Prospective, Multi-center Phase I/II Trial of Lenalidomide and Dose-Adjusted EPOCH-R in MYC-Associated B-Cell Lymphomas
Phase: PHASE1
Conditions: Adult Grade III Lymphomatoid Granulomatosis, B-cell Chronic Lymphocytic Leukemia, Contiguous Stage II Adult Diffuse Large Cell Lymphoma, Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma, Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma, Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma, Contiguous Stage II Grade 1 Follicular Lymphoma, Contiguous Stage II Grade 2 Follicular Lymphoma, Contiguous Stage II Grade 3 Follicular Lymphoma, Contiguous Stage II Mantle Cell Lymphoma, Contiguous Stage II Marginal Zone Lymphoma, Contiguous Stage II Small Lymphocytic Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma, Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma, Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma, Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma, Noncontiguous Stage II Grade 1 Follicular Lymphoma, Noncontiguous Stage II Grade 2 Follicular Lymphoma, Noncontiguous Stage II Grade 3 Follicular Lymphoma, Noncontiguous Stage II Mantle Cell Lymphoma, Noncontiguous Stage II Marginal Zone Lymphoma, Noncontiguous Stage II Small Lymphocytic Lymphoma, Progressive Hairy Cell Leukemia, Initial Treatment, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage 0 Chronic Lymphocytic Leukemia, Stage I Adult Diffuse Large Cell Lymphoma, Stage I Adult Diffuse Mixed Cell Lymphoma, Stage I Adult Diffuse Small Cleaved Cell Lymphoma, Stage I Adult Hodgkin Lymphoma, Stage I Adult Immunoblastic Large Cell Lymphoma, Stage I Chronic Lymphocytic Leukemia, Stage I Grade 1 Follicular Lymphoma, Stage I Grade 2 Follicular Lymphoma, Stage I Grade 3 Follicular Lymphoma, Stage I Mantle Cell Lymphoma, Stage I Marginal Zone Lymphoma, Stage I Small Lymphocytic Lymphoma, Stage II Adult Hodgkin Lymphoma, Stage II Chronic Lymphocytic Leukemia, Stage II Small Lymphocytic Lymphoma, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Adult Diffuse Mixed Cell Lymphoma, Stage III Adult Diffuse Small Cleaved Cell Lymphoma, Stage III Adult Hodgkin Lymphoma, Stage III Adult Immunoblastic Large Cell Lymphoma, Stage III Chronic Lymphocytic Leukemia, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage III Marginal Zone Lymphoma, Stage III Small Lymphocytic Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Hodgkin Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Small Lymphocytic Lymphoma, Testicular Lymphoma, Untreated Hairy Cell Leukemia, Waldenström Macroglobulinemia
Sponsor: University of Chicago

05/28/2019 
 
 
 
 
  
 
1
Protocol Number: IRB13-1406  
 
           Version date: 05/28/2019 
 
Study Title 
 
Prospective, Multi-Center Phase I/II Trial of Lenalidomide and Dose-Adjusted 
EPOCH-R in MYC-associated B-cell Lymphomas 
  
Support Provided By 
Celgene 
 
Principal Investigator 
Sonali M Smith, MD. 
Professor, Section of Hematology/Oncology 
Director, Lymphoma Program  
The University of Chicago 
5841 S. Maryland Avenue MC2115 
Chicago, IL 60637 
smsmith@medicine.bsd.uchicago.edu 
 
Statistician 
Theodore Karrison, PhD 
The University of Chicago Biological Sciences  
 
This is a multi-institutional study being conducted by institutional members of the 
Personalized Cancer Care Consortium (PCCC), as well as additional sites. 
 
Protocol History 
 
Version Date 
Description of Action 
01/10/2014 
Original submission 
06/16/2014 
Modified submission 
12/11/2014 
Amended inclusion criteria 
03/16/2015 
Correlative studies section added  
06/15/2016 
Clarification on study entry requirements and treatment during 
consolidation. Closure of Phase I portion of study and opening 
of Phase II portion.  
05/30/2017 
Added a new exclusion criterion and revised lenalidomide dose 
modifications. 
10/23/2017 
Reformatting of schema in Appendix B 
10/30/2018 
Clarified inclusion criteria, timing requirements of study 
assessments, and how to attribute adverse events.  
5/28/2019 
Clarified eligibility criteria, PJP and HSV prophylaxis 
requirements, and dose modifications for lenalidomide.  
 

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2
 
 
TABLE OF CONTENT 
 
 
 
 
 
 
Page                                              
1.0      INTRODUCTION 
 
 
 
 
 
 
4 
1.1      Rationale for lenalidomide dosing  
 
 
           8 
1.2      Lenalidomide Background  
 
 
 
           9 
2.0 
OBJECTIVES 
 
 
 
 
 
 
11 
2.1 
Primary Objectives  
 
 
 
 
 
11 
2.2 
Secondary Objectives 
 
 
 
 
 
12 
3.0 
STUDY DESIGN 
 
 
 
 
 
 
12 
4.0 
STUDY POPULATION 
 
 
 
 
 
13 
4.1 
Number of Subjects   
 
 
 
 
 
13 
4.2  
Inclusion Criteria 
 
 
 
 
 
 
13 
4.3 
Exclusion Criteria 
 
 
 
 
 
 
14 
5.0 
REGISTRATION PROCEDURES  
 
 
 
15 
5.1 
General Guidelines  
 
 
 
 
 
15 
5.2 
Registration Process 
 
 
 
 
 
16 
6.0 
TREATMENT PLAN 
 
 
 
 
 
17 
6.1 
Induction Phase 
 
 
 
 
 
 
17 
6.2 
CNS Prophylaxis 
 
 
 
 
 
 
18 
 
6.3 
Dose-Adjustment Paradigm 
 
 
 
 
18 
 
 
6.4 
Consolidation and Maintenance Phase  
 
 
19 
7.0 
DOSE MODIFICATION / TOXICITY MANAGEMENT  
19 
7.1 
EPOCH-R Dose Modifications 
 
 
 
 
20 
7.2 
Lenalidomide Dose Modifications  
 
 
 
20 
8.0 
CRITERIA FOR SUBJECT DISCONTINUATION 
 
21 
8.1 
Lenalidomide Specific Criteria 
 
 
 
 
21 
8.2 
General Criteria 
 
 
 
 
 
 
21 
9.0  
CRITERIA FOR STUDY DISCONTINUATION  
 
21 
9.1 
Study Subject Replacement 
 
 
 
 
22 
10.0 CLINICAL AND LABORATORY EVALUATIONS 
 
22 
10.1 Pre-Treatment Evaluations  
 
 
 
 
22 
10.2 Evaluations During Treatment 
 
 
 
 
23 
10.3 Post-Treatment Evaluations 
 
 
 
 
24 
10.4 Evaluations During Maintenance Treatment 
 
 
24 
10.5 Follow-up Evaluations    
 
 
 
 
   
24 
10.6 Correlative Studies  
 
 
 
 
 
25 
11.0 REPORTING OF ADVERSE EVENTS(AE) 
 
 
26 
11.1    Adverse Event (AE)  
 
 
 
 
 
26 
11.2   Serious Adverse Event (SAE) 
 
 
 
 
26 
11.3   Unexpected Events  
 
 
 
 
 
27 
11.4   Routine AE Reporting Requirements  
 
 
 
27                                                  
11.5   SAE Reporting to the Coordinating Center (CC)                      27 
11.6   Serious and Unexpected AE Reporting by the CC                   28  
11.7  Serious Adverse Event Reporting to Celgene                           28           
11.8  Abnormal Laboratory Values                                                     29 

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11.9  Second Primary Malignancies                                                   30 
11.10 Pregnancies                                                                              30 
11.12 Male Subjects                                                                            31 
11.13 Expedited Reporting by Investigator to Celgene                       31 
11.14 Report of Adverse Event to Institutional Review Board (IRB)   32 
11.15 Investigator Reporting to the FDA                                             32                                         
12.0    DATA REPORTING 
 
 
 
 
           32 
13.0    STUDY MANAGEMENT AND REGULATORY AFFAIRS      33 
13.1 Multicenter Guidelines      
 
 
 
 
 
33 
13.2 IRB Approval and Consent  
 
 
 
 
33 
13.3 Required Documentation 
 
 
 
 
 
33 
13.4 Data and Safety Monitoring  
 
 
 
 
34 
13.5 Auditing  
 
 
 
 
 
 
 
35 
13.6 Amendments to the Protocol  
 
 
 
 
35 
13.7 Annual IRB Renewals, Continuing Review and Final Reports    36 
13.8 Record Retention 
 
 
 
 
 
           36 
13.9 Obligations of Study Site Investigators 
 
 
 
37 
14.0 EVALUATION OF RESPONSE AND SAFETY  
 
37 
15.0 STATISTICAL CONSIDERATIONS 
 
 
 
38 
15.1 Primary Outcome Measures  
 
 
 
 
38 
15.2 Secondary Outcome Measures 
 
 
 
 
38 
15.3 Safety Outcome Measures  
 
 
 
 
38 
15.4 Statistical Methods and Sample Size 
 
 
 
38 
 
REFERENCES/BIBLIOGRAPHY  
 
 
 
 
41 
 
APPENDICES 
          
Appendix A: Study Flowchart 
Appendix B: Study Schema 
Appendix C: Current NCI Common Terminology Criteria for Adverse Events  
v 4.0 (CTCAE) 
Appendix D: MULTICENTER GUIDELINES  
Appendix E: DA-EPOCH-R detailed schedule and dose modification 
Appendix F: Other Study Drug(s) Background, including Safety Profile   
 

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1.0 
INTRODUCTION 
 
Non-Hodgkin Lymphoma (NHL) is a malignancy that involves the lymphoid and 
hematopoietic systems with an expected incidence in the United States (US) of 
approximately 66,000 cases in 2012 and 25,000 deaths. 1 NHL is divided into several 
histologic subtypes that continue to be refined as better understanding of the molecular 
basis of lymphomagenesis continues to evolve. 2 Treatment approaches vary between 
observation, immunotherapy, chemoimmunotherapy, and stem cell transplantation.  
These choices of therapy largely depend on the histologic subtype, stage of the 
disease, goals of care, performance status, and the age of the patient.  
 
Diffuse large B-cell lymphoma (DLBCL) comprises 25-30% of all NHL cases 
representing the most commonly diagnosed lymphoid malignancy in the US.  DLBCL is 
a potentially curable entity but the likelihood of cure depends on the stage of disease 
and variable clinical and molecular prognostic factors that predict long-term outcomes. 
3,4 For decades, CHOP multi-agent chemotherapy (cyclophosphamide, oncovoin, 
Adriamycin, and prednisone) has been the backbone therapy for DLBCL standing the 
rigorous randomized studies that compared that regimen with other second and third 
generation programs such as m-BACOD, MACOP-B, and ProMACE-CytaBOM. 5 
However, the past decade has witnessed improvement in overall survival (OS) for 
DLBCL patients when rituximab, a chimeric monoclonal anti-CD20 antibody, was added 
to CHOP chemotherapy. 6,7 The R-CHOP chemoimmunotheapy program has become 
the standard front-line treatment for all patients with DLCBCL 8 but despite this 
improvement, almost one third of patients fail this curative therapy and ultimately 
succumb to their disease. 9 Predicting the subset of patients with the high possibility of 
treatment failure has become a priority in lymphoma research as this allows for 
selecting better and more suitable therapies that have higher chances of long term 
durable remissions. 
 
The International Prognostic index (IPI) has historically been a reproducible prognostic 
guide in patients who have received CHOP alone or with rituximab. 3,10 This index 
divides patients into various risk categories that differ in their complete remissions 
(CRs) and overall survival (OS). While the IPI has been a clinically-based model that 
relies heavily on stage, performance status, and LDH, the more sophisticated gene 
expression profiling (GEP) studies have demonstrated that DLBCL can be divided into 
three main categories irrespective of the IPI. 4,11 GEP analyses divide DLBCL based on 
the cell of origin into germinal center B-cell (GCB), non-germinal center or the activated 
B-cell (ABC), and primary mediastinal B-cell lymphoma types.  These 3 subtypes differ 
in outcomes even when similar regimens such as R-CHOP are delivered.  In all studies, 
patients with ABC-DLBCL had inferior OS compared with other subtypes.  This finding 

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led to designing clinical trials targeting signaling pathways known to be active in the 
ABC type.  To that end, bortezomib a known NF-Kappa-B pathway inhibitor was added 
to R-CHOP in a phase II study of patients with DLBCL and mantle cell lymphoma, 
showing similar responses and survival in ABC and GCB subtypes of treated DLBCL 
patients. 12 Based on further understanding that NF-kappa-B is an active pathway in the 
ABC subtype of lymphoma, a randomized study comparing R-CHOP alone or with 
bortezomib has recently been concluded and its results are expected shortly. 
 
 
 
Another high-risk molecular feature in DLBCL has been the presence of abnormalities in 
the C-myc proto-oncogene signature. 13,14 The human C-myc oncogene is responsible 
for malignant transformation of several types of lymphomas, and is the sine qua non 
mutation associated with Burkitt Lymphoma (BL). 15,16 However, evidence of C-myc 
mutation or up-regulation is also found in about ~15-20% of DLBCL and in a recently-
recognized provisional diagnostic category termed B-cell lymphoma, unclassifiable, with 
features intermediate between Diffuse Large B-cell and Burkitt Lymphoma (BCLU). 2 
Alterations in C-myc may be detected either via cytogenetics (including regular 
karyotype analysis or fluorescent in-situ hybridization (FISH) for the chromosomal 
rearrangement, breaks or gain of copy number) or by immunohistochemistry (IHC) for 
C-myc. 17,18 While the finding of breaks or translocation by FISH is universally 
recognized as evidence of clinically meaningful activation of this oncogene, the 
significance of gain of copy number, and of IHC positivity, is less certain. 19 When C-
myc abnormalities coincide with other adverse prognostic markers, a new genre of 
lymphomas, defined more by biologic features than by histologic features, emerge. 
These lymphomas, which classically include C-myc along with BCL-2 abnormalities, 
have been dubbed “double hit” lymphomas (DHL), and are an emerging therapeutic 
challenge. 20,21 Importantly, DHL are not restricted to any one histologic subtype, and 
can be DLBCL, BCLU, follicular lymphoma (FL; particularly in transformed cases), and 
mantle cell lymphoma (MCL), among others. 
 
 
There are no prospective data that defines the optimal approach for C-myc associated 
lymphoid malignancies. In an attempt to analyze characteristics of patients diagnosed 
with C-myc lymphoma, Savage and colleagues noted no statistically significant 
differences in median age, gender, performance status, LDH, IPI score, or BCL-2 
protein expression, or cell-of-origin between DLBCL patients who had or lacked the C-
myc rearrangement. 22 In contrast, a Japanese study of 252 DLBCL found that the 28 
(11%) patients with 8q24/C-myc aberrations were more likely to have a poor 
performance status (PS), increased LDH, and increased bone marrow involvement at 
presentation. 13 Given that the cell of origin has been associated with differential survival 
outcome in DLBCL patients, understanding the impact of C-myc on GCB and ABC 
subtypes is critical.  Hu et al showed recently that C-myc translocation when associated 

05/28/2019 
 
 
 
 
  
 
6
with another mutation (BCL-2 or BCL-6) has more prognostic implication than the cell of 
origin. 23 
 
Despite variability in the IPI scores and cell of origin phenotype, DHL patients have 
consistently shown inferior outcomes compared with other DLBCL patients when 
treated with R-CHOP or similar regimens. 24,25 Both C-myc aberrancy and DHL 
phenotype, whether by FISH or IHC, correlate with high IPI score.  Moreover, salvage 
chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell 
transplantation (HDT-ASCT) produces inferior CR rates, PFS, and OS in patients with 
DLBCL with C-myc rearrangements, irrespective of presence or absence of DHL 
phenotype, as compared to those with DLBCL without C-myc rearrangement (2-year 
OS less than 30%). 26 Given the above, identifying an effective regimen for C-myc 
associated lymphomas is of critical importance. 
 
In an effort to improve on the outcomes achieved with R-CHOP chemoimmunotherapy, 
the dose-adjusted (DA) EPOCH-R regimen was developed based on in vitro 
pharmacodynamics principles to help overcome drug resistance. 27 In this regimen, 
doxorubicin, vincristine, and etoposide are administered as a 96-hour continuous 
infusion, and cyclophosphamide and prednisone are administered on a bolus schedule. 
Rituximab is administered as per standard infusion protocol.  The rationale for the 
administration schedule derived from the laboratory observation that human tumor cell 
lines, including those with a multi-drug resistance phenotype, are more sensitive to 
cytotoxic natural products given for prolonged periods at low concentrations than to the 
same agents given for brief periods at higher concentrations. EPOCH was initially 
developed and tested in 131 patients with relapsed or refractory NHL. 28 The response 
rate in these heavily pre-treated patients was 74% with 24% of patients achieving CR. 
In the front-line setting, Wilson et al adjusted the doses of this regimen based on the 
nadir counts after each cycle. 29  
 
The doses of doxorubicin, etoposide and cyclophosphamide were escalated 20% on 
every cycle in which the nadir absolute neutrophil count (ANC) exceeded 500/μL, or 
reduced 20% if the ANC was less than 500/μL for more than 2 CBC measurements 
(CBC obtained twice weekly only) or the platelet nadir was < 25,000/μL. The rationale 
for dose adjustment in each patient was based on the fact that dose intensity has been 
associated with improved outcome in aggressive lymphomas and that small changes in 
steady state concentrations for infused agents could significantly affect efficacy.  Fifty 
patients with untreated de novo DLBCL were enrolled. Patients had an IPI distribution of 
56% low and 44% high risk disease. CRs were obtained in 45 patients (92%) and partial 
responses (PRs) in 4 patients. There was no difference in CR rate among the IPI risk 
groups with 19 of 22 high risk and 26 of 27 low risk patients achieving CR. With a 

05/28/2019 
 
 
 
 
  
 
7
median follow-up of 62 months, the actuarial progression-free survival (PFS) was 70% 
and OS was 73%. The regimen was well tolerated with an 8% incidence of fever and 
neutropenia.  In further analyses on DLBCL patients treated with DA-EPOCH with 
rituximab (R), the regimen appeared to benefit both GCB and ABC subtypes although 
there was a marginal benefit favoring the GCB subtype. 30 
 
The favorable outcomes noted using DA-EPOCH-R regimen led to a prospective phase 
III study comparing this program to the standard R-CHOP regimen.  This intergroup 
study was recently closed to accrual and results are forthcoming.  Importantly, several 
retrospective studies have supported that DA-EPOCH-R might have a superior outcome 
in C-myc lymphomas when compared to historical controls.  Abramson et al reported on 
34 patients with DHL by FISH noting that median OS was 34 months in those treated 
with DA-EPOCH-R versus 8 months in others who received R-CHOP. 31 Gandhi et al 
reported on a 106 patients with DHL by FISH noting that DA-EPOCH-R achieved higher 
CR rates compared with other used programs.  The numbers were too small in this 
study to evaluate the role of stem cell transplantation. 
 
