase II clinical trial of rituximab plus CHOP (R-CHOP), 
published in 2001, Vose et al. reported an ORR of 94% in untreated DLBCL 
patients, including 15 of 16 patients with an International Prognostic Index (IPI) 
score of 2 or higher.(18)  
 
The IPI is a clinical prognostic system created from pre-treatment factors from 
patients with DLBCL treated with CHOP, including age, stage, performance status, 
number of extranodal sites, and lactate dehydrogenase.(19) Despite the fact that the 
IPI does not directly account for the biology of DLBCL, it has yet to be supplanted as 
a clinically relevant prognostic tool. In the era of R-CHOP, the IPI has been revisited 
to determine if it remains relevant. The Revised IPI demonstrates that patients with 3 
or greater adverse clinical predictors achieve poor outcomes, with a 4 year 
progression free survival (PFS) and OS of 53 and 55%, respectively (Appendix 
B).(20) The striking similarity between PFS and OS for this group implies that of the 
47% of patients who have progressed in the first 4 years, less than 10% were still 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
7 
alive 4 years after initial therapy. This speaks to the need to improve therapy for 
patients with relapsed DLBCL, but perhaps an even greater need to improve 
frontline therapy to prevent relapse for patients with high-risk DLBCL. 
2.2 Standard Treatment of DLBCL, R-CHOP 
DLBCL is a systemic disease and requires treatment at the time of diagnosis with 
systemic immunochemotherapy. The standard therapy of DLBCL is R-CHOP based 
on a consecutive series of clinical trials as detailed in section 2.1. The therapy of 
DLBCL has not been influenced to date by our rapidly increasing knowledge of the 
disease biology.(3, 21) Patients with localized disease (either stage I or contiguous 
stage II) may be treated with either standard R-CHOP x 6 cycles, or R-CHOP x 3 
cycles followed by involved field radiotherapy, based upon a cooperative group 
study evaluating CHOP x 8 vs CHOP x 3 with radiation.(22) However, patients with 
high IPI or elevated Ki-67 are often considered to have increased chance of 
relapsing outside a radiation field, and thus may be offered R-CHOP x 6 cycles and 
involved field radiotherapy. For patients not appropriate for local therapy approaches 
(Stage II non-contiguous, or Stage III/IV), R-CHOP x 6 remains the standard 
approach. There is an ongoing randomized phase III [NCT00118209] clinical trial 
comparing the CHOP-variant regimen R-EPOCH against R-CHOP for newly 
diagnosed patients with DLBCL. The preliminary results show no difference of EFS 
between the two regimens and will be presented at the American Society of 
Hematology (ASH) conference of 2016. 
 
2.3 Dose Adjusted Rituximab EPOCH 
R-EPOCH (etoposide, prednisone vincristine, cyclophosphamide, doxorubicin) is a 
CHOP-like regimen which employs infusional chemotherapy. The schedule for DA-
EPOCH includes infusional doxorubicin, etoposide, and vincristine over 4 days, 
followed by cyclophosphamide on day 5. The doses of these four chemotherapy 
drugs are typically adjusted based upon hematologic values, essentially a 
pharmacodynamics biomarker. DA-EPOCH was designed to improve the therapeutic 
index of chemotherapy by taking advantage of increased sensitivity of highly 
proliferative tumors to prolonged exposure to low concentrations of chemotherapy. A 
prospective multi-institutional study of R-DA-EPOCH in 50 patients with previously 
untreated large B-cell lymphomas showed that highly proliferative tumors were 
sensitive to treatment, unlike CHOP-based treatments.(23) In previously untreated 
DLBCL, EPOCH (without rituximab) showed a complete response rate of 92%, and 
70% of patients remained free of progression at the median follow up of 62 
months.(23) Subsequent clinical trials have found that response to R-DA-EPOCH 
(DA, dose adjusted) may be different in certain subsets of DLBCL.(24) A randomized 
phase III trial comparing R-CHOP with R-DA-EPOCH in untreated DLBCL patients 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
8 
has recently completed accrual, and the highly anticipated results are expected in 
2015. This trial will include evaluation of the above-mentioned subsets to determine 
if there is truly a differential response. 
2.4 Cell of Origin subtypes:  
In 2000, Dr. Louis Staudt et al described DLBCL as at least two unique subtypes, 
defined by their putative cell of origin. These subtypes, known as the activated B-cell 
(ABC) and germinal center B-cell (GCB) subtypes, are known to be as different from 
each other as acute myeloid and lymphoid leukemias.(25) The ABC DLBCL subtype 
is occasionally referred to as “non-GCB DLBCL”, a historical term that originates 
from the concept that all DLBCL were presumed to originate from the germinal 
center. The currently available CLIA certified and clinically utilized methods of 
assigning cell of origin are largely immunohistochemically (IHC) based, which result 
in assignment into GCB and “non-GCB”, which is largely equivalent to the ABC 
subtype.(26) For the remainder of this protocol, the terms “ABC DLBCL” and “non-
GCB DLBCL” will be considered interchangeable unless otherwise specified. The 
most prevalently utilized method is that of Hans et al (2004) in which samples are 
analyzed for expression levels of CD10, Bcl-6, and MUM1.  
 
Among the prominent differences are the utilization of B-cell-receptor, MyD88, and 
NF-kappaB signaling pathways combined with PRDM1 disruption in ABC-DLBCL. 
GCB-DLBCL has frequent alterations in epigenetic regulators EZH2, CREBBP, and 
EP300.(11, 12, 27-30) These differences have subsequently been confirmed to have 
significant clinical relevance, with R-CHOP achieving 5-year OS rates in activated B-
cell (ABC) and germinal center B-cell subtypes (GCB) DLBCL of ~50% and ~70%, 
respectively.(21) 
 
A phase II study using bortezomib, a proteasome inhibitor, in relapsed DLBCL 
patients confirmed the pathway-based prediction of efficacy restricted to ABC 
patients, when used in combination with a standard multi-drug regimen.(14) In 
addition, a recent phase I/II trial demonstrated that rituximab plus lenalidomide, an 
immunomodulatory agent, is dramatically more effective vs. the ABC subtype.(31) In 
previous trials, R-DA-EPOCH has shown excellent outcomes in GCB DLBCL, 
although ABC DLBCL remains poorly treated with ~4/10 patient suffering relapse in 
< 24 months (Figure 1). 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
9 
 
Figure 1. ABC (non-GCB analog) vs GCB DLBCL subtypes time to progression 
when treated with dose adjusted R-EPOCH (adapted from (24)). 
2.5 PET/CT Scans in lymphoma 
PET/CT scans are used in NHL to evaluate residual masses detected on CT after 
completion of chemotherapy, with the negative predictive values for outcome of 80% 
to 100%.(32, 33) Results from a PET scan after one cycle of chemotherapy were 
essentially equivalent to results from a PET scan obtained at the completion of 
chemotherapy in predicting PFS in NHL and HD.(34)  
Moskowitz et al evaluated the predictive value of an FDG PET in patients with 
high risk untreated DLBCL after 3 cycles of conventional chemotherapy.(35) Of the 
38 patients with a positive interim FDG PET, only 5 (13%) had biopsy-confirmed 
persistent disease. Interestingly, the patients with positive interim FDG PET and 
negative biopsy had no significant difference in long-term outcomes from patients 
with negative interim FDG PET (p=0.27). As a result of this important trial, the 
positive predictive value of an interim FDG PET is considered low enough that a 
biopsy for confirmation is mandatory prior to altering the treatment plan. Essentially, 
interim FDG PET scans have an excellent negative predictive value, however the 
positive predictive value is not clinically viable. 
2.6 Non-imaging based disease monitoring 
A novel technology (LymphoSIGHT, Sequenta) has been shown to allow a detection 
of a tumor-specific clonotype (DoC) in blood and to correlate with therapeutic 
response and identification of relapse prior to imaging findings.(36-38) This novel 
technology amplifies the immunoglobulin (Ig) gene segments from tumor biopsy 
DNA, which can allow detection of a tumor-specific clonotype (DoC) in blood, and to 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
10 
correlate with therapeutic response and identification of relapse prior to imaging 
findings.(39) 
 
Genomic DNA from tumor is isolated using standard kits from Qiagen, and is 
subsequently amplified using locus-specific primer sets for all known alleles of 
germline 
immunoglobulin 
heavy 
chain 
(IgH) 
and 
T-cell 
receptor 
(TCR) 
sequences.(36) The tumor-specific sequences identified at diagnosis are then used 
as a target to assess the presence of tumor-specific clonotype in follow-up samples. 
For quantitation, multiple sequencing reads (~10X coverage) are generated for each 
rearranged B cell in the reaction.  
 
To determine the absolute measure of the tumor-specific clonotype present in the 
follow-up sample, a known quantity of reference IgH sequence is added into the 
reaction and the associated sequencing reads are counted. The resulting number of 
reference IgH reads per sequence are then applied to the tumor-specific clonotype 
reads to obtain an absolute measure of the total tumor-specific clonotype in the 
reaction.  
 
The tumor-specific clonotype reads and the absolute number of total leukoctyes in 
the reaction metrics can be combined to calculate a final tumor-specific clonotype 
measurement, which is the number of tumor-specific clonotype reads divided by the 
total leukocytes in the sample. 
 
In addition to LymphoSIGHT, recent advances in detection of circulating tumor DNA 
(ctDNA) have allowed for the possibility of “liquid biopsies”.(40) The detection of 
ctDNA is related to the release of DNA by apoptotic/necrotic cells, and potentially by 
spontaneous release for unclear reasons. Various methods have been employed to 
detect ctDNA, including the cancer personalized profiling by deep sequencing 
(CAPP-Seq).(41) The creation of CAPP-Seq was initially piloted in samples from 
patients with lung cancer by creation of a multiphase bioinformatics approach to 
create a ‘selector’, consisting of biotinylated DNA oligonucleotides that target 
recurrently mutated gene regions. This approach identified a median 4 single 
nucleotide variations per patient with lung cancer, without modification of the 
selector for genomic aberrations found in any given individual patient’s tumor. Thus, 
this approach has the advantage of being “off the shelf”, meaning that it is broadly 
applicable. 
2.7 Targeted Therapy Opportunities in the ABC DLBCL subtype: 
ABC DLBCL requires constitutive activity of the targetable B-cell receptor and NF-κB 
pathways for survival. Recent work has demonstrated the subtype-selective activity 
of lenalidomide in ABC DLBCL comes from inhibition of the expression of the 


Smart Start: A Phase II Study of Rituximab, Lenalidomide, Ibrutinib and 
Chemotherapy in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma 
Protocol 2015-0147, Version 7.0 
11 
survival-critical transcription factors IRF4 and SPIB, which are not essential for other 
lymphoma subtypes (Figure 2, adapted from (42) ). Confirmation of these data come 
from multiple clinical trials which demonstrate either significant single agent activity 
of lenalidomide in ABC DLBCL (ORR 53%)(15, 43) or equivalent activity in ABC and 
GCB DLBCL of the well tolerated combination of R-CHOP + lenalidomide (ORR 
~90%, CR ~90%).(44-46)  
 
Not surprisingly due to the reliance on BCR signaling, the same pattern of an 
impressive response rate in ABC DLBCL has been seen for ibrutinib, the first in 
class BTK inhibitor. The Phase I trial found an ORR of 22% in relapsed refractory 
DLBCL patients, but 40% in the non-GCB (similar to ABC) subtype achieved 
response.(47) The phase Ib trial of ibrutinib with RCHOP showed an ORR of 100% 
in patients with untreated B-cell lymphomas.(48) Additional data detailed in Section 
2.11 provide strong pre-clinical rationale for the combination of lenalidomide with 
ibrutinib (Figure 2, adapted from (42). Importantly, the three trials which have added 
lenalidomide to R-CHOP and the single trial which added ibrutinib to R-CHOP in 
DLBCL have found no synergistic toxicity. Investigators were able to dose escalate 
lenalidomide and ibrutinib to clinically active dose levels without adding toxicity 
beyond what is expected from R-CHOP alone. 
 
Together, these data strongly suggest that lenalidomide and ibrutinib 1) have a 
strong rationale for use in non-GCB (ABC) DLBCL based on pre-clinical and clinical 
data, and 2) have been well tolerated when combined with standard immuno-
chemotherapy. Randomized registration trials comparing R-CHOP with both R-
CHOP + lenalidomide and with R-CHOP + ibrutinib are ongoing.  
 


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Figure 2. Lenalidomide and the BCR and TLR pathways in ABC DLBCL 
 
2.8 Lenalidomide 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent 
with anti-angiogenic properties. Lenalidomide is indicated for the treatment of 
patients with transfusion-dependent anemia due to low- or Intermediate-1-risk 
myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality 
with or without additional cytogenetic abnormalities.  Revlimid® is also approved in 
combination with dexamethasone for the treatment of patients with multiple myeloma 
that have received at least one prior therapy.  
 
Lenalidomide, an oral agent, is a thalidomide derivative that belongs to a new class 
of agents known as immunomodulatory drugs (IMiDs). Lenalidomide has clinical 
activity in non-Hodgkin’s lymphoma (NHL) and has been shown to possess several 
immunomodulatory properties. In addition to its known effect on various cytokines, 
lenalidomide 
may 
affect 
the 
immune cellular 
component 
of 
the 
tumor 
microenvironment. Potential effects include inducing lymphocyte proliferation, 
increasing the production of IL-2/INF-g by effector cells and angiogenesis inhibition. 
 
The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2, 
6-dione and it has the following chemical structure:  
 
 
Figure 3 Chemical Structure of Lenalidomide 


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The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular 
weight is 259.3. Lenalidomide is an off-white to pale-yellow solid powder. It is soluble 
in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is 
more soluble in organic solvents and low pH solutions. Solubility was significantly 
lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has 
an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), 
and is produced as a racemic mixture with a net optical rotation of zero. 
2.8.1 Clinical Pharmacology: 
Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. 
Lenalidomide 
possesses 
immunomodulatory 
and 
antiangiogenic 
properties.  
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased 
the secretion of anti-inflammatory cytokines from peripheral blood mononuclear 
cells.  Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) in 
some but not all cell lines.  Of cell lines tested, lenalidomide was effective in 
inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a deletion 
of one chromosome 5) but was much less effective in inhibiting growth of KG-1 cells 
(human myeloblastic cell line, also with a deletion of one chromosome 5) and other 
cell lines without chromosome 5 deletions.  Lenalidomide inhibited the expression of 
cyclooxygenase-2 (COX-2) but not COX-1 in vitro.   
 
Pharmacokinetics and Drug Metabolism 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration 
with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-
dose. Co administration with food does not alter the extent of absorption (AUC) but 
does reduce the maximal plasma concentration (Cmax) by 36%. The 
pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC increase 
N
N
H
O
O
O
NH2


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proportionately with increases in dose. Multiple dosing at the recommended dose-
regimen does not result in drug accumulation. 
 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated 
in the phase I studies.  Absorption was found to be rapid on both Day 1 and Day 28 
with time to maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels 
(5mg, 10mg, 25mg, and 50mg).  No plasma accumulation was observed with 
multiple daily dosing.  Plasma lenalidomide declined in a monophasic manner with 
elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 28 at all 4 
doses.  Peak and overall plasma concentrations were dose proportional over the 
dosing range of 5mg to 50mg (5).  Exposure (AUC) in multiple myeloma patients is 
57% higher than in healthy male volunteers.  
 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged 
through urinary excretion. The process exceeds the glomerular filtration rate and 
therefore is partially or entirely active.  Half life of elimination is approximately 3 
hours.  
 
Lenalidomide is available in 5 mg and 10 mg capsules for oral administration. Each 
capsule contains lenalidomide as the active ingredient and the following inactive 
ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, 
and magnesium stearate. The 5 mg capsule shell contains gelatin, titanium dioxide 
and black ink. The 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron 
oxide, titanium dioxide and black ink.  
 
2.8.2 Lenalidomide in NHL  
Lenalidomide induced growth arrest and apoptosis of lymphoma cell lines as well as 
enhancing NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) of 
rituximab. (Wu et al 2006) In addition, using a lymphoma xenograft mouse model 
(Hernandez-Ilizaliturri et al 2005) demonstrated that IMiD molecules enhanced the 
antitumor activity of rituximab, resulting in improved survival of tumor-bearing 
animals.  
2.8.3 Lenalidomide in Aggressive NHL  
Wiernik et al reported preliminary results of lenalidomide monotherapy in patients 
with relapsed or refractory non-Hodgkin's lymphoma. Lenalidomide (25 mg/d) was 
administered on days 1 to 21 of a 28-day cycle and continued for 52 weeks as 
tolerated or until disease progression. Patients with various aggressive histologic 
subtypes (including diffuse large B-cell, follicular center cell, mantle cell, and 


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transformed NHL) were enrolled. Forty-one of the 50 patients were assessable for 
response. Clinical responses were observed in all lymphoma subtypes. The ORR 
was 34% (n = 14) including five patients with CR unconfirmed (CRu), with a median 
progression-free survival in patients achieving a CRu of more than 239 (> 191 to > 
373 days) days. (Witzig et al 2007) An ongoing multicenter clinical trial is further 
investigating clinical efficacy of single agent lenalidomide in patients with aggressive 
NHL.  
 
