Conditions: Lymphoma
Keywords: contiguous stage II adult diffuse large cell lymphoma noncontiguous stage II adult diffuse large cell lymphoma stage III adult diffuse large cell lymphoma stage IV adult diffuse large cell lymphoma contiguous stage II grade 3 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 3 follicular lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 138
Healthy volunteers: no

Brief summary:
RATIONALE: Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with rituximab and combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of lenalidomide when given together with rituximab and combination chemotherapy and to see how well they work in treating patients with newly diagnosed stage II, stage III, or stage IV diffuse large cell or follicular B-cell lymphoma.

Detailed description:
OBJECTIVES:

Primary

* To determine the maximum tolerated dose of lenalidomide when given in combination with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone in patients with newly diagnosed stage II-IV diffuse large cell or grade 3 follicular B-cell lymphoma. (Phase I)
* To assess the efficacy of this regimen, in terms of event-free survival and response rate, in these patients. (Phase II)
* To assess the safety of this regimen in these patients. (Phase II)

Secondary

* To assess the host immune function at baseline and after treatment and correlate these parameters with tumor response and event-free survival.

OUTLINE: This is a multicenter, phase I dose-escalation study of lenalidomide followed by a phase II study.

* Phase I: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine IV on day 1, oral prednisone on days 1-5, and oral lenalidomide on days 1-10. Patients also receive pegfilgrastim subcutaneously on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
* Phase II: Patients receive lenalidomide at the maximum tolerated dose determined in phase I and rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone, and pegfilgrastim as in phase I.

Blood is collected at baseline, before course 3, and after completion of study treatment for translational research studies. Research studies include immune function and cytokine analysis, T- and B- quantitative lymphocyte analysis, and single nucleotide polymorphism analysis.

After completion of study therapy, patients are followed every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 3 years.

Arms:

Interventions: intervention 1: pegfilgrastim intervention 2: rituximab intervention 3: cyclophosphamide intervention 4: doxorubicin hydrochloride intervention 5: lenalidomide intervention 6: prednisone intervention 7: vincristine sulfate intervention 8: polymorphism analysis intervention 9: laboratory biomarker analysis
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None

Protocol document:
Prot_SAP_000.pdf: 


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Index 
 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation   
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Consent Form 
Appendix I – 
Ann Arbor Staging System 
Appendix II –  ECOG Performance Status Scale  
Appendix III –  Patient Medication Diary 
 




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Brand name(s):  Revlimid®      
 
Mayo abbreviation: CC5013 
Availability:  Provided by Celgene 
Brand name:  Rituxan 
Mayo abbreviation: RITUX 
Availability:  Commercial  
Generic name:  Cyclophosphamide 
 
Brand name:  Cytoxan  
 
 
 
Mayo abbreviation:  CTX 
Availability:  Commercial 
Generic name:   Doxorubicin 
 
Brand name: 
Adriamycin 
 
 
 
Mayo abbreviation: ADR 
Availability:  Commercial 
Generic name:   Vincristine 
 
Brand name: 
 
 
 
Mayo abbreviation: VCR 
Availability:  Commercial 
Generic name:   Prednisone 
 
Brand name: 
 
 
 
 
 
Mayo abbreviation:  PRED 
Availability:  Commercial 
 


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1.0 
Background   
 
1.1 
Diffuse large cell lymphoma and follicular grade III B cell lymphoma.  
 
Non-Hodgkin’s lymphoma (NHL) is a heterogeneous group of malignancies of the 
lymphatic system, with a clinical course ranging from very indolent to highly 
aggressive(Armitage and Weisenburger 1998). Aggressive NHLs constitute 
approximately 60% of NHL, with diffuse large B-cell lymphoma (DLCL) being the most 
common (approximately half of all aggressive NHL cases). Follicular grade III NHL is 
thought to have similar biology and outcome to DLCL(Rodriguez, et al 1999) and 
traditionally the treatment approach to follicular grade III A and B lymphoma has been 
the same as to DLCL (Anderson, et al 1993, Bierman 2007). The following protocol 
treatment options will use the term DLCL broadly, with the inclusion of follicular grade 
III lymphoma unless specified otherwise. 
 
1.2 
Current treatment of diffuse large cell lymphoma. 
 
Anthracycline-containing combination chemotherapy remains the standard of care for the 
initial therapy of patients with advanced DLCL (Cooper, et al 1994, Gordon, et al 1992); 
of available combinations, a regimen of cyclophosphamide, doxorubicin, vincristine, and 
prednisone (CHOP) is the widely accepted choice due to its efficacy and favorable 
toxicity profile.  Recent studies have shown  an improvement in response rate (RR), event 
free survival (EFS) and overall survival (OS) rates with the addition of rituximab to the 
CHOP regimen (R-CHOP)(Coiffier, et al 2002, Habermann, et al 2006, Pfreundschuh, et 
al 2004).  The results of representative studies are summarized in Table 1.  
 
Table 1. Results of Phase 3 Studies in First-Line Treatment of Diffuse Large B-Cell Lymphoma 
 
Regiment 
N 
CR/C
Ru 
OS 
EFS/PFS 
Reference 
CHOP vs.  
RCHOP1 
197 
202 
63% 
75% 
45% at 5 yrs 
58% at 5 yrs 
EFS 29% at 5 yrs 
EFS 47% at 5 yrs 
Coiffier et al. 2002, 
Feugier et al. 2005 
CHOP-like vs. 
RCHOP like2 
411 
413 
67% 
81% 
84% at 3 yrs 
93% at 3 yrs 
EFS 59% at 3 yrs 
EFS 79% at 3 yrs 
Pfreundschuh et al. 
2006 
CHOP vs.  
RCHOP 
140 
152 
NR 
NR 
52% at 2 yrs 
78% at 2 yrs 
PFS 51% at 2 yrs 
PFS 69% at 2 yrs 
Sehn et al. 2005 
CHOP 
RCHOP3 
314 
318 
NR 
NR 
NS4 
 
EFS 46% at 3 yrs 
EFS 56% at 3 yrs 
Habermann et al. 2006 
1. Patients age 60 yrs and older. 
2. Patients age 18-60 yrs. 
3. RCHOP plus CHOP with R maintenance.  
4. Difference not significant, however, secondary randomization to maintenance was performed. 
 
As evident from the above cited studies, despite the improvements observed with the 
addition of rituximab, a significant proportion of patients will relapse, especially the 
elderly, those with bulky disease and high IPI score at diagnosis. Although some of the 
relapsed patients will be salvaged with second line chemotherapy (usually followed by 


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high dose chemotherapy with autologous stem cell transplantation for transplant eligible 
patients), the majority will succumb to the disease (Seyfarth, et al 2006, Singer and 
Goldstone 1986). Improvements in initial therapy leading to decreased relapse rates are 
clearly needed.   
 
1.3 
Lenalidomide in hematological malignancies. 
 
Lenalidomide (REVLIMID, Celgene Corp., NJ, USA) is a proprietary IMiD® 
compound. The mechanism of action of lenalidomide is complex and involves immune 
modulation(Haslett, et al 2003), antiangiogenetic potential(Zhang, et al 2005) and impact 
on the microenvironment and tumor itself(Pellagatti, et al 2007).  Lenalidomide is 
marketed in the United States for the treatment of subjects with transfusion dependent 
anemia due to low- or intermediate-1 risk myelodysplastic syndrome (MDS) associated 
with a deletion 5-q cytogenetic abnormality with or without additional cytogenetic 
abnormalities based on the improvement of anemia(List, et al 2005).  It is also used in 
combination with dexamethasone for subjects with previously treated multiple myeloma 
based on significant antitumor activity(Rajkumar, et al 2005, Richardson, et al 2002).  
 