Lenalidomide is an immunomodulatory agent with anti-angiogeneic properties that is 
currently approved for the treatment of multiple myeloma, myelodysplasia, and mantle 
cell lymphoma. 32 While these antiangiogeneic and immmunomodulatory effects for 
lenalidomide are well known, the precise mechanisms of action remain unknown. 33 In 
general, its effects include inhibition of regulatory T-cells, co-stimulation of other T cell 
subsets, VEGF inhibition, Akt inhibition, inhibition of cell cycle regulatory proteins and 
down-regulation of a variety of cytokines including IL-6 and TNF. 34,35 Phase I trials with 
lenalidomide were prompted by preclinical data suggesting anti-tumor effects with doses 
up to 50 mg daily being evaluated in both hematologic and solid tumor populations. 36 
Lenalidomide has less myelosuppression when a 7-day break is introduced, and the 
most common schedule selected for further development is 25 mg daily on Days 1-21, 
followed by a 7-day rest period. 37,38 The vast majority of side effects is mild, and 
includes rash, pruritus, diarrhea, and fatigue.  Grade 3 and 4 toxicities observed in these 
trials include neutropenia and thrombocytopenia in approximately 10% of patients. 
Importantly, severe constipation, neuropathy and somnolence that characterize 
thalidomide effects were not seen.  
 
There are several trials investigating lenalidomide monotherapy in patients with 
relapsed lymphomas. Wiernik and colleagues recently published a final analysis of 
lenalidomide 25 mg daily on Days 1-21 repeated every 28 days in 49 patients with 
relapsed aggressive lymphomas. 39 Approximately half of patients had DLBCL, with the 
remaining patients comprised of grade 3 FL, MCL, and transformed FL. The overall 
response rate (ORR) was 35%, with a median duration of response 6.2 months and 

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8
median PFS 4.0 months. This was a heavily pretreated population of patients, with a 
median of 4 prior regimens, and 30% of patients having failed a prior autologous stem 
cell transplant.  Witzig and colleagues reported on the same schedule of lenalidomide in 
patients with heavily pretreated relapsed indolent lymphomas. 40 Importantly, 50% of 
enrolled patients were refractory to their last treatment and all had received prior 
rituximab. In this study, the ORR was 23% in all patients, and 27% in relapsed FL 
patients. What is interesting, however, is that although the median PFS was 4.4 months, 
the median duration of response for responding patients was not reached at the time of 
that report and exceeded 16.5 months.  
 
Importantly, Hernandez-Ilizaliturri et al retrospectively evaluated clinical outcomes of 
patients with GCB versus ABC DLBCL treated with salvage lenalidomide. 41 Forty 
patients (ABC type in 17) with relapsed/refractory DLBCL who received a median of 4 
prior therapies were included. The subgroups were similar in terms of stage, 
international prognostic index score, prior number of treatments, and rituximab 
resistance. A significant difference in clinical response to lenalidomide was observed in 
ABC versus GCB patients. ORR was 52.9% versus 8.7% (P = .006); CRs were 23.5% 
versus 4.3%. Median PFS was 6.2 versus 1.7 months (P = .004), although no difference 
in OS was observed.  While lenalidomide appears to exert enhanced activity in the ABC 
subset of DLBCL patients, it also inhibits the NF-kappa-B pathway that can enhance the 
activity of the translocated C-myc gene in Burkitt's lymphoma. 42 This might suggest that 
lenalidomide could have activity in lymphoid malignancies that are C-myc driven. 
 
The documented experience with the DA-EPOCH-R regimen coupled with retrospective 
analyses and few small prospective studies supporting the activity of this program in C-
myc associated lymphomas and specifically DHL makes it the ideal backbone for the 
incorporation of novel agents.  Lenalidomide appears to have antineoplastic and 
molecular properties that support further investigation in these difficult to treat 
lymphomas.  Accordingly, we initiated this phase I/II DA-EPOCH-R study to will 
evaluate the feasibility, response, and PFS of DA-EPOCH-R plus lenalidomide in DHL 
lymphomas. 
 
1.1 
Rationale for Lenalidomide Dosing  
 
On the basis of the activity of lenalidomide in relapsed lymphomas including mantle cell 
lymphoma, this agent was added to rituximab (lenalidomide 20 mg/day, days 1-21/28, 
plus rituximab 375 mg/m2 weekly in cycle 1) to examine patients with 
relapsed/refractory aggressive NHL (mainly DLBCL) (wang reference below). ORR was 
33%, with a median DOR, PFS, and OS of 10.2, 3.7, and 10.7 months, respectively. 
Although this R2 treatment led to a comparable ORR to that shown with lenalidomide 

05/28/2019 
 
 
 
 
  
 
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alone, the CR rate was elevated with the combination. In elderly patients (age ≥ 65 
years), the R2 combination (lenalidomide 20 mg/day, days 1-21/28, plus rituximab 375 
mg/m2 on days 1 and 21 for 4 cycles) was given along with lenalidomide maintenance 
in patients with at least stable disease (zinzani below).  Following induction, patients 
receiving R2 showed a 35% ORR and 30% CR; 8 of 10 patients in maintenance 
achieved CR and with a median 32-month DOR. 
  
Because R-CHOP has been used as a standard first-line therapy in DLBCL, it was 
rational to investigate the possible enhancement of its activity when lenalidomide was 
added in (i.e., R2-CHOP). Multiple phase II studies showed that not only was R2-CHOP 
active without increased toxicity, but that it could in part overcome the negative 
prognostic impact of the non-GCB phenotype. As has been seen with other combination 
studies, multiple dosing schema for lenalidomide have been identified in both FL and 
DLBCL with standard R-CHOP21, including lenalidomide 25 mg/day on days 1-14 in FL 
patients, (both Tilly's references below), and 25 mg on days 1-10 (the JCO 2015 
reference below) and 15 mg/day on days 1-14 in DLBCL patients (Vitolo below). 
Efficacy outcomes showed very high ORR (92%-98%) and CR/CRu (74%-86%) rates, 
with similar 24-month PFS and OS in both non-GCB and GCB-type DLBCL patients. 
 
1.2 
Lenalidomide Background 
 
As discussed above, lenalidomide is a proprietary IMiD® compound of Celgene 
Corporation.  IMiD® compounds have both immunomodulatory and anti-angiogenic 
properties which could confer antitumor and anti-metastatic effects.  Lenalidomide has 
been demonstrated to possess anti-angiogenic activity through inhibition of bFGF, 
VEGF and TNF-alpha induced endothelial cell migration, due at least in part to inhibition 
of Akt phosphorylation response to bFGF. 33 In addition, lenalidomide has a variety of 
immunomodulatory effects.  Lenalidomide stimulates T cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-
12 production.  Up-regulation of T cell derived IL-2 production is achieved at least in 
part through increased AP-1 activity. 34  
 
1.2.1 Safety Profile 
 
Embryo-Fetal Toxicity 
The drug is not to be used during pregnancy. Lenalidomide caused limb abnormalities 
in a developmental monkey study. If lenalidomide is used during pregnancy, it may 
cause birth defects or embryo-fetal death. Females of reproductive potential must use 2 
forms of contraception or continuously abstain from heterosexual sex during and for 4 
weeks after lenalidomide treatment. 

05/28/2019 
 
 
 
 
  
 
10
 
Hematologic Toxicity (Neutropenia and Thrombocytopenia) 
Lenalidomide can cause significant neutropenia and thrombocytopenia. Eighty percent 
of patients with del 5q myelodysplastic syndrome (MDS) had to have a dose 
delay/reduction during the major study. Thirty-four percent of patients had to have a 
second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of 
patients enrolled in the study. Patients on therapy for del 5q MDS should have their 
complete blood counts monitored weekly for the first 8 weeks of therapy and at least 
monthly thereafter. Patients may require dose interruption and/or reduction. Patients 
may require use of blood product support and/or growth factors. 
 
Venous Thromboembolism: 
Lenalidomide has demonstrated a significantly increased risk of deep vein thrombosis 
(DVT) and pulmonary embolism (PE) in patients with multiple myeloma (MM) who were 
treated with lenalidomide and dexamethasone therapy. Patients and physicians are 
advised to be observant for the signs and symptoms of thromboembolism. Patients 
should be instructed to seek medical care if they develop symptoms such as shortness 
of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic 
anticoagulation or antiplatelet therapy prescribed in conjunction with lenalidomide may 
lessen the potential for venous thromboembolism. The decision to take prophylactic 
measures should be done carefully after an assessment of an individual patient’s 
underlying risk factors. 
 
Allergic Reactions 
Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome 
(SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be 
fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment 
should not receive lenalidomide. Lenalidomide interruption or discontinuation should be 
considered for Grade 2-3 skin rash. Lenalidomide must be discontinued for 
angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected 
and should not be resumed following discontinuation for these reactions. Lenalidomide 
capsules contain lactose. Risk-benefit of lenalidomide treatment should be evaluated in 
patients with lactose intolerance. 
 
Tumor Lysis Syndrome 
Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with 
lenalidomide. The patients at risk of TLS are those with high tumor burden prior to 
treatment. These patients should be monitored closely and appropriate 
precautions taken. 
 

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11
Tumor Flare Reaction 
Tumor flare reaction (TFR) occurred during investigational use of lenalidomide for 
chronic lymphocytic leukemia (CLL) and lymphoma, and is characterized by tender 
lymph node swelling, low-grade fever, pain and rash. Treatment of CLL with 
lenalidomide outside of a well-monitored clinical trial is discouraged.  Monitoring and 
evaluation for TFR is recommended in patients with MCL and other lymphomas. Tumor 
flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is 
recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. 
In the MCL trial, approximately 10% of subjects experienced TFR; all reports were 
Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed 
TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 
TFR without interruption or modification, at the physician’s discretion. Patients with 
Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-
inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR 
symptoms. Patients with Grade 3 or 4 TFR may be treated for management of 
symptoms per the guidance for treatment of Grade 1 and 2 TFR. 
 
Hepatotoxicity  
Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide 
in combination with dexamethasone. The mechanism of drug-induced hepatotoxicity is 
unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and 
concomitant medications may be risk factors. Monitor liver enzymes periodically. 
Stopping lenalidomide upon elevation of liver enzymes is recommended. After return to 
baseline values, treatment at a lower dose may be considered. 
 
Second Primary Malignancies 
Patients with myeloma treated with lenalidomide in studies including melphalan and 
stem cell transplantation had a higher incidence of second primary malignancies, 
particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma (HL), 
compared to patients in the control arms who received similar therapy but did not 
receive lenalidomide. Monitor patients for the development of second malignancies. 
Take into account both the potential benefit of lenalidomide and the risk of second 
primary malignancies when considering treatment with lenalidomide. 
 
2.0 
OBJECTIVES 
 
2.1 
Primary objectives  
 
The primary objective of the phase I portion of the study is to determine the maximum 
tolerated dose (MTD) of lenalidomide when added to DA-EPOCH-R in patients with 
DHL lymphomas. 

05/28/2019 
 
 
 
 
  
 
12
 
The primary objective of the phase II portion of the study is to determine the 1- and 2-
year PFS of DA-EPOCH-R in subjects with DHL lymphomas. 
 
2.2 
Secondary objectives 
 Determine the overall response rate, complete response, and duration of 
response  
 Measure the Quality of Life (QOL) using standardized scale; 
 Assess the toxicity profile using version 4.0 of the NCI-CTCAE criteria 
 Evaluate the OS at 1 and 2 years 
 
3.0 
STUDY DESIGN 
 
 
This is a multi-center single arm phase I/II study with DA-EPOCH-R plus lenalidomide 
in DHL non-Burkitt non-Hodgkin lymphomas. In the phase 1 portion of the study, a 
standard 3+3 dose escalation schema will be followed in order to establish the safest 
dose for this combination schedule. Lenalidomide will be taken orally on days 1-14 of 
every 21 day cycle. The initial dose of lenalidomide will be 10 mg and the dose will be 
escalated to a maximum dose of 25 mg unless the MTD is established during an earlier 
dosing schedule. NOTE: Phase I of the clinical trial was completed and published 
(Cancer. 2019 Jun 1;125(11):1830-1836. doi: 10.1002/cncr.31877 PMID: 30707764). 
The recommended phase II starting dose of lenalidomide is 15mg/d on Days 1-41, 
repeated every 21 days.  
 
 
Three subjects will be accrued to the first cohort (10 mg of lenalidomide). If 0 of 3 
subjects experience a dose limiting toxicity (DLT), then the dose will be escalated and a 
subsequent cohort of 3 subjects will be enrolled at the next highest dose level of 
lenalidomide.  If 1 of 3 subjects experiences a DLT, then 3 additional subjects will be 
enrolled at that same dose level and if no further DLTs are observed then the dose will 
be escalated.  If 2 or more DLTs occur at any dose level, then the MTD will have been 
exceeded.  A minimum of 6 subjects will be treated at the MTD, which will be the 
recommended dose of lenalidomide in the phase II portion, before proceeding to the 
next phase. Please refer to Table 1-1 and Appendix F for the complete lenalidomide 
dose escalation schedule.  
 Table 1-1 Lenalidomide Dose Escalation Schedule  
Dose Level  
Lenalidomide Dose (days 1-14, q21 days) 
Dose Level -1 
5mg 
Dose Level 1 (starting dose level) 
10mg 
Dose Level 2 
15mg 
Dose Level 3 
20mg 
Dose Level 4 
25mg 
 

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13
A DLT is defined as any non-hematologic grade 4 toxicity (based on the CTCAE 
version-4.0) and/or any recurrent grade 3 non-hematologic toxicity despite optimal 
medical management that occurs in Cycle 1 ONLY (a cycle equals 21 days). During the 
lenalidomide dose escalation portion of the study, a hematologic toxicity will not count 
as a DLT since this regimen is being adjusted based on nadir counts. 
 
Subjects can be treated for a maximum of 6 induction cycles provided they continue to 
demonstrate a response.  After completion of induction therapy, subjects who are 
transplantation-eligible, can proceed to transplant and will be taken off study. Subjects 
who receive a transplant will be followed for survival, please refer to Section 10.5 for 
follow-up requirements.   Those subjects who do not move forward with transplant will 
proceed to maintenance therapy with lenalidomide. During maintenance therapy 
subjects will take 10mg of lenalidomide on days 1-14 of every 21 day cycle. Subjects 
can receive up to 12 cycles of maintenance therapy, which will be followed by 
observation and surveillance as defined in Section 10.4. 
 
4.0 
STUDY POPULATION 
 
4.1  
Number of Subjects 
55 subjects with either MYC and BCL2 rearranged or MYC and BCL2 overexpressing 
non-Burkitt non-Hodgkin lymphomas who meet eligibility criteria and have none of the 
exclusion criteria will be enrolled into this study.  
 
4.2  
Inclusion Criteria 
Subjects must fulfill ALL of the following criteria: 
1. B-cell lymphoma stage 2-4 with comprehensive immunohistochemistry (IHC) 
panel establishing lineage (CD20, CD3) and cell of origin (CD10, BCL6 and 
MUM1) in addition to proliferative/prognostic markers (Ki-67, C-myc and BCL2). 
DHL will be identified using cytogenetics and/or immunohistochemistry as 
detailed in section 4.1.2 below. 
2. To define DHL, patients must have evidence of C-myc [defined as: Cytogenetic 
evidence (FISH or karyotype) of C-myc breaks (Increased copy number in itself 
is not considered positivity for C-myc) OR Positive IHC defined as >40% of the 
lymphoma cells staining for MYC] PLUS either: 
a) Breaks in BCL-2 via cytogenetic studies or  
b) BCL-2 immunopositivity in >70% of lymphoma cells during phase           
I portion of the trial and > 50% of lymphoma cells during the phase II 
portion of the trial.  
3. At the investigator’s discretion and for subjects who are unstable, one cycle of an 
anthracycline based chemotherapy in the phase II portion of the trial is allowed 

05/28/2019 
 
 
 
 
  
 
14
prior to enrollment, but no more than one cycle.  For purposes of this trial, 
prednisone or other corticosteroids used for non-lymphomatous conditions will be 
allowed. In addition, a prior/recent short course (< 2 weeks) of steroids for 
symptom relief of lymphoma-related symptoms will be allowed. 
4. AST and ALT < 3 x upper limit of normal (ULN), and total bilirubin <1.5 x ULN 
(with exception of patients with Gilbert's syndrome, asymptomatic gallstones, 
liver involvement with NHL or stable chronic liver disease per investigator 
assessment). 
5. Patients must have adequate renal function by virtue of GFR > 50 ml/minute 
using Cockroft-Gault formula. 
6. Patients must have adequate bone marrow function (platelets >100,000 and ANC 
>1,200).  Patients with bone marrow involvement are allowed at the investigator’s 
discretion regardless of cytopenias. 
7. ECOG PS 0-2. 
8. Age ≥ 18 years. 
9. All study participants must be registered into the mandatory lenalidomide 
REMS® program, and be willing and able to comply with the requirements of the 
REMS® program. 
10. Females of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the lenalidomide REMS® program. (Please see study 
schema for further details) 
11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients 
intolerant to ASA may use warfarin or low molecular weight heparin or alternative 
anti-platelet agents). 
12. Ability to read, understand, and sign a written informed consent approved by 
each institutional IRB.  Alternatively, patients with legal guardians who can read, 
understand, and sign written informed consent may also enroll. 
 
4.3  
Exclusion Criteria 
1.  Prior therapy for lymphoma 
2.  Known CNS involvement 
3.  Known HIV positive status 
4.  Pregnant females 
5.  Burkitt and/or precursor lymphoblastic leukemia/lymphoma. 
6. Prior pomalidomide exposure 
7. Known hypersensitivity to lenalidomide or thalidomide 
8. The development of erythema nodosum if characterized by a desquamating rash 
while taking thalidomide or similar drugs. 