Kaufman et al first reported the clinical efficacy of thalidomide combined with 
rituximab in patients with relapsed/refractory mantle-cell lymphoma (MCL). The ORR 
and CR rate in this study was 81% and 31%, respectively with a median 
progression-free survival of 20.4 months. (Kaufman et al 2004) On the basis of these 
findings, a phase I clinical trial of lenalidomide (5 to 25 mg) in combination with 
rituximab was initiated for MCL. The MTD was 20 mg/d, 21 of 28 days. The DLT was 
prolonged neutropenia. Thirteen of 15 patients were assessable and had a median 
of three (range 1-4) prior therapies. Although there were no responses in the 10- and 
15-mg dose cohorts, five of six patients in the 20-mg cohort responded including a 
complete response. (Wang et al 2007) On the basis of the important single-agent 
activity of lenalidomide and bortezomib in MCL, CALGB is currently conducting a 
phase II trial of the combination of the two agents in patients with relapsed or 
refractory MCL. 
2.8.4 Clinical trials evaluating lenalidomide combined with R-CHOP in DLBCL 
Investigators from the Mayo Clinic conducted a phase II clinical trial which evaluated 
lenalidomide 25mg orally daily along with full dose R-CHOP (R2CHOP) in patients 
with previously untreated stage II – IV, CD20+ DLBCL. Lenalidomide was 
administered on days 1 – 10 of a 21 day cycle for a total of 6 cycles of therapy.(49) 
All patients received a pegfilgrastim 6 mg subcutaneously on day 2 and low-dose 
aspirin 81 mg per day prophylaxis throughout, unless they were on therapeutic dose 
warfarin or low molecular weight heparin for intercurrent conditions. The treatment 
continued for a maximum of six cycles or until disease progression. Tumor lysis 
prophylaxis, antiemetics, and supportive care were standard of care and at the 
discretion of the treating physician. In the 60 evaluable patients, 59 patients 
achieved a response to therapy (98%) with 48 achieving a complete response 
(80%). The median duration of response was not reached in the manuscript, with a 
median follow up of surviving patients of 23.5 months. The progression free survival 
was 70% at 12 months and 59% at 24 months, and the overall survival was 90% at 
12 months and 78% at 24 months. There was no difference identified between the 
cell of origin subtypes in the 2 year progression free survival or 2 year overall 
survival. However, the investigators compared the patients treated with R2CHOP 
with a matched historical cohort of patients treated with RCHOP and found that the 


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non-GCB subtype achieved superior outcomes with R2CHOP. The 2 year 
progression free survival in non-GCB patients treated with R2CHOP was 60% vs. 
28% in non-GCB patients treated with RCHOP. The 2 year overall survival in non-
GCB patients treated with R2CHOP was 83% vs. 46% in non-GCB patients treated 
with RCHOP (p<0.001). 
 
Therapy was well tolerated, with only one patient experiencing a toxic death on trial 
thought related to intestinal perforation due to significant gut involvement with 
DLBCL responding to therapy. Two patients experienced a grade 4 non-hematologic 
toxicity (intra-abdominal hemorrhage, thrombosis), and other non-hematologic 
toxicities were generally grade 2 or less. Although neutropenia was common (Grade 
3: 13% and Grade 4: 75%), neutropenic fever was rare at 9%. The dose intensity 
was excellent, with 87% of cycles administered containing the full lenalidomide 
dosage. 
 
Investigators from the Fondazione Italiana Linfomi conducted the REAL07 phase II 
clinical trial which evaluated lenalidomide 15mg orally daily with full dose RCHOP in 
patients with previously untreated stage II – IV, CD20+ DLBCL or grade 3b FL who 
were aged 60-80 years. Lenalidomide was administered on days 1 - 14 of a 21 day 
cycle for a total of 6 cycles of therapy.(50) All patients received prophylaxis for 
neutropenia with granulocyte colony-stimulating factors, for deep vein thrombosis 
with low-molecular-weight heparins, and for Pneumocystis jirovecii infection with co-
trimoxazole or a pentamidine aerosol. Occult carriers of hepatitis B virus were given 
lamivudine. In the 49 evaluable patients, 45 achieved a response to therapy (92%); 
42 achieved a complete response (86%) and 3 achieved a partial response (6%). At 
a median follow up of 28 months, the 2 year overall survival was 92% and 2 year 
progression free survival was 80%. Of the 32 patients with adequate tissue for cell of 
origin determination, 16 (50%) had GCB and 16 had non-GCB DLBCL. In the GCB 
patients, 14 (88%) achieved a response, with 13 (81%) achieving a complete 
response. In the non-GCB patients, 14 (88%) achieved a response, with all 
achieving a complete response. The 2 year progression free survival was 71% in the 
patients with GCB DLBCL, and 81% in the patients with non-GCB DLBCL. The 2 
year overall survival was 88% in the patients with GCB DLBCL, and 94% in the 
patients with non-GCB DLBCL. 
 
Therapy was well tolerated, with hematologic toxicities appearing similar to the trial 
from the Mayo Clinic and no toxic deaths on trial reported. Although neutropenia was 
common (Grade 3: 14% and Grade 4: 55%), neutropenic fever was rare at 10%. The 
dose intensity was excellent, with a median dosage of lenalidomide of 94% of the 
planned dosage for the entire trial. 


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2.8.5 Adverse events described in prior lenalidomide clinical trials  
Most frequently reported adverse events during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to 
study 
medication 
include: 
anemia, 
neutropenia, 
thrombocytopenia 
and 
pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, 
itching, infections, sepsis, pneumonia, UTI, Upper respiratory infection, atrial 
fibrillation, congestive heart failure, myocardial infarction, chest pain, weakness, 
hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, 
dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, 
pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal 
cord compression, syncope, disease progression, death not specified and fractures. 
 
Patients with cancer have a higher risk of developing a second new cancer when 
compared to people without cancer. In clinical studies of newly diagnosed multiple 
myeloma, a higher number of second cancers were reported in patients treated with 
lenalidomide as induction therapy (treatment for several cycles to reduce number of 
cancer cells) and/or bone marrow transplant followed by lenalidomide  for a long 
period of time compared to patients treated with induction therapy and/or bone 
marrow transplant then placebo (a capsule containing no lenalidomide). Patients 
should make their doctors aware of their medical history and any concerns they may 
have regarding their own increased risk of other cancers.  
2.9 Ibrutinib 
Ibrutinib (PCI-32765; JNJ-54179060) is a first-in-class, potent, orally administered, 
covalently-binding, small molecule Bruton’s tyrosine kinase (BTK) inhibitor currently 
being co-developed by Janssen Scientific Affairs, LLC, and Pharmacyclics, Inc for 
the treatment of B-cell malignancies. Ibrutinib (IMBRUVICA™) is approved for small 
lymphatic lymphoma for approved indications by the U.S. Food and Drug 
Administration for the treatment of adult patients with mantle cell lymphoma (MCL) 
who have received at least 1 prior therapy, as well as chronic lymphocytic leukemia 
(CLL) patients who have received at least one prior therapy or have a deletion of 
17p, and Waldenstrom’s macroglobulinemia. Ibrutinib and PCI-32765 refer to the 
same molecule; hereafter, ibrutinib will be used. For additional details, refer to 
appendix F. Ibrutinib is not approved for large B-cell lymphoma and combination use 
of products not approved for indication.  
 
 
Figure 4 Chemical Structure of Ibrutinib 


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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. 
 
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 BTK, phosphorylation of BTK’s 
physiological substrate, phospholipase-C gamma (PLCγ), and phosphorylation of a 
further downstream kinase, extracellular signal-regulated kinase. Ibrutinib inhibited 
the proliferation of cell lines derived from DLBCL patients with a median effective 
concentration of 1 or 2 nM. 
2.9.1 Ibrutinib Pharmacokinetics and Drug Metabolism:  
In vitro preclinical data show that ibrutinib is metabolized primarily by CYP3A. 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). Guidance on concomitant use of ibrutinib with CYP3A 
inhibitors or inducers is provided in Appendix E and F. 
 
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 


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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. 
 
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 is the main route of elimination for ibrutinib. It is metabolized to several 
metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by 
CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with 
inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib.  
 
Ibrutinib is metabolized in the liver. In a hepatic impairment trial, a single dose of 140 
mg of ibrutinib was administered in non-cancer subjects. Ibrutinib AUC increased 
2.7-, 8.2- and 9.8-fold, respectively, in subjects with mild (n=6), moderate (n=10) and 
severe (n=8) hepatic impairment relative to subjects with normal liver function. 
Ibrutinib Cmax increased 5.2-, 8.8- and 7.0-fold, respectively, in subjects with mild, 
moderate and severe hepatic impairment relative to subjects with normal liver 
function.  
 
2.9.2 Pharmacodynamics of Ibrutinib 
In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site 
in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib 
doses of ≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg). 
 
2.9.3 Clinical Efficacy of Ibrutinib in Diffuse Large B-cell Lymphoma 
Efficacy results from Studies PCYC-04753 and PCYC-1106-CA demonstrate that 
ibrutinib has robust activity as a single agent in subjects with relapsed or refractory 
DLBCL, with possible lower response rates in subjects with the GCB subtype. 
2.9.3.1 Study PCYC-04753 
This is a completed, Phase 1, multicenter, open-label, dose escalation study in 66 
subjects with recurrent NHL. 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, with the 


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objective of escalating 3 dose levels above that which achieved full BTK occupancy 
based on the fluorescent probe assay. 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 at ≥2.5 mg/kg/day; consequently, per 
protocol, 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]); these events occurred in different dose cohorts, 
with neither in the highest-dose nor a continuous dosing cohort. The 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 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). 
2.9.3.2 Study PCYC-1106-CA 
This is a Phase 2, multicenter, open-label, single-arm study in subjects with relapsed 
or refractory DLBCL. Subjects are enrolled and retrospectively assigned to 1 of 2 
cohorts by subtype: ABC versus GCB as per central GEP. All subjects have 
received a continuous fixed dose of ibrutinib 560 mg/day. The objectives include 
studying the efficacy of ibrutinib in DLBCL and the safety of this dosing regimen. The 
study has completed enrollment. Seventy subjects were enrolled with a median age 
of 63 years (range: 28 to 92 years) and a median of 3 prior systemic therapies 
(range: 1 to 7). 
Median time from diagnosis was 19 months. In a subset of samples, a comparison of 
the central IHC by Hans algorithm to the GEP algorithm that was used in this Phase 
2 clinical study (ie, Sensation algorithm; 200 genes) was performed (unpublished 
data on file).55 Non-GCB by central IHC, blinded to the GEP assignment and clinical 
data, had a 92% concordance (12/13) with GEP. For the 60 response evaluable 
subjects, the overall response rate (ORR) was 21.7% (13/60 subjects). Median PFS 
was 1.64 months (Table 3).55 In the ABC subtype, ORR was 40% (10/25 subjects; 
95% confidence interval [CI]: 21% to 61%), CR 8% (2/25 subjects), and PR 32% 
(8/25 subjects). Only 1 PR (1/19 subjects; 5.3%) was observed in the GCB subtype 
and none in unclassifiable cases. Thus, while the 2 subgroups were clinically not 
well balanced, ibrutinib showed less activity in the GCB DLBCL subtype (p=0.0126, 
Fisher’s exact test). 


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Table 1 Study PCYC-1106-CA Efficacy Results 
 
ABC 
Subtype 
N = 29 
GCB 
Subtype 
N = 20 
UnclassifiableA 
N = 16 
UnknownB 
N = 5 
Total 
N = 70 
Evaluable 
for 
Response 
25 
19 
13 
3 
60 
ORR (CR 
+ PR) 
10 (40%) 
1 (5.3%) 
0 
2 (66.7%) 
13 
(21.7%) 
CR 
2 (8%) 
0 
0 
1 (33.3%) 
3 (5%) 
PR 
8 (32%) 
1 (5.3) 
0 
1 (33.3%)  
10 
(16.7%) 
PFS 
(months) 
2.5 
1.28 
0.95 
NR 
1.64 
ABC=activated B-like DLBCL; CR=complete response, GCB=germinal center B-
cell; NR=not reached; ORR=overall response rate; PFS=progression-free 
survival; PP=per-protocol population; PR=partial response 
A  Gene expression profiling performed, but not assignable to ABC or GCB 
subtypes. 
B  Gene expression profiling not yet performed or tissue not available 
 
A post hoc analysis of pooled data from the DLBCL expansion cohort of Study 
PCYC-04753 and Study PCYC-1106-CA was conducted. The effect of a prior 
response to chemotherapy on subsequent response to ibrutinib was assessed for all 
subjects with DLBCL and for subjects in the ABC DLBCL and non-ABC DLBCL 
subsets. More subjects in the ABC DLBCL subset who were chemo-sensitive had a 
response (11/14 subjects, 78.6%) compared with the chemo-sensitive non-ABC 
DLBCL subset (4/16 subjects, 25.0%). Fewer subjects with ABC DLBCL who were 
chemo-refractory (defined as failure to achieve a response to the last prior 
chemotherapy regimen) had a response (4/25 subjects, 16%), but the response was 
still favorable as compared with the chemo-refractory non-ABC DLBCL subset (0/25 


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subjects, 0%). Based on these results, ibrutinib appears to be more active in 
subjects with chemo-sensitive DLBCL. Therefore use of ibrutinib in earlier lines of 
therapy and in the non-GCB subtype of DLBCL may have the greatest clinical effect. 
2.9.3.3 Study PCI-32765DBL1002 
This is a multicenter, dose-escalation and expansion study in subjects with newly 
diagnosed CD20-positive B-cell NHL including DLBCL, follicular lymphoma, and 
MCL. Thirty-three subjects have been enrolled in this study of whom 24 subjects 
have DLBCL; 18 subjects with newly diagnosed DLBCL were treated at the 
recommended Phase 2 dose (ibrutinib 560 mg daily) in combination with R-CHOP. 
In the dose-escalation phase of this study, subjects were assigned to cohorts of 
increasing oral daily doses of ibrutinib 280 mg (n=7), 420 mg (n=4), and 560 mg 
(n=6) administered in combination with R-CHOP. A Study Evaluation Team (SET) 
reviewed all available data upon completion of the first cycle for all subjects at each 
dose cohort to determine DLTs. After the recommended Phase 2 dose was 
determined (560 mg), 16 subjects with newly diagnosed DLBCL were enrolled into 
the expansion cohort. Subjects are allowed to continue to receive ibrutinib and R-
CHOP up to a maximum of 6 cycles.  
In patients who received ≥1 dose of ibrutinib and R-CHOP (n = 32), 15 (46·9%) 
patients received full doses of R-CHOP. Single-dose reductions of vincristine (11/32; 
34·4% of patients) were most frequently reported, and one patient each (3%) had 
one or two dose reductions of cyclophosphamide, doxorubicin, or prednisone. 
Additionally, four patients had a single ibrutinib dose withheld once. 
In the 32 evaluable patients, the ORR was 93.8%, and for individual ibrutinib doses 
of 280 mg, 420 mg, and 560 mg, the ORR was 85.7%, 100.0%, and 95.2%, 
respectively. The complete response rate for the patients who received ≥1 dose of 
ibrutinib + R-CHOP (n = 32) was 71.9%. Among the DLBCL patients (n = 23), the 
ORR was 95.7%. Of these 23 patients, 18 were treated at the recommended phase 
II dose of 560mg and all responded. The complete response rate at 560mg in 
DLBCL patients was 15/18 (83.3%), and the partial response rate was 3/18 (16.7%). 
Among the DLBCL patients, 13 had cell of origin subtype determined, of which 11 
were evaluable; Seven with GCB subtype and four with non-GCB. The ORR for 
these 13 patients was 100.0%, regardless of subtype. Five patients with GCB 
subtype achieved a complete response (71.4%) and two had a partial response. All 
four patients with confirmed non-GCB subtype achieved a complete response. 
The pharmacokinetics of vincristine were evaluated and determined to not be 
impacted by co-administration of ibrutinib. In addition, the pharmacokinetics of 


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ibrutinib were also evaluated and appeared not to be affected by the presence of the 
other components of R-CHOP. 
2.9.4 Adverse events described in prior ibrutinib clinical trials  
There are reports of hemorrhagic events in subjects treated with ibrutinib, both with 
or without thrombocytopenia in both monotherapy and combination clinical studies. 
The majority of these hemorrhagic adverse events were of Grade 1 or 2 in severity; 
those included contusion, epistaxis, and petechiae. Hemorrhagic events of Grade 3 
or higher, including central nervous system hemorrhage of any grade severity, 
occurred in 3.4% (17/506) of subjects treated in monotherapy studies and in 3.1% 
(4/130) of subjects treated in combination therapy studies; none were reported in the 
healthy volunteer studies (N=100). In the extension study, PCYC-1103-CA, 2 
additional Grade 3 events associated with bleeding were reported (‘gastrointestinal 
haemorrhage’ and ‘haematotympanum’). Details of these events are provided in the 
Appendix F, Section 5 Warnings and Precautions. 
It is not clear whether or not these events are attributable to ibrutinib. However, it is 
possible that treatment with ibrutinib could increase the risk of bruising or bleeding. 
Subjects in the current study will be monitored closely for hemorrhagic adverse 
events.  
Other malignant diseases have been observed in subjects who have been treated 
with ibrutinib, including skin cancers, adenocarcinomas, and other hematologic 
malignancies. It is not clear whether or not these events are attributable to ibrutinib. 
Subjects in the current study will be monitored for other malignancies. 
Mild to moderate rashes have been observed with ibrutinib alone or in combination 
with other drugs. A single case of Stevens-Johnson Syndrome (SJS) was reported in 
a male subject with CLL treated with ibrutinib 420 mg/day. The subject was also 
receiving multiple concomitant medications known to be associated with SJS. 
Subjects should be monitored closely for signs and symptoms suggestive of SJS. 
Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and 
angioedema have been reported. 
In non-randomized clinical trials, infections (including sepsis, bacterial, viral, or 
fungal infections) were observed in subjects with MCL (≥ Grade 3; 25.2%) and 
CLL/SLL (≥ Grade 3; 37.6%). Some of these infections have been associated with 
hospitalization and death. Subjects should be monitored for fever and infections and 
appropriate anti-infective therapy should be instituted as indicated. 
2.10 Background drug information of R-DA-EPOCH and R-CHOP 
 


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2.10.1 Information on the drugs which are included in R-DA-EPOCH (rituximab, 
etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and 
in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and 
prednisone) are included in Appendix A.  
2.11 Overall Rationale for the Study 
DLBCL is the most common lymphoid malignancy, with ~30,000 new cases in the 
US annually. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) 
was first reported as therapy for DLBCL in 1976, when its molecular pathobiology 
was virtually unknown, and has changed only with the addition of the anti-CD20 
antibody rituximab (R).(1, 25) DLBCL is now known to be molecularly 
heterogeneous, largely by the cell-of-origin (COO) distinction between germinal 
center B-cell (GCB) and activated B-cell (ABC) subtypes.(4, 6, 7) Multiple 
vulnerabilities of each COO subtype are known, and corresponding inhibitors are 
now in clinical trials, but subtyping is essentially ignored in DLBCL standard-of-care 
(SOC) therapy.(21, 51) Aside from R, there is no obvious mechanistic specificity of 
RCHOP for either COO subtype, but it remains the frontline SOC therapy despite 
advances in knowledge of DLBCL biology, development of targeted agents, and 
tools for molecular diagnosis.(21, 52) Justification for this disconnect is largely due 
to the relative efficacy of RCHOP, which achieves 5-year overall survival (OS) rates 
of ~50% and ~70% in ABC and GCB subtypes, respectively, but with significant 
toxicity.(5, 53) Infusional etoposide (E) in R-DA-EPOCH may incrementally improve 
frontline DLBCL SOC efficacy, including in high-risk disease,(24, 54) but it further 
adds to toxicity and perpetuates the practice of non-targeted, one-size-fits-all 
frontline SOC therapy for DLBCL.  
 