Lenalidomide has also shown activity in refractory/relapsed chronic lymphocytic 
leukemia/small lymphocytic leukemia (CLL/SLL) (Chanan-Khan, et al 2006). Of forty-
five enrolled patients, the majority of which were fludarabine refractory, 47% had 
evidence of a response, with 9% of the patients attaining complete remission. Fatigue, 
thrombocytopenia, and neutropenia were the most common adverse effects noted in 83%, 
78%, and 78% of the patients respectively. “Flare reaction” – inflamed and often enlarged 
lymph nodes, was seen in 58% of patients, usually during the first cycle of therapy. The 
onset was usually seen within 24 hours of the first dose, with a median duration of 14 
days. The initial 29 patients did not receive any prophylaxis, and on development of the 
flare reaction, ibuprofen was used for treatment.  However, a few patients required 
additional oral morphine for pain control. Prednisone prophylaxis was used for the 
subsequent 16 patients, preventing flare. None of the patients (with or without the 
prophylaxis) required interruption, discontinuation, or dose reduction of therapy because 
of flare reaction. It appears that presence of flare reaction correlated with a high NK cell 
numbers prior to therapy and with clinical benefit (prolonged progression free survival) 
(Asher Chanan-Khan, personal communication, August 2007).  
 
1.4 
Lenalidomide in diffuse large cell lymphoma 
 
The phase II study of lenalidomide (Celgene 002) in patients with relapsed/refractory 
aggressive non-Hodgkin's lymphoma has been conducted and the initial results reported 
by Wiernik and Habermann et al document single-agent activity of lenalidomide in 
relapsed large cell NHL (Wiernik, 2007). Patients received 25 mg of lenalidomide orally 
once daily on days 1-21 every 28 days and continued therapy for 52 weeks as tolerated or 
until disease progression. As of enrollment cut-off, 50 patients were enrolled and 49 
received the drug. Forty-one patients were evaluable for response. The median age was 
65 (46-84) and 18 were female. Histology was DLBCL (n=21), follicular center 
lymphoma grade 3 [FL] (n=3), mantle cell lymphoma [MCL] (n=14) and transformed 
[TSF] (n=3). Fourteen patients (34%) exhibited an objective response (5 complete 
responses unconfirmed (CRu) and 9 partial responses (PR)), 12 had stable disease (SD) 


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for a tumor control rate (TCR) of 63% and 15 progressive disease (PD). Responses were 
seen in each of the aggressive histologic subtypes studied: DLBCL (5/21), MCL (6/14), 
FL (2/3), and TSF (1/3). Progression-free survival (PFS), although ongoing, is currently 
> 239 (>191 - >373) days in patients experiencing CRu and > 160 (>54 - >251) days in 
patients with PR. The drug was well-tolerated with the most common Grade 4 adverse 
events were neutropenia (8.2%) and thrombocytopenia (8.2%), while most common 
Grade 3 adverse events were neutropenia (22%), leukopenia (14%) and 
thrombocytopenia (12%). In contrast to CLL, tumor flare reaction was not seen. 
Preliminary data from the Celgene 003 trial of lenalidomide in relapsed aggressive NHL 
suggest that the absolute lymphocyte count is a factor in response (Submitted ASH 2007).  
 
The significant activity of single agent lenalidomide in relapsed diffuse large cell 
lymphoma, the novel mechanism of action with lenalidomide compared with traditional 
cytotoxic therapy, and the need to further improve the RCHOP regimen provides a strong 
rationale for bringing lenalidomide to upfront therapy in DLCL.  
 
1.5 
Rationale for Expansion Cohort 
 
Gene expression profiling revealed 3 molecular subsets of DLBCL: germinal-center B-
cell-like (GCB) vs. activated B-cell-like (ABC) vs. unclassified lymphoma subtype 
(UCL). The ABC DLBCL constitutes approximately 40% of all DLBCL and is 
associated with inferior outcome despite introduction of rituximab to therapy. The 2 year 
progression free survival for ABC DLBCL treated with RCHOP is 40% in contrast to 
82% for GCB type (Lenz et al, 2008).   
 
Therefore, there is a critical need to evaluate impact of therapy on outcomes of patients 
with DLBCL based on molecular subtype. Recent data indicate that there are significant 
differences in response rates and progression free survival for patients treated with 
lenalidomide based on molecular DLBCL subtype in a setting of refractory/relapsed 
disease (Czuczman et al., ASCO Annual Meeting, 2010 Abstract 8038). In this study of 
40 patients with relapsed DLBCL, lenalidomide treatment is associated with higher 
response rates and progression free survival in ABC-like DLBCL versus GCB-like 
DLBCL (50% vs. 11% and median PFS of 336 vs. 42 days). Importantly, lenalidomide 
was associated with meaningful clinical benefit in patients with both molecular subtypes 
of DLBCL. Indeed responding patients with GCB –like subtype enjoyed progression free 
survival similar to ABC group (median over 200 days). It is unknown if degree of the 
clinical benefit of lenalidomide in combination with chemotherapy is dependent on 
molecular DLBCL subtype in patients with newly diagnosed DLBCL. The expansion 
cohort allows analysis of outcomes of patients treated with R2CHOP based on DLBCL 
molecular subtype. 
 


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2.0 
Goals    
 
2.1 
Primary goals 
 
2.11 
To assess the safety and efficacy of lenalidomide in combination with standard 
induction therapy (rituximab, cyclophosphamide, doxorubicin, vincristine and 
prednisone - RCHOP) in patients with newly diagnosed diffuse large cell and 
follicular grade IIIA/B B-cell lymphoma.  
 
2.12  
Phase I trial: To establish the maximum tolerated dose of lenalidomide in 
combination with RCHOP chemotherapy.  
 
2.13  
Phase II trial: To assess the efficacy (event-free survival and response rate) and 
safety of this combination.  
 
2.2 
Secondary goals 
 
2.21  
To assess the host immune function at baseline and after treatment and how these 
parameters relate to tumor response and event-free survival.  
 
2.22 
To assess the efficacy of this combination in DLBCL patients with activated B-
cell-like lymphoma. 
 
2.23 
To assess the safety and efficacy of R2CHOP in patients with transformed or 
composite follicular lymphoma. 
 
3.0 
Patient Eligibility   
 
Phase I only: Prior to checking eligibility contact the Registration Office 
) for study 
status and dose level. 
 
3.1 
Inclusion Criteria 
 
3.11 
≥18 years of age. 
 
3.12 
One of the following untreated, histological confirmed lymphoma expressing 
CD20 antigen.  Criteria for diagnosis can be found in the following reference:  J 
Clin Oncol 17(4):1244-53, 1999:  
• 
DLBCL with disconcordant and/or composite pathology e.g. low grade 
follicular  lymphoma within bone marrow or lymph node are eligible 
• 
DLBCL transformation FL – untreated with anthracyclines or high dose 
chemotherapy/autologous stem cell transplantation; patients treated with 
rituximab alone, non-anthracycline containing regiments and previously 
observed only are eligible 
 
3.13 
Stages II, III, or IV (Ann Arbor Staging: see Appendix I). 
 
3.14  
Measurable disease (at least 1 lesion of ≥ 1.5 cm in one diameter) as detected by 
CT or the CT images of the PET/CT (PET/CT fusion).  Skins lesions can be used 
if the area is greater than or equal to 2cm in at least one diameter and 


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photographed with a ruler. 
 
3.15 
ECOG Performance Status (PS) 0, 1, or 2 (see Appendix II). 
 
3.16 
The following laboratory values obtained ≤ 14 days prior to registration: 
• 
ANC ≥ 1500 
• 
PLT ≥ 100,000 
• 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) or if total bilirubin is 
>1.5 x ULN, the direct bilirubin must be normal 
• 
Alk. phosphatase ≤ 3 x ULN unless evidence of the direct liver involvement 
by lymphoma – then ≤ 5xULN 
• 
AST ≤ 3 x ULN unless evidence of the direct liver involvement by 
lymphoma – then ≤ 5xULN 
• 
Creatinine ≤ 2 x ULN 
 
3.17 
Females of reproductive potential must be willing to adhere to the scheduled 
pregnancy testing as required in the REVLIMID REMS™ program. 
 