05/28/2019 
 
 
 
 
  
 
15
9. Subjects who have currently active hepatic or biliary disease (with exception of 
patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with 
NHL or stable chronic liver disease per investigator assessment). 
10. Treatment with any known non-marketed drug substance or experimental 
therapy within 4 weeks prior to enrollment, or currently participating in any other 
interventional clinical study for NHL or any other illness (except observational, 
prevention, and/or registry trials). 
11. Prior radiation or chemotherapy exposure inclusive of low dose chemotherapy 
such as methotrexate for autoimmune conditions.  
12. No current malignancy.  Subjects with a prior malignancy are allowed if their 
physician believes they were treated with curative intent and they have a less 
than 10% risk of recurrence. Subjects with a history of completely resected non-
melanoma skin cancer, or successfully treated in situ carcinoma (any site) are 
eligible. Women with a history of cervical cancers are also allowed. 
13. Chronic or current active infectious disease requiring systemic antibiotics, 
antifungal, or antiviral treatment such as, but not limited to, chronic renal 
infection, chronic chest infection with bronchiectasis, tuberculosis and active 
Hepatitis C. 
14. History of significant cerebrovascular disease in the past 3 months or ongoing 
event with active symptoms or sequelae. 
15. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In 
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), 
a HB DNA test will be performed and if positive, the subject will be excluded if 
unable to tolerate and/or receive anti-Hepatitis-B therapy.  Positive serology 
because of prior vaccination is allowed. 
16. Positive serology for hepatitis C (HC) defined as a positive test for HCAb. 
 
16. Inability to comply with study or follow-up testing and procedures. 
 
5.0 
REGISTRATION PROCEDURES 
 
5.1 General Guidelines 
 
Prior to registration and any study-specific evaluations being performed, all patients 
must provide written informed consent for the study. It is recommended that prior to 
presenting the informed consent form to a potential patient you obtain confirmation of 
slot availability from with the University of Chicago Study Coordinator via email 
PhaseIICRA@medicine.bsd.uchicago.edu or via phone (773) 702-9885. Subjects must 
meet all of the eligibility requirements listed in Section 4.0 to participate in the study and 
must be registered on study centrally with the University of Chicago Study Coordinator. 
All required material to document the subject’s eligibility must be submitted at least 48 

05/28/2019 
 
 
 
 
  
 
16
hours prior to the planned commencement of study treatment to the University of 
Chicago Study Coordinator in order to allow for sufficient time to confirm eligibility. 
Details of the registration process are detailed in Section 5.2.   
 
5.2 Registration Process 
 
Upon confirmation that the subject meets all of the selection criteria listed in Section 4.0, 
please contact the University of Chicago Study Coordinator via email 
PhaseIICRA@medicine.bsd.uchicago.edu or via phone (773) 702-9885 to begin the 
registration process. Reservations for potential subjects will only be held for subjects 
who have signed the informed consent document for this study. 
 
The following information will need to be provided at time of registration:   
1. Provider of information’ name 
2. Study # and institution name 
3. Treating physician’s name  
4. Subject’s name and hospital ID number  
5. Subject's zip code of residence  
6. Race, gender, and date of birth of subject 
7. Diagnosis and date of initial diagnosis 
8. Planned study treatment study date 
 
Additionally, all required materials needed to document the subject’s eligibility must be 
submitted to the University of Chicago Study Coordinator at least 48 hours prior 
commencement of study treatment. The required materials that need to be submitted 
are the eligibility checklist, source documentation, and the signed informed consent 
form. The University of Chicago Study Coordinator will also need to verify the affiliate 
institute has received IRB approval for the correct version of the protocol/consent and 
has an annual update on file, if appropriate.  
 
Source documentation should include copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source 
documentation but rather as a checklist that original source documentation exists for 
each criterion. 
 
The University of Chicago Study Coordinator will review all provided information and 
documentation to ensure the potential subject is eligible to start treatment. If there are 
questions about eligibility, the University of Chicago Study Coordinator will discuss it 
with the Principal Investigator (PI). The PI may clarify, but not overturn, eligibility criteria.  
 

05/28/2019 
 
 
 
 
  
 
17
Affiliate sites must confirm registration of the subject by obtaining a subject study ID 
number and the lenalidomide dose level from the University of Chicago Study 
Coordinator via phone, fax or email. Following registration, subjects must begin protocol 
treatment within 14 business days. Issues that would cause treatment delays should be 
discussed with the PI.  If a subject does not receive protocol therapy following 14 days 
of registration, the subject’s registration on the study will be canceled.  The University of 
Chicago Study Coordinator should be notified of cancellations as soon as possible. 
 
Please note the date the subject receives treatment for the first time will be considered 
the subject’s “On Study Date.” Subjects that sign consent and do not go “On Study” will 
be recorded in the database with the date they signed consent and the reason for not 
going “On Study” (e.g., ineligible, screen failure or withdrawn consent).  
 
6.0 TREATMENT PLAN 
 
 
The phase I portion of the study has been completed and the maximum tolerated dose 
of lenalidomide has been identified as 15mg. During the phase II portion of the study all 
subjects will be treated with 15mg of lenalidomide during induction and 10mg of 
lenalidomide during maintenance daily on days 1 through 14 of a 21 day cycle.  All 
subjects will receive the same dose of DA-EPOCH-R as outlined in Section 6.1 no 
matter what portion of the study they are enrolled into. Aside from the lenalidomide and 
the prednisone, all other agents used in this protocol are administered intravenously. 
 
6.1 Induction phase 
 
During induction a treatment cycle is equal to 21 days (3 weeks) and subjects can 
receive a maximum of 6 cycles of treatment.  
 
Lenalidomide will be given orally on days 1-14 of every cycle at a dose of 15mg. 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers. Lenalidomide 
will be provided in accordance with the Celgene Corporation’s lenalidomide REMS® 
program.  Per standard lenalidomide REMS® program requirements, all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and all research 
subjects enrolled into this trial, must be registered in, and must comply with, all 
requirements of the lenalidomide REMS® program.  Only enough lenalidomide for one 
cycle of therapy will be supplied to the subject each cycle.  
 
The rest of the DA-EPOCH-R chemotherapy regimen is outlined below and will be 
administered as previously described in the standard fashion:  Wilson WH et al. Dose-

05/28/2019 
 
 
 
 
  
 
18
adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a 
pharmacodynamic approach with high efficacy. Blood 2002; 99:2685. 
 
• 
Etoposide (VP-16) 50 mg/m2/d civi days days 1-4 (continuous infusion) 
• 
Prednisone 60 mg/m2/BID po days 1-5 
• 
Vincristine 0.4 mg/m2/d civi days 1-4 (continuous infusion) 
• 
Doxorubicin (Adriamycin) 10 mg/m2/d civi days 1-4 (continuous infusion) 
• 
Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 min day 5 
• 
Rituximab 375 mg/m2 on day 1 every 21-days (per standard institutional 
guidelines) 
• 
Physicians can use their preference for PJP and HSV prophylaxis. Antifungal and 
other anti-bacterial prophylaxis is not required per protocol and is up to 
physician’s discretion.  Growth factor support is required, but specific medication 
is at the discretion of the physician.  
o Recommended: Filgrastim (Neupogen) 5 mcg/kg sc qd beginning on d6 till 
ANC > 5,000/uL or Neulasta on days 1 or 2 or 3 after finishing 
chemotherapy 
 
6. 2 CNS Prophylaxis 
 
If clinically indicated, subjects who are deemed appropriate for central nervous system 
(CNS) prophylaxis by their treating physician will receive a dose of intrathecal 
methotrexate between 12 to 15mg with each cycle of chemotherapy. Exact dose of 
intrathecal methotrexate will be left to the investigator’s discretion. 
 
6.3 Dose- Adjustment Paradigm 
Dose-adjustment paradigm is based on twice weekly CBC with differential laboratory 
reports. The dose adjustment rules apply to the starting doses of Etoposide (VP-16), 
Doxorubicin (Adriamycin) and Cyclophosphamide (Cytoxan) noted above.  
• 
If nadir ANC > 500/uL, 20% increase in Etoposide (VP-16), Doxorubicin 
(Adriamycin) and Cyclophosphamide (Cytoxan) above last cycle  
• 
If nadir ANC < 500/uL on 1 or 2 measurements, same doses as last cycle  
• 
If nadir ANC < 500/uL on at least 3 measurements, or nadir platelet < 25,000/uL 
on 1 measurement, 20% decrease in Etoposide (VP-16), Doxorubicin 
(Adriamycin) and Cyclophosphamide (Cytoxan) below last cycle 
 
See appendix at the end of the protocol for a detailed description of dose modifications 
based on nadir counts (Appendix E). 
 
The intended treatment plan is for subjects to receive 6 cycles of induction treatment 

05/28/2019 
 
 
 
 
  
 
19
with lenalidomide and DA-EPOCH-R before moving on to transplant or consolidation.  
If a subject has completed at least 4 cycles of induction treatment and is either unwilling 
or unable to tolerate further therapy with DA-EPOCH-R and lenalidomide, the treating 
physician may choose to complete a PET Scan to assess the subject’s response to 
treatment. If the subject is found to be in a complete remission, the subject may proceed 
to transplant or consolidation or maintenance as per the treating physician’s discretion.  
 
6.4 Consolidation & maintenance phase 
 
Subjects who are transplantation (HSCT)-eligible will receive the BEAM-conditioning 
program, followed by auto-HSCT, and then will be observed.  HSCT will be done if 
deemed appropriate by the treating physician. 
 
Subjects who do not undergo HSCT and are currently in first remission should receive 
maintenance therapy with lenalidomide. During maintenance therapy subjects will take 
10mg of lenalidomide on days 1-14 of every 21 day cycle.  Subjects can receive up to 
12 cycles of maintenance therapy, which will be followed by observation and 
surveillance as defined in Section 10.5. Maintenance treatment with lenalidomide 
should be started within 4 weeks of the PET Scan performed at end of treatment and 
within 8 weeks of their last dose of chemotherapy.  
 
7.0 
 DOSE MODIFICATION/TOXICITY MANAGEMENT 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and during their participation in this study.  Safety evaluations will consist of 
medical interviews, recording of adverse events, physical examinations, blood pressure, 
and laboratory measurements. Subjects will be evaluated for adverse events (all 
grades), serious adverse events, and adverse events requiring study drug interruption 
or discontinuation at each study visit for the duration of their participation in the study.   
 
During the lenalidomide dose escalation portion of the study, hematologic toxicity will 
not count as a DLT since this regimen is being adjusted based on nadir counts.  As 
mentioned previously, DLTs will be defined as any non-hematologic grade 4 toxicity 
(based on the CTCAE version 4.0) and/or any recurrent grade 3 non-hematologic 
toxicity despite optimal medical management occurring in cycle 1 of therapy. The 
remaining chemotherapeutic agents will stay at the same doses regardless of any 
hematologic toxicity.   
 
 
 

05/28/2019 
 
 
 
 
  
 
20
7.1 EPOCH-R Dose Modifications 
 
Dose modifications for non-hematologic toxicities are as follows: 
 For grades 1 and/or 2 non-hematologic toxicity, all drugs are to continue while 
maximum supportive care measures are being implemented. 
 For grade 3 and 4 non-hematologic toxicity, the regimen will be delayed until 
toxicities are resolved to grade 2 or less.  Upon resumption, doses of the 
chemotherapeutic agents will be decreased by 25% (except for rituximab and 
prednisone). 
 
7.2 Lenalidomide Dose Modifications  
 
During the phase II portion of the study, dose delays/modifications for lenalidomide are 
allowed as outlined below. During induction treatment, lenalidomide can be dose 
reduced to dose level -1, 10mg, and dose level -2, 5mg.  During maintenance, 
lenalidomide can be reduced from 10mg to 5mg. There are no lenalidomide dose 
modifications allowed below 5mg.  
 
Subjects who are not able to tolerate lenalidomide during induction treatment  due to 
cytopenias or toxicity can omit the lenalidomide from further induction cycles. If the 
subject’s counts recover in the allotted time to start maintenance treatment the subject 
may be re-evaluated for participation in maintenance treatment with lenalidomide. Prior 
approval from the overall study PI must be obtained.  
 
Neutropenia  
• For ≥ grade 3 neutropenia despite maximum supportive care on day 1 of a 
cycle, hold lenalidomide, and monitor CBC weekly. Resume therapy at next 
lower dose level when neutropenia resolves to ≤ grade 2. Hence, for 
neutropenia occurring on day 1 of a cycle, the cycle may be delayed.  
• For ≥ grade 3 neutropenia despite maximum supportive care during a cycle, 
hold lenalidomide and monitor CBC weekly. Resume therapy at next lower 
dose level when neutropenia resolves to ≤ grade 2.  
• If treatment is delayed for more than 6 weeks, discontinue all protocol therapy 
and remove patient from study.  
 
Thrombocytopenia 
• 
For ≥ grade 3 thrombocytopenia despite maximum supportive care on day 1 of a 
cycle, hold lenalidomide and monitor CBC weekly. Resume therapy at the next 
lower dose level for the next cycle when thrombocytopenia resolves to ≤ grade 2. 
•  For ≥ grade 3 thrombocytopenia despite maximum supportive care during a 
cycle, hold lenalidomide for remainder of the cycle. Resume therapy at the next 
lower dose level for the next cycle, provided thrombocytopenia has resolved to ≤ 
grade 2.  
•  If treatment is delayed for more than 6 weeks, discontinue all protocol therapy 
and remove patient from study. 

05/28/2019 
 
 
 
 
  
 
21
Anemia  
•  In the instance of drug-related anemia based on hemoglobin despite maximum 
supportive care on day 1 that has worsened by one or more grade levels from 
previous cycle, reduce lenalidomide by one dose level.  
•  In the instance of drug-related grade 4 hemoglobin at any time during a cycle, 
discontinue lenalidomide.  
•  Epoetin may be used to treat drug-related anemia. If epoetin is used, patients 
should receive either prophylactic aspirin or low molecular weight heparin unless 
contraindicated.  
 
Dermatologic Toxicity  
 
In the instance of any grade desquamating rash, lenalidomide must be stopped. In the 
instance of grade 3 non-desquamating rash despite maximum supportive care, the rash 
must resolve to grade 1 or less prior to restarting lenalidomide. Lenalidomide should be 
restarted 5mg less than prior dose.  
 
Other Non-Hematologic Toxicity  
 
In the instance of a related grade 3 or higher other non-hematologic toxicity, hold 
lenalidomide, notify the study Principal Investigator, and monitor toxicity at least weekly. 
If toxicity resolves to ≤ grade 2, then resume lenalidomide at next lower dose level. 
 
8.0 
CRITERIA FOR SUBJECT DISCONTINUATION 
 
8.1 
Lenalidomide-Specific Criteria 
 
Subjects who have a severe or life-threatening anaphylaxis or hypersensitivity reaction 
should be discontinued from the study. 
 
8.2 
General Criteria 
 
Subjects who meet the following criteria should be discontinued from the study: 
 inability of subject to comply with study requirements 
 determination by the investigator that it is no longer safe for the subject to 
continue therapy 
 
9.0 
CRITERIA FOR STUDY DISCONTINUATION    
      
Subjects will discontinue treatment after completion per the specified protocol. Subjects 
can be taken off treatment before completion if they progress while on treatment, 
develop unacceptable toxicity that precludes treatment resumption, withdraw voluntarily, 
or deemed best to be taken off treatment per their treating physician. Subjects will 

05/28/2019 
 
 
 
 
  
 
22
continue to be followed until study completion, subject withdrawal or per investigator 
discretion. 
 
9.1  
Study Subject Replacement  
 
In the phase I portion of the study, a subject will need to complete the prescribed 
treatment plan in cycle 1 in order to be included in the DLT assessment. If a subject 
does not complete cycle 1 of induction treatment, the subject will be replaced. In the 
phase II portion of the study, a subject must complete 6 cycles of induction treatment to 
be included in the determination of the 1- and 2-year PFS of DA-EPOCH-R in subjects 
with DHL lymphoma.  
 
10.0 CLINICAL AND LABORATORY EVALUATIONS 
 
10.1 Pre-Treatment Evaluations 
 
The following evaluations must be performed within four weeks prior to the date 
induction treatment on this study is initiated: 
 Medical history and documentation of the rationale for treatment of the subject's 
disease on this study 
 Physical examination, including vital signs, blood pressure, performance status 
(ECOG), height, weight, BSA, and BMI 
 Laboratory evaluations:  
CBC with differential   
uric acid 
Comprehensive Metabolic Panel (CMP) 
beta-2-microglobulins 
LDH 
quantitative immunoglobulins 
 Hepatitis B and C serology  
 HIV serology 
 Tumor assessments: CT scans of the chest, abdomen, and pelvis with IV and 
oral contrast (unless contraindicated).  
 PET scan  
 If indicated by the treating physician, a lumbar puncture can be done to screen 
for central nervous system (CNS) involvement with disease 
 Bone marrow biopsy and aspirate to be completed to assess if there is disease 
involvement.  
 MUGA and/or ECHO with documentation of the left ventricular ejection fraction  
 Quality of Life Questionnaire (QOL) 
 Documentation of C-myc and BCL-2 positivity by FISH/karyotype documenting 
breaks and/or IHC positivity based on the cutoffs defined in inclusion criteria # 2 

05/28/2019 
 
 
 
 
  
 
23
for both markers. It is acceptable for the documentation to be outside the 28 day 
screening window.  
 Pregnancy test for women of child bearing age (please refer to the study schema 
for details) 
 Blood draw for correlative studies   
 Fresh or archival tumor sample collection for correlative studies 
 
If a subject received one cycle of induction treatment prior to the initiation of study 
treatment, the following assessments do not need to be repeated if they were previously 
completed within 4 weeks of the initiation of induction treatment:  
 
 Hepatitis B and C serology  
 HIV serology 
 Tumor assessments: CT scans of the chest, abdomen, and pelvis with IV and 
oral contrast (unless contraindicated).  
 PET scan  
 MUGA and/or ECHO with documentation of the left ventricular ejection fraction  
 Bone marrow biopsy and aspirate to be completed to assess if there is disease 
involvement.  
 Lumbar puncture can be done to screen for central nervous system (CNS) 
involvement with disease, if deemed necessary by treating physcian 
 
10.2 Evaluations during Induction Treatment 
 
Unless otherwise specified, the following evaluations are done on day 1 of each 
induction treatment cycle plus or minus 3 days: 
 Physical examination, including vital signs, blood pressure, performance status, 
weight, BSA and BMI 
 Laboratory evaluations: CBC, CMP, LDH, beta-2 microglobulin, and quantitative 
immunoglobulins to be measured every cycle up to 5 days prior to treatment. 
Results must be available prior to the initiation of treatment with the exception of 
LDH, quantitative immunoglobulins and beta-2 microglobulin. 
o Bi-weekly CBC with differential to be obtain for nadir count observation  
 CT scan of known areas of disease involvement to be performed after the 
completion of cycle 3. The CT scan can be performed up to 1 week prior to the 
start of the next cycle.  
 QOL to be completed on day 1 of cycle 4 
 Blood draw for correlative studies to be completed on day 1 of cycle 4 
 

05/28/2019 
 
 
 
 
  
 
24
10.3 Post Induction Treatment Evaluations      
 
Unless otherwise specified, the following evaluations must be performed within 4 weeks 
after the completion of the last induction treatment cycle.  
 Physical examination, including vital signs, blood pressure, performance status, 
weight, BSA and BMI 
 Laboratory evaluations: CBC, CMP, LDH, Beta-2-microglobulin, and quantitative 
immunoglobulins  
 Blood draw for correlative studies  
 Bone marrow biopsy and aspirate in those individuals who had known marrow 
involvement before study initiation at the end of treatment 
 CT scans of chest, abdomen, and pelvis 
 PET-CT scan  
 MUGA or ECHO with documentation of the left ventricular ejection fraction  
 QOL  
 
10.4 Evaluations during Maintenance Treatment 
 
If a subject is continuing on with maintenance treatment, the evaluations listed below 
are strongly encouraged to be completed on day 1 of each maintenance treatment cycle 
plus or minus 3 days unless otherwise specified. At a minimum the evaluations must be 
completed every other cycle: 
 Physical examination, including vital signs, blood pressure, performance status, 
weight, BSA and BMI 
 Laboratory evaluations: CBC, CMP, LDH to be measured every cycle up to 5 
days prior to treatment. Results must be available prior to the initiation of 
treatment with the exception of LDH.  
 