The abysmal cure rate (~10%) for the 10,000 patients with DLBCL who relapse 
each year in the US, and long-term complications of frontline DLBCL SOC, mandate 
that we improve frontline therapy with novel agents against DLBCL-critical 
aberrancies.(20, 55, 56) However, improving frontline DLBCL therapy poses a 
particular challenge for the academic oncologist: how to develop new novel 
therapies without denying potentially curative SOC therapy.(52) The standard 
“SOC+X” approach, in which X is a drug with single agent efficacy in relapsed 
DLBCL patients, has drawbacks including: 1) how to measure what X adds to an 
already-effective SOC therapy; 2) how to avoid potential antagonism between X, 
which may be highly effective alone, and SOC agents; and 3) how to test more than 
one novel agent simultaneously. 
 
Gene expression profiling (GEP) shows that the ABC DLBCL subtype has 
constitutive similarities to normal B cells activated by acute ligation of their B-cell 
receptor (BCR). Among those similarities are high activity of the canonical NF-kB 


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pathway,(11, 57, 58) required for survival of ABC DLBCL (Figure 2).(27) CARD11, 
required for NF-κB activation by BCR signaling, has gain-of-function mutations 
(GOFM) in 10% of ABC DLBCL that can activate NF-κB independent of BCR 
signaling. In ABC DLBCL with wild type (WT) CARD11, mutations in the ITAM 
domain of the BCR subunits CD79A and CD79B, found in 24% of ABC DLBCL 
tumors, contribute to NF-κB activation by “chronic active BCR signaling”.(12) 
Inhibition of Bruton’s tyrosine kinase (BTK), a BCR signaling pathway mediator, is 
specifically toxic to CARD11-WT ABC DLBCL cell lines. NF-κB activation in ABC 
DLBCL is further driven by a specific GOFM in MYD88, found in 30% of tumors, 
resulting in toll-like receptor (TLR) signaling.(28) In addition to pro-survival factors, 
MYD88 GOFM paradoxically drive production of interferon-β (INF-β), which would be 
toxic to ABC DLBCL if not suppressed by interferon regulatory factor 4 (IRF4 or 
MUM1), an NF-κB-driven hallmark of ABC DLBCL. In addition to INF-β suppression, 
IRF4 further activates CARD11 to amplify NF-κB signaling.(42, 59) 
 
Lenalidomide partially reduces IRF4 expression in ABC DLBCL cell lines, producing 
a synthetically lethal type I interferon response.(42) Ibrutinib has significant activity 
against ABC DLBCL cell lines with chronic active BCR signaling.(12) When ibrutinib 
is combined with lenalidomide, IRF4 expression is completely suppressed, resulting 
in profound synergy in ABC DLBCL cell lines.(42) 
 
In addition to affecting lymphoma cells directly, lenalidomide and ibrutinib both 
modulate immune responses. In MM, CLL, and follicular lymphoma (FL), 
lenalidomide reverses immunosuppression of T cells by tumor cells.(60-62) 
Lenalidomide increases expression of T cell co-stimulatory molecules, T cell 
activating cytokines, and the number of cytotoxic T cells in MM patient samples. In 
indolent lymphomas including FL, we found that R-lenalidomide activated many 
different immune cell subsets, including T and natural killer cells, and enhanced 
tumor infiltration of CD8+ T cells.(63, 64) In addition to its irreversible BTK inhibition, 
ibrutinib also inhibits IL2-inducible kinase (ITK), which drives a shift towards an 
antitumor 
Th1-dominant 
response, 
and 
reduces 
a 
tumor-promoting 
Th2 
response.(65) In unpublished GEP studies, our group has also found that ibrutinib 
reduces expression of co-inhibitory receptors, most likely by T cells, in the blood of 
CLL patients. The relationship of these data to therapeutic immunomodulation in 
DLBCL is unknown; however, loss or aberrant expression of β2M and CD58, critical 
for tumor immuno-surveillance by T cells, is common in DLBCL and may correlate 
with immune-mediated response.(66) 
 
Clinical studies of lenalidomide and ibrutinib in ABC DLBCL: Lenalidomide and 
ibrutinib have both shown promising efficacy and tolerability as single agents and in 


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combination with chemotherapy in relapsed and frontline DLBCL, with increased 
activity in the ABC subtype   
(Table 2,(15, 47-50)). In phase I trials in combination with RCHOP, both drugs were 
escalated to their single-agent maximum tolerated doses (MTD) without increased 
toxicity, and both lenalidomide and ibrutinib are now being evaluated in separate 
“RCHOP+X” trials against placebo aiming for FDA approval in ABC DLBCL. Despite 
a strong pre-clinical rationale for use of these promising agents, no trial has 
examined this combination in untreated ABC DLBCL patients prior to the current 
proposal. 
 
In relapsed ABC DLBCL, mutations (M) in BCR and MYD88 pathway mediators 
correlate with clinical responses to ibrutinib (Table 3, (67)). Patients with CARD11-M 
(distal to BTK from BCR) had no response to ibrutinib in a phase II trial, matching 
ABC DLBCL cell line-based predictions,(12) suggesting the need to target 
downstream NF-κB drivers.(47, 67) In CLL, BTK and PLCγ2 mutations result in 
acquired resistance to ibrutinib, though their relevance in DLBCL is unknown.(68) 
Resistance to lenalidomide in DLBCL is not well characterized, but in MM, which 
shares many GEP features with ABC DLBCL, it can be driven by activation of the 
Wnt/β-catenin signaling pathway.(69)  
 
Based upon the above data, the below phase Ib/II clinical trial of rituximab, 


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lenalidomide, and ibrutinib (RLI), combined with CHOP or EPOCH in patients with 
untreated DLBCL will be conducted. The phase II trial will start with RLI alone prior 
to the use of chemotherapy (“Smart Start”) for ≤2 cycles, followed by RLI with 
CHOP or DA-EPOCH. The “Smart Start” portion will be restricted to ABC DLBCL 
due to the compelling evidence from our group and others that RLI efficacy is 
expected to have subtype specificity. 
 
DLBCL is clinically aggressive, but most frontline patients do not require immediate 
cytoreduction, and thus the Smart Start trial is feasible. The effect of innovative non-
cytotoxic RLI alone can be assessed on primary tumor cells in vivo, not only 
because it will not be given with confounding chemotherapy, but also because its 
efficacy may be greater without the immuno-suppressive effects of chemotherapy. 
The Smart Start trial, a first in frontline DLBCL therapy, will allow correlation of the 
efficacy of RLI alone with baseline and RLI-mediated features of the tumor and 
immune system, which may identify factors that could be used to understand and 
predict responses to RLI in future trials. New therapeutic approaches are measured 
by their efficacy, but also by their toxicity, A recent phase II trial showed that R-
lenalidomide had efficacy comparable to historical RCHOP controls as frontline 
therapy for FL, but with less toxicity.(64) While complete avoidance of cytotoxic 
therapy for DLBCL is not currently an option, the current trial will take a necessary 
first step toward that as a future possibility, at least for some identifiable patients. 
 
The Smart Start trial will demonstrate that novel drugs can be tested in the frontline 
setting, where they have the greatest chance of efficacy,(70) without denying access 
to the curative potential of SOC therapy. This trial may result in a needed paradigm 
shift in DLBCL therapy: 1) providing support for future trials comparing targeted 
therapy combinations vs. chemotherapy; 2) establishing RLI as a potential backbone 
for testing future combinations with additional targeted agents, possibly in an 
adaptively randomized context; and 3) stratifying treatment according to toxicity 
concerns or a high likelihood of a response to RLI therapy. 


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3 
Study Design and Rationale 
3.1 Study Design: 
This will be a single-center, open label, phase II clinical trial to determine the 
efficacy and safety of rituximab, lenalidomide, ibrutinib, and chemotherapy (R-
CHOP or R-DA-EPOCH) in patients with newly diagnosed high risk DLBCL. The 
treating physicians will have discretion to choose either R-CHOP of R-DA-
EPOCH as backbone chemotherapy, in keeping with our current standard 
practice. 
 
The feasibility of administrating lenalidomide and ibrutinib in combination with 
rituximab with chemotherapy (DA-EPOCH) and the MTD have been previously 
determined in the PCYC-1124-CA clinical trial, conducted in patients with 
relapsed DLBCL. In this ongoing Phase 1b/2, open-label, non-randomized 
multicenter study, the safety and efficacy of ibrutinib and lenalidomide in 
combination with R-DA-EPOCH are being evaluated in subjects with 
relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL). A standard 3+3 
design was employed in Part 1 to determine the maximum tolerated dose (MTD), 
which has been determined to be 560mg by mouth daily, and the MTD of 
lenalidomide was 25mg by mouth daily. The preliminary data from the trial was 
presented at the 2015 Annual Meeting of the American Society of Hematology 
(abstract 1527). In the dose escalation portion of the trial, no MTD was identified. 
Dose escalation was completed through the maximum dosing level. One DLT of 
diffuse alveolar damage was seen at the highest dose of lenalidomide tested. In 
this trial, the grade ≥3 adverse events (AEs) occurred in 14 (93%) patients. The 
most common grade ≥3 AEs (which occurred in >20% of patients) were anemia 
(60%), febrile neutropenia (47%), leukopenia (40%), neutropenia (40%), 
thrombocytopenia (40%), hypokalemia (40%), and hypotension (33%), which are 
considered generally in line with what would be expected from EPOCH 
chemotherapy alone. Serious AEs (SAEs) occurred in 14 patients (93%) 
including 2 cases (13%) of grade 2 atrial fibrillation.  
 
Regarding the efficacy in this heavily pretreated population, in the 10 response 
evaluable patients (with at least one post-baseline radiological assessment), 2 
patients had complete response (CR), 3 had partial response (PR), 2 patients 
had best response of stable disease, and 3 had progressive disease; 4 (67%) of 
6 response evaluable non-GCB patients achieved objective response (CR/PR). 
Three patients continue treatment, 2 patients completed the protocol-specified 
treatment, and 10 patients discontinued treatment. Reasons for treatment 


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discontinuation included AEs (n=3), progressive disease (n=3), stem cell 
transplant after achieving CR/PR (n=2), disease worsening (n=1), and death 
(n=1) 
 
As R-DA-EPOCH is more likely to result in toxicities than RCHOP, and because 
all of the drugs included in RCHOP are included in R-DA-EPOCH, we think it is 
appropriate to extrapolate the above data with R-DA-EPOCH to include R-
CHOP. As mentioned in Section 2.11, the combination of RCHOP with ibrutinib 
and with lenalidomide has already been established as safe, and both drugs 
were increased to their single agent maximum dose without increased toxicity.  
 
Based upon these results, we will utilize the previously determined MTD to 
evaluate efficacy of the rituximab, lenalidomide, and ibrutinib (“Smart Start”) for 
up to two cycles prior to start of chemotherapy, followed by six cycles of 
rituximab, lenalidomide, ibrutinib, and chemotherapy (R-CHOP or DA-EPOCH) in 
patients with high risk non-GCB DLBCL.  
3.2 Rationale of Study Design: 
The phase II clinical trial is designed to determine the efficacy and safety of 
rituximab, lenalidomide, and ibrutinib alone and combined with chemotherapy. 
 
Although the study design is novel for patients with untreated DLBCL, it has been 
utilized in previous clinical trials. As the “Smart Start” component of clinical trial 
will be given prior to standard cytotoxic chemotherapy, patients who have 
confirmed disease progression may start chemotherapy at any time during the 
first 2 cycles of “Smart Start” therapy, previously demonstrated to be tolerable in 
the PCYC-1124-CA trial. 
 
This study design will allow for evaluation of the efficacy of both rituximab, 
lenalidomide, and ibrutinib without chemotherapy for up to two cycles and of 
rituximab, lenalidomide, ibrutinib combined with chemotherapy for six cycles. 
 
 


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4 
PATIENT ELIGIBILITY 
4.1 Inclusion criteria: 
1. Histopathologically confirmed diagnosis of DLBCL of the non-GCB DLBCL 
subtype (appendix C). 
2. No prior treatment except a prior limited-field radiotherapy, a short course 
of glucocorticoids ≤25mg daily of prednisone equivalent which must cease 
prior to day 1 of cycle 1, and/or cyclophosphamide for an urgent 
lymphoma related problem at diagnosis (e.g. epidural cord compression, 
superior vena cava syndrome).  
3. Patient or durable power of attorney (DPA) for healthcare must be able to 
understand and voluntarily sign an IRB-approved informed consent form. 
4. Age ≥ 18 years at the time of signing the informed consent. 
5. Patients must have bi-dimensional measurable disease, as defined as 
radiographically apparent disease with the longest dimension of ≥1.5cm. 
6. Patients with performance status of ≤3 (3 only allowed if decline in status 
is deemed related to lymphoma and felt potentially reversible by the 
treating physician) (Appendix D). 
7. Serum bilirubin <1.5x ULN except in patients with Gilbert’s syndrome as 
defined by > 80% unconjugated bilirubin; AST (SGOT) and ALT (SGPT) ≤ 
3x ULN or < 5x ULN if hepatic metastases are present; ANC >1000/mm3 
and platelets >100,000/mm3 unless deemed related to lymphoma 
involvement in the bone marrow and felt potentially reversible by the 
treating physician. 
8. Renal function assessed by calculated creatinine clearance: 
a. Calculated creatinine clearance ≥ 30ml/min by Cockcroft-Gault 
formula.  See section below, “Dosing Regimen”, regarding 
lenalidomide dose adjustment for calculated creatinine clearance ≥ 
30ml/min and < 60ml/min. 
9. Patients must be willing to receive transfusions of blood products. 
10. All study participants must be registered into the mandatory Revlimid 
REMS® program, and be willing and able to comply with the requirements 
of the REMS® program. 
11. Women of childbearing potential must have a negative serum (β-human 
chorionic gonadotropin [β-hCG]) at screening and must adhere to the 
scheduled pregnancy testing as required in the Revlimid REMS® 
program.  
12. Women of childbearing potential and men who are sexually active with a 
woman of childbearing potential must be practicing a highly effective 
method of birth control during and after the study (12 months for women 


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and 3 months for men), consistent with local regulations regarding the use 
of birth control methods for subjects participating in this clinical study.  
Men must agree to not donate sperm during and for up to 3 months after 
their conclusion of therapy on study. For females, these restrictions apply 
for 1 month after the last dose of study drug. 
13. Able to take aspirin (81 mg) daily or alternative therapy as prophylactic 
anticoagulation  
4.2 Exclusion Criteria:  
1. Any serious medical condition including but not limited to uncontrolled 
hypertension, uncontrolled congestive heart failure within past 6 months 
prior to screening (Class 3 (moderate) or Class 4 (severe) cardiac disease 
as defined by the New York Heart Association Functional Classification), 
uncontrolled diabetes mellitus, active/symptomatic coronary artery 
disease, COPD, LVEF less than 40%, renal failure, active infection, history 
of invasive fungal infection, moderate to severe hepatic disease (Child 
Pugh Class B or C), active hemorrhage, laboratory abnormality, or 
psychiatric illness that, in the investigators opinion places the patient at 
unacceptable risk and would prevent the subject from signing the informed 
consent form. Patients with history of cardiac arrhythmias should have 
cardiac evaluation and clearance. 
2. Pregnant or lactating females. 
3. Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab, 
etoposide, vincristine, doxorubicin, cyclophosphamide, or prednisone. 
4. Known HIV infection. Patients with active hepatitis B infection (not 
including patients with prior hepatitis B vaccination; or positive serum 
Hepatitis B antibody). Known hepatitis C infection is allowed as long as 
there is no active disease and is cleared by GI consultation. 
5. All patients with central nervous system involvement with lymphoma. 
6. Diagnosis of prior malignancy within the past 2 years with the exception of 
successfully treated basal cell carcinoma, squamous cell carcinoma of the 
skin, carcinoma "in situ" of the cervix or breast. History of other 
malignancies are allowed if in remission (including prostate cancer 
patients in remission from radiation therapy, surgery or brachytherapy), 
not actively being treated, with a life expectancy > 3 years. 
7. Significant neuropathy (Grades 2 or Grade 1 with pain) within 14 days 
prior to enrollment 
8. Contraindication to any of the required concomitant drugs or supportive 
treatments or intolerance to hydration due to preexisting pulmonary or 
cardiac impairment including pleural effusion requiring thoracentesis or 
ascites requiring paracentesis not due to lymphoma. 


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9. Patients with active pulmonary embolism or deep vein thrombosis 
(diagnosed within 30 days of study enrollment). 
10. Patients with severe bradycardia (heart rate <40 bpm, hypotension, light-
headedness, syncope). 
11. Major surgery within 4 weeks of study entry, or wound that is not healed 
from prior surgery or trauma. 
12. History of stroke or intracranial hemorrhage within 6 months prior to study 
entry. 
13. Requires anticoagulation with warfarin or equivalent vitamin K antagonists.  
14. Requires chronic treatment with strong CYP3A inhibitors (see Appendix 
E). 
15. Vaccinated with live, attenuated vaccines within 4 weeks of study entry. 
 
 


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5 
Dosage and Administration Schedule: 
5.1 Smart Start: 
Patients will begin therapy on this clinical trial with the “Smart Start” portion of the 
trial. The Smart Start portion of the trial will be defined as shown in Table 4. 
 
Table 4. Doses of “Smart Start” portion of the clinical trial 
Drug Name 
Dose 
Route 
Frequency per 
cycle 
Day 
of 
therapy 
Rituximab 
375mg/m2 
IV 
Once 
1 
Ibrutinib 
560mg  
PO 
Daily 
1-21 
Lenalidomide 
25mg 
PO 
Daily 
1-10 
 
The dose of lenalidomide and ibrutinib in the Smart Start portion of the trial will 
be based on the recommended phase II dose (RP2D) determined in the PCYC-
1124-CA clinical trial. Patients may decrease lenalidomide and ibrutinib (Table 9) 
if significant toxicities occur (as defined in Section 5.3.1). 
 