3.18 
Willingness to provide informed written consent. 
 
3.19a 
Willingness to return to enrolling institution for follow-up. 
 
3.19b Patient willing to provide blood samples for research purposes (see Sections 6.2 
and 14.0).  
 
3.19c 
Patients who are not already on anticoagulation should be able to take low-dose 
aspirin (81 mg) daily.  NOTE: If aspirin is contraindicated for other reasons, the 
patient may be considered for the study after consultation with the study chair 
regarding other alternatives including the possible use of warfarin or low 
molecular weight heparin.  Patients unable to take any form of prophylaxis are 
not eligible. 
 
3.19d Willing to be registered into the mandatory REVLIMID REMS™ program, and 
willing and able to comply with the requirements of the REVLIMID REMS™ 
program.


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3.2 
Exclusion Criteria  
 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown:  
• 
Pregnant women 
• 
Nursing women (lactating females are eligible provided that they agree not to 
breast feed while taking lenalidomide) 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception  
 
3.22   CNS lymphoma or cerebrospinal fluid involvement with malignant lymphoma 
cells. 
 
3.23 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.24 
Known to be HIV positive or immunocompromised with posttransplant 
lymphoproliferative disorder (PTLD). 
 
3.25 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.26 
Receiving any other agent which would be considered as a treatment for the 
lymphoma.  
 
3.27 
Another active malignancy requiring therapy such as radiation, chemotherapy, or 
immunotherapy.  Exceptions to this are as follows: localized nonmelanotic skin 
cancer and any cancer that in the judgment of the investigator has been treated 
with curative intent and will not interfere with the study treatment plan and 
response assessment.  Patients with ≥ 25% of the bone marrow radiated for other 
diseases are not eligible. 
 
3.28 
History of myocardial infarction ≤ 6 months, or congestive heart failure requiring 
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. 
 
3.29a    Ejection fraction of <45% by either MUGA or ECHO.  
 
3.29b    History of life threatening or recurrent thrombosis/embolism.  Patients may 
participate if they are on anticoagulation during the treatment. 
 
3.29c 
Receiving erythroid stimulating agents (EPO: Procrit, Aranesp). 


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4.0 
Test Schedule  
 
Active Monitoring Phase 
 
 
Active treatment 
Observation 
Tests and procedures 
≤ 14 days 
prior to 
registration 
≤ 2 days (±2 days) prior 
to 
subsequent 
treatment (cycles 2-6) 
During interval 
between 
cycles 
After completion of 
therapy (4-6 weeks 
after  day 1 of cycle 
6) 
Every 3 
months for 
 year 1 
Every 4 months 
for year 2 
History and exam, weight,  
X 
X 
 
X 
X 
X 
Adverse event assessment 
X 
X 
 
X 
X 
X 
Height, ECOG PS 
X 
 
 
 
 
 
Registered in the REVLIMID 
REMS™  program 
X16 
X16 
X16 
X16 
 
 
Serum  or urine pregnancy 
test1 
X1 
X1 
X1 
X1 
 
 
Tumor tissue sample for 
confirmation of diagnosis 
X2 
 
 
 
 
 
Hematology group 
 CBC (HgB, WBC, 
Differential, PLT) 
X 
X 
Weekly 
X 
X 
X 
Chemistry group 
Total bilirubin, AST, Alk. 
Phosphatase, LDH, 
Creatinine, Sodium, 
Potassium, Calcium 
X 
X 
 
X 
X 
X 
Direct bilirubin4 
X 
 
 
 
 
 
Hepatitis B and C screen3 
X 
 
 
 
 
 
HIV screen 
X 
 
 
 
 
 
Tumor 
Measurement/Evaluation of 
indicator lesion (CT chest, 
abdomen, pelvis; other CT 
and/or MRI when indicated)12 
X14 
Before cycle 3 
 
X 
X 
X 
PET scan 
X17 
Before cycle 313 
 
X5 
 
 
Bone marrow aspirate and 
biopsy (unilateral or bilateral) 
X15 
 
 
X6 
 
 
 


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Active Monitoring Phase 
 
 
Active treatment 
Observation 
Tests and procedures 
≤ 14 days 
prior to 
registration 
≤ 2 days prior to 
subsequent 
treatment (cycles 2-6) 
During interval 
between 
cycles 
After completion of 
therapy (4-6 weeks 
after day 1 of cycle 
6) 
Every 3 
months for 
 year 1 
Every 4 months 
for year 2 
Electrocardiogram 
X17 
 
 
 
 
 
Left ventricular function 
measurement 
X7, 17 
 
 
 
 
 
Cerebrospinal fluid analysis 
X8 
 
 
 
 
 
Research blood samples R 
X 
Before cycle 3R 
 
XR 
 
 
Research tissue samples R9 
X 
X10,11 
 
 
 
 
1.  Pregnancy tests for females of childbearing potential.  Patient must follow pregnancy testing requirements as outlined in the REVLIMID 
REMS™ program. 
2.  Central review of pathology is required for confirmation of diagnosis and CD20 positivity. Completion of central pathology review is not 
required prior to registration for patients requiring urgent treatment in opinion of investigator (see Section 17.0), however materials for central 
review must be submitted within 42 days after registration.  
3.   Hepatitis B surface antigen (HbsAg) and antibody to Hepatitis B core (anti-HBc); Hepatitis C antibody  
4.  To be done only if the total bilirubin is abnormal. 
5.  If positive after the completion of cycle 6, a biopsy of PET positive area may be done at MD discretion.  
6.  Repeat BM only required if initial BM was positive.  
7.  MUGA or Echo. 
8.  A lumbar puncture and cytologic examination of the cerebrospinal fluid is not required, but should be performed if clinically indicated. 
9.  Paraffin blocks of tumor tissue from initial diagnosis will be requested for research, Section 17. Patients undergoing excisional biopsies should 
have excess tissue frozen as part of Mayo IRB118-01 (SPORE Cell Bank). 
10.  Prior to cycle 2 a core needle biopsy will be performed for research purposes in consenting patients with easily accessible tumor; the biopsy is 
not mandatory for study treatment. 
11.  For patients who have a repeat biopsy for any reason while on study, excess tissue will be submitted for research purposes.  
12.  Measurements should preferably be done by dedicated CT or MRI; however, they can be done off the CT images of a PET/CT if that 
demonstrates the lesion more clearly.  The image number should be included with the measurements.  If patient has had PET/CT that can 
satisfy the PET and CT requirement.  If questions, call the study chair. 


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13.  PET is mandatory pre- and post-treatment.  It is optional after 2 cycles; however, if PET/CT being used for the measureable lesion then it will 
be required before cycle 3.   
14. CT must be done ≤ 28 days prior to study registration. 
15. Bone marrow must be done ≤ 6 weeks prior to study registration. 
16. All unused lenalidomide must be returned as instructed through the REVLIMID REMS™ program. 
17. Must be done ≤ 28 days prior to study registration. 
R.   Research funded study. 


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5.0 
Grouping Factors:  
 
5.1 
Phase I vs. Phase II. 
 
6.0  
Registration/Randomization Procedures 
6.1 
Registration Procedures 
 
6.11 
Phase I Dose Escalation – Prior to discussing protocol entry with the patient, call 
the Registration Office to insure that a place on the protocol is open to the 
patient. 
 
6.111 To register a patient, call 
) a completed eligibility 
checklist to the Registration Office between 8 a.m. and 4:30 p.m. central 
time Monday through Friday. 
 