Please note that for subjects receiving maintenance therapy the first-year follow-up 
evaluations described in Section 10.5 must also be completed and can be done in 
conjunction with a maintenance day 1 cycle visit. 
 
10.5 Follow -up Evaluations     
 
Subjects will be followed from the date of induction treatment completion until 2 years, 
date of removal from study, or date of death, whichever occurs first.  For subjects who 
will receive maintenance therapy the follow-up evaluations can be done in conjunction 
with a day 1 maintenance cycle visit. Subjects removed from this study for unacceptable 
adverse event(s) will be followed until date of disease progression or death, whichever 
occurs first. Additionally, the unacceptable adverse event(s) should be followed until 

05/28/2019 
 
 
 
 
  
 
25
resolution or stabilization of the adverse event. After two years, subjects should be 
followed as clinically indicated based on the physician’s discretion.  
 
Unless otherwise specified, the following evaluations must be performed every 3 
months for 2 years (+ 1 week) following induction treatment completion. Physical 
examination, including vital signs, blood pressure, performance status, weight, BSA and 
BMI 
 Laboratory evaluations: CBC, CMP, LDH, Beta-2-microglobulin, and quantitative 
immunoglobulins  
 CT scans of chest, abdomen, and pelvis every 6 months 
 PET-CT scan as clinically indicated  
 Subjects who are carriers of hepatitis B at the time of discontinuation from study 
treatment will need to be followed for clinical and laboratory signs of active HBV 
infection of hepatitis. Hepatitis serology should be drawn every 3 months for the 
first 12 months after discontinuation from study. 
 
10.6    Correlative Studies  
 
The current clinical trial budget only covers costs associated with the collection, 
processing, and storage of the specimens collected for the purposes of future 
correlative studies. Additional funding will be sought via the University of Chicago 
Cancer Center, Clinical & Translational Science Awards (CTSA) grant, or other funding 
agencies to secure funds for the analysis of the specimens. Such a follow-up proposal 
will contain the detailed methodology. Until funding is secured the processed collected 
specimens will be stored in within Human Tissue Resource Center at the University of 
Chicago.  
 
The future correlative studies will be centered around (1) evaluating markers of 
response to the lenalidomide and EPOCH-R regimen, and (2) to assess pretreatment B-
cell lymphoma characteristics. The selected collection time points will allow us to 
analyze baseline characteristics of the disease and see how the disease changes over 
the course of the subject's treatment course. Pre-treatment biomarker may be 
correlated with clinical responses to lenalidomide and EPOCH-R treatment in order to 
detect biomarkers that are predictive of clinical responsive subject populations. Future 
analysis of the collected specimens may include assays centered on immunology, 
proteomics, gene expression, and genetic variants.  
 
The correlative studies will include blood specimens and primary tumor samples. The 
blood draw for correlative studies will occur at baseline, day 1 of cycle 4, and at the end 
of treatment visit. Each blood collection will consist of: 

05/28/2019 
 
 
 
 
  
 
26
 8 mL of blood for PBMC isolation  
 16 to 20 mL of blood for plasma biomarkers & DNA isolation  
 6 mL of blood for serum  
 
If archival tissue from a tumor biopsy completed prior to treatment is available, 10 to 20 
unstained slides should be obtained and sent to the University of Chicago Study 
Coordinator. Please refer to the Laboratory Manual for further details on the collection, 
handling, processing, and shipment of blood and tissue specimens. 
 
11.0 REPORTING OF ADVERSE EVENTS 
 
11.1 Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product that does not necessarily 
have a causal relationship with the treatment. An adverse event can be any unfavorable 
and unintended sign (including a laboratory finding), symptom or disease temporally 
associated with the use of a medicinal investigational product, whether or not related to 
the medicinal investigational product. 
 
At each evaluation subjects should be interviewed in a non-directed manner to elicit 
potential adverse reactions from the subject. The occurrence of an adverse event will be 
based on changes in the subject’s physical examination, laboratory results, and/or signs 
and symptoms, and review of the subject’s own record of adverse events. Each adverse 
event that is recorded and its relationship to lenalidomide and chemoimmunotherapy 
(EPOCH-R) regimen documented.   
 
Adverse events will be followed until resolution while the subject remains on-study. 
Adverse events will be collected from the time of signing the informed consent until 30 
days after the last dose of lenalidomide. Once the subject is removed from study, 
events thought to be related to the study medication will be followed until resolution or 
stabilization of the adverse event, or until the subject starts a new treatment regimen, or 
death, whichever comes first. 
 
11.2 Serious Adverse Event Definition 
 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death 
2) Life-threatening (e.g. places subject at immediate risk of death, this does not 
include events that might have caused death if they occurred a greater severity) 

05/28/2019 
 
 
 
 
  
 
27
3) Results in in subject hospitalization or prolongation of existing hospitalization for 
≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
5) A congenital anomaly/birth defect.  
 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
the event may jeopardize the subject and/or may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
11.3 Unexpected Events  
 
Unexpected events are those not listed at the observed specificity or severity in the 
protocol, informed consent, investigator brochure, or FDA-approved package insert.  An 
event is considered unexpected if it is listed as occurring within the class of drugs or 
otherwise expected from the drug’s pharmacological properties but which has not been 
previously observed with this specific investigational agent. 
 
11.4 Routine Adverse Event Reporting Requirements  
 
All Adverse Events (AEs) must be reported in routine study data submissions.  AEs that 
meet SAE reporting criteria must also be reported via the Serious Event Reporting Form 
in eVelos.   
 
11.5 Serious Adverse Event Reporting to the Coordinating Center 
 
The University of Chicago Comprehensive Cancer Center (UC CCC) protocol number, 
the Celgene assigned protocol number, and the protocol-specific subject ID assigned 
during trial registration should be noted on all reporting forms.  
 
All serious adverse events (SAEs) occurring on this study require expedited reporting to 
the UC CCC) Clinical Trials Office (CCTO).  The responsible Research Nurse or other 
designated individual at the treating site should report the SAE to the Study Lead 
Principal Investigator, the University of Chicago Study Coordinator, and the CCTO by 
the end of the business day when s/he becomes aware of the event.  Events occurring 
after business hours should be reported to the CCTO by 12pm (noon) the next business 
day.  Reports should be made using the ‘Serious Event Report’ Form.  Please send via 
fax or scan and send via email (preferred) to the following:  
 

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28
Phase II General  
Phone – 773-702-7716 
Fax – 773-702-4889 
Email-PhaseIICRA@medicine.bsd.uchicago.edu and qaccto@bsd.uchicago.edu 
 
11.6 Serious & Unexpected Adverse Event reporting by the Coordinating Center 
 
The designated UC CCC Regulatory Manager will notify all participating sites of all 
unexpected and serious adverse reactions that occur on this clinical trial and which are 
reported to the UC Institutional Review Board (IRB).   
 
11.7 Serious Adverse Event Reporting to Celgene 
 
All SAEs must be reported to Celgene Drug Safety by the responsible University of 
Chicago Study Coordinator or other designated individual at the lead coordinating site 
within 24 hours of the Study Lead Investigator’s knowledge of the event by facsimile, or 
other appropriate method, using the SAE Report Form, or approved equivalent form.                            
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to investigational product (IP), action taken regarding IP, and outcome. 
 
Severity / Intensity                                                                                                                        
For both AEs and SAEs, the investigator must assess the severity / intensity of 
the event. The term “severe” is often used to describe the intensity of a specific 
event (as in mild, moderate or severe myocardial infarction); the event itself, 
however, may be of relatively minor medical significance (such as severe 
headache). This criterion is not the same as “serious” which is based on 
subject/event outcome or action criteria associated with events that pose a threat 
to a subject’s life or functioning. Seriousness, not severity, serves as a guide for 
defining regulatory obligations. 
 
Causality 
The Investigator must determine the relationship between the administration of IP 
and the occurrence of an AE/SAE as Not Suspected or Suspected as defined 
below: 
 Not suspected: Means a causal relationship of the adverse event to IP 
administration is unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient explanation for 
the observed event. 
 Suspected: Means there is a reasonable possibility that the administration 
of IP caused the adverse event. ‘Reasonable possibility’ means there is 

05/28/2019 
 
 
 
 
  
 
29
evidence to suggest a causal relationship between the IP and the adverse 
event. 
 
Causality should be assessed and provided for every AE/SAE based on currently 
available information. Causality is to be reassessed and provided as additional 
information becomes available.  
 
If an event is assessed as suspected of being related to a comparator, ancillary 
or additional IP that has not been manufactured or provided by Celgene, please 
provide the name of the manufacturer when reporting the event. 
 
Duration  
For both AEs and SAEs, the Investigator will provide a record of the start and 
stop dates of the event. 
 
Action Taken 
The Investigator will report the action taken with IP as a result of an AE or SAE, 
as applicable (e.g., discontinuation, interruption, or reduction of IP, as 
appropriate) and report if concomitant and/or additional treatments were given for 
the event. 
 
Outcome  
All SAEs that have not resolved upon discontinuation of the subject’s 
participation in the study must be followed until recovered, recovered with 
sequelae, not recovered or death (due to the SAE). 
 
11.8 Abnormal Laboratory Values 
 
An abnormal laboratory value is considered to be an AE if the abnormality: 
 Results in discontinuation from the study; 
 Requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention;  
 Or is judged to be of significant clinical importance. 
 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness 
criterion need to be documented as a serious adverse event. If a laboratory abnormality 
is one component of a diagnosis or syndrome, then only the diagnosis or syndrome 
should be recorded on the AE page/screen of the CRF. If the abnormality was not a part 
of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the 
AE. If possible, the laboratory abnormality should be recorded as a medical term and 

05/28/2019 
 
 
 
 
  
 
30
not simply as an abnormal laboratory result (e.g., record thrombocytopenia rather than 
decreased platelets). 
 
11.9 Second Primary Malignancies 
 
Second Primary Malignancies (SPMs) are considered events of interest and should be 
included as part of the assessment of adverse events throughout the course of the 
study.  Investigators are to report any second primary malignancies as serious adverse 
events regardless of causal relationship to lenalidomide, occurring at any time for the 
duration of the study.  For all subjects who develop second primary malignancies, sites 
will be required to submit all diagnostic reports (e.g. pathology, cytogenetics, flow 
cytometry results) from the indication diagnostic confirmation samples submitted at 
screening and all reports for the tumor samples from the SPM diagnosis.  For SPMs 
diagnosed at another institution (outside the investigational site), sites are to make 
every effort to obtain these reports for the SPM confirmation. 
 
11.10 Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject occurring while the subject is on 
lenalidomide, or within 28 days of the subject’s last dose of lenalidomide, are 
considered immediately reportable events in which case, lenalidomide is to be 
discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy 
test must be reported to Celgene Drug Safety immediately by facsimile or email using 
the Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and 
must notify Celgene Drug Safety immediately about the outcome of the pregnancy 
(either normal or abnormal outcome) using the Pregnancy Follow-up Report Form.  If 
the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the 
abnormal outcome meets any of the serious criteria, it must be reported as an SAE to 
Celgene Drug Safety immediately by facsimile, or other appropriate method, within 24 
hours of the Investigator’s knowledge of the event using the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 28 days that the Investigator 
suspects is related to the in utero exposure to the IP should also be reported to Celgene 

05/28/2019 
 
 
 
 
  
 
31
Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of 
the Investigator’s knowledge of the event using the SAE Report Form.  
 
11.12 Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, 
the male subject taking lenalidomide should notify the Investigator, and the pregnant 
female partner should be advised to call their healthcare provider immediately. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: (908) 673-9115 
           E-mail: drugsafety@celgene.com     
 
All adverse experience reports must include the subject number, age, sex, weight, 
severity of reaction (e.g. mild, moderate, severe), relationship to drug (e.g. probably 
related, unknown relationship, definitely not related), date and time of administration of 
test medications and all concomitant medications, and medical treatment provided.   
The investigator is responsible for evaluating all adverse events to determine whether 
criteria for “serious” and as defined above are present.  The investigator is responsible 
for reporting adverse events to Celgene as described below. 
 
11.13 Expedited Reporting by Investigator to Celgene 
 
SAEs are defined above.  The investigator must inform Celgene in writing using a 
Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being 
aware of the event.  The written report must be completed and supplied to Celgene by 
facsimile within 24 hours/1 business day.  The initial report must be as complete as 
possible, including an assessment of the causal relationship between the event and the 
investigational product(s).  Information not available at the time of the initial report (e.g., 
an end date for the adverse event or laboratory values received after the report) must 
be documented on a follow-up report.  A final report to document resolution of the SAE 
is required.  The Celgene tracking number (RV-CL-NHLMIXED-PI-003856) and the 
institutional protocol number should be included on SAE reports (or on the fax cover 
letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to 
Celgene should be attached to the SAE and retained with the subject records. 
 

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32
Since this is a multicenter trial, all SAEs must be reported to Celgene as described and 
within 24 hours of awareness.  Participating sites should first report all SAEs to the 
University of Chicago. 
 
11.14 Report of Adverse Events to the Institutional Review Board 
 
The principal Investigator is required to notify his/her (IRB of a serious adverse event 
according to institutional policy.   
 
11.15 Investigator Reporting to the FDA 
 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to 
Celgene and the University of Chicago.  The University of Chicago, as lead study site, 
will determine if additional reporting is required. 
 
12.0 DATA REPORTING  
 
Data reporting will be performed utilizing the eVelos electronic data capture system.  
The University of Chicago Study Coordinator will provide you with the applicable user 
registration information.  
 
All required data must be recorded in the eVelos database at the completion of each 
cycle.  AEs are to be entered in real time. SAEs are to be entered on the Serious Event 
Form within 24 hours of the site’s knowledge of the event and sent via fax or scanned 
and sent via email to the University of Chicago (see section 11.5). All case report forms 
must be completed by designated study personnel. Each screened (consented) subject 
should be entered into eVelos within 48 hours of enrollment approval.   
 
In addition to direct data entry, supporting source documentation submission to the 
University of Chicago Study Coordinator is required. Source documentation includes 
original documents, data, and records (e.g., medical records, raw data collection forms, 
pharmacy dispensing records, recorded data from automated instruments, laboratory 
data) that are relevant to the clinical trial. Each site will prepare and maintain adequate 
and accurate source documents. These documents are designed to record all 
observations and other pertinent data for each subject enrolled in this clinical trial. 
Source records must be adequate to reconstruct all data transcribed onto the case 
report form. 
 

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33
13.0 STUDY MANAGEMENT  
 
13.1 Multicenter Guidelines 
 
The specific responsibilities of the Principal Investigator and the Coordinating Center 
are presented in Appendix C.  Clinical studies coordinated by The University of Chicago 
must be conducted in accordance with the ethical principles that are consistent with 
Good Clinical Practices (GCP) and in compliance with other applicable regulatory 
requirements. The Study Lead PI/Coordinating Center is responsible for distributing all 
official protocols, amendments, and Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required.   
 
13.2 Institutional Review Board Approval and Consent 
 
Unless otherwise specified, each participating institution must obtain its own IRB 
approval. It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the consent 
form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice 
(GCP) and to ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
 
13.3 Required Documentation 
 
Prior to the selection of a study site that is not a full member of the Personalized Cancer 
Care Consortium, the audit and trial oversight processes for the site must be reviewed 
and approved by the UC CCC Clinical Research Advisory Committee   
 

05/28/2019 
 
 
 
 
  
 
34
Before the study can be initiated at any site, the following documentation must be 
provided to the CCTO at the University of Chicago Comprehensive Cancer Center: 
• A copy of the official IRB approval letter for the protocol and informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-investigators 
who will be involved in the study 
• CAP and CLIA Laboratory certification numbers and institution lab normal values 
• Investigational drug accountability standard operating procedures 
• Additionally, before the study can be initiated at any site, the required executed 
research contract/subcontract must be on file with the University of Chicago. 
 
13.4 Data and Safety Monitoring  
 
This study will be remotely monitored by the designated University of Chicago Clinical 
Research Associate (CRA) in accordance with the University of Chicago, Section of 
Hematology/Oncology standard operating procedure titled Monitoring of Multi-
Institutional Investigator Initiated Clinical Trials. 
 
Prior to subject recruitment, and unless otherwise specified, a participating site will 
undergo a Site Initiation Teleconference to be conducted by the designated University 
of Chicago research team. The site’s principal investigator and his or her study staff 
must attend the site initiation meeting.  
 
Monitoring will be conducted to verify the following: 
• Adherence to the protocol 
• Completeness and accuracy of study data and samples collected 
• Compliance with regulations  
• Submission of required source documents  
 
Participating sites will also undergo a site close-out teleconference upon completion, 
termination or cancellation of a study to ensure fulfillment of study obligations during the 
conduct of the study, and to ensure that the site Investigator is aware of his/her ongoing 
responsibilities. 
 
Unless otherwise specified, this protocol will undergo weekly review at the multi-
institutional data and safety monitoring teleconference as per procedures specified by 
the UC CCC NCI-approved Data and Safety Monitoring Plan.  
 