Rituximab, lenalidomide, and ibrutinib will all start on Day 1 of a 21 day cycle in 
the Smart Start portion of the trial, and will be dosed for 1 day (Rituximab), 10 
days (lenalidomide) and continuously (ibrutinib) for up to two cycles of therapy. 
The ibrutinib and lenalidomide capsules are to be taken around the same time 
each day with approximately 240 mL of water (ie, 8 ounces). The capsules 
should be swallowed whole and should not be opened, broken, or chewed. A 
cycle of therapy is defined as 21 days +/- 72 hours for holidays or other 
scheduling issues that will not allow the patient to be dosed exactly on schedule. 
After two cycles of Smart Start, or if disease progression is identified prior to the 
end of two cycle of Smart Start (as defined in Sections 6.3 and 7.1), all patients 
will start therapy with rituximab, lenalidomide, and ibrutinib combined with CHOP 
or DA-EPOCH chemotherapy as defined in Section 5.2.  
 
As defined in Section 9, if the response rate in the Smart Start portion of the trial 
does not meet specified targets, the Smart Start portion of the trial may be closed 
prior to the completion of the trial. If so, all patients would start therapy with 
rituximab, lenalidomide, and ibrutinib combined with chemotherapy as defined in 
Section 5.2 as their initial cycle of therapy. 
 
At the end of each cycle of the Smart Start portion of the trial, patients will bring 
their pill bottles to the clinic for evaluation by the research nurse to evaluate the 
number of remaining pills and assessment of compliance. 
 


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5.2 Chemotherapy: 
5.2.1 Chemotherapy selection 
The selection of R-DA-EPOCH or R-CHOP will be made by the treating physician 
based upon their preference. Factors that will be included in this decision are 
patient age, fitness to tolerate aggressive chemotherapy, and clinical trial 
adherence. The current standard practice at MD Anderson is to select either R-
DA-EPOCH or R-CHOP based upon the above factors at the treating physician’s 
discretion, which we will replicate in this protocol. The research team will 
document the rationale the treating physician provides for the selection for each 
patient. The selection of R-DA-EPOCH or R-CHOP will be specified prior to start 
of cycle 1 to avoid any possibility of bias favoring either chemotherapy regimen 
(e.g., selection of R-CHOP in patients who achieve a CR to RLI, or selection of 
R-DA-EPOCH in patients with stable disease after RLI). 
 
As R-DA-EPOCH is considered to be equally effective as R-CHOP in treating 
newly diagnosed DLBCL based upon the phase III trial reported at the ASH 2016 
meeting (NCT00118209), these chemotherapies will be considered equivilent for 
the current protocol.   
 
After the Smart Start portion of the trial, patients will start therapy with rituximab, 
lenalidomide, and ibrutinib combined with chemotherapy (R-CHOP or DA-
EPOCH) for six cycles. A cycle of therapy is defined as 21 days +/- 72 hours for 
holidays or other scheduling issues that will not allow the patient to be dosed 
exactly on schedule. 
 
5.2.2 EPOCH 
Dose-adjusted EPOCH will be administered in cycle 1 as shown in Table 5 at 
dose level 0.  
 
Table 5. Doses of R-EPOCH at level 0  
Drug Name 
Dose 
Route 
Frequency 
per cycle 
Day 
of  
Therapy 
Rituximab 
375mg/m2 
IV 
Once 
1 
Etoposide 
50mg/m2/day 
IV 
Continuous 
IV infusion 
1 – 4 
Prednisone 
100mg /day  
PO 
Daily 
1 – 5 
Vincristine 
0.4mg/m2/day IV 
Continuous 
IV infusion 
1 – 4 
Cyclophosphamide 750mg/m2 
IV 
Once 
5 
Doxorubicin 
10mg/m2/day 
IV 
Continuous 
IV infusion 
1 – 4 
 


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5.2.2.1 EPOCH Dose Adjustments: 
Cycles will be every 21 days, and each patient will start their subsequent cycle 
providing that the ANC is at least 1 × 109/L and the platelet count is at least 
100 × 109/L. 
Pharmacodynamic 
dosing 
adjustment 
of 
doxorubicin, 
cyclophosphamide, and etoposide will occur based on twice weekly monitoring of 
complete blood counts to achieve limited absolute neutropenia count (ANC) 
below 500/μL. Dosing adjustments will proceed based upon relevant toxicities as 
shown in Table 6. 
 
Table 6. Dose adjustment of doxorubicin, cyclophosphamide, and 
etoposide 
Nadir Measurement 
Dose Adjustment 
ANC ≥ 0.5  × 109/L 
20% increase from previous cycle 
ANC < 0.5  × 109/L on 1 or 2 
measurements 
No change 
ANC < 0.5  × 109/L on > 2 
measurements 
20% 
decrease 
from 
previous 
cycle 
Platelet < 25  × 109/L  
20% 
decrease 
from 
previous 
cycle 
 
Rituximab, prednisone, vincristine, lenalidomide, and ibrutinib will not be dose 
adjusted based upon the schema in Table 6. 
 
Dose adjustments for toxicity below starting dose level (level 0) apply to 
cyclophosphamide, etoposide, and doxorubicin. Increases of the doses of 
doxorubicin, cyclophosphamide, and etoposide will be capped at dose level +2 
(Table 7). 
 
If a patient is dose escalated to receive cyclophosphamide 1080mg/m2 (dose 
level 2), they will also receive mesna at a one to one ratio to the 
cyclophosphamide dose. The dose of mesna will be equivalent to the 
cyclophosphamide dose (mg/m2) and administered via continuous IV infusion 
beginning 1 hour prior to cyclophosphamide infusion and continuing for 12 hours 
by continuous infusion. 
 
A cycle of therapy may be delayed up to 14 days for unresolved hematologic 
toxicity. In order to start the subsequent cycle, thrombocytopenia must be 
resolved to at least grade 1, and neutropenia must be resolved to at least grade 
2, in keeping with standard of care management. There will be no hold for 
anemia, but transfusion is up to the treating physician and is strongly suggested 


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if the hemoglobin is <8g/dL.If hematologic toxicities are not resolved by day 15, 
the patient will need to be removed from the trial.  
 
At the end of each cycle of the RLI-EPOCH portion of the trial, patients will bring 
their pill bottles to the clinic for evaluation by the research nurse to evaluate the 
number of remaining pills and assessment of compliance. 
 
 
Table 7. Dose adjustment values 
Drugs 
Drug Doses per Dose Levels (mg/mg/day) 
-2 
-1 
0 
1 
2 
Doxorubicin 
8 
10 
10 
12 
14.4 
Etoposide 
40 
40 
50 
60 
72 
Cyclophosphamide 
480 
600 
750 
900 
1080 
 
 
Dose reduction of chemotherapy agents for toxicity is further defined in Section 
5.7. 
 
5.2.3           R-CHOP  
R-CHOP will be administered at standardized dosing in cycle 1 as shown in 
Table 8.    
 
Table 8. Doses of R-CHOP  
Drug Name 
Dose 
Route 
Frequency 
per cycle 
Day 
of  
Therapy 
Rituximab 
375mg/m2 
IV 
Once 
1 
Cyclophosphamide 750mg/m2 
IV 
Once 
1 
Doxorubicin 
50mg/m2 
IV 
Once 
1  
Vincristine 
1.4mg/m2 
(max 
dose 
2mg) 
IV 
Once 
1  
Prednisone 
100mg  
PO 
daily 
1 – 5 
 
 
Dose reduction of chemotherapy agents for toxicity is further defined in Section 
5.7.  
5.3 Lenalidomide and ibrutinib dosing: 
The dose of lenalidomide and ibrutinib will be based on the recommended phase 


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II dose (RP2D) determined in the PCYC-1124-CA clinical trial. Patients may 
decrease lenalidomide (Tables9 and 10) if significant toxicity (as defined in 
Section 5.3.1) occur. 
 
Table 9. Lenalidomide and Ibrutinib Dosing Modifications for 
toxicity during chemotherapy phase 
 
Level 
Lenalidomide 
Ibrutinib 
for 
<65 years of 
age 
Ibrutinib for >/= 
65 
years 
of 
age 
EPOCH or 
CHOP 
1 
25mg  
560mg 
420mg 
Standard 
-1 
20mg  
560mg  
420mg 
Standard 
-2 
10mg 
560mg 
420mg 
Standard 
-3 
10mg 
420mg 
280mg 
Standard 
 
Table 10. Lenalidomide and Ibrutinib Dosing 
Modifications for toxicity during Smart Start  
Level Lenalidomide 
Ibrutinib  
1 
25mg  
560mg 
-1 
20mg  
560mg  
-2 
10mg 
560mg 
-3 
10mg 
420mg 
 
 
Lenalidomide and Ibrutinib will both start on Day 1 of a 21 day cycle along with 
R-EPOCH or R-CHOP, and will be dosed for 10 days (lenalidomide) and 
continuously for the six cycles of therapy (ibrutinib), respectively. If it is identified 
that dose reductions are required in ≥ 4 of the first 10 patients, all subsequent 
patients would start at dose level -1. If dose reductions are required in ≥ 4 of the 
first 10 patients at dose level -1, all subsequent patients would start at dose level 
-2. If dose reductions are required in ≥ 4 of the first 10 patients at dose level -2, 
all subsequent patients would start at dose level -3. 
 
Based upon information available as of July 2018 from the DBL3001 trial 
(PHOENIX), a Janssen-sponsored, randomized, double-blind, placebo-controlled 
phase 3 study of ibrutinib in combination with rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) versus placebo in 


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combination with R-CHOP, in subjects with newly diagnosed non-germinal center 
b-cell subtype of diffuse large B-cell lymphoma (DLBCL), the protocol is being 
modified for patients ≥65 years of age. When a patient age ≥65 is enrolled on 
study, they will receive a maximum dose of 420mg of ibrutinib when administered 
in combination with chemotherapy. 
 
For any patient enrolled on this study who is >=65 years of age and still on active 
therapy at the time of IRB approval of this amendment, they will receive ibrutinib 
420mg for all subsequent cycles of therapy when combined with chemotherapy. 
 
5.3.1 Dose Reduction plan for lenalidomide and ibrutinib: 
 
Relevant toxicities for the adjustment of lenalidomide and ibrutinib will be defined 
as any toxicity during either the smart start period and the 6 cycles of treatment 
with R-CHOP or R-DA-EPOCH that meets one of the following criteria, where 
toxicity was defined as an adverse event at least possibly related to study 
treatment:  
1. Any grade 3 or higher non-hematological toxicity possibly related to study 
medications and not controlled by appropriate medications per National 
Cancer Institute Common Terminology Criteria for Adverse Events v4.0 
excluding grade 3 rash that resolves to < Grade 2 within 10 days with 
systemic corticosteroid treatment, fatigue, anorexia, nausea, fever without 
neutropenia, and tumor lysis syndrome. 
2. Grade 3 rash that does not resolve to < Grade 2 within 10 days with 
corticosteroid treatment 
3. Any grade Stevens-Johnson syndrome or toxic epidermal necrolysis 
4. Grade 3-4 bullous dermatitis;  
5. Any grade 2 or greater hemorrhagic event requiring medical intervention 
or any intracranial hemorrhage;  
6. Any non-hematological toxicity requiring a delay of the next cycle of 
therapy for greater than 10 days;  
7. Grade 4 neutropenia, thrombocytopenia, or anemia which does not 
respond to supportive care measures including transfusions or results in a 
delay of the next cycle of therapy for greater than 10 days. 
8. If a patient requires a dose reduction of R-CHOP or R-EPOCH based 
upon hematologic toxicity as defined in Table 6, they would also have a 
mandatory dose reduction of ibrutinib and lenalidomide to the next lowest 
level as defined in Tables 9 and 10  for their next cycle of therapy. If the 
same patient is able to have a dose increase of R-CHOP or R-EPOCH on 
subsequent cycles, the dosing of ibrutinib and lenalidomide could be 


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increased to the previous level at the following cycle (e.g., from EPOCH 
level -1 on cycle 3 to R-CHOP or EPOCH level 0 on cycle 4, consider 
resume previous ibrutinib and lenalidomide on cycle 5 if cycle 4 R-CHOP 
or EPOCH increase was tolerable) after discussion of the principle 
investigator and the treating physician.   
9. Based upon Bayesian toxicity monitoring rules established in section 9.2, 
if >3 patients in a cohort size of 10 require dose reduction of R-CHOP or 
R-EPOCH below level 0, future patients would require a mandatory dose 
reduction of ibrutinib and lenalidomide to the next lowest level as defined 
in Table 8. 
10. If criteria 9 occurs (all future patients have a dose reduction of ibrutinib 
and lenalidomide based upon dose reductions in R-CHOP or R-EPOCH), 
a new safety criterion would be established. If ≥2 patients in the next 10 
patients required a dose reduction of R-CHOP or R-EPOCH below level 0 
despite the reduction in ibrutinib and lenalidomide, the trial would be 
placed on hold for new patient accrual and would be examined for the 
etiology of the unexpected hematologic toxicity. The trial may be re-
opened only after the principal investigator modified the protocol to ensure 
safety of future patients in coordination with and with approval from the 
M.D. Anderson Cancer Center IND office and FDA monitors. 
Renal Dysfunction dose adjustment for lenalidomide:  
 
• CrCl > 60mL/minute:  No dosage adjustment necessary 
• CrCl 30 to 60 mL/minute:  10 mg once daily 
• CrCl <30 mL/minute (non-dialysis dependent):  15 mg every 48 hours 
 
Due to the known occurrence of hematologic toxicities with R-CHOP or DA-
EPOCH, and the dose modification based upon occurrence of cytopenias, grade 
4 hematologic toxicities will not be considered significant toxicities unless they 
meet the above time constraints. In addition, neutropenic fever incidence will be 
closely monitored, but will also not be considered a significant toxicity due to the 
known high rate of neutropenic fever with dose adjusted R-EPOCH and R-CHOP 
(20 – 30%). 
 
If a significant toxicity is definitely attributed to ibrutinib or lenalidomide per the 
investigator’s assessment, dosing with ibrutinib and or lenalidomide will be 
withheld. Ibrutinib and or lenalidomide treatment may resume as specified in 
Tables 9 and 10  after toxicity has resolved to grade 1 or completely.  If the 
toxicity attributed the ibrutinib or lenalidomide as defined in Section 5.3.1 was 
considered life threatening such as Stevens-Johnson Syndrome or toxic 


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epidermal 
necrolysis, 
ibrutinib 
and 
lenalidomide 
will 
be 
discontinued 
permanently. If the toxicity attributed the ibrutinib or lenalidomide as defined in 
Section 5.3.1 does not resolve to at least grade 1 within 28 days (7 days beyond 
the expected 21 days cycles) of the start of a given therapeutic cycle, ibrutinib 
and lenalidomide will be discontinued for that cycle. Resumption of ibrutinib or 
lenalidomide would be only considered if the toxicity has resolved to baseline 
prior to the start of the next cycle, and the patient could be treated at a lower 
dose level (i.e., a patient treated at dose level -3 prior to this toxicity would not be 
eligible to resume ibrutinib or lenalidomide as they could not further dose 
reduce).  
  
It should be noted that the dose reductions listed in Tables 9 and 10  will only be 
mandatory for future patients if the toxicity monitoring rule thresholds detailed in 
Section  9.2 are surpassed (i.e. dose reductions are required in ≥ 4 of the first 10 
patients at the previous dose level). For an individual patient who experiences a 
toxicity detailed in Section 5.3.1 as significant, a mandatory dose reduction to the 
next lower level in tables 9 and 10 will occur for the following cycle. If the patient 
has no significant toxicities at the lower dose level during the following cycle, the 
principal investigator may allow re-escalation to the prior dosing level. 
 
5.3.2 Drug Accountability: 
The study drugs of ibrutinib and lenalidomide must be handled in strict 
accordance with the protocol and the container label, and must be stored at the 
study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drugs, and study drug returned by the 
subject, must be available for verification. The return of unused study drug 
(ibrutinib or lenalidomide), or used returned study drug for destruction, will be 
documented. Ibrutinib and lenalidomide should be dispensed under the 
supervision of the investigator or a qualified member of the study-site personnel, 
or by a hospital/clinic pharmacist. Study drugs will be supplied only to subjects 
participating in the study. Returned study drugs must not be dispensed again, 
even to the same subject. Study drugs may not be relabeled or reassigned for 
use by other subjects.  
 
5.4 Prophylactic medications: 
5.4.1 Prophylaxis for Tumor Lysis Syndrome (TLS) 
All patients with bulky lymphadenopathy must receive prophylaxis for TLS prior to 
the initiation of study treatment.  This includes appropriate hydration consisting of 
a fluid intake of approximately 2 L/day starting 1 day prior to the first dose of 


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rituximab, lenalidomide, and ibrutinib and administration of allopurinol (300 
mg/day orally) or a suitable alternative treatment starting prior to Cycle 1, Day 1 
for the first cycle of therapy. Allopurinol can be continued longer than the first 
cycle if the treating physician wishes, however this will not be mandated. All 
patients should then be carefully monitored during the initial weeks of treatment.   
 
5.4.2 Venous Thrombosis: 
Based upon prior trial data, it will be required for all patients to receive either 
aspirin (81 – 325 mg PO daily) or another prophylaxis agent while on 
lenalidomide. Exceptions will be made if a patient has a previous history of 
significant bleeding or other condition which makes anticoagulation unsafe in the 
determination of the principal investigator, as ibrutinib may increase the risk of 
hemorrhage in patients receiving antiplatelet or anticoagulant therapies. For 
further instructions for invasive procedures, see Section 5.7.6.  
 
The choice of VTE prophylaxis agent relies upon the investigator’s discretion and 
should be tailored to the subject’s individual risk/benefit profile by taking into 
account the individual thrombotic risk, bleeding risk, and the quality of 
compliance with the VTE prophylaxis. 
 
VTE prophylaxis may need to be held during therapy due the potential of 
thrombocytopenia associated with either DA-EPOCH, CHOP, lenalidomide, or 
ibrutinib. 
For 
guidelines 
regarding 
VTE 
management 
related 
to 
thrombocytopenia, refer to Table 11. 
 