6.12 
Phase II 
 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the remote registration/randomization application.  The remote 
registration/randomization application is available 24 hours a day, 7 days a week. 
 Back up and/or system support contact information is available on the Web site. 
 If unable to access the Web site, call the MCCC Registration Office at 
 
 between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
 
The instructions for the registration/randomization application are available on 
the MCCC web page 
and detail the process 
for completing and confirming patient registration.  Prior to initiation of protocol 
treatment, this process must be completed in its entirety and a MCCC subject ID 
number must be available as noted in the instructions.  It is the responsibility of 
the individual registering the patient to confirm the process has been successfully 
completed prior to release of the study agent.  Patient registration via the remote 
system can be confirmed in any of the following ways: 
 
 
• 
Contact the MCCC Registration Office 
.  If the patient was 
fully registered, the Registration Office staff can access the information from 
the centralized database and confirm the registration. 
 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 
6.2 
Translational Research  
 
A mandatory translational research component for blood specimens is part of this study; 
the patient will be automatically registered onto this component (Sections 3.19 and 14.0).  
 
An optional correlative research component is part of this study, there will be an option to 
select if the patient is to be registered onto this component (see Section 17.0). 
 


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• 
Patient has/has not given permission to allow previously collected tumor tissue 
biopsy to be used for research studies. 
 
6.3 
A signed HHS 310 form must be on file in the Registration Office before an investigator 
may register any patients.  Ongoing approval documentation must be submitted (no less 
than annually) to the Registration Office.  
 
6.4 
Prior to the patient being registered, the following will be verified: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
At the time of registration/randomization, the following will also be recorded: 
• 
Patient has/has not given permission to store sample(s) for present and future 
research of lymphoma or other health problems at Mayo and to give his/her sample to 
other researchers at other institutions for research. 
 
• 
Patient has/has not given permission to participate in the optional lymphoma research 
tissue biopsy before treatment, prior to cycle two, and to allow any excess tissue 
collected while on this study to be used for research studies. 
 
6.5 
Treatment on this protocol must commence at a Mayo Clinic Institution under the 
supervision of a hematologist/oncologist.  
 
6.6 
Treatment cannot begin prior to registration and must begin ≤ 7 days after registration. 
 
6.7 
Pretreatment tests must be completed within the guidelines specified on the test schedule. 
 
6.8 
All required baseline symptoms must be documented and graded. 
 
6.9 
Study drug availability checked. 
 


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7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule. 
 
7.11 
Pretreatment medications. Standard antiemetic prophylaxis will be given per 
RCHOP guidelines.  
 
7.12  
Phase I Cohort:  Lenalidomide RCHOP regimen 
 
Agent 
Dose 
Route 
 Day 
 Cycle Length 
Rituximab1 
375 mg/m2 
IV 
Day 1 
Every 21 days 
Cyclophosphamide2 
750 mg/m2 
IV 
Day 1 
Every 21 days 
Doxorubicin3 
50 mg/m2 
IV 
Day 1 
Every 21 days 
Vincristine 
1.4 mg/m2 
(max 2 mg) 
IV 
Day 1 
Every 21 days 
Prednisone4 
100 mg/m2 
po 
Day 1-5 
Every 21 days 
Lenalidomide5 
As assigned by 
Randomization 
Center 
po 
Day 1-10 
Every 21 days 
Pegfilgrastim 
6 mg 
SC 
Day 2 
Every 21 days 
1. Rituximab may be rounded to nearest 50 mg. 
2. Cyclophosphamide dose may be rounded to nearest 50 mg 
3. Doxorubicin dose may be rounded to nearest 5 mg 
4. Prednisone dose rounding to nearest 10 mg 
5. See Ancillary Treatment section 9.1 regarding anticoagulation recommendations. 
 
7.13  
Phase 2 Cohort:  Lenalidomide RCHOP regimen (at MTD from phase I) 
 
Agent 
Dose 
Route 
 Day 
 Cycle Length 
Rituximab1 
375 mg/m2 
IV 
Day 1 
Every 21 days 
Cyclophosphamide2 
750 mg/m2 
IV 
Day 1 
Every 21 days 
Doxorubicin3 
50 mg/m2 
IV 
Day 1 
Every 21 days 
Vincristine 
1.4 mg/m2 (max 
2 mg) 
IV 
Day 1 
Every 21 days 
Prednisone4 
100 mg/m2 
po 
Day 1-5 
Every 21 days 
Lenalidomide5 
25 mg 
po 
Day 1-10 
Every 21 days 
Pegfilgrastim 
6 mg 
SC 
Day 2 
Every 21 days 
1. Rituximab may be rounded to nearest 50 mg. 
2. Cyclophosphamide dose may be rounded to nearest 50 mg 
3. Doxorubicin dose may be rounded to nearest 5 mg 
4. Prednisone dose rounding to nearest 10 mg 
5. See Ancillary Treatment section 9.1 regarding anticoagulation recommendations. 
 
 


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7.2 
Phase I dose escalation and determination of MTD. 
 
7.21 
Dose escalation of lenalidomide 
 
Dose level 
 
 Dose 
 Day 
 Route 
-2 
Lenalidomide 
5 mg 
Day 1-10 
orally 
-1 
Lenalidomide 
 10 mg 
Day 1-10 
orally  
*1 
Lenalidomide 
 15 mg 
Day 1-10 
orally  
2 
Lenalidomide 
20 mg  
Day 1-10 
orally  
3 
Lenalidomide 
25 mg  
Day 1-10 
orally  
 
 
*starting dose level  
 
7.211  Three patients will be treated at each dose level and observed for a 
 
minimum of 3 weeks (1 cycle), to assess toxicities, before new patients 
are treated.  Doses will not be escalated in any individual patient 
because of the risk of cumulative toxicity. 
 
 
 
 
7.212 Investigators are to contact the Study Chair as soon as any dose-limiting 
toxicity occurs. 
 
7.22 
Definitions of Dose Limiting Toxicity (DLT) 
 
7.221 For this protocol, dose-limiting toxicity (DLT) will be defined as 
follows: an adverse event attributed (definitely, probably or possibly 
related) to the study treatment and meeting following criteria with the 
first cycle: 
 
 
 
Toxicity 
Definition 
Hematologic 
Either: 
1. PLT <25,000 for ≥7days or platelet nadir <10,000 at 
anytime 
2. Failure to recover counts to PLT ≥ 75,000 and/or ANC 
≥1500 by day 28 after initiation of cycle 1 treatment. 
Infection 
Grade 4 
Non-hematologic 
Either: 
1. ≥ grade 3 as per NCI Common Terminology Criteria 
for Adverse Events v3.0*  
2. Any toxicities that caused dose delay of > 1 week of 
the intended next dose 
*Grade 3 nausea, vomiting, or diarrhea with maximal supportive treatment(s) will be 
considered dose-limiting. Fatigue and mouth sores that are considered Grade 3 and are 
considered to be due to treatment (definitely, probably, or possibly related) will be 
considered as dose-limiting. 
 
 
7.23 
Maximal Tolerated Dose (MTD) Determination 
 
 
The MTD in this study will be defined as the dose level below the lowest dose 
that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a 
maximum of 6 new patients). This will be defined on cycle 1 data; however, 


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toxicity data will be collected during all cycles and monitored for cumulative 
toxicity. 
 
7.24 
Dose Escalation 
 
7.241 Three patients will be treated at a given dose level combination and 
observed for at least 3 weeks to assess toxicity. 
 
7.242 If dose-limiting toxicity (DLT) is not seen in any of the 3 patients, up to 
3 new patients will be accrued and treated at the next higher dose level 
(as specified in 7.21). If DLT is seen in 2 or 3 of 3 patients treated at a 
given dose level, then the next 3 patients will be treated at the next lower 
dose level, if only 3 patients were enrolled and treated at this lower dose 
level.  
 
7.243 If a DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. If 
DLT is seen in at least one of these additional three patients (≥2 of 6), the 
MTD will have been exceeded, and further accrual will cease to this 
cohort. If potentially dose-limiting toxicity (DLT) is not seen in any of 
the three additional patients, 3 new patients will be accrued and treated at 
the next higher dose level. 
 