The conference will review: 
• Enrollment rate relative to expectations, characteristics of participants 

05/28/2019 
 
 
 
 
  
 
35
• Safety of study participants (SAE & AE reporting) 
• Adherence to protocol (protocol deviations) 
• Completeness, validity and integrity of study data 
• Retention of study participants 
 
Protocol deviations are to be documented using the Protocol Deviation Form in the 
eVelos clinical trial management system. Deviations that are considered major because 
they impact subject safety or alter the risk/benefit ratio, compromise the integrity of the 
study data, and/or affect subjects’ willingness to participate in the study must be 
reported into the eVelos system within 7 days. 
 
13.5 Auditing 
 
In addition to the clinical monitoring procedures, the CCTO will perform routine Quality 
Assurance Audits of investigator-initiated clinical trials as described in the NCI-approved 
UC CCC DSM Plan. Audits provide assurance that trials are conducted and study data 
are collected, documented and reported in compliance with the protocol. Further, they 
ensure that study data are collected, documented and reported in compliance with GCP 
guidelines and regulatory requirements by performing annual quality assurance audits. 
The CCTO will review subjects enrolled at the University of Chicago and at institutions 
who are formal members of the Personalized Cancer Care Consortium (PCCC) in 
accordance with audit procedures specified in the Data and Safety Monitoring plan.  
 
Auditing procedures for participating sites that are not full members of the PCCC must 
be specified and approved by the UC CCC Clinical Research Advisory Committee prior 
to site approval to participate in the study.  In general, for sites that are not full members 
of the PCCC, auditing responsibility will be delegated to the participating center, with the 
annual audit report forwarded to the University of Chicago for review.   
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, 
during its conduct or even after its completion. If an inspection has been requested by a 
regulatory authority, the site investigator must immediately inform the University of 
Chicago Cancer Clinical Trials Office and Regulatory Manager that such a request has 
been made 
 
13.6 Amendments to the Protocol 
 
All modifications to the protocol, consent form, and/or questionnaires will be submitted 
to the University of Chicago IRB for review and approval. A list of the proposed 
modifications or amendments to the protocol and/or an explanation of the need of these 

05/28/2019 
 
 
 
 
  
 
36
modifications will be submitted, along with a revised protocol incorporating the 
modifications. Only the Study Lead PI can authorize any modifications, amendments, or 
termination of the protocol. Once a protocol amendment has been approved by the 
University of Chicago IRB, the Regulatory Manager will send the amended protocol and 
consent form (if applicable) to the affiliate institutions electronically.  
 
Upon receipt of the packet the affiliate institution is expected to do the following: 
• The affiliate site must reply to the email from the Regulatory Manager indicating 
that the amendment was received by the institution and that it will be submitted to 
the local IRB.  
• The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.  
• The University of Chicago version date and/or amendment number must appear on 
the affiliate consent form and on the affiliate IRB approval letter. The version dates 
can be found on the footer of every page of the protocol and consent form.  The 
amendment number can be found on the University of Chicago IRB amendment 
approval letter that is sent with the protocol/amendment mailing.  
• The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to the designated UC 
Regulatory Manager as soon as it is received.  
 
13.7 Annual IRB Renewals, Continuing Review and Final Reports 
 
The annual IRB renewal approvals for participating institutions should be forwarded 
promptly to the Regulatory Manager. If the institution’s IRB requires a new version of 
the consent form with the annual renewal, the consent form should be included with the 
renewal letter. 
 
13.8 Record Retention 
 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of marketing 
application in an International Conference on Harmonization (ICH) region.  In all other 
cases, study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 
 

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37
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). Additionally, all recordings of observations or 
notations of clinical activities and all reports and records necessary for the evaluation 
and reconstruction of the clinical research study should also be maintained. 
 
13.9 Obligations of Study Site Investigators 
 
The Study Site Principal Investigator is responsible for the conduct of the clinical trial at 
the site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Study Site Principal Investigator is responsible for 
personally overseeing the treatment of all study subjects.  He/she must assure that all 
study site personnel, including sub-investigators and other study staff members, adhere 
to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical 
trials both during and after study completion. 
 
The Study Site Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the CRFs. 
Periodically, monitoring visits or audits will be conducted and he/she must provide 
access to original records to permit verification of proper entry of data.  
 
14.0 EVALUATION OF RESPONSE AND SAFETY 
 
1- Response evaluation will take place after the completion of induction treatment 
cycles 3 and 6 using CT and/or PET as per the investigator’s discretion.  
Response will be assessed as mentioned above using Cheson et al.43  Subjects 
will be given either: CR, PR, SD, or PD. 
2- PET scan is mandatory at baseline (prior to cycle 1) and at completion of 
induction therapy for each subject   
3- Bone marrow biopsy is to be done at end of therapy to document complete 
response if initial bone marrow showed disease involvement. 
 
Once subjects enter the follow up phase of the study, they will be seen every 3 months 
for laboratory assessment including LDH, CBC, CMP, and immunoglobulin levels. 
Imaging studies using CT-Scans of the chest, abdomen, and pelvis will be done every 6 
months for two years following the completion of induction treatment and then at the 
physician’s discretion. 
 

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38
Duration of response is calculated as the duration from detecting any objective 
response until progression or death from any cause.  Duration of CR is calculated as 
time from first CR documentation until progression or death.  PFS is calculated from 
date of study entry (first treatment date) until progression, secondary malignancy, or 
death from any cause.  OS is calculated from study entry until death from any cause. 
 
15.0    STATISTICAL ANALYSIS 
 
15.1   Primary Outcome Measures 
  
The primary endpoint, PFS, will be defined as the time elapsed between treatment 
initiation and tumor progression or death from any cause (whichever occurs first), with 
censoring of subjects who are lost to follow up.  Subjects will not be censored if/when 
proceeding to HSCT. Subjects who do not receive 6 cycles of induction treatment will 
not be included in the primary endpoint analysis.  
 
15.2 Secondary Outcome Measures 
 
Secondary end points include studying the feasibility of combining lenalidomide with 
DA-EPOCH-R during the phase I portion of the study as described above as well as 
calculating the overall response rate defined as the sum of PR and CR by CT of 
PET/CT and/or resolution of marrow-only involvement (if originally involved).  Anti-tumor 
activity will be calculated as the sum of SD, PR, and CR.  Assessing response will be 
according to the Revised Response Criteria for Malignant Lymphoma. 43 Assessment of 
response will be after cycles 3 and 6.  Duration of response will be defined as the time 
elapsed between initial documented PR or CR and first progression event.   
 
15.3 Safety Outcome Measures 
 
The secondary endpoint of safety will be defined as the occurrence of all grades of 
toxicity (using CTCAE v 4.0), experienced during study treatment (up to 21 days from 
last treatment).  The occurrence and severity of each event will be recorded.  
 
15.4 Statistical Methods and Sample Size 
 
In the phase I portion of this trial, our primary objective is to determine the safety, 
tolerability, and feasibility of adding lenalidomide to the DA-EPOCH-R regimen as a 
front-line therapy in subjects with DHL lymphomas.  We will utilize a standard “3+3” 
design starting at a dose level of 10 mg of lenalidomide.  Three patients will be accrued 
to the first cohort (10 mg of lenalidomide).  If 0 of 3 subjects experience a DLT, then the 

05/28/2019 
 
 
 
 
  
 
39
dose will be escalated and the subsequent cohort of 3 subjects will be enrolled at a 
dose level of 15 mg of lenalidomide.  DLT is defined above within the body of the 
protocol (sections 3.0 and 7.0) and is assessed during cycle # 1 only.  If 1 of 3 subjects 
experiences a DLT, then 3 additional subjects will be enrolled at that same dose level 
and if no further DLTs are observed then the dose will be escalated.  If 2 or more DLTs 
occur at any dose level, then the MTD will have been exceeded.  A minimum of 6 
subjects will be treated at the MTD, which is the recommended dose of lenalidomide in 
the phase II portion, before proceeding to the next phase. 
 
In the phase II portion of the study, our primary end point is to assess PFS at 1 and 2 
years from enrollment.  We believe that the combination of DA-EPOCH-RR would 
warrant further validation if we could improve one-year PFS by approximately 20%, to a 
rate of 60%. We propose an Optimal Two-Stage Design to test the null hypothesis that 
P</=0.40 versus the alternative that P>=0.60, where P represents one-year PFS.  We 
propose error probability limits of α=0.05 and β=0.20.  The Optimal Two-Stage Design 
provides for early stopping of the trial if there is sufficient indication of futility.  Under 
these conditions, if seven or fewer of the first 16 subjects are alive and progression-free 
at one year, the trial will be terminated, and DA-EPOCH-RR will be considered to have 
no greater efficacy than previously reported treatment regimens.  However, if 8 or more 
subjects are alive and progression-free, the trial will proceed, to a total enrollment of 46 
subjects.  If the number of subjects that are progression-free at this point is less than or 
equal to 23, the combination will not be considered superior to previously reported 
regimens. 
 
Although interim analysis for futility is planned, enrollment will not stop at any time 
unless it is evident that seven or fewer of the first 16 evaluable for one-year 
progression-free survival (PFS) will not achieve this outcome (i.e., we will not stop 
enrollment after the first 16 subjects are enrolled in order to wait for one-year PFS data 
for that population). 
 
The sample size of 46 subjects that will be evaluated for primary efficacy endpoint of 
one-year PFS will be defined as those having DHL by IHC criteria (i.e., MYC+>/=40% 
AND BCL2+>/= 70%).  An additional total of nine subjects (for a total of 55) will be 
permitted to enroll, so long as they otherwise meet the inclusion/exclusion criteria as 
specified by this protocol.  The rationale for the additional 9 allowed subjects to be 
enrolled is to account for screen failures and subjects who might withdraw consents or 
are taken off study. Those subjects that do not begin protocol-specified treatment for 
any reason may be removed from the trial and replaced with additional subject(s) in 
order to satisfy total enrollment as specified. 
 

05/28/2019 
 
 
 
 
  
 
40
 
We recognize that HSCT (either autologous or allogeneic) may be employed at the 
choice of the treating physician, and that this might complicate the interpretation of 
efficacy results.  However, recent reports indicate that HSCT in first CR is still seldom 
used, and we are lacking data indicative of a clear benefit for such a strategy. The 
ultimate decision regarding HSCT in first remission will be at the discretion of the 
treating physician, and would propose an exploratory analysis in which such subjects 
are audited (either at time of enrollment or at time of transplant) to evaluate whether 
HSCT seems to benefit these subjects.  Subjects who undergo HSCT will be censored 
when evaluating progression but will also be evaluated separately to document 
progression after HSCT as subjects will be followed for 48 months from the date of 
study treatment completion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

05/28/2019 
 
 
 
 
  
 
41
 
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Niesvizky R, Naib T, Christos PJ, et al: Lenalidomide-induced 
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39. 
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Hodgkin's Lymphoma. J Clin Oncol 27:5404-9, 2009 
 
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05/28/2019 
 
 
 
 
45
 APPENDIX A:  STUDY FLOW CHART/SCHEMA 
 
 
 
 
  
1 Does not need to be repeated for C1D1 if screening visit is done within 7 days of starting 
treatment 
2 Labs can be drawn up to 5 days prior to treatment. Results must be available prior to 
treatment except for LDH.  
 3 Pregnancy test requirements for females of Reproductive Potential:  Obtain a negative 
pregnancy test 10 to 14 days prior to writing an initial prescription for lenalidomide and again 
within 24 hours prior to writing an initial prescription for lenalidomide even if continuous 
abstinence is the chosen method of birth control.  The pregnancy test must be sensitive to at 
least 50 mlU/mL. Pregnancy testing should occur weekly during the first 4 weeks of use.  
Pregnancy testing should be repeated every 4 weeks if patient has regular menses or is 
amenorrheic, or every 2 weeks if irregular menses.  If a patient misses her period or if there is 
any abnormality in menstrual bleeding, lenalidomide should be discontinued immediately. 
Obtain a pregnancy test and counsel the patient.  If pregnancy does occur during treatment, 
lenalidomide must be immediately discontinued 
4 If clinically indicated, intrathecal therapy can be done between days 1-5 of each cycle of 
chemotherapy. 12 to 15 mg of intrathecal methotrexate will be used for any patient receiving 
intrathecal therapy, but the exact dose will be left to the investigator’s discretion. 
5 Blood draw for correlative studies may be drawn prior to study treatment on day 1.  
6 Assessment should only be completed on day 1 of cycle 4.  
 
7 Assessment should only be completed if marrow involvement was present at baseline.  
8 Assessment should only be completed as clinically indicated. 
9 Subjects will also need to adhere to the year one follow-up schedule. Follow-up assessments 
can be completed in conjunction with a maintenance day 1 cycle visit. It is encouraged for 
patients to have evaluations done at the start of every cycle, but at a minimum must be 
completed every other cycle.  
10 CT-scan of chest, abdomen, and pelvis should be completed every 6 month during follow-up. 
 
Screening* 
Day 1 of each 
Induction Cycle 
End of Induction 
Treatment Visit 
Day 1 of each 
Maintenance Cycle9 
Follow-up 
 
Window 
Within 4 
weeks 
(± 3 days) 
Within 4 weeks of 
last induction 
treatment 
(± 3 days) 
Every 3 months for 2 
years post induction 
completion   
Physical exam, vital signs, 
height, weight, performance 
status, BMI, BSA 
x 
x1 
x 
x 
x 
CBC, CMP, LDH 
x 
x2 
 
x 
 
Quantitative 
immunoglobulins (IgG, IgM, 
IgA), beta-2-microglobulin 
x 
x2 
 
 
x 
Uric Acid, Hepatitis B and 
C, HIV 
x 
 
 
 
 
Quality of life assessment 
using FACT-L (QOL) 
x 
x6 
x 
 
 
Documentation of C-myc 
and BCL 2positivity 
x 
 
 
 
 
MUGA or ECHO 
x 
 
x 
 
 
CT scan of chest, abdomen, 
and pelvis 
x 
x6 
x 
 
X10 
Bone marrow biopsy and 
aspirate 
x 
 
x7 
 
 
PET-CT scans 
x 
 
x 
 
x8 
Pregnancy testing3  
x 
 
 
 
 
Follow carriers of hepatitis 
B for active HBV infection 
or signs of hepatitis 
 
 
x 
 
x 
Lumbar puncture and 
intrathecal-MTX 
 
x4 
 
 
 
Blood draw for correlative 
studies 
x5 
x6 
x 
 
 

05/28/2019 
 
 
 
 
46
 APPENDIX B: STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

05/28/2019 
 
 
 
 
47
APPENDIX C:  CURRENT NCI COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS (CTCAE) 
 
[Please refer to the following web link:] 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

05/28/2019 
 
 
 
 
48
APPENDIX D: MULTICENTER GUIDELINES  
 
Responsibility of the Study Lead PI  
• The Study Lead PI will be the single liaison with regulatory and data 
management staff, outside sponsor/s, FDA, and funding agencies. The 
Study Lead PI is responsible for the coordination, development, submission, 
and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Study 
Lead PI.  There will be only one version of the protocol, and each 
participating institution will use that document.  The Study Lead PI is 
responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
• The Study Lead PI is responsible for the overall conduct of the study at all 
participating institutions and for monitoring its progress.  All reporting 
requirements are the responsibility of the Study Lead PI.  
• The Study Lead PI is responsible for the timely review of Adverse Events 
(AE) to assure safety of the patients. 
• The Study Lead PI will be responsible for the review of and timely 
submission of data for study analysis. 
 
Responsibilities of the Coordinating Center 
• The Coordinating Center is responsible for maintaining copies of IRB 
approvals from each participating site.  
• The Coordinating Center is responsible for central patient registration.  The 
Coordinating Center is responsible for assuring that IRB approval has been 
obtained at each participating site prior to the first subject registration from 
that site. 
• The Coordinating Center is responsible for the preparation of all submitted 
data for review by the Study Lead PI. 
• The Coordinating Center will maintain documentation of AE reports.  The 
Coordinating Center will submit AE reports to the Study Lead PI for timely 
review. 
 
 
 
 
 
 
 
 
 
 
 

05/28/2019 
 
 
 
 
49
APPENDIX E: DA-EPOCH-R Dose Modifications and Levels 
 
(DA-EPOCH-R) Dose Modifications 
 
Hematologic Toxicity 
 
Delay cycle by up to 2 weeks if ANC < 1000/µL or platelets < 100,000/µL. 
Filgrastim may be used for several days to increase ANC. If no recovery after 2 weeks, 
contact the PI for guidance. 
Doses for doxorubicin, etoposide and cyclophosphamide will be 
based on measurements of the previous cycle ANC or platelet 
nadir whichever is lower (i.e., twice weekly starting 3-4 days 
after completion of chemotherapy). 
 
If ANC 500/µL on all measurements: 
one dose level* 
If ANC 500/µL on 1 or 2 measurements 
(3-4 days apart): 
maintain dose level 
If ANC 500/µL 3 measurements: 
(3-4 days apart): 
one dose level** 
OR 
If platelet 25,000/µL on 1 measurement: 
one dose level 
*   to a maximum of Dose Level 7. 
** to a minimum of Dose Level –2. D u r i n g  i n d u c t i o n  r e c u r r e n c e  o f  
a  t o x i c i t y  r e q u i r i n g  a  d o s e  m o d i f i c a t i o n  b e l o w  D o s e  L e v e l  -
2  w i l l  r e q u i r e  t h e  l e n a l i d o m i d e  t o  b e  o m i t t e d  f o r  r e m a i n i n g  
t r e a t m e n t  c y c l e s .  I f  t h e  s u b j e c t ’ s  c o u n t s  r e c o v e r  i n  t h e  
a l l o t t e d  t i m e  t o  s t a r t  m a i n t e n a n c e  t r e a t m e n t  t h e  s u b j e c t  
m a y  b e  r e - e v a l u a t e d  f o r  p a r t i c i p a t i o n  i n  m a i n t e n a n c e  
t r e a t m e n t  w i t h  l e n a l i d o m i d e .  P r i o r  a p p r o v a l  f r o m  t h e  
o v e r a l l  s t u d y  P I  m u s t  b e  o b t a i n e d .  D u r i n g  m a i n t e n a n c e  
recurrence of a toxicity requiring a dose reduction below Dose Level –2 will 
result in removal of patient from protocol therapy. 
 
DA-EPOCH Dose Levels 
 
Dose adjustments for hematologic toxicity apply only to etoposide, doxorubicin and 
cyclophosphamide. Only cyclophosphamide is reduced in Dose Levels –1 through –3. 
 