Table 11 
NCI CTCAE Toxicity Grade v 4.0 
Action Required 
Thrombocytopenia* 
*UDGH

(platelet 
count 
<50,000/mm³ 
 
 Withhold anticoagulation 
 Monitor CBC at least every seven 
days 
 If thrombocytopenia resolves to < 
Grade 
3 
(>50,000/mm3), 
restart 
anticoagulation 
unless 
other 
contraindication 
 
5.4.3 Administration of Granulocyte Colony-Stimulating Factor 
Neutropenia prophylaxis with granulocyte-colony stimulating factor (G-CSF) is 
required during all cycles which include R-DA-EPOCH and R-CHOP. However, 
the selection of a particular drug, for example filgrastim, pegfilgrastim, or other is 
per treating physician discretion.. 


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5.4.4 Infections Prophylaxis 
Pneumocystis jirovecii pneumonia prophylaxis is required. However, the drug, 
dose and schedule selection are per treating physician discretion.  
Additional antibiotic, antiviral, and antifungal prophylaxis is not required. 
However, treating physicians will be allowed to administer antibiotic, antiviral, and 
antifungal prophylactic medications if they desire. The use of live viral vaccines is 
contraindicated. 
 
5.4.5 CNS Lymphoma Prophylaxis 
Subjects at risk for CNS involvement may receive CNS lymphoma prophylaxis 
treatment. At risk for CNS involvement is defined as high LDH with ≥2 extranodal 
disease sites, testicular, vertebral body, bone marrow, paranasal sinus, renal, or 
adrenal involvement, or at the discretion of the treating physician. The following 
may be considered by the investigator: 4 – 8 doses of intrathecal methotrexate 
and/or cytarabine administered during the systemic treatment. CNS prophylaxis 
with IV drugs is not permitted. For further instructions for invasive procedures, 
see Section 5.7.6.  
 
5.4.6 Hepatitis B Prophylaxis 
To prevent Hepatitis B reactivation, patients who are hepatitis B Core Ab+ but 
hepatitis B sAg - negative may have low levels of hepatitis B viremia and should 
undergo a blood PCR test for hepatitis B viral load. All patients at risk of 
reactivation will have a PCR analysis of blood for viral loads performed 
pretreatment and during treatment. If the PCR test can detect a quantifiable 
hepatitis B viral load, patients should have this value repeated every therapeutic 
cycle. Additionally, these patients will receive appropriate treatment for hepatitis 
B reactivation prophylaxis. If the PCR analysis is unable to detect a quantifiable 
hepatitis B viral load, no further hepatitis B testing will be required. 
 
5.4.7 Bowel Prophylaxis  
In addition, it is suggested that all patients be treated with a bowel regimen to 
avoid constipation. The goal of this regimen to ensure at least one soft bowel 
motion every 24 hours while on study. The treating physician should consider 
sodium docusate 100mg capsule; take one to two capsules once a day Days 1-7 
of each cycle. If needed can double the frequency to two capsules every 12 
hours. If needed add oral lactulose 15-30 ml prn/ every 6 hours. 


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5.5 Radiation Therapy: 
The treating physician may prospectively, prior to start of initial therapy, choose 
to give local radiotherapy after study chemotherapy has completed for the 
treatment of a particular site of bulky disease or a large mass. In the case of 
consolidation treatment, bulky disease is defined as ≥ 7.0 cm. However, the 
decision to treat and the location to be treated must be determined during the 
Screening Period. In this case, the consolidation radiotherapy will not count as a 
treatment event for the progression endpoints, unless there is evidence of active 
disease at the site and radiation is indicated for treating active disease. 
 
If the investigator should decide at anytime after Cycle 1 Day 1 to give 
consolidation treatment, or to switch treatment to a different lesion, receipt of 
consolidation treatment will count as a progression endpoint and data will be 
censored. 
 
5.6 Treatment for Subjects who Develop CNS Disease While on Study: 
Patients with known CNS lymphoma are excluded from this study. For those 
subjects who develop CNS disease after they are enrolled in this study, CNS 
disease will be treated according to standard institutional guidelines and will be 
removed from the study. 
5.7 Dose modifications of chemotherapy drugs for adverse events: 
5.7.1 Ileus and constipation: 
Symptomatic ileus/constipation may occur as a result of neurotoxicity from 
vincristine, however it is usually unnecessary to stop the vincristine altogether. 
Every 
effort 
should 
be 
made 
to 
not 
unnecessarily 
reduce 
doses. 
Ileus/constipation is usually worse during the first cycle, and thus prophylactic 
bowel care is important. If vincristine dose is reduced for this toxicity, it can often 
be returned to full dose on subsequent cycles without recurrence of severe 
ileus/constipation. If ileus or constipation requires hospitalization, reduce 
vincristine 25% on the subsequent cycle. If symptoms resolve after vincristine 
reduction, increase dose to previous level on subsequent cycles. 
Suggested Bowel Regimen – goal of at least one soft bowel motion every 24 
hours while on study  
Adults: Sodium Docusate 100mg capsule; take one to two capsules once a day 
Days 1-7 of each cycle. If needed can double the frequency to two capsules 
every 12 hours. If needed add oral lactulose 15-30 ml prn/ every 6 hours.  
5.7.2 Sensory neuropathy 
 


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Table 12 
Sensory Neuropathy Dosing Adjustments 
Grade 
% Dose of Vincristine 
1 
100% 
2 
100% 
3 
50% 
4 
0% 
 
5.7.3 Motor neuropathy 
Table 13 
Motor Neuropathy Dosing Adjustments 
Grade 
% Dose of Vincristine 
1 
100% 
2 
75% 
3 
25% 
4 
0% 
 
If neuropathy resolves to a lower grade, doses for that lower grade may be 
reinstituted at investigator discretion. If the grade of neuropathy increases after 
being re-escalated, doses must be reduced for the appropriate toxicity grade and 
may not be re-escalated, even if neuropathy resolves again to a lower grade. 
 
5.7.4 Hepatic and Renal Dysfunction 
No dose modifications of chemotherapy are required for hepatic dysfunction 
thought related to DLBCL manifestations.  
 
Etoposide should be reduced 25% on cycle one for creatinine clearance < 50 
cc/min. If the creatinine clearance remains low on subsequent cycles, etoposide 
should remain at the reduced level as in the previous cycle. Etoposide should be 
returned to full dose (or escalated if indicated) once creatinine clearance > 50 
cc/min. No other dose modifications for abnormal renal indices will be made for 
enrolled patients. 
 
Monitor patients with liver dysfunction 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).  
 


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5.7.5 Dose Modification for Obese Patients: 
All dosing is based on the patient’s BSA as calculated from actual weight. There 
is no documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight.  
 
5.7.6 Dose Modification for patients who require invasive procedures: 
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, lumbar 
puncture, 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. 
 
5.7.7 Dose modifications for use with CYP3A inhibitors: 
As stated in the exclusion criteria, patients who require use of a strong CYP3A 
inhibitor will not be eligible for enrollment on this clinical trial. If a patient requires 
a moderate CYP3A inhibitor (Appendix E: e.g., fluconazole, darunavir, 
erythromycin, diltiazem, atazanavir, 
aprepitant, 
amprenavir, fosamprevir, 
crizotinib, imatinib, verapamil, and ciprofloxacin), the dose of ibrutinib should be 
reduced to 140mg daily. If a patient requires use of a strong CYP3A inducer 
(e.g., carbamazepine, rifampin, phenytoin, or St. John’s Wort), ibrutinib should be 
held temporarily while the patient is on the strong CYP3A inducer. Ideally, the 
treating physician could avoid usage of moderate CYP3A inhibitors or CYP3A 
inducers and keep ibrutinib at full dosing. 
 
5.8 Management of rash: 
 
For Grade ≥3 rash, hold ibrutinib and lenalidomide until rash improves to Grade 
≤1, then resume at original dose if duration of grade 2 or greater rash was <10 
days with corticosteroids (for the first episode), or lower dose as clinically 


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indicated as detailed in Tables 9 and 10. Treatment with topical hydrocortisone is 
preferred as initial therapy along with antihistamines PO daily is recommended. If 
worsening or not improving, 40 mg prednisone PO or equivalent daily for 10 days 
(with or without taper) may be utilized. Allopurinol should be discontinued if rash 
is thought to be at least possibly related to allopurinol. If the rash fails to resolve 
to < grade 2 within 10 days of corticosteroid therapy, then resume at the next 
lower dosing level in Tables 9 and 10. 
 
 
 
 


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6 
STUDY EVALUATIONS 
6.1 Screening Evaluations 
• A history and physical examination, including determination of height, 
weight and performance status should be performed within 28 days prior 
to enrollment 
• The following laboratory studies should be performed within 28 days prior 
to enrollment: 
o CBC with differential, Serum chemistries – sodium (Na), potassium 
(K), chloride (Cl), glucose, bicarbonate (CO2), blood urea nitrogen 
(BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, 
total 
protein, 
albumin, 
alkaline 
phosphatase, 
aspartate 
transaminase (AST), alanine transaminase (ALT), total bilirubin, 
fractionated bilirubin, uric acid, lactate dehydrogenase (LDH), β-2 
microglobulin, and urinalysis.  
• Females of reproductive potential will undergo serum pregnancy testing 
with β-HCG within 28 days prior to enrollment.  
• Quantitative immunoglobulins (IgG, IgA, and IgM) within 28 days prior to 
enrollment. 
• Baseline blood test for occult fungal infection (+/- 3 days). The test, either 
Galactomannan or Fungitell, will be determined case by case based upon 
availability. 
• HIV, Hepatitis C viral antibody, Hepatitis B surface antigen, Hepatitis B 
core antibody within 28 days prior to enrollment. Hepatitis B DNA PCR will 
be obtained as needed, detailed in Section 5.4.6. 
• The following staging studies should be performed within 28 days prior to 
enrollment:  
o CT scans of neck, chest, abdomen, and pelvis;  
o PET/CT Scan 
o Chest X-ray – PA and lateral; 
o Magnetic Resonance Imaging of head will be required for the next 
15 patients enrolled as of 7/13/16, and at the investigator’s 
discretion beyond. Imaging of the spine may be obtained if clinically 
indicated 
o Unilateral Bone marrow biopsy and aspirate 
o An electrocardiogram  
o A transthoracic echocardiogram or nuclear medicine heart scan to 
determine the ejection fraction  
o Lumbar Puncture for flow cytometry, glucose, protein, cell count 
and cytology only if clinically indicated at the discretion of the 
treating physician. 


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6.2 Pretreatment Evaluation 
 A lymphoma-specific history and physical examination should be 
performed within 3 working/business days prior to the start of therapy 
  weight and performance status 
 The following laboratory studies should be performed within 3 
working/business days prior to the start of therapy: 
o CBC with differential, Serum chemistries – sodium (Na), potassium 
(K), chloride (Cl), glucose, bicarbonate (CO2), blood urea nitrogen 
(BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, 
total 
protein, 
albumin, 
alkaline 
phosphatase, 
aspartate 
transaminase (AST), alanine transaminase (ALT), total bilirubin, 
fractionated bilirubin, uric acid, lactate dehydrogenase (LDH), and 
urine analysis. Serum β-HCG in women of child-bearing potential. 
 For correlative studies, 70 ml of blood sample [one purple top tube (10 ml) 
and 6 heparin containing green top tubes (60 ml)] will be collected within 3 
working/business days prior to the first dose of “Smart Start” therapy. 
These samples will be transported within 6 hours of collection to Dr. 
Neelapu’s laboratory for processing at the South Campus Research 
Building I, Room 2.2206, at M. D. Anderson Cancer Center (MDACC). 
Blood from purple top and green top tubes will be processed for isolation 
of plasma and peripheral blood mononuclear cells (PBMC), respectively 
using standard laboratory protocols. 
  In consenting patients, (optional) core needle biopsies and fine needle 
aspirates (FNA) will be obtained by Interventional Radiology (IR) from 
accessible lymph node under ultrasound or CT-scan guidance within 28 
days prior to the first dose of “Smart Start” therapy, and will be processed 
and stored under our IRB-approved Lymphoma Tissue Bank protocol 
2005-0656. All patients who enroll on this trial will be consented for 2005-
0656, and will have their samples protected under our standard 
procedures outlined in 2005-0656. Whenever feasible, up to 3 cores will 
be obtained using 18 (preferred) or 20 gauge needles as deemed 
appropriate by an Interventional Radiologist. The three cores will be 
processed as follows: i) the first core biopsy specimen will be preserved in 
RNAlater for microarray studies; ii) second core will be formalin-fixed and 
paraffin-embedded for IHC; and iii) third core will be viably frozen for DNA, 
RNA, or protein isolation and possible flow cytometry if FNA is not usable. 
FNA sample will be analyzed by flow cytometry. These samples will be 
transported in RNAlater (core # i)/formalin (core # ii)/normal saline (cores 
# iii and FNA) within 6 hours of collection on ice to Dr. Davis’/Neelapu’s 
laboratory for processing at the South Campus Research Building I, Room 


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4.3206, at MDACC. If fresh biopsies are not feasible at baseline, archival 
tissue from prior tumor biopsy may be used for biomarker studies. If there 
is no lymph node safely accessible for FNA, as deemed by the FNA clinic 
or IR, this biopsy will not be obtained and the patient will proceed with 
therapy regardless of this biopsy. 
6.3 Evaluation during therapy 
 A lymphoma-specific history and physical examination should be 
performed within 3 working/business days prior to the start of each 
therapeutic cycle  
  weight and performance status assessment within 3 working/business 
days prior to the start of each therapeutic cycle 
 The following laboratory studies should be performed within 3 
working/business days prior to the start of each therapeutic cycle: 
o CBC with differential, Serum chemistries – sodium (Na), potassium 
(K), chloride (Cl), glucose, bicarbonate (CO2), blood urea nitrogen 
(BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, 
total 
protein, 
albumin, 
alkaline 
phosphatase, 
aspartate 
transaminase (AST), alanine transaminase (ALT), total bilirubin, 
fractionated bilirubin, uric acid, lactate dehydrogenase (LDH). 
Serum β-HCG in women of child-bearing potential. 
 Blood test for occult fungal infection (+/- 3 days). The test that was 
obtained in 6.1 for a given patient, either Galactomannan or Fungitell, will 
be obtained prior to start of cycle 2 and cycle 3, which may proceed will 
the test results are pending. 
 The following staging studies should be performed at the conclusion of 
cycle 2 (or earlier if the treating physician has a strong clinical suspicion of 
disease progression prior to the end of “Smart Start” therapy):  
o PET/CT scan 
 The following staging studies should be performed at the conclusion of 
cycle 4 (assuming 2 cycles of “Smart Start”, 2 cycles of rituximab, 
lenalidomide, ibrutinib, with chemotherapy) if PET/CT scan after cycle 2 
had less than CR:  
o PET/CT Scan 
 If the scan at the end of “Smart Start” occurred prior to the end of cycle 2, 
and as a result of progressive disease the patient received less than 2 
cycles of “Smart Start” therapy, the scan detailed above to occur after 
cycle 4 would occur after conclusion of 2 cycles of rituximab, lenalidomide, 
ibrutinib, with chemotherapy. 
 The following laboratory studies should be performed twice weekly after 
the completion of therapy during each therapeutic cycle: 


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o CBC with differential. Additional laboratory studies can be obtained 
at the discretion of the treating physician. 
 For correlative studies, 70 ml of blood sample [one purple top tube (10 ml) 
and 6 heparin containing green top tubes (60 ml)] will be collected on day 
8 (+/- 72 hours) of the first cycle of “Smart Start” therapy, and pre-therapy 
on day 1 of the second cycle of “Smart Start” therapy. The same samples 
will collected pre-therapy on day 1 of the third cycle of chemotherapy 
(cycle 5 of therapy total if receiving 2 cycles of “Smart Start”. A single 
purple top tube (10ml) will be collected pre-therapy on day 1 of each 
therapeutic cycle. These samples will be transported within 6 hours of 
collection to Dr. Neelapu’s laboratory for processing at the South Campus 
Research Building I, Room 2.2206, at M. D. Anderson Cancer Center 
(MDACC). Blood from purple top and green top tubes will be processed 
for isolation of plasma and peripheral blood mononuclear cells (PBMC), 
respectively using standard laboratory protocols. 
 In consenting patients, (optional) core needle biopsies and fine needle 
aspirates (FNA) will be obtained by IR from an accessible lymph node 
which is deemed to be low-risk for complication by MD Anderson IR staff, 
using ultrasound or CT-scan guidance 10 days (+/- 96 hours) after the first 
dose of “Smart Start” therapy, following the guidelines for holding ibrutinib 
detailed in Section 5.7.6.  Whenever feasible, up to 3 cores will be 
obtained using 18 (preferred) or 20 gauge needles as deemed appropriate 
by an Interventional Radiologist. The three cores will be processed as 
follows: i) the first core biopsy specimen will be preserved in RNAlater for 
microarray studies; ii) second core will be formalin-fixed and paraffin-
embedded for IHC; and iii) third core will be snap frozen for DNA, RNA, or 
protein isolation. FNA sample will be analyzed by flow cytometry. These 
samples will be transported in RNAlater (core # i)/formalin (core # 
ii)/normal saline (cores # iii and FNA) within 6 hours of collection on ice to 
Dr. Davis’/Neelapu’s laboratory for processing at the South Campus 
Research Building I, Room 4.3206, at MDACC.  
6.4  Evaluation after conclusion of therapy 
 A history and physical examination should be performed within 3-4 weeks 
after the start of the final therapeutic cycle 
 The following laboratory studies should be performed within 3-4 weeks 
after the start of the final therapeutic cycle: 
o CBC with differential, Serum chemistries – sodium (Na), potassium 
(K), chloride (Cl), glucose, bicarbonate (CO2), blood urea nitrogen 
(BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, 


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total 
protein, 
albumin, 
alkaline 
phosphatase, 
aspartate 
transaminase (AST), alanine transaminase (ALT), total bilirubin, 
fractionated bilirubin, uric acid, lactate dehydrogenase (LDH). 
 The following staging studies should be performed 3 weeks (+/- 1 week) 
after the start of the final therapeutic cycle (scan at end of therapy, EOT) :  
o PET/CT scan 
o Unilateral Bone marrow biopsy and aspirate (only if positive at the 
pre-treatment bone marrow obtain in 6.1.6 was positive for 
lymphoma) 
o Core needle biopsy or fine needle aspiration of lymph nodes with 
suspicion of residual lymphoma. 
o For correlative studies, 70 ml of blood sample [one purple top tube 
(10 ml) and 6 heparin containing green top tubes (60 ml)] will be 
collected. The same samples will collected pre-therapy on day 1 of 
the third cycle of chemotherapy (cycle 5 of therapy total if receiving 
2 cycles of “Smart Start”. These samples will be transported within 
6 hours of collection to Dr. Neelapu’s laboratory for processing at 
the South Campus Research Building I, Room 2.2206, at M. D. 
Anderson Cancer Center (MDACC). Blood from purple top and 
green top tubes will be processed for isolation of plasma and 
peripheral blood mononuclear cells (PBMC), respectively using 
standard laboratory protocols. 
6.5 Post-Treatment Follow Up 
 A history and physical examination should be performed every 3 months 
(+/- 4 weeks) during the first year after the EOT scan 
 The following laboratory studies should be performed every 3 months (+/- 
4 weeks) during the first year after the EOT scan: 
o CBC with differential, Serum chemistries – sodium (Na), potassium 
(K), chloride (Cl), glucose, bicarbonate (CO2), blood urea nitrogen 
(BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, 
total 
protein, 
albumin, 
alkaline 
phosphatase, 
aspartate 
transaminase (AST), alanine transaminase (ALT), total bilirubin,  
uric acid, lactate dehydrogenase (LDH). 
o For correlative studies, 10 ml of blood sample [one purple top tube}. 
This sample will be transported within 6 hours of collection to Dr. 
Neelapu’s laboratory for processing at the South Campus Research 
Building I, Room 2.2206, at M. D. Anderson Cancer Center 
(MDACC). Blood from purple top tube will be processed for 
isolation of plasma and peripheral blood mononuclear cells 
(PBMC), respectively using standard laboratory protocols. 