7.245 If DLT is observed in at least 2 of 6 patients after enrolling 6 patients on 
a specific dose level, then the MTD will have been exceeded and defined 
as the previous dose unless only 3 patients were treated at the lower dose 
level. In that case, 3 additional patients will be treated at this lower dose 
level such that a total of 6 patients are treated at the MTD to more fully 
assess the toxicities associated with the MTD.  
 
7.25 
Dose De-escalation from Dose Level 1 
 
7.251  If 2 treatment-related DLTs are observed at the starting dose level, 
patients will be accrued to level -1. The accrual rules based on observed 
DLT will be as outlined in 7.24 with deceleration to dose -2 if necessary.  
 
7.26 
If a patient in phase I part fails to complete cycle 1 for reasons other than 
toxicity, the patient will be regarded as inevaluable and will be replaced.  In each 
instance, however, a specific notification needs to be made for review by the 
Oncology Research Executive Committee. 
 


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8.0 
Dosage Modification Based on Adverse Events - Strictly follow the modifications in this table 
for the first two cycles, until individual treatment tolerance can be ascertained.  Thereafter, these 
modifications should be regarded as guidelines to produce mild-to-moderate, but not debilitating, 
side effects.  If multiple adverse events are seen, administer dose based on greatest reduction 
required for any single adverse event observed.  Reductions or increases apply to treatment given 
in the preceding cycle and are based on adverse events observed since the prior dose. 
 
Omit = The current dose(s) during a cycle is skipped. The patient does not make up the omitted dose(s) at 
a later time. 
Hold = Refers to decision made at the beginning of the cycle to delay the start of the cycle until the 
patient meets the protocol criteria to restart drug. 
 
 
NOTE: Patients in whom one or more R2CHOP study treatment agents have been discontinued will 
remain on study unless all R2CHOP study treatment agents are discontinued.  Patients in whom all the 
R2CHOP study treatment agents were discontinued will proceed to event monitoring (see Section 18.0). 
 
 
 
 
 
Table 8.1 Dose Levels (Based on Adverse Events in Table 8.2) 
 
Dose level 
 
 Dose 
 Day 
 Route 
-2 
Lenalidomide 
5 mg 
Day 1-10 
orally 
-1 
Lenalidomide 
 10 mg 
Day 1-10 
orally  
1 
Lenalidomide 
 15 mg 
Day 1-10 
orally  
2 
Lenalidomide 
20 mg  
Day 1-10 
orally  
3 
Lenalidomide 
25 mg  
Day 1-10 
orally  
 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
Table 8.2 Adverse Events and Dose Modifications.  
 
Use Common Terminology Criteria for Adverse Events (CTCAE) v3.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Blood/Bone marrow 
Hematologic nadirs: 
ANC<500 for ≥7 days 
or 
PLT<25,000 for ≥7 
days or <10,000 at any 
time 
Lenalidomide/ 
CTX/ADR 
 
Decrease lenalidomide to the next lowest dose 
level. If AE reoccurs with subsequent cycles, 
decrease lenalidomide to the next lowest dose 
level etc. If the lowest dose level is reached and 
AE occurs, discontinue lenalidomide. If AE 
occurs after lenalidomide discontinued, decrease 
CTX and ADR by 25% and follow standard 
dosing guidelines.  
Cardiac General 
Left ventricular systolic 
dysfunction ≥ grade 3 
ADR 
Discontinue ADR.  
Renal/Genitourinary 
Cystitis ≥ grade 2 
CTX 
Omit CTX until resolution of cystitis. Decrease 
CTX 50% of preceding dose for next cycle of 
treatment. If subsequent cycle is well tolerated 
and there is no grade ≥2 renal/GU adverse events, 
increase CTX to 100% of the original dose. 
Neurology 
Neuropathy – motor 
Grade 2 
VCR 
 
Omit VCR until neuropathy < grade 2 and resume 
at 50% dose reduction. 
Neuropathy – motor 
Grade ≥ 3  
Discontinue VCR. 
Neuropathy – sensory 
Grade 3  
Omit VCR until neuropathy <grade 2 and resume 
at 50% dose reduction. 
Neuropathy – sensory 
Grade 4 
Discontinue VCR 
Allergy/Immunology 
Allergic reaction or 
hypersensitivity: 
Grade 2 
Lenalidomide 
 
Omit treatment until ≤ grade 1 and restart with 
prophylaxis. If questions, call study chair. 
 
Allergic reaction or 
hypersensitivity: 
Grade 3 
Omit therapy; treat the reaction and restart at MD 
discretion. 
 
Allergic reaction or 
hypersensitivity:  
Grade 4 
If attributable to lenalidomide, discontinue 
treatment with lenalidomide. 
Vascular 
Venous 
thrombosis/embolism 
Grade 3 or 4 
Discontinue lenalidomide. 
 
 
Use Common Terminology Criteria for Adverse Events (CTCAE) v3.0 unless otherwise specified  


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Gastrointestinal 
Nausea/Vomiting ≥ 
Grade 3 
Lenalidomide/ 
RCHOP 
 
Maximize antiemetic therapy; if maximized 
antiemetic treatment ineffective, take off 
treatment at physician discretion.  
Mucositis/Stomatitis ≥ 
Grade 2  
ADR 
Decrease ADR by 25% of preceding dose for next 
cycle. If no grade ≥3 GI toxicities in subsequent 
cycle, increase ADR to 100% of original dose. 
Constipation grade 2 
 
 
Constipation ≥ grade 3 
Lenalidomide 
Initiate bowel regimen and continue lenalidomide. 
 
Omit lenalidomide until grade 2, initiate bowel 
regimen and restart lenalidomide. 
Dermatology/ 
Skin 
Desquamating 
(blistering rash) grade 3 
Lenalidomide 
Omit lenalidomide until ≤ grade 2 and restart at 
next lower dose level. If Lenalidomide held for 
more that 21 days, call study chair. 
Desquamating 
(blistering rash) grade 4 
Discontinue lenalidomide. 
Non desquamating rash 
grade 4 
Discontinue lenalidomide. 
Infection 
 
Infection with 
ANC ≥ 1,000/μL 
 
Lenalidomide/ 
RCHOP 
 
Hold drugs in case of an infection requiring IV 
antibiotics or hospitalization and restart when 
infection is controlled. If dosing is held ≥ 21 days 
call study chair.  
 
If adverse event reoccurs on subsequent cycles, 
decrease lenalidomide to next lower dose level 
and consider prophylactic antibiotics. If AE re-
occurs at this dose level call study chair. 
 
Infection with 
ANC < 1,000/μL 
Hold drugs in case of an infection requiring IV 
antibiotics or hospitalization and restart when 
infection is controlled, decrease lenalidomide to 
the next lowest dose level. If dosing is held ≥ 21 
days call study chair.  
 
If adverse event reoccurs despite discontinuation 
of lenalidomide, then on subsequent cycle reduce 
CTX by 25% and ADR by 25%, consider 
prophylactic antibiotics. If dosing is held ≥ 21 
days, call study chair. 
 
New or reactivation of 
viral hepatitis  
Discontinue treatment, treat hepatitis.  


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
 
Use Common Terminology Criteria for Adverse Events (CTCAE) v3.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
BASED ON INTERVAL ADVERSE EVENT 
Other non-
hematologic 
Grade 3 or 4* 
Lenalidomide/ 
RCHOP 
 
Hold drugs until toxicity has resolved to grade 2 
or baseline grade then restart drugs.   If questions, 
contact the study chair. 
*Nausea and vomiting of grade 3 or 4 after full anti-emetic therapy will then follow dose reduction 
guidelines. 
 