Dose Levels 
 Adjusted agents 
-3 
-2 
-1 
1 
2 
3 
4 
5 
6 
7 
Doxorubicin (mg/m2/day) 
10 
10 
10 
10 
12 
14.4 
17.3 
20.7 
24.8 
29.8 
Etoside (mg/m2/day) 
50 
50 
50 
50 
60 
72 
86.4 
103.7 
124.4 
149.3 
Cyclophosphamide  (mg/m2) 
384 
480 
600 
750 
900 
108 
0 
1296 
1555 
1866 
2239 
   Non-adjusted agents 
Rituximab (mg/m2) 
375 
375 
375 
375 
375 
375 
375 
375 
375 
375 
Vincristine   (mg/m2/day)   
(No Cap) 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
0.4 
Prednisone (mg/m2 BID) 
60 
60 
60 
60 
60 
60 
60 
60 
60 
60 
 
 
 

05/28/2019 
 
 
 
 
50
APPENDIX F: Other Study Drug(s) Background, including Safety Profile   
 
 
 
Etoposide 
 
Etoposide (also commonly known as VP-16) is a semisynthetic derivative of 
podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4'-
demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-β-D-glucopyranoside]. It is 
very soluble in methanol and chloroform, slightly soluble in ethanol and sparingly 
soluble in water and ether. It is made more miscible with water by means of 
organic solvents. It has a molecular weight of 588.58 and a molecular formula of 
C29H32O13. Etoposide Injection USP is available for intravenous use as 20 
mg/mL solution in 100 mg (5 mL), 500 mg (25 mL), and 1 g (50 mL) sterile, 
multiple-dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. 
Each mL contains 20 mg etoposide USP, 2 mg citric acid, 30 mg benzyl alcohol, 
80 mg modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 
30.5 percent (v/v) alcohol. 
 
The structural formula is: 
 
 
Clinical Pharmacology 
Etoposide has been shown to cause metaphase arrest in chick fibroblasts. Its 
main effect, however, appears to be at the G2 portion of the cell cycle in 
mammalian cells. Two different dose-dependent responses are seen. At high 
concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed. 
At low concentrations (0.3 to 10 mcg/mL), cells are inhibited from entering 
prophase. It does not interfere with microtubular assembly. The predominant 
macromolecular effect of etoposide appears to be the induction of DNA strand 
breaks by an interaction with DNA topoisomerase II or the formation of free 
radical 

05/28/2019 
 
 
 
 
51
 
Pharmacokinetics 
On intravenous administration, the disposition of etoposide is best described as a 
biphasic process with a distribution half-life of about 1.5 hours and terminal 
elimination half-life ranging from 4 to 11 hours. Total body clearance values 
range from 33 to 48 mL/min or 16 to 36 mL/min/m2 and, like the terminal 
elimination half-life, are independent of dose over a range of 100 to 600 mg/m2. 
Over the same dose range, the areas under the plasma concentration vs. time 
curves (AUC) and the maximum plasma concentration (Cmax) values increase 
linearly with dose. Etoposide does not accumulate in the plasma following daily 
administration of 100 mg/m2 for 4 to 5 days. 
 
The mean volumes of distribution at steady state fall in the range of 18 to 29 
liters or 7 to 17 L/m2. Etoposide enters the CSF poorly. Although it is detectable 
in CSF and intracerebral tumors, the concentrations are lower than in extra-
cerebral tumors and in plasma. Etoposide concentrations are higher in normal 
lung than in lung metastases and are similar in primary tumors and normal 
tissues of the myometrium. In vitro, etoposide is highly protein bound (97%) to 
human plasma proteins. An inverse relationship between plasma albumin levels 
and etoposide renal clearance is found in children. In a study determining the 
effect of other therapeutic agents on the in vitro binding of carbon-14 labeled 
etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and 
aspirin displaced protein-bound etoposide at concentrations achieved in vivo. 
 
Etoposide binding ratio correlates directly with serum albumin in patients with 
cancer and in normal volunteers. The unbound fraction of etoposide significantly 
correlated with bilirubin in a population of cancer patients. Data have suggested 
a significant Inverse correlation between serum albumin concentration and free 
fraction of etoposide.  
 
After intravenous administration of 14C-etoposide (100 to 124 mg/m2), mean 
recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of 
which was excreted as etoposide: fecal recovery of radioactivity was 44% of the 
dose at 120 hours. 
 
In children, approximately 55% of the dose is excreted in the urine as etoposide 
in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m2 or 
about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. 
Etoposide, therefore, is cleared by both renal and non-renal processes, i.e., 
metabolism and biliary excretion. The effect of renal disease on plasma 
etoposide clearance is not known. 
 

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52
Absorption  
Biliary excretion of unchanged drug and/or metabolites is an important route of 
etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous 
dose. The hydroxy acid metabolite [4’-demethylepipodophyllic acid-9-(4,6-0-(R)-
ethylidene-β-D-glucopyranoside)], formed by opening of the lactone ring, is found 
in the urine of adults and children. It is also present in human plasma, 
presumably as the trans isomer. Glucuronide and/or sulfate conjugates of 
etoposide are also excreted in human urine. Only 8% or less of an intravenous 
dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide. In 
addition, 0-demethyulation of the dimethoxyphenol ring occurs through the 
CYP450 3A4 isoenzyme pathway to produce the corresponding catechol. After 
intravenous infusion, the Cmax and AUC values exhibit marked intra- and inter-
subject variability. 
 
There is no evidence of a first-pass effect for etoposide. For example, no 
correlation exists between the absolute oral bioavailability of etoposide capsules 
and non-renal clearance. No evidence exists for any other differences in 
etoposide metabolism and excretion after administration of oral capsules as 
compared to intravenous infusion. 
 
In adults, the total body clearance of etoposide is correlated with creatinine 
clearance, serum albumin concentration, and nonrenal clearance. Patients with 
impaired renal function receiving etoposide have exhibited reduced total body 
clearance, increased AUC and a lower volume of distribution at steady state. Use 
of cisplatin therapy is associated with reduced total body clearance. In children, 
elevated serum SGPT levels are associated with reduced drug total body 
clearance. Prior use of cisplatin may also result in a decrease of etoposide total 
body clearance in children. Although some minor differences in pharmacokinetic 
parameters between age and gender have been observed, these differences 
were not considered clinically significant. 
 
Adverse Reactions 
The following data on adverse reactions are based on intravenous administration 
of etoposide as a single agent, using several different dose schedules for 
treatment of a wide variety of malignancies. 
 
Hematologic Toxicity 
Myelosuppression is dose-related and dose-limiting, with granulocyte nadirs 
occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 
16 days after drug administration. Bone marrow recovery is usually complete by 
day 20, and no cumulative toxicity has been reported. Fever and infection have 

05/28/2019 
 
 
 
 
53
also been reported in patients with neutropenia. Death associated with 
myelosuppression has been reported. 
 
The occurrence of acute leukemia with or without a preleukemic phase has been 
reported rarely in patients treated with etoposide in association with other 
antineoplastic agents.  
 
Gastrointestinal Toxicity 
Nausea and vomiting are the major gastrointestinal toxicities. The severity of 
such nausea and vomiting is generally mild to moderate with treatment 
discontinuation required in 1% of patients. Nausea and vomiting can usually be 
controlled with standard antiemetic therapy. Mild to severe mucositis/esophagitis 
may occur. Gastrointestinal toxicities are slightly more frequent after oral 
administration than after intravenous infusion. 
 
Hypotension 
Transient hypotension following rapid intravenous administration has been 
reported in 1% to 2% of patients. It has not been associated with cardiac toxicity 
or electrocardiographic changes. No delayed hypotension has been noted. To 
prevent this rare occurrence, it is recommended that etoposide be administered 
by slow intravenous infusion over a 30- to 60-minute period. If hypotension 
occurs, it usually responds to cessation of the infusion administration of fluids or 
other supportive therapy as appropriate. When restarting the infusion, a slower 
administration rate should be used. 
 
Allergic Reactions 
Anaphylactic-like reactions characterized by chills, fever, tachycardia, 
bronchospasm, dyspnea, and/or hypotension have been reported to occur in 
0.7% to 2% of patients receiving intravenous etoposide and in less than 1% of 
the patients treated with oral capsules. These reactions have usually responded 
promptly to the cessation of the infusion, antihistamines, or volume expanders as 
appropriate; however, the reactions can be fatal. Hypertension and/or flushing 
have also been reported. Blood pressure usually normalizes within a few hours 
after cessation of the infusion. Anaphylactic-like reactions have occurred during 
the initial infusion of etoposide. 
 
Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, 
laryngospasm, back pain, and/or loss of consciousness have sometimes 
occurred in association with the above reactions. In addition, an apparent 
hypersensitivity-associated apnea has been reported rarely. 
 

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54
Rash, urticaria, and/or pruritus have infrequently been reported at recommended 
doses. At investigational doses, a generalized pruritic erythematous 
maculopapular rash, consistent with perivasculitis, has been reported. 
 
Skin  
Reversible alopecia, sometimes progressing to total baldness was observed in 
up to 66% of patients. 
 
Other Toxicities 
The following adverse reactions have been infrequently reported: abdominal 
pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, 
transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary 
fibrosis, fever, seizure (occasionally associated with allergic reactions), Stevens-
Johnson syndrome, and toxic epidermal necrolysis, pigmentation, and a single 
report of radiation recall dermatitis. 
 
Hepatic toxicity, generally in patients receiving higher doses of the drug than 
those recommended, has been reported with etoposide. Metabolic acidosis has 
also been reported in patients receiving higher doses. Reports of extravasation 
with swelling have been received post marketing. Rarely extravasation has been 
associated with necrosis and venous induration. 
 
The incidences of adverse reactions in the table that follows are derived from 
multiple databases from studies in 2,081 patients when etoposide was used 
either orally or by injection as a single agent. 
 
ADVERSE DRUG EFFECT 
PERCENT RANGE OF REPORTED 
INCIDENCE 
Hematologic toxicity 
 
   Leukopenia (less than 1,000 WBC/mm3) 
3–17  
   Leukopenia (less than 4,000 WBC/mm3) 
60–91  
   Thrombocytopenia (less than 50,000 
platelets/mm3) 
1–20 
   Thrombocytopenia (less than 100,000 
platelets/mm3) 
22–41  
   Anemia 
0–33 
Gastrointestinal toxicity 
 
   Nausea and vomiting 
31–43 
   Abdominal pain 
0–2 
   Anorexia 
10–13 
   Diarrhea 
1–13  
   Stomatitis 
1–6  

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55
Hepatic 
0–3 
Alopecia 
8–66 
Peripheral neurotoxicity 
1–2 
Hypotension 
1–2 
Allergic reaction 
1–2 
 
Overdosage 
No proven antidotes have been established for etoposide overdosage. 
 
Dosage and Administration 
Note: Plastic devices made of acrylic or ABS (a polymer composed of 
acrylonitrile, butadiene, and styrene) has been reported to crack and leak when 
used with undiluted etoposide injection. 
 
Etoposide Injection 
The usual dose of etoposide Injection in testicular cancer in combination with 
other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on 
days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5. In small cell lung 
cancer, the etoposide Injection dose in combination with other approved 
chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day 
for 5 days. 
 
For recommended dosing adjustments in patients with renal impairment. 
Chemotherapy courses are repeated at 3- to 4-week intervals after adequate 
recovery from any toxicity. The dosage should be modified to take into account 
the myelosuppressive effects of other drugs in the combination or the effects of 
prior x-ray therapy or chemotherapy, which may have compromised bone 
marrow reserve. 
 
Administration Precautions 
As with other potentially toxic compounds, caution should be exercised in 
handling and preparing the solution of etoposide. Skin reactions associated with 
accidental exposure to etoposide may occur. The use of gloves is recommended. 
If etoposide solution contacts the skin or mucosa, immediately and thoroughly 
wash the skin with soap and water and flush the mucosa with water. 
 
Preparation for Intravenous Administration 
Etoposide injection must be diluted prior to use with either 5% Dextrose injection, 
or 0.9% Sodium Chloride injection, to give a final concentration of 0.2 to 0.4 
mg/mL. If solutions are prepared at concentrations above 0.4 mg/mL, 
precipitation may occur. Hypotension following rapid intravenous administration 
has been reported; hence, it is recommended that the etoposide solution be 

05/28/2019 
 
 
 
 
56
administered over a 30- to 60-minute period. A longer duration of administration 
may be used if the volume of fluid to be infused is a concern. Etoposide should 
not be given by rapid intravenous injection. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration 
whenever solution and container permit. 
 
Stability 
Unopened vials of etoposide injection are stable for 24 months at room 
temperature (25°C). Vials diluted as recommended to a concentration of 0.2 or 
0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature 
(25°C) under normal room fluorescent light in both glass and plastic containers. 
Procedures for proper handling and disposal of anticancer drugs should be 
considered. Several guidelines on this subject have been published. There is no 
general agreement that all of the procedures recommended in the guidelines are 
necessary or appropriate. 
 
Vincristine 
 
Description 
Vincristine Sulfate Injection, USP is the salt of an alkaloid obtained from a 
common flowering herb, the periwinkle plant (Vinca rosea Linn). Originally known 
as leurocristine, it has also been referred to as LCR and VCR. The molecular 
formula for Vincristine Sulfate, USP is C46H56N4O10•H2SO4. It has a molecular 
weight of 923.04. 
 
The structural formula is as follows: 
 
Vincristine Sulfate, USP is a white to off–white powder. It is soluble in methanol, 
freely soluble in water, but only slightly soluble in 95% ethanol. In 98% ethanol, 
Vincristine Sulfate, USP has an ultraviolet spectrum with maxima at 221 nm 
(∈+47,100). 
 

05/28/2019 
 
 
 
 
57
Vincristine sulfate injection, USP is a sterile, preservative–free, single use only 
solution available for intravenous use in 2 mL (1 mg and 2 mg) vials. Each mL 
contains 1 mg Vincristine Sulfate, USP, 100 mg mannitol and Water for Injection, 
USP. Q.S. Sulfuric acid or sodium hydroxide has been added for pH control. The 
pH of Vincristine Sulfate Injection, USP ranges from 4.0 to 5.0. At the time of 
manufacture, the air in the containers is replaced by nitrogen. 
 
Clinical Pharmacology 
The mechanisms of action of vincristine sulfate remain under investigation. The 
mechanism of action of vincristine sulfate has been related to the inhibition of 
microtubule formation in mitotic spindle, resulting in an arrest of dividing cells at 
the metaphase stage. Central nervous system leukemia has been reported in 
patients undergoing otherwise successful therapy with vincristine sulfate. This 
suggests that vincristine does not penetrate well into the cerebrospinal fluid. 
 
Pharmacokinetic studies in patients with cancer have shown a triphasic serum 
decay pattern following rapid intravenous injection. The initial, middle and 
terminal half–lives are 5 minutes, 2.3 hours, and 85 hours respectively; however, 
the range of the terminal half–life in humans is from 19 to 155 hours. The liver is 
the major excretory organ in humans and animals. The metabolism of vinca 
alkaloids have been shown to be mediated by hepatic cytochrome P450 
isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired 
in patients with hepatic dysfunction or who are taking concomitant potent 
inhibitors of these isoenzymes. About 80% of an injected dose of vincristine 
sulfate appears in the feces and 10% to 20% can be found in the urine. Within 15 
to 30 minutes after injection, over 90% of the drug is distributed from the blood 
into tissue, where it remains tightly, but not irreversibly, bound.  
 
Current principles of cancer chemotherapy involve the simultaneous use of 
several agents. Generally, each agent used has a unique toxicity and mechanism 
of action so that therapeutic enhancement occurs without additive toxicity. It is 
rarely possible to achieve equally good results with single–agent methods of 
treatment. Thus, vincristine sulfate is often chosen as part of polychemotherapy 
because of lack of significant bone–marrow suppression (at recommended 
doses) and of unique clinical toxicity (neuropathy).  
 
Indication and Usage 
Vincristine sulfate injection is indicated in acute leukemia. Vincristine sulfate 
injection has also been shown to be useful in combination with other oncolytic 
agents in Hodgkin’s disease, non–Hodgkin’s malignant lymphomas, 
rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor. 
 

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58
Precautions 
General  
Acute uric acid nephropathy, which may occur after the administration of 
oncolytic agents, has also been reported with vincristine sulfate. In the presence 
of leukopenia or a complicating infection, administration of the next dose of 
vincristine sulfate injection warrants careful consideration. If central nervous 
system leukemia is diagnosed, additional agents may be required, because 
vincristine does not appear to cross the blood–brain barrier in adequate amounts. 
 
Particular attention should be given to dosage and neurologic side effects if 
vincristine sulfate injection is administered to patients with preexisting 
neuromuscular disease and when other drugs with neurotoxic potential are also 
being used. 
 
Acute shortness of breath and severe broncospasm have been reported 
following the administration of vinca alkaloids. These reactions have been 
encountered most frequently when the vinca alkaloid was used in combination 
with mitomycin–C and may require aggressive treatment, particularly when there 
is preexisting pulmonary dysfunction. The onset of these reactions may occur 
minutes to several hours after the vinca alkaloid is injected and may occur up to 
2 weeks following the dose of mitomycin. Progressive dyspnea requiring chronic 
therapy may occur. Vincristine sulfate should not be readministered. 
 
Care must be taken to avoid contamination of the eye with concentration of 
vincristine sulfate injection used clinically. If accidental contamination occurs 
severe irritation (or, if the drug was delivered under pressure, even corneal 
ulceration) may result. The eye should be washed immediately and thoroughly. 
 
Laboratory Tests  
Because dose–limiting clinical toxicity is manifested as neurotoxicity clinical 
evaluation (e.g., history, physical examination) it is necessary to detect the need 
for dosage modification. Following administration of vincristine sulfate injection, 
some individuals may have a fall in the white blood cell count or platelet count, 
particularly when previous therapy or the disease itself has reduced bone–
marrow function. Therefore, a complete blood count should be done before 
administration of each dose. Acute elevation of serum uric acid may also occur 
during induction of remission in acute leukemia; thus, such levels should be 
determined frequently during the first 3 to 4 weeks of treatment or appropriate 
measures taken to prevent uric acid nephropathy. The laboratory performing 
these tests should be consulted for its range of normal values. 
 
 

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59
Drug Interactions  
The simultaneous oral or intravenous administration of phenytoin and 
antineoplastic chemotherapy combinations that included vincristine sulfate has 
been reported to reduce blood levels of the anticonvulsant and to increase 
seizure activity. Dosage adjustment should be based on serial blood level 
monitoring. The contribution of vincristine sulfate to this interaction is not certain. 
The interaction may result from reduced absorption of phenytoin and an increase 
in the rate of its metabolism and elimination. 
 