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 The following staging studies should be performed every 3 months (+/- 4 
weeks) during the first year after the EOT scan:  
o PET/CT Scan or CT Scan with IV/oral contrast (CT is preferred if 
EOT PET/CT showed no FDG avid or suspicious lesions) 
 A history and physical examination should be performed every 4 months 
(+/- 8 weeks) during the second year after the EOT scan 
 The following laboratory studies should be performed every 4 months (+/- 
8 weeks) during the second year after the EOT scan: 
o CBC with differential, Serum chemistries – sodium (Na), potassium 
(K), chloride (Cl), glucose, bicarbonate (CO2), blood urea nitrogen 
(BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, 
total 
protein, 
albumin, 
alkaline 
phosphatase, 
aspartate 
transaminase (AST), alanine transaminase (ALT), total bilirubin, 
uric acid, lactate dehydrogenase (LDH). 
o For correlative studies, 10 ml of blood sample [one purple top tube] 
will be collected. This sample will be transported within 6 hours of 
collection to Dr. Neelapu’s laboratory for processing at the South 
Campus Research Building I, Room 2.2206, at M. D. Anderson 
Cancer Center (MDACC). Blood from purple top tube will be 
processed for isolation of plasma and peripheral blood 
mononuclear cells (PBMC), respectively using standard laboratory 
protocols.  
 
 The following staging studies should be performed every 4 months (+/- 8 
weeks) during the second year after the EOT scan:  
o PET/CT Scan or CT Scan with IV/oral contrast (CT is preferred if 
EOT PET/CT showed no FDG avid or suspicious lesions) 
 For active surveillance on this clinical protocol, patients will be followed for 
two years from completion of therapy. Beyond the second year after EOT 
scan, restaging imaging, laboratory studies, and history and physical 
examination schedule will not be controlled by the protocol and will be 
determined by the treating physician. When available, information from the 
medical record related to clinical outcomes beyond two years may be 
recorded by the research team, but will not be utilized for initial outcomes 
analysis. 
 
. 
 
 
 
 


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7 
CRITERIA FOR RESPONSE 
7.1 Response Criteria: 
This trial will use the Lugano criteria(71) when evaluating primary end 
points.  Responses must last for at least 4 weeks off treatment. 
For detailed explanations, please refer to J Clin Oncol, 2014. 
http://jco.ascopubs.org/content/early/2014/08/11/JCO.2013.54.8800.abstr
act. 
Table 14 Lugano Staging Criteria 
Response  
PET-CT Based Response 
CT-Based Responses 
CR 
Complete metabolic response 
Score 1, 2, or 3 with or without a residual mass on 
5 point scale 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake or 
with activation within spleen or marrow (eg, with 
chemotherapy 
or 
myeloid 
colony-stimulating 
factors), uptake may be greater than normal 
mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater 
than surrounding normal tissue even if the tissue 
has high physiologic uptake 
Complete Radiographic Response 
Target Nodes/nodal masses must regress to <= 1.5cm in 
longest dimension 
No extralymphatic sites of disease 
 
PR 
Partial Metabolic Response 
Score 4 or 5 with reduced uptake compared with 
baseline and residual masses of any size 
At interim, these findings suggest responding 
disease 
As end of treatment, these findings indicate 
residual disease 
Partial Remission (all of the following): 
>=50% decrease in sum of the product of diameters of 
up to 6 target measureable nodes and extranodal sites 
When a lesion is too small to measure on CT, assign 5 
mm x 5mm as default value 
When no longer visible on CT, assign 0 x 0 mm 
For a node 5 mm x 5mm, but smaller than normal, use 
actual measurement 
 
SD 
No metabolic response 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of 
treatment 
Stable disease  
< 50% decrease in sum of the product of diameters of up 
to 6 target measureable nodes and extranodal sites, no 
criteria for disease progression are met 
 
PD 
Progressive metabolic disease 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
New FDG-avid foci consistent with lymphoma at 
interim or 
end-of-treatment assessment 
Progressive disease requires at least one of the 
following: 
An individual node/lesion must be abnormal with: 
LDi _ 1.5 cm and 
Increase by _ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions _ 2 cm 
1.0 cm for lesions _ 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by _ 50% of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen must increase to 
_ 16 cm). If no prior splenomegaly, must increase by at 
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8 
SUBJECT COMPLETION/WITHDRAWAL 
8.1 Completion 
A subject will be considered to have completed the study if he or she has died 
before the end of the study, has not been lost to follow up, or has not withdrawn 
consent before the end of study. 
8.2 Discontinuation of Study Treatment 
Subjects who discontinue any component of therapy without disease progression 
will continue study drugs (lenalidomide and/or ibrutinib) until therapy is 
completed, disease progression, or unacceptable toxicity, whichever occurs first. 
If study drugs are discontinued for persistent toxicities as defined in Section  
5.3.1, any remaining study treatment (i.e., rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone [or equivalent]) may continue.  
Investigators are encouraged to keep subject experiencing clinical benefit (ie, 
PR, CR, or stable disease) in the study unless significant toxicity puts the subject 
at risk or routine noncompliance puts the study outcomes at risk. If a subject's 
study treatment must be discontinued, this will result in automatic withdrawal of 
the subject from the study. 
 
A subject's study treatment should be discontinued if: 
-The subject experiences overt disease progression or relapse 
-Unacceptable toxicity 
-The subject becomes pregnant 
-The subject refuses further treatment 
-A serious protocol violation has occurred, as determined by the principal 
investigator 
-The investigator believes that for safety reasons (eg, adverse event) it is in the 
best interest of the subject to discontinue study treatment 
 
If a subject discontinues study treatment before the onset of disease progression, 
End-of-Treatment and post-treatment assessments should be obtained and 
follow up of scheduled assessments should be continued. Refer to Section 6.4 
for instructions regarding post-treatment efficacy assessments. The reason(s) a 
subject discontinues treatment will be recorded. 
 
8.3 Withdrawal From the Study 
A subject will be withdrawn from the study for any of the following reasons: 
-Withdrawal of consent 


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-The principal investigator discontinues the study 
-Lost to follow up 
If a subject is lost to follow up, every reasonable effort must be made by the 
study site personnel to contact the subject and determine the reason for 
discontinuation/withdrawal. The measures taken to follow up must be 
documented. When a subject withdraws before completing the study, the reason 
for withdrawal is to be documented. Subjects who withdraw may be replaced at 
the discretion of the principal investigator. 
 
 


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9 
Statistical Considerations  
9.1 Study Design 
This will be a single-center, Phase II clinical trial in patients with newly diagnosed 
diffuse large B-cell lymphoma. The tolerability and efficacy of administrating 
rituximab with lenalidomide and ibrutinib alone (“Smart Start”) and with 
chemotherapy (RLI-EPOCH or RLI-CHOP) will be evaluated. The attribution of 
the backbone chemotherapy R-CHOP of DA-EPOCH will not be randomized. 
The treating physician will have discretion to choose either R-CHOP of R-DA-
EPOCH as backbone chemotherapy. DA-EPOCH dosing will be adjusted based 
upon published criteria in DA-EPOCH containing cycles 2 – 6, and will be capped 
at dose level +2).  
9.2 Phase 2 clinical trial dosing and sample size 
Based upon data from the PCYC-1124-CA, dosing has been selected for testing 
in up to 60 patients with newly diagnosed ABC DLBCL. It is anticipated that we 
will accrue approximately a 1:1 ratio of R-CHOP and R-DA-EPOCH treated 
patients, but the trial will not restrict the allocation. Patients will start with RLI 
alone prior to the use of chemotherapy (“Smart Start”) for ≤2 cycles, followed 
by 6 cycles of RLI with R-CHOP or dose adjusted (DA) EPOCH. The primary 
objective is to determine the overall response rate (ORR) defined as either 
complete response (CR) or partial response (PR) of RLI alone up to 2 cycles, 
and CR rate observed at the end of 6 cycles of RLI with chemotherapy. 
Secondary objectives include determination of the ORR at the end of the 
treatment, survival outcomes (progression free and overall survival at 1 year), 
and safety of RLI with R-CHOP or DA-EPOCH.  
In this trial, we are going to both monitor the standard futility and toxicity and 
evaluate the feasibility of introducing the smart start portion within the trial. Two 
independent monitoring rules will be proposed for each of them. Note that the 
overall trial will not be stopped due to lack of efficacy in the smart start portion.     
 
A Bayesian method by Thall et al (1995) will be used for futility and toxicity 
monitoring. The relevant toxicities for dose adjusting ibrutinib and lenalidomide 
as defined in section 5.3.1 will be referred to as “Tox”. The trial will be stopped 
early if: 
  
                                    Pr (CR rate < 0.70 |data) > 0.90  
or 
                                    Pr(Tox rate > 0.30 | data)  > 0.90 
 
That is, the trial will be stopped early if there is more than a 90% probability that 


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the CR rate at the end of all therapy including 6 cycles of RLI-chemotherapy is 
lower than 70% or if there is more than a 90% probability that the Tox rate is 
higher than 30%. We assume that CR and Tox follow a prior distribution of beta 
(0.7, 0.3) and beta (0.3, 0.7), respectively. 
 
The above futility and toxicity monitoring rules will be implemented by a cohort 
size of 10, starting from the 10th patient enrolled. The corresponding stopping 
boundaries are listed in the following Table 15.1 and Table 15.2. For example, if 
there are less than 5 patients to achieve CR in the first 10 patients who complete 
RLI-chemotherapy, stop the trial early due to futility. The trial also needs to be 
stopped early due to the agent is too toxic if there are 6 or more patients to 
experience Tox, as defined in Section 5.3.1, among the first 10 patients. If a 
toxicity threshold (Table 13.1) is achieved prior to completing a 10 patient-sized 
cohort, the trial would be stopped prior to completing the 10 patient-sized cohort. 
In addition, an additional safety rule will be implemented that if >3 patients per 10 
patient cohort require a dose reduction of R-CHOP or R-EPOCH, all future 
patients would be treated starting at the next lowest level of ibrutinib and 
lenalidomide as defined in Table 8.  
 
If >3 patients require a dose reduction below level 0 of chemotherapy, a new 
safety criterion would be established. If ≥2 patients in the next 10 patients 
required a dose reduction of chemotherapy below level 0 despite the reduction in 
ibrutinib and lenalidomide, the trial would be placed on hold for new patient 
accrual and would be examined for the etiology of the unexpected hematologic 
toxicity. The trial may be re-opened only after the principal investigator modified 
the protocol to ensure safety of future patients in coordination with and with 
approval from the M.D. Anderson Cancer Center IND office and FDA monitors. 
 
 
Table 15.1: The stopping boundaries of Phase II trial 
Number of patients 
evaluated 
Recommend stopping if 
≤ Complete Responses 
observed 
Recommend stopping 
if ≥ Toxicities observed 
10 
0-4 
6-10 
20 
0-11 
9-20 
30 
0-17 
13-30 
40 
0-24 
16-40 
50 
0-30 
20-50 
60 
Always stop with this many patients 
 


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Table 15.2: The operating characteristics are summarized in the following table 
(based on simulations from 10,000 trials). 
True CR Rate 
True Toxicity 
Rate 
Prob (stop the trial 
early) 
Average number of 
patients treated 
0.55 
0.10 
0.874 
27.1 
 
0.30 
0.900 
25.2 
 
0.50 
0.996 
16.1 
0.70 
0.10 
0.205 
52.7 
 
0.30 
0.367 
46.7 
 
0.50 
0.972 
19.9 
0.85 
0.10 
0.003 
59.9 
 
0.30 
0.207 
52.6 
 
0.50 
0.965 
20.9 
 
In addition, we use an independent Bayesian futility monitoring for the innovative 
smart start feature in our design. The smart start portion will be ceased early if 
 
Pr (OR rate of RLI alone < 0.50 |data) > 0.90 
 
i.e., there is more than a 90% posterior probability that the ORR of up to 2 cycles 
of RLI alone is lower than 50%, and thus treat all remaining patients with RLI plus 
chemotherapy in cycle 1. The corresponding stopping boundaries are listed in 
the following Table 15.3 and Table 15.4. The monitoring rule will be implemented 
by a cohort size of 10, with a prior distribution of beta (0.5, 0.5) for OR.                            
 
Table 15.3: The stopping boundaries of Smart Start. 
Number of patients 
evaluated 
Recommend stopping if ≤ Overall 
Responses observed in Smart Start 
10 
0-2 
20 
0-7 
30 
0-11 
40 
0-15 
50 
0-20 
60 
Always stop with this many patients 
 
Table 15.4: The operating characteristics are summarized in the following table 
(based on simulations from 10,000 trials). 


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True OR Rate 
of Smart Start 
Prob(stop the trial 
early) 
Average number of 
patients treated 
0.30 
0.969 
20.5 
0.50 
0.219 
52.0 
0.70 
0.003 
59.9 
The above stopping boundaries and operating characteristics are calculated 
using 
Multc 
Lean 
(v.2.1.0) 
design 
software 
downloaded 
from 
http://biostatistics.mdanderson.org/SoftwareDownload.  
 
A total accrual of 60 patients without early termination will provide 95% 
confidence interval of the CR rate with a maximum width of 0.26. 
A 1:1 repartition of the backbone chemotherapy R-CHOP of DA-EPOCH will be 
targeted, with the goal of having approximately 30 patients treated in both arms. 
As the chemotherapy regimens of R-CHOP and R-DA-EPOCH are considered 
equally effective, we will analyze the groups of R-CHOP and R-EPOCH together 
for the Primary Objective of CR after RLI-chemotherapy, and separately for 
secondary end points, however the trial will not be powered to directly compare 
the groups. 
9.3 Analysis Plan 
Data analysis will be performed using SAS or R, as appropriate. The OR rate of 
smart start, CR rate of RLI+chemotherapy, DLT rate, and OS/PFS rate at the 
landmark time point of 1 year will be summarized by frequency and 95% 
confidence interval. Patients who received at least one dose of the treatment 
drug will be evaluable for toxicity outcomes.  Toxicities will be summarized by 
dose levels, by grade and by their relationship to the treatment. The intent-to-
treat patients will be used for the primary efficacy analysis, patients who lost-to-
follow up in the first 3 cycles will be treated as failures. The distribution of time-to-
event endpoints including OS and PFS will be estimated by Kaplan -Meier 
Estimate.  Comparison of time-to-event endpoints by important subgroups will be 
made using the log-rank test.  Cox proportional hazard regression will be 
employed for multivariate analysis on time-to-event outcomes. 
9.4 Correlative Study endpoints 
The following correlative studies will be performed in Dr. Neelapu, Dr. Davis, or 
an MD Anderson Core laboratory using the blood, serum, and biopsy samples.  
9.4.1 To determine whether rituximab, lenalidomide, and ibrutinib enhances the 
frequency and function of tumor-specific T-cells in the peripheral blood, 
the phenotype and function of T cells will be assessed as follows: 
Phenotypic studies for T cells. PBMC (1 x 105 per tube) will be analyzed by 


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multiparametric flow cytometry on 6-color, 8 parameter FACS Canto (BD 
Pharmingen) after staining with a panel of antibodies in 2 separate tubes. Tube 
1: PBMC will be stained with CD3, CD4, CD8, CD45RO, CD69, and PD-1 to 
determine the percentage of total T cells, CD4+ T cells, CD8+ T cells, 
effector/memory (CD45RO+) T cells within each subset, activation status 
(CD69+) of T cells within each subset, and PD-1 expression within each subset. 
Tube 2: PBMC will be stained with CD3, CD4, CD8, CD45RO, CD62L, CD27, 
CD127 and CCR7 to determine the percentage of effector memory T cells 
(CD45RO+CD27-CCR7-, CD62L-CD127+) and central memory T cells 
(CD45RO+CD27+CCR7+, CD62L+CD127+) within CD4+ and CD8+ T-cell 
subsets. The absolute number of each of these T-cell subsets in the peripheral 
blood of the patients will be calculated using the following formula: (absolute 
number of lymphocytes per µl of blood on the CBC analysis) x (% of T-cell subset 
in lymphocyte gate).  
 
9.4.2 To determine whether rituximab, lenalidomide, and ibrutinib enhances the 
CD4+ and/or CD8+ T-cell infiltration in the tumor, the following studies will 
be performed on the core biopsy samples:  
Immunofluorescence studies. To determine whether administration of rituximab, 
lenalidomide, and ibrutinib enhances the CD4+ and/or CD8+ T cell numbers at the 
tumor site, we will perform flow cytometry as described in 9.5.1 on FNA samples 
from baseline and day 14 after rituximab, lenalidomide, and ibrutinib.  
 