Use Common Terminology Criteria for Adverse Events (CTCAE) v3.0 unless otherwise specified  
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
AGENT 
 
DOSAGE CHANGE 
AT TIME OF RETREATMENT 
Blood/Bone marrow 
ANC<1500 
PLT< 75,000 
 
 
 
 
Lenalidomide/ 
RCHOP 
 
Hold drugs. Repeat CBC/diff and if counts 
recover anytime before or on d28 to ANC ≥1500 
and PLT ≥75,000 proceed with full dose. 
Between days 29-35: 
ANC ≥1500,   PLT 
≥75,000 
Decrease lenalidomide to the next lowest dose 
level, continue 100% RCHOP. If lenalidomide at 
the lowest dose level, discontinue.  If not 
recovered continue to hold. 
Day 36 and beyond: 
ANC ≥1500,  
PLT ≥75,000 
Discontinue lenalidomide, resume RCHOP with 
25% ADR and 25% CTX dose reduction.  Future 
dose modifications of RCHOP should follow 
standard RCHOP guidelines. 
Other non-
hematologic 
Grade ≥ 3* 
 
Hold drugs until toxicity has resolved to grade 2 
or baseline grade then restart lenalidomide at next 
lower dose level. If lenalidomide is at lowest 
level, discontinue. If next cycle is delayed by ≥ 2 
weeks, contact study chair.  
*Nausea and vomiting of grade 3 or 4 after full anti-emetic therapy will then follow dose reduction 
guidelines. 
 
9.0 
Ancillary Treatment 
 
9.1 
Patients who are not already on anticoagulation should receive low-dose aspirin (81 mg) 
daily.  This should be discontinued if platelets are <50,000 or if the patient is intolerant of 
aspirin or develops bleeding complications irrespective of the platelet count.  If aspirin is 
contraindicated for other reasons – call study chair.  
 
9.2 
Patients should be given a proton pump inhibitor while on aspirin or other prophylaxis 
per MD discretion. 
 
9.3 
Antiemetics may be used at the discretion of the attending physician. 
 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
9.4 
Tumor lysis syndrome prophylaxis will be used at the discretion of the treating physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  Pegfilgrastim support will be 
given with each cycle. Treat as needed.  
 
9.3 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
9.4 
Diarrhea:  This could be managed conservatively with anti-diarrheal agents such as 
loperamide.  The recommended dose of loperamide is 4 mg at first onset, followed by 2 
mg every 2-4 hours until diarrhea free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
9.5 
Use of statin drugs (i.e. Lipitor, Zocor, etc.) is strongly discouraged while on study 
treatment.  If statins are strongly indicated patients may continue at discretion of treating 
MD.  If questions contact the study chair. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) 
v3.0 for adverse event monitoring and reporting.  The CTC v3.0 can be accessed via the 
CTEP home page: http://ctep.cancer.gov/.  All appropriate treatment areas should have 
access to a copy of the CTCAE v3.0. 
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE.  Next, 
determine whether the event is expected or unexpected (refer to Sections 10.12 
and 15.0) and if the adverse event is related to the medical treatment or procedure 
(see Section 10.13).  With this information, determine whether an adverse event 
should be reported as an expedited report (see Section 10.2) in addition to the 
routinely reported clinical data (see Sections 10.31 and 18.0). 
 
Expedited adverse event reporting requires submission of a written report, but 
may also involve telephone notifications.  Telephone and written reports are to be 
completed within the timeframes specified in Section 10.2.  All expedited 
adverse event reports should also be submitted to the local Institutional Review 
Board (IRB).   


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
 
10.12 Expected vs. Unexpected 
• 
The determination of whether an AE is expected is based on agent-specific 
adverse event information provided in Section 15.0 of the protocol. 
• 
Unexpected AEs are those not listed in the agent-specific adverse event 
information provided in Section 15.0 of the protocol. 
 
10.13 Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the investigational agent(s). 
Probable - The adverse event is likely related to the investigational agent(s). 
Possible - The adverse event may be related to the investigational agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational 
agent(s) 
 
10.14 When a study includes both investigational and commercial agents, the following 
apply: 
 
• 
When an investigational agent(s) is used in combination with a commercial 
agent(s), the combination is considered investigational.  Expedited reporting 
of adverse events follows the guidelines for investigational agents. 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
10.2 
Expedited Adverse Event Reporting Requirements  
 
 
Grade 4 or 51 
Unexpected  
with  
Attribution of Possible, 
Probable, or Definite 
Other Grade 4 or 5 
or  
Any hospitalization 
during treatment4 
Secondary 
AML/MDS2 
 
 
 
 
Submit written report within 5 working 
days3, 5 
X 
 
 
submit written report within 15 working 
days3 
 
 
X 
Submit Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form 
within 5 working days.4  
 
X4 
 
1. Includes all deaths within 30 days of the last dose of investigational agent regardless of attribution or 
any death attributed to the agent(s) (possible, probable, or definite) regardless of timeframe.  
2. Reporting for this AE required during or after treatment. 
3. Use Adverse Event Expedited Report – Single Agent or Multiple Agents report form.  Provide copies, 
along with the UPIRTSO cover sheet, by fax 
to the MCCC Regulatory Affairs Unit 
(RAU) Risk Information Specialist who will determine and complete IRB reporting. The RAU will 
submit to the MCCC SAE Coordinator and the MCCC IND Coordinator to determine if FDA 
submission is needed. 
4.  Complete a Notification Form: Grade 4 or 5 Non-AER Reportable Events/Hospitalization Form 
electronically via the MCCC Remote Data Entry System within 5 working days of the date the 
clinical research associate (CRA) is aware of the event(s) necessitating the form.  If an expedited 
written report has been submitted, this form does not need to be submitted. See exceptions to the 
submission of this notification form in section 10.21.  
5. See Section 10.21 for Celgene specific reporting requirements. 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
 
10.21  Special Situations for Expedited Reporting and Submission of 
Notification Form 
 
Exceptions to Expedited Reporting and Submission of Notification Form: 
EXPECTED Serious Adverse Events 
 
An expedited report or notification form may not be required for specific Grade 
1, 2, 3, and 4 Serious Adverse Events where the AE is EXPECTED. Any 
protocol specific reporting procedures MUST BE SPECIFIED BELOW and will 
supercede the standard Expedited Adverse Event Reporting Requirements:  
 
System Organ Class (SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the 
event will not be 
expeditedly reported. 
Investigations 
Leukocyte count decreased 
≤4 
Neutrophil count decreased 
≤4 
Platelet count decreased 
≤4 
 
Lymphocyte count decreased 
≤4 
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event.  These exceptions 
only apply if the adverse event does not result in hospitalization.  If the adverse event 
results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed. 
 
10.22 Celgene Reporting Requirements: 
 
10.221  Serious Adverse Event (SAE) Reporting  
 
A serious adverse event is one that at any dose (including overdose): 
• 
Results in death 
• 
Is life-threatening1 
• 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
• 
Results in persistent or significant disability or incapacity2 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event3 
• 
Suspected positive pregnancy 
 
 1“Life-threatening” means that the subject was at immediate risk of 
death at the time of the serious adverse event; it does not refer to a 
serious adverse event that hypothetically might have caused death if it 
were more severe. 
2“Persistent or significant disability or incapacity” means that there is a 
substantial disruption of a person’s ability to carry out normal life 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
functions. 
3Medical and scientific judgment should be exercised in deciding 
whether expedited reporting is appropriate in situations where none of 
the outcomes listed above occurred.  Important medical events that may 
not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed in the definition above should also usually 
be considered serious.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  
A new diagnosis of cancer during the course of a treatment should be 
considered as medically important.  
 
10.222 Expedited reporting by investigator to Celgene 
 
Serious adverse events (SAE) are defined above.  The investigator must 
inform Celgene in writing 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 MEDWATCH. A final report to 
document resolution of the SAE is required.  The Celgene protocol 
number (RV-NHL-PI-325) and 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 patient records. 
 