Caution should be exercised in patients concurrently taking drugs known to 
inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A 
subfamily, or in patients with hepatic dysfunction. Concurrent administration of 
vincristine sulfate with itraconazole (a known inhibitor of the metabolic pathway) 
has been reported to cause an earlier onset and/or an increased severity of 
neuromuscular side effects. This interaction is presumed to be related to 
inhibition of the metabolism of vincristine. 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility – Neither in vivo nor in vitro 
laboratory tests have conclusively demonstrated the mutagenicity of this product. 
Fertility following treatment with vincristine sulfate alone for malignant disease 
has not been studied in humans. Clinical reports of both male and female 
patients who received multiple–agent chemotherapy that included vincristine 
sulfate indicate that azoospermia and amenorrhea can occur in post-pubertal 
patients. Recovery occurred many months after completion of chemotherapy in 
some but not all patients. When the same treatment is administered to pre-
pubertal patients, permanent azoospermia and amenorrhea are much less likely. 
 
Patients who received chemotherapy with vincristine sulfate in combination with 
anti–cancer drugs known to be carcinogenic have developed second 
malignancies. The contributing role of vincristine sulfate in this development has 
not been determined. No evidence of carcinogenicity was found following 
intraperitoneal administration of vincristine sulfate in rats and mice, although this 
study was limited. 
 
Usage in Pregnancy – Pregnancy Category D. 
Nursing Mothers – It is not known whether this drug is excreted in human milk. 
Because many drugs are excreted in human milk and because of the potential for 
serious adverse reactions due to vincristine sulfate in nursing infants, a decision 
should be made either to discontinue nursing or the drug, taking into account the 
importance of the drug to the mother. 
 
 

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60
Adverse Reactions:  
Prior to the use of this drug, patients and/or their parents/guardian should be 
advised of the possibility of untoward symptoms. In general, adverse reactions 
are reversible and are related to dosage. The most common adverse reaction is 
hair loss; the most troublesome adverse reactions are neuromuscular in origin. 
 
When single, weekly doses of the drug are employed, the adverse reactions of 
leukopenia, neurotic pain, and constipation occur but are usually of short duration 
(ie., less than 7 days). When the dosage is reduced, these reactions may lessen 
or disappear. The severity of such reactions seems to increase when the 
calculated amount of drug is given in divided doses.  
 
Other adverse reactions, such as hair loss, sensory loss, paresthesia, difficulty in 
walking, slapping gait, loss of deep–tendon reflexes, and muscle wasting, may 
persist for at least as long as therapy is continued. Generalized sensorimotor 
dysfunction may become progressively more severe with continued treatment. 
Although most such symptoms usually disappear by about the sixth week after 
discontinuance of treatment, some neuromuscular difficulties may persist for 
prolonged periods in some patients. Regrowth of hair may occur while 
maintenance therapy walking, slapping gait, loss of deep–tendon reflexes, and 
muscle wasting, may persist for at least as long as therapy is continued.  
 
Generalized sensorimotor dysfunction may become progressively more severe 
with continued treatment. Although most such symptoms usually disappear by 
about the sixth week after discontinuance of treatment, some neuromuscular 
difficulties may persist for prolonged periods in some patients. Regrowth of hair 
may occur while maintenance therapy continues. 
 
The following adverse reactions have been reported: Hepatic veno-occlusive 
disease has been reported in patients receiving vincristine, particularly in 
pediatric patients, as part of standard combination chemotherapy regimens. 
Some of the patients had fatal outcomes; some who survived had undergone 
liver transplantation. 
 
Hypersensitivity  
Rare cases of allergic–type reactions, such as anaphylaxis, rash and edema, that 
are temporally related to vincristine therapy have been reported in patients 
receiving vincristine as a part of multidrug chemotherapy regimens. 
 
Gastrointestinal  
Constipation, abdominal cramps, weight loss, nausea, vomiting, oral ulceration, 
diarrhea, paralytic ileus, intestinal necrosis and/or perforation, and anorexia have 

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61
occurred. Constipation may take the form of upper–colon impaction, and, on 
physical examination, the rectum may be empty. Colicky abdominal pain coupled 
with an empty rectum may mislead the physician. A flat film of the abdomen is 
useful in demonstrating this condition. All cases have responded to high enemas 
and laxatives. A routine prophylactic regimen against constipation is 
recommended for all patients receiving vincristine sulfate injection. 
 
Paralytic ileus (which mimics the “surgical abdomen”) may occur, particularly in 
young pediatric patients. The ileus will reverse itself with temporary 
discontinuance of vincristine sulfate injection and with symptomatic care. 
 
Genitourinary  
Polyuria, dysuria, and urinary retention due to bladder atony have occurred. 
Other drugs known to cause urinary retention (particularly in the elderly) should, 
if possible, be discontinued for the first few days following administration of 
vincristine sulfate injection. 
 
Cardiovascular   
Hypertension and hypotension have occurred. Chemotherapy combinations that 
have included vincristine sulfate, when given to patients previously treated with 
mediastinal radiation, have been associated with coronary artery disease and 
myocardial infarction. Causality has not been established. 
 
Neurologic  
Frequently, there is a sequence to the development of neuromuscular side 
effects. Initially, only sensory impairment and paresthesia may be encountered. 
With continued treatment, neurotic pain and, later, motor difficulties may occur. 
There have been no reports of any agent that can reverse the neuromuscular 
manifestations that may accompany therapy with vincristine sulfate. Loss of 
deep–tendon reflexes, foot drop, ataxia, and paralysis have been reported with 
continued administration. Cranial nerve manifestations, such as isolated paresis 
and/or paralysis of muscles controlled by cranial motor nerves including 
potentially life–threatening bilateral vocal cord paralysis, may occur in the 
absence of motor impairment elsewhere; extra-ocular and laryngeal muscles are 
those most commonly involved. Jaw pain, pharyngeal pain, parotid gland pain, 
bone pain, back pain, limb pain, and myalgias have been reported; pain in these 
areas may be severe. Convulsions, frequently with hypertension, have been 
reported in a few patients receiving vincristine sulfate. Several instances of 
convulsions followed by coma have been reported in pediatric patients. Transient 
cortical blindness and optic atrophy with blindness have been reported. 
Treatment with vinca alkaloids has resulted in both vestibular and auditory 
damage to the eighth cranial nerve. Manifestations include partial or total 

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62
deafness which may be temporary or permanent and difficulties with balance 
including dizziness, nystagmus, and vertigo. Particular caution is warranted when 
vincristine is used in combination with other agents known to be ototoxic such as 
the platinum–containing oncolytics. 
 
Endocrine  
Rare occurrences of a syndrome attributable to inappropriate antidiuretic 
hormone secretion have been observed in patients treated with vincristine 
sulfate. This syndrome is characterized by high urinary sodium excretion in the 
presence of hyponatremia; renal or adrenal disease, hypotension, dehydration, 
azotemia, and clinical edema are absent. With fluid deprivation, improvement 
occurs in the hyponatremia and in the renal loss of sodium. 
 
Hematologic 
Vincristine sulfate injection does not appear to have any constant or significant 
effect on platelets or red blood cells. Serious bone–marrow depression is usually 
not a major dose–limiting event. However, anemia, leukopenia, and 
thrombocytopenia have been reported. Thrombocytopenia, if present when 
therapy with vincristine sulfate injection is begun, may actually improve before 
the appearance of bone marrow remission. 
 
Skin  
Alopecia and rash have been reported. 
 
Other 
Fever and headache have occurred. 
 
Overdosage 
Side effects following the use of vincristine sulfate injection are dose related. In 
pediatric patients under 13 years of age, death has occurred following doses of 
vincristine sulfate that were 10 times those recommended for therapy. Severe 
symptoms may occur in this patient group following dosages of 3 to 4 mg/m2. 
Adults can be expected to experience severe symptoms after single doses of 
3 mg/m2 or more. Therefore, following administration of doses higher than those 
recommended, patients can be expected to experience exaggerated side effects. 
Supportive care should include the following: (1) prevention of side effects 
resulting from the syndrome of inappropriate antidiuretic hormone secretion 
(preventive treatment would include restriction of fluid intake and perhaps the 
administration of a diuretic affecting the function of Henle’s loop and the distal 
tubule); (2) administration of anticonvulsants; (3) use of enemas or cathartics to 
prevent ileus (in some instances, decompression of the gastrointestinal tract may 

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63
be necessary); (4) monitoring the cardiovascular system; (5) determining daily 
blood counts for guidance in transfusion requirements. 
 
Folinic acid has been observed to have a protective effect in normal mice that 
were administered lethal doses of vincristine sulfate.  Isolated case reports 
suggest that folinic acid may be helpful in treating humans who have received an 
overdose of vincristine sulfate. It is suggested that 100 mg of folinic acid be 
administered intravenously every 3 hours for 24 hours and then every 6 hours for 
at least 48 hours. Theoretically (based on pharmacokinetic data), tissue levels of 
vincristine sulfate can be expected to remain significantly elevated for at least 72 
hours. Treatment with folinic acid does not eliminate the need for the above 
mentioned supportive measures. 
 
Most of an intravenous dose of vincristine is excreted into the bile after rapid 
tissue binding. Because only very small amounts of the drug appear in dialysate, 
hemodialysis is not likely to be helpful in cases of overdosage. An increase in the 
severity of side effects may be experienced by patients with liver disease that is 
severe enough to decrease biliary excretion. 
 
Enhanced fecal excretion of parenterally administered vincristine has been 
demonstrated in dogs pretreated with cholestyramine. There are no published 
clinical data on the use of cholestyramine as an antidote in humans. There are 
no published clinical data on the consequences of oral ingestion of vincristine. 
Should oral ingestion occur, the stomach should be evacuated. Evacuation 
should be followed by oral administration of activated charcoal and a cathartic. 
Treatment of patients following intrathecal administration of vincristine sulfate 
injection has included immediate removal of spinal fluid and flushing with 
Lactated Ringer’s, as well as other solutions and has not prevented ascending 
paralysis and death.  
 
In one case, progressive paralysis in an adult was arrested by the following 
treatment initiated immediately after the intrathecal injection: 
 
As much spinal fluid was removed as could be safely done through lumbar 
access. 
 
The subarachnoid space was flushed with Lactated Ringer’s solution infused 
continuously through a catheter in a cerebral lateral ventricle at the rate of 150 
mL/h. The fluid was removed through a lumbar access. 
 
As soon as fresh frozen plasma became available, the fresh frozen plasma, 25 
mL, diluted in 1 L of Lactated Ringer’s solution was infused through the cerebral 

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64
ventricular catheter at the rate of 75 mL/h with removal through the lumbar 
access. The rate of infusion was adjusted to maintain a protein level in the spinal 
fluid of 150 mg/dL.  
 
Glutamic acid, 10 g, was given intravenously over 24 hours followed by 500 mg 3 
times daily by mouth for 1 month or until neurological dysfunction stabilized. The 
role of glutamic acid in this treatment is not certain and may not be essential. 
 
Dosage and Administration 
This preparation is for intravenous use only. Neurotoxicity appears to be dose 
related. Extreme care must be used in calculating and administering the dose of 
Vincristine Sulfate Injection, USP since overdosage may have a very serious or 
fatal outcome. The usual dose of Vincristine Sulfate Injection, USP for pediatric 
patients is 1.5–2 mg/m2. For pediatric patients weighing 10 kg or less, the 
starting dose should be 0.05 mg/kg, administered once a week. The standard 
dose of Vincristine Sulfate Injection, USP for adults is 1.4 mg/m2. A 50% 
reduction in the dose of Vincristine Sulfate Injection, USP is recommended for 
patients having a direct serum bilirubin value above 3 mg/100 mL. 
 
The drug is administered intravenously at weekly intervals. TO REDUCE THE 
POTENTIAL FOR FATAL MEDICATION ERRORS DUE TO INCORRECT 
ROUTE OF ADMINISTRATION, VINCRISTINE SULFATE INJECTION SHOULD 
BE DILUTED IN A FLEXIBLE PLASTIC CONTAINER AND PROMINENTLY 
LABELED FOR INTRAVENOUS USE ONLY. The concentration of Vincristine 
Sulfate Injection, USP is 1 mg/mL. Do not add extra fluid to the vial prior to 
removal of the dose. Withdraw the solution of Vincristine Sulfate Injection, USP 
into an accurate dry syringe, measuring the dose carefully. Do not add extra fluid 
to the vial in an attempt to empty it completely. 
 
Preparation for flexible plastic container 
Vincristine Sulfate Injection, USP when diluted with 0.9% Sodium Chloride 
Injection in concentrations from 0.0015 mg/mL to 0.08 mg/mL is stable for up to 
24 hours when protected from light or 8 hours under normal light at 25°C. 
Preparation for syringe 
Special Dispensing Information: when dispensing vincristine sulfate injection, usp 
in a syringe, it is imperative that it be packaged in the provided overwrap which 
bears the following statement: “DO NOT REMOVE COVERING UNTIL MOMENT 
OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY 
OTHER ROUTES”. A syringe containing a specific dose must be labeled, using 
the auxiliary sticker provided, to state: “FOR INTRAVENOUS USE ONLY – 
FATAL IF GIVEN BY OTHER ROUTES.” 
 

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65
Caution: It is extremely important that the intravenous needle or catheter be 
properly positioned before any vincristine is injected. Leakage into surrounding 
tissue during intravenous administration of Vincristine Sulfate Injection, USP may 
cause considerable irritation. If extravasation occurs, the injection should be 
discontinued immediately and any remaining portion of the dose should then be 
introduced into another vein. Local injection of hyaluronidase and the application 
of moderate heat to the area of leakage will help disperse the drug and may 
minimize discomfort and the possibility of cellulitis. 
 
Vincristine Sulfate Injection, USP must be administered via an intact, free–
flowing intravenous needle or catheter. Care should be taken that there is no 
leakage or swelling occurring during administration. 
 
The solution may be injected either directly into a vein or into the tubing of a 
running intravenous infusion (see Drug Interactions below). Injection of 
Vincristine Sulfate Injection, USP should be accomplished within 1 minute. 
 
Patients Receiving Radiation Therapy - Vincristine Sulfate Injection, USP should 
not be given to patients while they are receiving radiation therapy through ports 
that include the liver. When Vincristine Sulfate Injection, USP is used in 
combination with L–asparaginase, Vincristine Sulfate Injection, USP should be 
given 12 to 24 hours before administration of the enzyme in order to minimize 
toxicity; administering L–asparaginase before Vincristine Sulfate Injection, USP 
may reduce hepatic clearance of vincristine. 
 
Drug Interactions  
Vincristine Sulfate Injection, USP should not be diluted in solutions that raise or 
lower the pH outside the range of 3.5 to 5.5. It should not be mixed with anything 
other than normal saline or glucose in water. Whenever solution and container 
permit, parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration. 
 
Handling and Disposal  
Procedures for proper handling and disposal of anticancer drugs should be 
considered.1  
 
Rituximab 
 
Rituximab is a genetically engineered, chimeric, murine/human monoclonal 
antibody directed against the CD20 antigen found on the surface of normal and 
malignant pre-B and mature B cells.  The antibody is an IgG1 κ immunoglobulin 
containing murine light-and heavy-chain variable region sequences and human 

05/28/2019 
 
 
 
 
66
constant region sequences.  Rituximab is composed of two heavy chains of 451 
amino acids and two light chains of 213 amino acids (based on cDNA analysis) 
and has an approximate molecular mass of 145 kD.  Rituximab has a binding 
affinity for the CD20 antigen of ~8.0 nM. 
 
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 cases 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 in patients 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 

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67
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 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 
Rituxan induced B-cell depletion in 70% to 80% of patients with NHL 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 Rituxan 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 Rituxan 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 

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patients with hematologic malignancies who have received rituximab.  The 
majority of these patients had received rituximab 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. 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 gastrointestinal 
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. 
 
 

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Cyclophosphamide 
 
Description 
Cyclophosphamide for Injection, USP is a sterile white powder containing 
cyclophosphamide monohydrate. Cyclophosphamide is a synthetic antineoplastic 
drug chemically related to the nitrogen mustards. Cyclophosphamide is a white 
crystalline powder with the molecular formula C7H15CI2N2O2P•H2O and a 
molecular weight of 279.1. The chemical name for cyclophosphamide is 2-[bis(2-
chloroethyl) amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate. 
Cyclophosphamide is soluble in water, saline, or ethanol and has the following 
structural formula: 
 
Clinical Pharmacology 
Cyclophosphamide is biotransformed principally in the liver to active alkylating 
metabolites by a mixed function microsomal oxidase system. These metabolites 
interfere with the growth of susceptible rapidly proliferating malignant cells. The 
mechanism of action is thought to involve cross-linking of tumor cell DNA. 
Cyclophosphamide is well absorbed after oral administration with a bioavailability 
greater than 75%. The unchanged drug has an elimination half-life of 3 to 12 
hours. It is eliminated primarily in the form of metabolites, but from 5 to 25% of 
the dose is excreted in urine as unchanged drug. Several cytotoxic and non-
cytotoxic metabolites have been identified in urine and in plasma. Concentrations 
of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous 
dose. Plasma protein binding of unchanged drug is low but some metabolites are 
bound to an extent greater than 60%. It has not been demonstrated that any 
single metabolite is responsible for either the therapeutic or toxic effects of 
cyclophosphamide. Although elevated levels of metabolites of cyclophosphamide 
have been observed in patients with renal failure, increased clinical toxicity in 
such patients has not been demonstrated. 
 
Warnings 
Carcinogenesis, Mutagenesis, and Impairment of Fertility 
Second malignancies have developed in some patients treated with 
cyclophosphamide used alone or in association with other antineoplastic drugs 
and/or modalities. Most frequently, they have been urinary bladder, 
myeloproliferative, or lymphoproliferative malignancies. Second malignancies 
most frequently were detected in patients treated for primary myeloproliferative or 
lymphoproliferative malignancies or nonmalignant disease in which immune 
processes are believed to be involved pathologically. 

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In some cases, the second malignancy developed several years after 
cyclophosphamide treatment had been discontinued. In a single breast cancer 
trial utilizing two to four times the standard dose of cyclophosphamide in 
conjunction with doxorubicin a small number of cases of secondary acute 
myeloid leukemia occurred within two years of treatment initiation. Urinary 
bladder malignancies generally have occurred in patients who previously had 
hemorrhagic cystitis. In patients treated with cyclophosphamide-containing 
regimens for a variety of solid tumors, isolated case reports of secondary 
malignancies have been published. One case of carcinoma of the renal pelvis 
was reported in a patient receiving long-term cyclophosphamide therapy for 
cerebral vasculitis. The possibility of cyclophosphamide-induced malignancy 
should be considered in any benefit-to-risk assessment for use of the drug. 
 