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9.4.3 Statistical considerations for 9.4.1 and 9.4.2. The percentage of various T-
cell subsets will be collected at each of the planned time points. Spaghetti 
plots will be used to show the biomarker measurements change overtime. 
Longitudinal analysis including mixed effects model for time dependent 
outcomes will be performed. The percentage change for the biomarkers 
from 14 days after the first infusion to a follow-up time point will be 
calculated. The correlations among the percentage changes for different 
biomarkers will be assessed by scatter plots and Spearman’s correlation 
coefficient. The association between the percentage change and patient’s 
clinical outcome such as overall response will be evaluated. Wilcoxon rank 
sum test will be used to test the difference in percentage change of 
biomarker between the response group and the non-response group. The 
percentage change will also be dichotomized into two categories (high vs. 
low) based on a cutoff point which will be determined after examination of 
the data.  Fisher’s exact test will be used to assess the associations 
between the dichotomized variables for percentage change and clinical 
response. 
 
9.4.4 To evaluate changes in T-cell subsets by phenotypic studies before and 
after rituximab, lenalidomide, and ibrutinib treatment at the different time 
points, we will perform a two-sided paired t-test (significance level of 0.05) 
for the experiments proposed under 9.5.1 and 9.5.2.  
 


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9.4.5 To evaluate the mutational and gene expression data from RNA-Seq of 
tumor biopsy material, the following analyses will be performed. We will 
effectively have 3 clinically defined patient clinical groups, represented by 
Groups A-C. Group A: Responsive to RLI; Group B: non-responsive to RLI 
but responsive to RLI with chemotherapy; and Group C: Non-responsive 
to RLI or RLI with chemotherapy. The baseline biopsy from all groups will 
be evaluated with RNA sequencing (RNA-Seq)(72), in comparison with 
germline DNA, to determine gene expression, translocations, and 
mutations including those known to correlate with ibrutinib resistance (e.g., 
BTK, PLCγ2, MYD88, CARD11, CD79A/B).(5, 66-68, 73) To attempt 
correlation of GEP data with clinical responses to RLI and RLI-
chemotherapy separately by comparing baseline aggregate expression 
data between response groups A-C, a regression analysis will be 
performed. We will also perform RNA-Seq on the paired FNA biopsies 
from day 14 to compare the baseline and on-therapy data to evaluate for 
therapy-induced GEP changes. It is assumed that the majority of patients 
will be in Group A, but we will attempt to compare aggregate expression 
data from baseline and on therapy across Groups A-C. Data from RNA-
Seq will be processed using published methods, including standard quality 
assessments and R software packages.(72, 74, 75) Gene expression will 
be compared against the continuous variable of tumor regression 
percentage and/or changes in LymphoSIGHT values, and analyzed using 
Gene Set Enrichment Analysis (GSEA)(76) to evaluate for processes in 
the tumor cells and microenvironment which are associated with response 
to R-CHOP, but have an unknown relevance to RLI.(5) RNA-Seq will also 
allow detection and quantification of mutated genes in each sample, either 
present in baseline samples or arising de novo in day 14 samples: these 
will be analyzed for correlation with response, to identify those which may 
help to understand or predict resistance to RLI. Comparison of intra-
patient paired samples will help to overcome inter-patient differences in 
GEP and mutation analyses, as shown in the analysis of our pidilizumab 
trial.(77) We will also perform RNA-Seq on biopsies of residual disease, 
and potentially perform focused deep sequencing of DNA from residual 
tumor, PBMC (germline), and initial biopsy. The RNA-Seq will be carried 
out at Center for Lymphoid Cancer-BC Cancer Agency at Vacouver, BC, 
Canada. 
9.4.6 Analysis of LymphoSIGHT data 
We will utilize a stratified Cox regression model to evaluate the 
association between LymphoSIGHT values and imaging response data.  


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10 REPORT OF ADVERSE EVENTS 
10.1 REPORTING REQUIREMENTS 
All adverse clinical experiences must be recorded and reported, regardless of 
attribution, according to the table “Recommended Adverse Events Recording 
Guidelines”, after they were documented in the treating physician’s clinic note, 
utilizing the NCI CTC v4.0 to determine terminology and grade.  Serious adverse 
events will be captured from the time of the first protocol-specific intervention, 
until 30 days after the last dose of drug, unless the participant withdraws 
consent. For discontinued patients, follow up on serious adverse events will be 
conducted up to 30 days from last treatment by study drug. 
 
10.2 Adverse event classifications 
Adverse Event (AE) – Any untoward or unfavorable medical occurrence in a 
human subject, including any abnormal sign (for example, abnormal physical 
exam or laboratory finding), symptom, or disease, temporally associated with the 
subject’s participation in the research, whether or not considered related to the 
subject’s participation in the research in which a subject is administered a 
medicinal (investigational or non-investigational) product.  An adverse event does 
not necessarily have a causal relationship with the treatment. 
 
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. 
 
Expected AE - Any AE with specificity or severity that is consistent with the 


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current Investigator Brochure (IB) or consistent with the risk information 
described in the Informed Consent Document (ICD) or general investigational 
plan.  
 
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) 
• 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.,  autoinjector button not 
working, needle detaching from syringe 
• Suspected Contamination 


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• Suspected Counterfeit 
 
Serious Adverse Event (SAE) – Any AE associated with the subject’s 
participation in research that:   
• results in death;  
• is life-threatening, (places the subject at immediate risk of death from the 
event as it occurred). An adverse event or suspected adverse reaction is 
considered ‘‘life-threatening’’ if, in the view of Principal Investigator, its 
occurrence places the patient or subject at immediate risk of death. It does 
not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death; 
• results 
in 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization; 
• results in persistent or significant disability/incapacity;  
• is a suspected transmission of any infectious agent via a medicinal 
product 
• results in a congenital anomaly/birth defect; or 
• Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
o Important medical events as defined above may also 
be considered serious adverse events. Any important 
medical event can and should be reported as an SAE 
if deemed appropriate by the Principal Investigator or 
the IND Sponsor, the IND Office. 
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. 
 
Unexpected (Unanticipated) AE - Any AE, with specificity or severity that is not 
consistent with the current IB, or the applicable product reference safety 
information, or not consistent with the risk information described in the informed 
consent document or general investigational plan. 
 
http://www.imbruvica.com/hcp/?utm_source=google&utm_medium=cpc&utm_campaign=Imbruvic
a&utm_term=imbruvica&utm_content=ibrutinib-+Exact|mkwid|ssjPpM0Gh_dc|pcrid|39412243694 
 
 
10.3 Adverse event relationship to study drug 
The following classification will be used to determine whether an AE is related to 
the study drug, CT-011:  
• Definite - It is clearly related  
• Probable - It is likely related  
• Possible - It may be related  
• Unlikely - It is doubtfully related  
• Unrelated - It is clearly NOT related  
Definitely related – Events directly or indirectly attributed to study drug, and/or 
study participation. Events occurring with sufficient frequency to suggest that 


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they are not random. The event follows a temporal sequence from the time of 
drug administration and follows a known response pattern to the study drug.  It 
occurs immediately following the study drug administration, improves on stopping 
the drug, or reappears on repeat exposure. 
Probably related – The event follows a reasonable temporal sequence from the 
time of drug administration, and follows a known response pattern to the study 
drug and cannot be reasonably explained by other factors. There is a reasonable 
response to withdrawal of the drug. Rechallenge information is not available or 
advisable. 
Possibly related – The event has a reasonable temporal relationship to the study 
drug administration and follows a known response pattern to the study drug.  
However, a potential alternate etiology may be responsible for the event. The 
effect of drug withdrawal is unclear. Rechallenge information is unclear or 
lacking. 
Unlikely – The adverse event is doubtfully related to the investigational agent. 
Unrelated – Events that would occur regardless of study participation, including 
events that are clearly random occurrences. If the frequency of the event 
suggests a possible connection to the study intervention, then it should be 
considered related. If the event is clearly related to other factors, such as a 
patient's clinical state, therapeutic interventions, or concomitant medications, the 
event would be considered unrelated to therapy. 
10.4 Adverse Events of Special Interest  
Events that Janssen Scientific Affairs is actively monitoring as a result of a 
previously identified signal (even if non-serious), and are listed below: 
• 
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. 
 


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10.5 Pregnancy  
All initial reports of pregnancy must be reported to Janssen Scientific Affairs by 
the study-site personnel within 24 hours of their knowledge of the event. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and 
congenital anomaly) are considered serious adverse events and must be 
reported as a Serious Adverse Event.  
 
Any subject who becomes pregnant during the study must discontinue further 
study treatment. 
 
Because the effect of the study drug on sperm is unknown, pregnancies in 
partners of male subjects included in the study will be reported by the study-site 
personnel within 24 hours of their knowledge of the event. Please reference 
Appendix F and G for additional information. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
 
10.6 Special Reporting Situations  
When a report contains a Janssen product, an identifiable patient, and 
identifiable reporter, the following events represent Special Reporting Situations: 
• Drug exposure during pregnancy (maternal and paternal) 
• 
overdose of a Janssen medicinal product  
• 
pregnancy exposure (maternal and paternal) 
• 
exposure to a Janssen medicinal product from breastfeeding  
• 
suspected abuse/misuse of a medicinal Janssen product 
• 
inadvertent or accidental exposure to a medicinal Janssen medicinal 
product  
• 
any failure of expected pharmacological action (i.e., lack of effect) of a 
Janssen medicinal product 
• 
unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
• 
medication error involving a Janssen product (with or without patient 
exposure to the medicinal Johnson & Johnson product, e.g., name confusion) 
• 
suspected transmission of any infectious agent via a medicinal product. 
 
These safety events may not meet the definition of an adverse event; however, 
from Janssen Scientific Affairs, LLC perspective, they are treated in the same 
manner as adverse events. Special situations should be recorded on the Adverse 
Event page of the CRF. 


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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 
Janssen Scientific Affairs, LLC within 24 hours of becoming aware of the 
event. 
 
10.7 Adverse event reporting 
General guidelines – Toxicity will be scored using CTC AE Version 4.0 for toxicity 
and adverse event reporting. A copy of the CTCAE Version 4.0 can be 
downloaded from the CTEP homepage (http://ctep.info.nih.gov). All appropriate 
treatment areas should have access to a copy of the CTC AE Version 4.0. All 
adverse clinical experiences must be recorded according to the table 
“Recommended Adverse Events Recording Guidelines”, after they were 
documented in the treating physician’s clinic note, utilizing the NCI CTC v 4.0 to 
determine terminology and grade.  Serious adverse events will be captured from 
the time of the first protocol-specific intervention, until 30 days after the last dose 
of drug, unless the participant withdraws consent. For discontinued patients, 
follow up on serious adverse events will be conducted up to 30 days from last 
treatment of study drug. 
 
When an adverse event occurs, the following information and assessments 
should be recorded: 
i) The signs, symptoms, or diagnosis of the event. 
ii) The adverse event severity, using the criteria outlined above. 
iii) The relationship of the event to the study drug as outlined above. 
iv) The description of any action taken regarding study drug disposition. 
v) Any required therapy, medication, treatment, or diagnostic procedure. 
The Principal Investigator (PI) or physician designee is responsible for the 
appropriate medical management of all adverse events. The PI or physician 
designee must evaluate each adverse experience for its seriousness and 
determine attribution to study drug. 
The investigator must appraise all abnormal laboratory results for their clinical 
significance. If any abnormal laboratory result is considered clinically significant, 
the investigator must provide details about the action taken with respect to the 
test drug and about the patient’s outcome. 
 


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10.7.1 Serious adverse events reporting – All events occurring during the 
conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting 
Unanticipated Adverse Events for Drugs and Devices”. Unless stated 
otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to the IND Office, regardless of attribution (within 5 working days 
of knowledge of the event). 
 
All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office.  
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution 
of the event.  
• Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
 
10.8 Maintenance of Safety Information 
Safety information will be maintained in a clinical database/repository in a 
retrievable format. At a minimum, at the end of the treatment phase (=”last 
patient off treatment”) as well as the end of the follow-up phase (=”last patient 
out”) of the Study, the Institution/Principal Investigator shall provide all adverse 
events, both serious and non-serious, in report format. However, in certain 
circumstances more frequent review of the safety data may be necessary, e/g/ to 


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fulfill a regulatory request, and as such the data shall be made available within a 
reasonable timeframe at Janssen Scientific Affairs’ request. 
RedCAP will be used for data entry. REDCap will be the AE database. Concomitant 
medications will be captured in the medical record.  
 
10.9 Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Janssen 
Scientific Affairs will provide to the Principal Investigator, a listing of all SAEs 
reported to Janssen Scientific Affairs.  Principal Investigator will review this listing 
and provide any discrepancies to the Janssen Scientific Affairs. 
 
Upon request, Principal Investigator shall provide Janssen Scientific Affairs with 
a summary list of all SAEs, and AEs of Special Interest and Special Reporting 
Situation reports to date, for reconciliation purposes. 
 
 
1. Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Janssen Medicinal Products to the COMPANY 
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. 
 
1.1. 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) 
 


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The  INVESTIGATOR will transmit all SAEs and special situations 
following exposure to a Janssen product under study in a form provided by 
Janssen Scientific Affairs, LLC in accordance with the section entitled 
Transmission Methods, in English within 24-hours of becoming aware of 
the event(s). 
 
In the event the study is blinded, the INVESTIGATOR will submit an 
unblinded SAE or pregnancy exposure report to Janssen Scientific Affairs, 
LLC. 
 
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 INVESTIGATOR, within 24 hours becoming 
aware, to Janssen Scientific Affairs, LLC using the Janssen Scientific 
Affairs, LLC Serious Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related 
SAE, or special situation is required. 
 
• The 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 in Section 10 within 24 hours of such report or 
correspondence being sent to applicable health authorities. 
 
1.2. Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific 
Affairs, LLC according to the timeframe outlined in the Research Funding 
Agreement section entitled Reporting of Data. 
 
1.3. 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 Scientific Affairs, LLC, and are mandated by regulatory agencies 
worldwide. Janssen Scientific Affairs, LLC has established procedures in 


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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 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 
INVESTIGATOR must report the PQC to Janssen Scientific Affairs, LLC 
according to the serious adverse event reporting timelines.  A sample of 
the suspected product should be maintained for further investigation if 
requested by Janssen Scientific Affairs, LLC. 
 
2. 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  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. 
3. 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). 
 
 


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11 Study Calendar 
 
 
Screening 
Obtain ≤ 
28d of 
cycle 1 
Obtain ≤3 
d pre-cycle 
1 – 2 of 
Smart Start  
Obtain d 
8 cycle 1 
of Smart 
Start  
Obtain 
d10 
cycle 1 
of Smart 
Start 
Obtain at end 
of Smart 
Start (cycle 2 
or sooner if 
progression) 
Obtain <3 
d pre-cycle 
3-8 (RLI-
chemother
apy cycles) 
Obtain at end 
of cycle 4 (after 
2 cycles of RLI-
chemotherapy) 
Obtain twice 
weekly during 
cycle 3-8 (RLI-
chemotherapy 
cycles) 
Obtain within 3 to 4 
weeks after start of 
cycle 8 
(End of Therapy) 
Obtain every 3 months 
during year 1 and every 4 
months during year 2 after 
End of Therapy testing  
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
Lymphoma-
relevant History 
and Physical 
 
X 
X 
 
 
 
X 
 
 
X 
X 
Performance 
status Assessment 
 
X 
X 
 
 
 
X 
 
 
 
 
MRI 
 
X 
 
 
 
 
 
 
 
 
 
Blood  test for 
occult infection 
 
X8,9 
 
 
X8,9 
 
 
 
 
 
 
Vital Signs 
 
 
X 
 
 
 
X 
 
 
 
 
Routine Clinical 
Laboratory 
Assessment1 
 
X 
X 
 
 
 
X 
 
 
X 
X 
Urinalysis 
 
x 
x 
 
 
 
 
 
 
 
 
CBC 
 
 
 
 
 
 
 
 
X 
 
 
Pregnancy testing7 
 
X 
x 
 
 
 
x 
 
 
 
 
Quantitative 
Immunoglobulins 
 
X 
 
 
 
 
 
 
 
 
 
HIV, HCV, HBV 
testing 
 
X 
 
 
 
 
 
 
 
 
 
DLBCL 
Confirmation 
Biopsy 
X2 
X2 
 
 
 
 
 
 
 
 
 
FDG PET/CT 
X2 
X2 
 
 
 
X 
 
X 
 
X 
X5 
CT with IV contrast 
of neck – pelvis3 
X2 
X2 
 
 
 
 
 
 
 
 
X5 
Chest X-ray 
X2 
X2 
 
 
 
 
 
 
 
 
 
ECG 
X2 
X2 
 
 
 
 
 
 
 
 
 
Echo or MUGA 
X2 
X2 
 
 
 
 
 
 
 
 
 
Correlative Blood 
Draw 
 
X 
X6 
X 
 
 
X 
 
 
X 
X4 
Correlative Tumor 
Biopsy 
 
X 
 
 
X 
 
 
 
 
 
 


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Bone Marrow 
Biopsy 
 
X 
 
 
 
 
 
 
 
X4 
 
Lumbar Puncture 
 
X4 
 
 
 
 
 
 
 
 
 
1: Routine clinical laboratory assessment will include: CBC with differential, Serum chemistries – sodium (Na), potassium (K), chloride (Cl), 
glucose, bicarbonate (CO2), blood urea nitrogen (BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, 
alkaline phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, uric acid, and lactate dehydrogenase (LDH), 
fractionated bilirubin, Beta 2 Mircoglobulin (only at 28D prior to treatment), and other testing at the discretion of the treating physician. 
2: These tests are standard of care tests required of all patients treated by the M.D. Anderson Department of Lymphoma for newly diagnosed 
DLBCL. As these tests are not protocol specific, they may be obtained at the discretion of the treating physician during the screening period (i.e., 
they will be allowed for protocol analysis if they are obtain as routine standard of care testing prior to the patient undergoing screening for the 
protocol) as long as completed within 28 days of start of therapy. 
3: CT with IV contrast may be obtained simultaneously with FDG PET/CT scans as per MD Anderson Diagnostic Imaging protocols. 
4: This test is not required by the protocol and will be obtained at the discretion of the treating physician if deemed necessary for initial disease 
workup or follow up of initial results to evaluate for response. 
5. At follow up time points, either FDG PET/CT or CT with IV and oral contrast are acceptable 
6. Per Section 6.3 and 6.4 an additional purple top tube (10ml) will be obtained prior to the start of each additional cycle of therapy and in follow up 
7. Within 24 hours prior to starting lenalidomide, then weekly for the first 28 days. 
8.Baseline blood test for occult fungal infection (+/- 3 days). The test, either Galactomannan or Fungitell, will be determined case by case based 
upon availability. 
9.Blood test for occult fungal infection (+/- 3 days). The test that was obtained in 6.1 for a given patient, either Galactomannan or 
Fungitell, will be obtained prior to start of cycle 2 and cycle 3, which may proceed will the test results are pending. 
N.B.: All time points mentioned in the Study Flowchart are detailed in Section 7, and are included in this table format for easy visualization. The 
time points in section 6 include +/- time windows to account for scheduling issues/delays. Any discrepancies between Section 6 and the Study 
Flowchart will be resolved in favor of Section 6. 
 