 
 
10.223 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.  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 subject until completion of the 
pregnancy, and must notify Celgene Drug Safety immediately of 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 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
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  






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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
10.3 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per Common Terminology Criteria for Adverse Events (CTCAE) 
v3.0 grading unless otherwise stated: 
 
Category 
Adverse Event/Symptoms 
Baseline 
Each 
evaluation 
Blood/Bone marrow 
Neutrophils/granulocytes (ANC/AGC) 
X 
X 
 
Platelets 
X 
X 
Infection 
Febrile neutropenia (fever of unknown 
origin without clinically or 
microbiologically documented infection) 
(ANC ≤1.0 x 109/L, fever ≥ 38.5°C) 
X 
X 
 
10.31 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.3: 
 
10.311 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.312 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure 
 
10.313 Grade 5 AEs (Deaths) 
 
10.3131 Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure 
 
10.3132 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, with a 
CTCAE type and attribution assigned. 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
11.0 
Treatment Evaluation 
 
11.1 
Definition for clinical response for patients with lymphoma are from the Cheson et al. 
Revised Response Criteria for Malignant Lymphoma (Cheson, et al 2007), aggressive 
PET positive lymphomas section. Lymph node measurements should be taken from CT, 
CT portion of the PET/CT, or MRI scans where applicable.  Measurement of 
lymphadenopathy will be determined by adding the sum of the products of the maximal 
perpendicular diameters of measured lesions (SDP).  Measurable extranodal disease 
should be assessed in a manner similar to that for nodal disease. For these 
recommendations, the spleen is considered nodal disease. Disease that is only assessable 
(eg, pleural effusions, bone lesions) will be recorded as present or absent only, unless, 
while an abnormality is still noted by imaging studies or physical examination, it is found 
to be histologically negative 
 
Response is based on CT alone or the CT component of PET/CT or MRI where 
applicable and the PET.  
 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
Response criteria, modified from Cheson et al. 2007. DLCL and follicular grade III lymphoma are 
considered FDG avid. 
 
Response Category 
Definition 
Nodal Masses 
Spleen, liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease. 
Mass of any size 
permitted if PET 
negative  
 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate by 
morphology, 
immunohistochemi
stry should be 
negative 
PR 
Regression of 
measurable disease 
and no new sites 
50% decrease in 
SPD of up to 6 
largest dominant 
masses; no 
increase in size of 
other nodes 
and 
one or more PET 
positive at 
previously 
involved site 
50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be specified 
SD 
Failure to attain 
CR/PR or PD 
PET positive at 
prior sites of 
disease and no 
new sites on CT or 
PET 
 
 
Relapse/Progressive 
disease 
Any new lesion or 
increase by 50% 
of previously 
involved sites from 
nadir 
Appearance of a 
new lesion(s) > 1.5 
cm in any axis, 
50% increase from 
nadir in SPD of 
more than one 
node, or 50% 
increase in longest 
diameter of a 
previously 
identified node > 1 
cm in short axis. 
The lesions 
referred to above 
are required to be 
PET positive.  
> 50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission 
tomography; CT, computed tomography; PR, partial remission; SPD, sum of the product of the diameters; 
SD, stable disease; PD, progressive disease. 
11.2 
Complete Response (CR) 
 


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Protocol Version Date:  30Nov2017 
11.21 Complete disappearance of all detectable clinical evidence of disease and 
definitely disease-related symptoms if present before therapy.  
 
11.22 DLCL and follicular lymphoma are FDG-avid lymphomas: in patients with no 
pretreatment PET scan or when the PET scan was positive before therapy, a post-
treatment residual mass of any size is permitted as long as it is PET negative. 
 
11.23 The spleen and/or liver, if considered enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination 
and should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear. However, determination of splenic involvement is 
not always reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or causes other than lymphoma. 
 Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have decreased in 
size. 
 
11.24 If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must have cleared on repeat bone marrow biopsy. The biopsy sample on which 
this determination is made must be adequate (with a goal of > 20 mm unilateral 
core). If the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. A sample that is negative by immunohistochemistry but 
that demonstrates a small population of clonal lymphocytes by flow cytometry 
will be considered a CR until data become available demonstrating a clear 
difference in patient outcome.  
 
11.3 
Criteria for Partial Response (PR). The designation of PR requires all of the following: 
 
11.31 At least a 50% decrease in sum of the product of the diameters (SPD) of up to six 
of the largest dominant nodes or nodal masses. These nodes or masses should be 
selected according to all of the following:  
• 
they should be clearly measurable in at least 2 perpendicular dimensions 
• 
if possible they should be from disparate regions of the body 
• 
they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved 
 
11.32 No increase should be observed in the size of other nodes, liver, or spleen. 
 
11.33 Splenic and hepatic nodules must regress by 50% in their SPD or, for single 
nodules, in the greatest transverse diameter.  
 
11.34 With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present. 
11.35 Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified 
(eg, large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR 
by the above criteria, but who have persistent morphologic bone marrow 


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Protocol Version Date:  30Nov2017 
involvement will be considered partial responders.  
When the bone marrow was involved before therapy and a clinical CR was 
achieved, but with no bone marrow assessment after treatment, patients should be 
considered partial responders. 
 
11.36 No new sites of disease should be observed. 
 
11.37 For patients with no pretreatment PET scan or if the PET scan was positive before 
therapy, the post-treatment PET should be positive in at least one previously 
involved site. 
 
11.4 
Criteria for Stable Disease (STAB) 
 
11.41  A patient is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR (see above), but does not fulfill those for progressive 
disease (see below).  
11.42  The PET should be positive at prior sites of disease with no new areas of 
involvement on the post-treatment CT or PET.  
 
11.5 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD): Lymph nodes should 
be considered abnormal if the long axis is more than 1.5 cm regardless of the short axis. If 
a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if its 
short axis is more than 1.0. Lymph nodes 1.0 x 1.0 cm will not be considered as 
abnormal for relapse or progressive disease.  
 
11.51 Appearance of any new lesion more than 1.5 cm in any axis during or at the end 
of therapy, even if other lesions are decreasing in size. Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive 
disease after confirmation with other modalities. In patients with no prior history 
of pulmonary lymphoma, new lung nodules identified by CT are mostly benign. 
Thus, a therapeutic decision should not be made solely on the basis of the PET 
without histologic confirmation. 
 
11.52 At least a 50% increase from nadir in the SPD of any previously involved nodes, 
or in a single involved node, or the size of other lesions (eg, splenic or hepatic 
nodules). To be considered progressive disease, a lymph node with a diameter of 
the short axis of less than 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 
cm or more than 1.5 cm in the long axis. 
 
11.53   At least a 50% increase in the longest diameter of any single previously identified 
node more than 1 cm in its short axis.  
 
11.54   Lesions should be PET positive if observed in a typical FDG-avid lymphoma or 
the lesion was PET positive before therapy unless the lesion is too small to be 
detected with current PET systems (< 1.5 cm in its long axis by CT).  
 
12.0 
Descriptive Factors  


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Protocol Version Date:  30Nov2017 
 
 
12.1  
Dose Level (to be assigned by Randomization Center): -2 vs. -1 vs. 1 vs. 2 vs. 3. 
 
12.2  
International Prognostic Index (IPI): Low (1-2) vs. high (≥3).  
 
12.3 
Subgroup (DLBCL patients only):   germinal center B-cell-like subtype (GCB) vs. non-
germinal center B-cell-like subtype (non-GCB). 
 
12.4 
Disease group: DLBCL or FLIII (Group 1) vs. transformed or composite follicular 
lymphoma (Group 2). 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
13.1 
Patients who are CR, PR, or STAB will continue treatment per protocol until a maximum 
of 6 cycles have been received. 
 
13.2 
Patients who develop progressive disease while receiving therapy will go to the event-
monitoring phase. 
 
13.3 
Patients who go off protocol treatment for unacceptable adverse events or patient refusal 
will go to the event-monitoring phase per Section 18.0. 
 
13.4 
Observation:  If the patient has achieved CR, PR, or STAB, at the post-treatment 
evaluation, the patient will be observed every 3 months for the first year then every 4 
months for the second year or until PROG and then they will go to event monitoring.   
 
13.5 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study.  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol.  
 