Cyclophosphamide can cause fetal harm when administered to a pregnant 
woman and such abnormalities have been reported following cyclophosphamide 
therapy in pregnant women. Abnormalities were found in two infants and a six-
month old fetus born to women treated with cyclophosphamide. Ectrodactylia 
was found in two of the three cases. Normal infants have also been born to 
women treated with cyclophosphamide during pregnancy, including the first 
trimester. If this drug is used during pregnancy, or if the patient becomes 
pregnant while taking (receiving) this drug, the patient should be apprised of the 
potential hazard to the fetus. Women of childbearing potential should be advised 
to avoid becoming pregnant. 
 
Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause 
sterility in both sexes. Development of sterility appears to depend on the dose of 
cyclophosphamide, duration of therapy, and the state of gonadal function at the 
time of treatment. Cyclophosphamide-induced sterility may be irreversible in 
some patients. 
 
Amenorrhea associated with decreased estrogen and increased gonadotropin 
secretion develops in a significant proportion of women treated with 
cyclophosphamide. Affected patients generally resume regular menses within a 
few months after cessation of therapy. Girls treated with cyclophosphamide 
during prepubescence generally develop secondary sexual characteristics 
normally and have regular menses. Ovarian fibrosis with apparently complete 
loss of germ cells after prolonged cyclophosphamide treatment in late 
prepubescence has been reported. Girls treated with cyclophosphamide during 
prepubescence subsequently have conceived. 
 

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Men treated with cyclophosphamide may develop oligospermia or azoospermia 
associated with increased gonadotropin but normal testosterone secretion. 
Sexual potency and libido are unimpaired in these patients. Boys treated with 
cyclophosphamide during prepubescence develop secondary sexual 
characteristics normally, but may have oligospermia or azoospermia and 
increased gonadotropin secretion. Some degree of testicular atrophy may occur. 
Cyclophosphamide-induced azoospermia is reversible in some patients, though 
the reversibility may not occur for several years after cessation of therapy. Men 
temporarily rendered sterile by cyclophosphamide have subsequently fathered 
normal children. 
 
 
Urinary System 
Hemorrhagic cystitis may develop in patients treated with cyclophosphamide. 
Rarely, this condition can be severe and even fatal. Fibrosis of the urinary 
bladder, sometimes extensive, also may develop with or without accompanying 
cystitis. Atypical urinary bladder epithelial cells may appear in the urine. These 
adverse effects appear to depend on the dose of cyclophosphamide and the 
duration of therapy. Such bladder injury is thought to be due to 
cyclophosphamide metabolites excreted in the urine. Forced fluid intake helps to 
assure an ample output of urine, necessitates frequent voiding, and reduces the 
time the drug remains in the bladder. This helps to prevent cystitis. Hematuria 
usually resolves in a few days after cyclophosphamide treatment is stopped, but 
it may persist. Medical and/or surgical supportive treatment may be required, 
rarely, to treat protracted cases of severe hemorrhagic cystitis. It is usually 
necessary to discontinue cyclophosphamide therapy in instances of severe 
hemorrhagic cystitis. 
 
Cardiac Toxicity 
Although a few instances of cardiac dysfunction have been reported following 
use of recommended doses of cyclophosphamide, no causal relationship has 
been established. Acute cardiac toxicity has been reported with doses as low as 
2.4 g/m2 to as high as 26 g/m2, usually as a portion of an intensive 
antineoplastic multi-drug regimen or in conjunction with transplantation 
procedures. In a few instances with high doses of cyclophosphamide, severe, 
and sometimes fatal, congestive heart failure has occurred after the first 
cyclophosphamide dose. Histopathologic examination has primarily shown 
hemorrhagic myocarditis. Hemopericardium has occurred secondary to 
hemorrhagic myocarditis and myocardial necrosis. Pericarditis has been reported 
independent of any hemopericardium. No residual cardiac abnormalities, as 
evidenced by electrocardiogram or echocardiogram appear to be present in 
patients surviving episodes of apparent cardiac toxicity associated with high 

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doses of cyclophosphamide. Cyclophosphamide has been reported to potentiate 
doxorubicin-induced cardiotoxicity. 
 
Infections 
Treatment with cyclophosphamide may cause significant suppression of immune 
responses. Serious, sometimes fatal, infections may develop in severely 
immunosuppressed patients. Cyclophosphamide treatment may not be indicated, 
or should be interrupted, or the dose reduced, in patients who have or who 
develop viral, bacterial, fungal, protozoan, or helminthic infections. 
Other 
Anaphylactic reactions have been reported; death has also been reported in 
association with this event. Possible cross-sensitivity with other alkylating agents 
has been reported. 
 
Precautions 
General 
Special attention to the possible development of toxicity should be exercised in 
patients being treated with cyclophosphamide if any of the following conditions 
are present: Leukopenia, Thrombocytopenia, Tumor cell infiltration of bone 
marrow, Previous X-ray therapy, and previous therapy with other cytotoxic 
agents, impaired hepatic function, and impaired renal function 
 
Laboratory Tests 
During treatment, the patient’s hematologic profile (particularly neutrophils and 
platelets) should be monitored regularly to determine the degree of 
hematopoietic suppression. Urine should also be examined regularly for red cells 
which may precede hemorrhagic cystitis. 
 
Drug Interactions 
The rate of metabolism and the leukopenic activity of cyclophosphamide 
reportedly are increased by chronic administration of high doses of 
phenobarbital. 
 
The physician should be alert for possible combined drug actions, desirable or 
undesirable, involving cyclophosphamide even though cyclophosphamide has 
been used successfully concurrently with other drugs, including other cytotoxic 
drugs. 
 
Cyclophosphamide treatment, which causes a marked and persistent inhibition of 
cholinesterase activity, potentiates the effect of succinylcholine chloride. 
If a patient has been treated with cyclophosphamide within 10 days of general 
anesthesia, the anesthesiologist should be alerted. 

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Adrenalectomy 
Since cyclophosphamide has been reported to be more toxic in 
adrenalectomized dogs, adjustment of the doses of both replacement steroids 
and cyclophosphamide may be necessary for the adrenalectomized patient. 
 
Wound Healing 
Cyclophosphamide may interfere with normal wound healing. 
 
Nursing Mothers 
Cyclophosphamide is excreted in breast milk. Because of the potential for 
serious adverse reactions and the potential for tumorigenicity shown for 
cyclophosphamide in humans, a decision should be made whether to discontinue 
nursing or to discontinue the drug, taking into account the importance of the drug 
to the mother. 
 
Geriatric Use 
Insufficient data from clinical studies of cyclophosphamide for malignant 
lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, 
retinoblastoma, and breast carcinoma are available for patients 65 years of age 
and older to determine whether they respond differently than younger patients. In 
two clinical trials in which cyclophosphamide was compared with paclitaxel, each 
in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 
154 (28%) of 552 patients who received cyclophosphamide plus cisplatin were 
65 years or older. Subset analyses (<65 versus >65 years) from these trials, 
published reports of clinical trials of cyclophosphamide-containing regimens in 
breast cancer and non-Hodgkin’s lymphoma, and post marketing experience 
suggest that elderly patients may be more susceptible to cyclophosphamide 
toxicities. In general, dose selection for an elderly patient should be cautious, 
usually starting at the low end of the dosing range and adjusting as necessary 
based on patient response. 
 
Adverse Reactions 
Information on adverse reactions associated with the use of cyclophosphamide is 
arranged according to body system affected or type of reaction. The adverse 
reactions are listed in order of decreasing incidence.  
 
Digestive System 
Nausea and vomiting commonly occur with cyclophosphamide therapy. Anorexia 
and, less frequently, abdominal discomfort or pain and diarrhea may occur. 
There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and 

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jaundice occurring during therapy. These adverse drug effects generally remit 
when cyclophosphamide treatment is stopped. 
 
 
Skin  
Alopecia occurs commonly in patients treated with cyclophosphamide. The hair 
can be expected to grow back after treatment with the drug or even during 
continued drug treatment, though it may be different in texture or color. Skin rash 
occurs occasionally in patients receiving the drug. Pigmentation of the skin and 
changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and 
toxic epidermal necrolysis have been received during post marketing 
surveillance; due to the nature of spontaneous adverse event reporting, a 
definitive causal relationship to cyclophosphamide has not been established. 
 
Hematopoietic System 
Leukopenia occurs in patients treated with cyclophosphamide, is related to the 
dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 
cells/mm3 develops commonly in patients treated with an initial loading dose of 
the drug, and less frequently in patients maintained on smaller doses. The 
degree of neutropenia is particularly important because it correlates with a 
reduction in resistance to infections. Fever without documented infection has 
been reported in neutropenic patients. 
 
Thrombocytopenia or anemia develops occasionally in patients treated with 
cyclophosphamide. These hematologic effects usually can be reversed by 
reducing the drug dose or by interrupting treatment. Recovery from leukopenia 
usually begins in 7 to 10 days after cessation of therapy. 
 
Urinary System 
Cystitis and urinary bladder fibrosis have been observed. Hemorrhagic ureteritis 
and renal tubular necrosis have been reported to occur in patients treated with 
cyclophosphamide. Such lesions usually resolve following cessation of therapy. 
 
Respiratory System 
Interstitial pneumonitis has been reported as part of the post marketing 
experience. Interstitial pulmonary fibrosis has been reported in patients receiving 
high doses of cyclophosphamide over a prolonged period. 
 
Other 
Anaphylactic reactions have been reported; death has also been reported in 
association with this event. Possible cross-sensitivity with other alkylating agents 
has been reported. SIADH (syndrome of inappropriate ADH secretion) has been 

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reported with the use of cyclophosphamide. Malaise and asthenia have been 
reported as part of the post marketing experience. 
 
Overdosage 
No specific antidote for cyclophosphamide is known. Overdosage should be 
managed with supportive measures, including appropriate treatment for any 
concurrent infection, myelosuppression, or cardiac toxicity should it occur. 
 
Dosage and Administration 
When used as the only oncolytic drug therapy, the initial course of 
cyclophosphamide for patients with no hematologic deficiency usually consists of 
40 to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days.  
 
Other intravenous regimens include 10 to 15 mg/kg given every 7 to 10 days or 3 
to 5 mg/kg twice weekly. 
 
Oral cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for 
both initial and maintenance dosing. 
 
Many other regimens of intravenous and oral cyclophosphamide have been 
reported. Dosages must be adjusted in accord with evidence of antitumor activity 
and/or leukopenia. The total leukocyte count is a good, objective guide for 
regulating dosage. Transient decreases in the total white blood cell count to 2000 
cells/mm3 (following short courses) or more persistent reduction to 3000 
cells/mm3 (with continuing therapy) are tolerated without serious risk of infection 
if there is no marked granulocytopenia. When cyclophosphamide is included in 
combined cytotoxic regimens, it may be necessary to reduce the dose of 
cyclophosphamide as well as that of the other drugs.Cyclophosphamide and its 
metabolites are dialyzable although there are probably quantitative differences 
depending upon the dialysis system being used. Patients with compromised 
renal function may show some measurable changes in pharmacokinetic 
parameters of cyclophosphamide metabolism, but there is no consistent 
evidence indicating a need for cyclophosphamide dosage modification in patients 
with renal function impairment. 
 
Storage 
Unopened vials of cyclophosphamide are stable until the date indicated on the 
package when stored at or below 25°C (77°F)  
 
Possible Adverse Reactions 
Possible adverse reactions include: fluid and electrolyte disturbances, sodium 
retention, fluid retention, congestive heart failure in susceptible patients, 

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potassium loss, hypokalemic alkalosis, hypertension, muscle weakness, steroid 
myopathy, osteoporosis, vertebral compression fractures, aseptic necrosis of 
femoral and humeral heads, tendon rupture, pathologic fracture of long bones, 
peptic ulcer with possible subsequent perforation and hemorrhage, perforation of 
the small and large bowel (particularly in patients with IBD), pancreatitis, 
abdominal distention, impaired wound healing, thin fragile skin, petechiae and 
ecchymosis, erythema, increased sweating, convulsions, increased intracranial 
pressure with papilledema (pseudotumor cerebri) usually after, treatment, 
vertigo, headache, psychic disturbances, menstrual irregularities, development of 
cushingoid state, secondary adrenocortical and pituitary unresponsiveness, 
particularly in times of stress, as in trauma, surgery, or illness decreased 
carbohydrate tolerance, manifestations of latent diabetes mellitus, increased 
requirements for insulin or oral hypoglycemic agents in diabetics, lip hirsutism, 
posterior subcapsular cataracts, increased intraocular pressure, glaucoma, 
exophthalmos negative nitrogen balance due to protein catabolism, myocardial 
rupture following recent myocardial infarction, anaphylactic or hypersensitivity 
reactions, thromboembolism, weight gain, increased appetite, nausea, malaise, 
and hiccups. 
 
Doxorubicin 
 
Warnings 
1. Severe local tissue necrosis will occur if there is extravasation during 
administration.  Doxorubicin must not be given by the intramuscular or 
subcutaneous route.  
2. Myocardial toxicity manifested in its most severe form by potentially fatal 
congestive heart failure (CHF) may occur either during therapy or months to 
years after termination of therapy. The probability of developing impaired 
myocardial function based on a combined index of signs, symptoms and decline 
in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total 
cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 
to 8% at 450 mg/m2 and 6 to 20% at 500 mg/m2. The risk of developing CHF 
increases rapidly with increasing total cumulative doses of doxorubicin in excess 
of 400 mg/m2. Risk factors (active or dormant cardiovascular disease, prior or 
concomitant radiotherapy to the mediastinal/pericardial area, previous therapy 
with other anthracyclines or anthracenediones, concomitant use of other 
cardiotoxic drugs) may increase the risk of cardiac toxicity. Cardiac toxicity with 
doxorubicin may occur at lower cumulative doses whether or not cardiac risk 
factors are present. Pediatric patients are at increased risk for developing 
delayed cardiotoxicity.  
3. Secondary AML or MDS has been reported in patients treated with 
anthracyclines, including doxorubicin.  The occurrence of refractory secondary 

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AML or MDS is more common when anthracyclines are given in combination with 
DNA-damaging anti-neoplastic agents or radiotherapy, when patients have been 
heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have 
been escalated.   
4. Dosage should be reduced in patients with impaired hepatic function.  
5. Severe myelosuppression may occur.  
6. Doxorubicin should be administered only under the supervision of a physician 
who is experienced in the use of cancer chemotherapeutic agents. 
 
Clinical Pharmacology 
The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on 
various organs are thought to be related to nucleotide base intercalation and cell 
membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide 
replication and action of DNA and RNA polymerases. The interaction of 
doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to 
be an important mechanism of doxorubicin cytocidal activity. Doxorubicin cellular 
membrane binding may affect a variety of cellular functions. Enzymatic electron 
reduction of doxorubicin by a variety of oxidases, reductases and 
dehydrogenases generates highly reactive species including the hydroxyl free 
radical OH•.  Free radical formation has been implicated in doxorubicin 
cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular level. Cells 
treated with doxorubicin have been shown to manifest the characteristic 
morphologic changes associated with apoptosis or programmed cell death. 
Doxorubicin-induced apoptosis may be an integral component of the cellular 
mechanism of action relating to therapeutic effects, toxicities, or both. Animal 
studies have shown activity in a spectrum of experimental tumors, 
immunosuppression, carcinogenic properties in rodents, induction of a variety of 
toxic effects, including delayed and progressive cardiac toxicity, 
myelosuppression in all species and atrophy to testes in rats and dogs. 
 
Indications and Usage 
Doxorubicin has been used successfully to produce regression in disseminated 
neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic 
leukemia, Wilms' tumor, neuroblastoma, soft tissue and bone sarcomas, breast 
carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid 
carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma and 
bronchogenic carcinoma in which the small cell histologic type is the most 
responsive compared to other cell types. Doxorubicin is also indicated for use as 
a component of adjuvant therapy in women with evidence of axillary lymph node 
involvement following resection of primary breast cancer. 
 
Contraindications 

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Patients should not be treated with doxorubicin if they have any of the following 
conditions: baseline neutrophil count <1500 cells/ mm3; severe hepatic 
impairment; recent myocardial infarction; severe myocardial insufficiency; severe 
arrhythmias; previous treatment with complete cumulative doses of doxorubicin, 
daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones; or 
hypersensitivity to doxorubicin, any of its excipients, or other anthracyclines or 
anthracenediones. 
 
Dosage and Administration 
 Care in the administration of doxorubicin will reduce the chance of peri-venous 
infiltration.  It may also decrease the chance of local reactions such as urticaria 
and erythematous streaking. On intravenous administration of doxorubicin, 
extravasation may occur with or without an accompanying burning or stinging 
sensation, even if blood returns well on aspiration of the infusion needle. If any 
signs or symptoms of extravasation have occurred, the injection or infusion 
should be immediately terminated and restarted in another vein. If extravasation 
is suspected, intermittent application of ice to the site for 15 min. q.i.d. x 3 days 
may be useful. The benefit of local administration of drugs has not been clearly 
established. Because of the progressive nature of extravasation reactions, close 
observation and plastic surgery consultation is recommended. Blistering, 
ulceration and/or persistent pain are indications for wide excision surgery, 
followed by split-thickness skin grafting. The most commonly used dose schedule 
when used as a single agent is 60 to 75 mg/m2 as a single intravenous injection 
administered at 21-day intervals. The lower dosage should be given to patients 
with inadequate marrow reserves due to old age, or prior therapy, or neoplastic 
marrow infiltration. Doxorubicin has been used concurrently with other approved 
chemotherapeutic agents. Evidence is available that in some types of neoplastic 
disease combination chemotherapy is superior to single agents. The benefits and 
risks of such therapy continue to be elucidated. When used in combination with 
other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 
to 60 mg/m2 given as a single intravenous injection every 21 to 28 days. 
 
Reconstitution 
 After adding the diluent, the vial should be shaken and the contents allowed 
dissolving. The reconstituted solution is stable for 7 days at room temperature 
and under normal room light (100 foot-candles) and 15 days under refrigeration 
(2° to 8°C). It should be protected from exposure to sunlight. Discard any unused 
solution from the 10 mg, 20 mg and 50 mg single dose vials. Unused solutions of 
the multiple dose vial remaining beyond the recommended storage times should 
be discarded.  
 

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Doxorubicin Hydrochloride Injection, USP is a sterile parenteral, isotonic, 
available in 5 mL (10 mg), 10 mL (20 mg), 25 mL (50 mg), and 37.5 mL (75 mg) 
single dose vials and a 100 mL (200 mg) multidose vial. Each mL contains 
doxorubicin HCl and the following inactive ingredients: sodium chloride 0.9% and 
water for injection q.s. Hydrochloric acid is used to adjust the pH to a target pH of 
3.0.