 


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12 Appendix A: Chemotherapy Information  
12.1 Rituximab  
Rituximab (Rituxan®) is a humanized monoclonal antibody against CD20 
a receptor in the surface of malignant B-cell lymphocytes. The drug has 
activity against aggressive and non-aggressive NHL of B-cell origin, and 
has been used in combination with chemotherapy. 
12.1.1 Supply 
Rituximab is commercially available. 
Rituximab is provided in pharmaceutical grade glass vials containing 10 
mL (100 mg) or 50 mL (500 mg) at a concentration of 10 mg of protein 
per milliliter. Please refer to the FDA-approved 
package insert for rituximab for product information, extensive 
preparation instructions, and a comprehensive list of adverse events. 
12.1.2 Storage 
Rituximab for clinical use should be stored in a secure refrigerator at 2º to 
8°C. 
12.1.3 Preparation 
Rituximab will be diluted to a final volume of 0.9% Sodium Chloride or 5% 
Dextrose Injection to prepare a standard product with concentration of 2 
mg/ml. Caution should be taken during the 
preparation of the drug, as shaking can cause aggregation and precipi 
 
 
 
tation of the antibody 
12.1.4 Stability 
After dilution, rituximab is stable at 2-8 degrees C (36-46 degrees F) for 
24 hours and at room temperature for an additional 24 hours. 
12.1.5 Administration 
A peripheral or central intravenous line will be established. During 
rituximab infusion, a patient's vital signs (blood pressure, pulse, 
respiration, temperature) should be monitored according to the standard 
of care. Medications readily available for the emergency management of 
anaphylactoid reactions should include: epinephrine (1:1000, 1 mg/mL) 
for 
subcutaneous 
injection 
diphenhydramine 
hydrochloride 
for 
intravenous injection, and resuscitation equipment. 
 


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Prophylaxis against hypersensitivity and infusion-related reactions 
associated with rituximab will include acetaminophen 650 mg and 
diphenhydramine hydrochloride 50-100 mg administered 30 to 60 
minutes prior to starting rituximab. Patients will also receive their first 
dose of prednisone 60 mg/m2 (or a glucocorticoid equivalent dose of an 
alternative steroid) at least 60 minutes before rituximab treatment 
commences. 
Rituximab will be administered as an intravenous infusion at 375 mg/m2 
on day 1 of each cycle of DA-EPOCH, immediately prior to starting 
etoposide + doxorubicin + vincristine administration. 
 
The initial dose rate at the time of the first rituximab infusion should be 
50mg/hour (25 mL/hr) for the first 30 minutes. If no toxicity is seen, the 
dose rate may be escalated gradually in 50 mg/hour (25 mL/h) 
increments at 30 minute intervals) to a maximum of 400 mg/hour 
(maximum rate = 200 mL/h). 
 
Second and Subsequent Doses (select the appropriate administration 
timing based upon the following parameters): 
 
90-minute Administration 
If the first dose of rituximab was well tolerated, subsequent doses may be 
administered over 90 minutes with ~20% of the total dose given in the 
first 30 minutes, and remaining ~80% of the total dose administered over 
the subsequent 60 minutes. The 90-minute infusion scheme is not 
recommended for patients with clinically significant cardiovascular 
disease, previous significant rituximab infusional reactions, or high 
circulating lymphocyte counts (≥5000/mcL). 
 
Standard Administration for Second & Subsequent Infusions 
Patients who tolerate initial treatment without experiencing infusion-
related adverse effects but for whom the 90-minute infusion scheme 
during subsequent treatments is considered inappropriate, may receive 
subsequent rituximab doses at the Standard Rate for Subsequent 
Infusions, which is as follows: 
Begin at an initial rate of 100 mg/hour (50 mL/h) for 30 minutes. If 
administration is well tolerated, the administration rate may be escalated 
gradually in 100-mg/hour (50-mL/h) at 30-minute intervals to a maximum 
rate of 400 mg/hour (maximum rate = 200 mL/h). 
 


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12.1.6 Safety Profile 
No dose-limiting effects were observed in the Phase I/II studies. Reported 
adverse events including fever, chills, headache, nausea, vomiting, 
rhinitis, asthenia, and hypotension, occurred 
primarily during rituximab infusions and typically responded to an 
interruption of the infusion and resumption at a slower rate. 
Fatal Infusion Reactions: Severe and fatal cardiopulmonary events, 
including angioedema, hypoxia, pulmonary infiltrates, acute respiratory 
distress syndrome, myocardial infarction, and cardiogenic shock, have 
been reported. These severe reactions  typically occurred during the first 
infusion with time to onset of 30-120 minutes. 
 
Cardiac Events: Patients with preexisting cardiac conditions, including 
arrhythmia and angina, have had recurrences of these cardiac events 
during rituximab infusions. 
 
Tumor Lysis Syndrome: Tumor lysis syndrome, some with fatal outcome, 
has been reported and is characterized in patients with a high number of 
circulating malignant cells (≥25,000 ul) by rapid reduction in tumor 
volume, renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, 
and hyperphosphatemia. 
 
Renal Events: Rituximab has been associated with severe renal toxicity 
including acute renal failure requiring dialysis, and in some cases has led 
to death. Renal toxicity has occurred inpatients with high numbers of 
circulating malignant cells (≥25,000/mm2 ) or high tumor burden who 
experience tumor lysis syndrome and in patients administered 
concomitant cisplatin. 
 
Mucocutaneous Reactions: Severe bullous skin reactions, including fatal 
cases of toxic epidermal necrolysis and paraneoplastic pemphigus, have 
been reported in patients treated with rituximab. The onset of reaction 
has varied from 1 to 13 weeks following rituximab exposure. 
 
Hematologic Events: In clinical trials, Grade 3 and 4 cytopenias were 
reported in 48% of patients treated with rituximab; these include: 
lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), 
and thrombocytopenia (2%). The median duration of lymphopenia was 14 
days (range, 1 to 588 days) and of neutropenia was 13 days (range, 2 to 
116 days). A single occurrence of transient aplastic anemia (pure red cell 


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aplasia) and two occurrences of hemolytic 
anemia following Rituximab therapy were reported. 
In addition, there have been a limited number of post-marketing reports of 
prolonged pancytopenia, marrow hypoplasia, and late onset neutropenia. 
 
Infectious Events: rituximab induced B-cell depletion in 70% to 80% of 
patients with NHL and was associated with decreased serum 
immunoglobulins in a minority of patients; the lymphopenia lasted a 
median of 14 days (range, 1-588 days). Infectious events occurred in 
31% of patients: 19% of patients had bacterial infections, 10% had viral 
infections, 1% had fungal infections, and 6% were unknown infections. 
Serious infectious events (Grade 3 or 4), including sepsis, occurred in 2% 
of patients. 
 
Hepatitis B Reactivation: Hepatitis B virus (HBV) reactivation with 
fulminant hepatitis, hepatic failure, and death has been reported in some 
patients with hematologic malignancies treated with rituximab. The 
majority of patients received rituximab in combination with chemotherapy. 
The median time to the diagnosis of hepatitis was approximately four 
months after the initiation of rituximab and approximately one month after 
the last dose. 
 
Other Serious Viral Infections: The following additional serious viral 
infections, either new, reactivated or exacerbated, have been identified in 
clinical studies or post-marketing reports. The majority of patients 
received rituximab in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant. These viral infections included JC 
virus 
(progressive 
multifocal 
leukoencephalopathy 
[PML]), 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster 
virus, West Nile virus, and hepatitis C. In some cases, the viral infections 
occurred up to one year following discontinuation of rituximab and have 
resulted in death. 
 
Progressive multifocal leukoencephalopathy (PML) 
PML is a rare disease caused by the reactivation of latent JC virus in the 
brain. Immunosuppression allows reactivation of the JC virus which 
causes demyelination and destruction of oligodendrocytes resulting in 
death or severe disability. Rare cases of PML, some resulting in death, 
have been reported in patients with hematologic malignancies who have 
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in combination with chemotherapy or as part of a hematopoietic stem cell 
transplant. Cases of PML resulting in death have also been reported 
following the use of rituximab for the treatment of autoimmune diseases. 
The reported cases had multiple risk factors for PML, including the 
underlying disease and long-term immunosuppressive therapy or 
chemotherapy. Most cases of PML were diagnosed within 12 months of 
their last infusion of rituximab. 
Physicians should consider PML in any patient presenting with new onset 
neurologic manifestations. Consultation with a neurologist, brain MRI, 
and lumbar puncture should be considered as clinically indicated. In 
patients who develop PML, rituximab should be discontinued and 
reductions or discontinuation of any concomitant chemotherapy or 
immunosuppressive therapy should be considered. 
 
Bowel Obstruction and Perforation: Abdominal pain, bowel obstruction 
and perforation, in some cases leading to death, were observed in 
patients receiving Rituxan in combination with chemotherapy for DLBCL. 
In post-marketing reports, which include both patients with low grade or 
follicular NHL and DLBCL, the mean time to onset of symptoms was 6 
days (range 1−77) in patients with documented gastro-intestinal 
perforation. Complaints of abdominal pain, especially early in the course 
of treatment, should prompt a thorough diagnostic evaluation and 
appropriate treatment. 
 
Immunogenicity: Patients may develop a human anti-chimeric antibody 
(HACA) response with rituximab treatment. The clinical significance of 
this is unclear. 
 
Pregnancy: B-cell lymphocytopenia generally lasting less than 6 months 
can occur in infants exposed to rituximab in utero. 
 
Immunization: Response rates may be reduced with non-live vaccines. 
Additional Safety Signals: The following serious adverse events have 
been reported to occur in patients following completion of rituximab 
infusions: arthritis, disorders of blood vessels (vasculitis, serum sickness 
and lupus-like syndrome), eye disorders (uveitis and optic neuritis), lung 
disorders including pleuritis and scarring of the lung (bronchiolitis 
obliterans), that may result in fatal outcomes, and fatal cardiac failure. 
 
See the rituximab Investigator Brochure for additional details regarding 


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safety experience with rituximab. 
 
12.2 Cyclophosphamide: 
Cyclophosphamide is an alkylating agent. The usual dosing in lymphoma 
patients is 750mg/m2 IV once or 300mg/m2 IV q12 hours over 3 days. 
The main adverse effects include cytopenias, nausea, vomiting, 
hemorrhagic cystitis, and alopecia. 
 
Refer to the FDA approved package insert for complete product 
information. 
 
12.2.1 Supply: 
Commercially available in white crystalline formulation for intravenous 
injection, in vials containing 100 mg, 200 mg, 500 mg, 1gm, and 2 gm. 
 
12.2.2 Storage and preparation: 
Intact vials stable at room temperature (not to exceed 30oC). 
Reconstitute with appropriate amounts of 0.9% NaCl to produce a final 
concentration of 20 mg/ml. Discard solution after 24 hours at room 
temperature. Stable up to 6 days if refrigerated (2-8C). 
 
12.2.3 Administration: 
Cyclophosphamide will be diluted in 100 mL of D5W or 0.9% NaCl and 
infused over 30 minutes or according to institutional standard. Patients 
will be instructed to drink an adequate amount of fluids and empty their 
bladders frequently during cyclophosphamide administration. 
 
12.2.4 Toxicities: 
Myelosuppression, nausea and vomiting, hemorrhagic cystitis, and 
alopecia. Cystitis can be largely prevented by maintaining a good state of 
hydration and good urine flow during and after drug administration using 
the following. Please refer to the package insert for a complete listing of 
all toxicities. 
 
12.2.5 Hydration Guidelines: 
All 
patients 
should 
receive 
0.9% 
NS 
at 
500 
mL/h 
during 
cyclophosphamide infusion. 
 


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12.3 Vincristine: 
Vincristine is a vinca alkaloids commonly utilized in lymphomas, 
leukemias, and other tumors. The main adverse effects include 
constipation, and peripheral neuropathy. The usual dosing in lymphoma 
is 1.4 mg/m² to a maximum of 2 mg, or 0.4mg/m2/day over 4 days in the 
DA-EPOCH or CHOP regimen. 
 
Refer to the FDA approved package insert for complete product 
information. 
 
12.3.1 Supply: 
Commercially available in 1 mg, 2 mg, and 5 mg vial sizes. Each ml 
contains 1 mg of vincristine, 100 mg mannitol, 1.3 mg methylparaben, 
and 0.2 mg propylparaben. Drug should be stored at 2-8C and should be 
protected from light. 
 
12.3.2 Toxicities: 
Peripheral neuropathy, autonomic neuropathy, and alopecia. Local 
necrosis if injected subcutaneously. Please refer to the package insert for 
a complete listing of all toxicities. 
 
12.4 Doxorubicin 
Doxorubicin is an anthracycline, which is commonly used in the treatment 
of lymphomas and sarcomas. The usual dosing is 50mg/m2 either as a 
bolus, or 25mg/m2 IV continuous infusion over 48 hours, although the 
DA-EPOCH regimen doses doxorubicin at 10mg/m2 continuous infusion 
daily over 4 days.   
 
Refer to the FDA approved package insert for complete product 
information. 
 
12.4.1 Supply: 
Commercially available in 10, 20, 50, 100 and 150 mg vials with 50, 100, 
250, 500 and 750mg of lactose, respectively. 
 
12.4.2 Toxicities: 
Myelosuppression, stomatitis, alopecia, nausea and vomiting, and acute 
and chronic cardiac toxicity, manifested as arrhythmias or a congestive 


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cardiomyopathy, the latter uncommon at total cumulative doses less than 
500 mg/m2. The drug causes local necrosis if infiltrated into 
subcutaneous tissue. Please refer to the package insert for a complete 
listing of all toxicities.  
 
The rate of anthracycline-induced cardiomyopathy is generally described 
as <5%, though the risk increases with increased drug exposure. 
 
12.4.3 Administration: The maximum concentration is 5 mg/mL, which can be 
given as in a standard IVPB fluid volume of 50 mL at a maximal IVPB rate 
of 15 minutes. 
 
12.5 Etoposide 
Refer to the FDA approved package insert for complete product 
information. 
 
12.5.1 Supply: 
Commercially available as a concentrate for parenteral use in 100 mg 
vials; each ml contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl 
alcohol, 80 mg polysorbate 80, 650 mg of polyethylene glycol 300, and 
30.5% alcohol. 
 
12.5.2 Toxicities: 
Myelosuppression, nausea, vomiting, anaphylactoid reactions, alopecia, 
and hypotension if infusion is too rapid. Please refer to the package insert 
for a complete listing of all toxicities. 
 
12.6 Prednisone 
Prednisone is a steroid with multiple clinical applications, generally 
including anti-inflammation, although prednisone is known to have activity 
against lymphoproliferative disorders, including lymphoma and leukemia. 
The usual dosage is 10 to 100 mg orally daily. 
 
Refer to the FDA approved package insert for complete product 
information. 
 
12.6.1 Supply: 
Commercially available in a large number of oral dosage strengths 


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including pills and liquid formulations. Tablets should be stored in well-
closed containers at temperatures between 15-30C. 
 
12.6.2 Doses:  
Prednisone utilization will be simplified by using only 20- and 50-mg 
tablets to produce a fixed dose 
 
 
 
12.6.3 Toxicities: 
Proximal muscle weakness, glucose intolerance, thinning of skin, 
redistribution of body fat, Cushingoid facies, immunosuppression, and 
propensity to gastrointestinal ulceration. Please refer to the package 
insert for a complete listing of all toxicities. 
 
 
 
 
 


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13 Appendix B. Revised IPI 
Revised International Prognostic Index 
The risk factors used in calculating the Revised International Prognostic Index 
are shown below. 
Give 1 point for each criterion met: 
a) Age >60 years 
b) Stage III or IV disease 
c) Serum LDH greater than upper limit of local normal range 
d) Eastern Cooperative Oncology Group performance status >=2  
e) More than 1 extranodal site of disease 
 
 


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14 Appendix C. Decision Tree for Immunohistochemistry Classification of 
DLBCL 
 
 
 
Source: Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the 
molecular classification of diffuse large 
B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 
2004;103(1):275-282 
 
 
 
 


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15 Appendix D  Eastern Cooperative Oncology Group Performance Status 
Scale 
 
 
 
 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-
655. 
 
 
 


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16 Appendix E. Inhibitors and Inducers of CYP3A 
Examples of inhibitors and inducers of CYP3A can be found at the following 
website: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
and 
http://www.pharmacologyweekly.com/content/pages/online-drug-therapy-tables 
 
The list below reflects information obtained from the Indiana University, Division 
of Clinical Pharmacology, Indianapolis, IN website  
 
 
 


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17 Appendix F. United States Product Insert for Ibrutinib 
N.B. The USPI is included for information purposes, but in the case of discrepant 
information between the protocol and USPI regarding information for this 
protocol, the language in the protocol will be utilized unless otherwise stated. For 
adverse events in prior clinical trials with ibrutinib, the data in the USPI is more 
detailed than the protocol and should be used as a reference if any questions 
arise about issues with hemorrhage, infections, cytopenias, atrial fibrillation, 
secondary primary malignancies, tumor lysis syndrome, and embryo-fetal 
toxicities.  
18 Appendix G. United States Produce Insert for Lenalidomide 
N.B. The USPI is included for information purposes, but in the case of discrepant 
information between the protocol and USPI regarding information for this 
protocol, the language in the protocol will be utilized unless otherwise stated. For 
adverse events in prior clinical trials with lenalidomide, the data in the USPI is 
more detailed than the protocol and should be used as a reference if any 
questions arise about issues with embryo-fetal toxicity, hematologic toxicities, 
venous and arterial thromboembolism, increased mortality, secondary primary 
malignancies, hepatotoxicity, allergic reaction, tumor lysis syndrome, tumor flare 
reactions, and impaired stem cell mobilization. 
 
 
 


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