13.51   Patients who are determined to have a histology other than diffuse large cell or 
follicular grade III A/B B-cell lymphoma on central pathology review but started 
on study (urgency to initiate treatment, see section 17.0) may continue on 
R2CHOP per discretion of treating MD; however,  for the purpose of analysis 
will be deemed ineligible and will go to the event-monitoring phase of the study. 
13.6 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 


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Protocol Version Date:  30Nov2017 
will be required per Section 18.0 of the protocol. 
 
13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 
 
14.0 
Body Fluid Biospecimens   
 
14.1 
Body Fluid Biospecimen Submission  
 
NOTE: Patients must have consented to submission of the following biospecimen(s). 
 
14.11 Summary Table of Body Fluid Biospecimens for this Protocol 
Type of 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for submission  
Where to 
find specific 
details for 
specimen 
submission 
Blood/blood 
products (EDTA 
whole blood) 
Mandatory 
Multiple draws (see 
Section 14.24 for 
schedule) 
Immunology studies (Section 
14.32) 
Section 14.2 
Blood/blood 
products (EDTA 
whole blood) 
Mandatory 
Multiple draws (see 
Section 14.24 for 
schedule) 
Banking (Section 14.31) 
Section 14.2 
 
14.2 
Blood/Blood Products Handling  
 
14.21  Blood samples prior to treatment, prior to cycle 3 and after treatment will be 
collected at treating centers.  
 
14.22 All samples must be collected Monday-Friday ONLY for specimens collected 
at Mayo Clinic Rochester and Monday-Thursday for all other locations.  
 
14.23 Label specimen tube(s) with protocol number, patient study ID number, and time 
and date blood drawn. 
 


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Protocol Version Date:  30Nov2017 
14.24 Collect and process all blood/blood products according to instructions and table below  
 
14.241 Summary Table of Research Blood/Blood Products to Be Collected for This Protocol 
Indicate if 
specimen is 
mandatory or 
optional 
Collection tube 
description and/or 
additive (color of 
tube top) 
Volume to collect 
per tube (number 
of tubes to be 
collected) 
Blood 
product 
being 
processed 
Component 
being 
harvested 
Before 
tx 
Before 
Cycle 3 
After completion of 
therapy (4-6 weeks after 
 day 1 of cycle 6) 
Process 
at site? 
Storage/ 
shipping 
conditions1 
Mandatory 
ACD (yellow) 
10 mL 
(1) 
Whole 
blood 
Plasma 
Cells for 
DNA/RNA, 
Protein 
X 
X 
X 
No 
Refrigerate
/cold pack 
(DO NOT 
FREEZE) 
Mandatory 
EDTA (purple) 
10 mL 
(1) 
Whole 
Blood 
Plasma 
Cells for 
DNA/RNA, 
Protein 
X 
X 
X 
No 
Refrigerate
/cold pack 
(DO NOT 
FREEZE) 
Mandatory 
Red top 
10 mL (1)  
Whole 
Blood 
Serum 
X 
X 
X 
No 
Refrigerate
/cold pack 
(DO NOT 
FREEZE) 
1. All specimens should be sent to 
. 
 


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Protocol Version Date:  30Nov2017 
 
14.3 
Background/Methodology Information 
 
14.31 Immunology Studies:  Blood/blood product samples (serum, plasma, and 
mononuclear cells) will be collected for assessment of immune function and 
cytokine analysis.  These assays will be performed in the Lymphoma SPORE 
Research lab on
 under grant CA97274. Excess samples will be stored 
for future assays that are within the realm of immune function and tumor biology 
and host immune response. These research test results will not be placed into the 
patient’s clinical record.       
 
14.32 T and B quantitative lymphocyte analysis will be performed in the clinical 
laboratory and will not be sent to 
 
 
14.33 Genetic polymorphisms:  Mononuclear cells (as a source of host germline DNA) 
will be banked or processed for DNA extraction for single nucleotide 
polymorphisms (SNPs) analysis, since genetic polymorphism may be responsible 
for differences in response to therapy.  These results will not be placed into the 
clinical record.  If, at any time, genetic results are obtained that may have clinical 
relevance, IRB review and approval will be sought regarding the most 
appropriate manner of disclosure and whether or not validation in a CLIA-
certified setting will be required.  Sharing of research data with individual 
patients should only occur when data have been validated by multiple studies and 
testing has been done in CLIA-approved laboratories. 


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Protocol Version Date:  30Nov2017 
 
15.0 
Drug Information 
 
15.1  
Lenalidomide (Revlimid, CC-5013, CDC-501)   
 
Please consult the most current Investigator’s Brochure and package insert for 
complete drug information. 
 
15.11 Background: Lenalidomide has a wide range of effects, including the inhibition 
of hematopoietic tumor cell proliferation, the enhancement of T cells and natural 
killer (NK) cell activity, the modulation of stem cell differentiation, the inhibition 
of angiogenesis, and the inhibition of inflammation. 
 
15.12 Formulation: For clinical study, lenalidomide is provided as 1.25-, 2.5-, 5-, 10-, 
15-, 20-, and 25-mg capsules for oral administration. Each capsule contains 
lenalidomide as the active ingredient and the following inactive ingredients: 
anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. 
 
Placebo capsules for the 1.25-, 2.5-, 5-, 10-, 15-, 20-, and 25-mg lenalidomide 
capsules are available for use in blinded studies. Each placebo capsule visually 
matches the drug product. 
 
The lenalidomide and placebo capsules are supplied in push-through blister foil 
or tamper-evident, child-resistant, opaque, high-density polyethylene (HDPE) 
containers with HDPE caps. 
 
15.13 Preparation and storage: Lenalidomide should be stored at room 
temperature, between 59 and 86ºF (15-30ºC).  Store drug away from direct 
sunlight.   
 
15.14 Administration:  Capsules are administered by mouth daily with water. Patients 
should not break, chew or open the capsules. 
 
 
15.15 Pharmacokinetic information: 
a)  Absorption – Lenalidomide is rapidly absorbed following oral administration 
to subjects with multiple myeloma or MDS, with maximum plasma 
concentrations occurring between 0.5 and 1.5 hours post-dose. Co-administration 
with a high-fat and high-calorie meal in healthy subjects reduced the extent of 
absorption, resulting in an approximately 20% decrease in AUC and 50% 
decrease in Cmax in plasma.   
 
In the pivotal MM and MDS registration trials where the efficacy and safety were 
established for lenalidomide, the drug was administered without regard to food 
intake. Thus, lenalidomide can be administered with or without food. 
 
Multiple dosing (up to 100 mg BID) did not cause marked drug accumulation.   
 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
 
b)  Distribution – In vitro (14C)-lenalidomide binding to plasma proteins 
binding to plasma proteins is approximately 30%. 
 
c)  Metabolism – Lenalidomide undergoes limited metabolism. Unchanged 
lenalidomide is the predominant circulating component in humans. Two 
identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each 
constitutes less than 5% of parent levels in circulation. 
 
d)  Excretion – Elimination is primarily renal.  Approximately 65% to 85% of 
lenalidomide is eliminated unchanged through urinary excretion in subjects with 
normal renal function. The half-life of elimination is approximately 3 to 4 hours 
(2 to 3 hours in patients 5 to 21 years) at the clinically relevant doses (5 to 50 
mg/day). Steady-state levels are achieved within 4 days. 
 
15.16 Potential Drug Interactions:  In vitro studies demonstrate that lenalidomide is 
not a substrate of CYP enzymes. In addition, lenalidomide shows little inhibitory 
or induction potential towards the CYP enzymes in vitro. Hence, 
coadministration of CYP substrates, inhibitors, or inducers with lenalidomide is 
not likely to result in clinically relevant drug-drug interactions in humans.  
 
In vitro, lenalidomide is not a substrate of BCRP, MRP1, MRP2, MRP3, OAT1, 
OAT3, OATP1B1, OCT1, OCT2, MATE1, OCTN1, or OCTN2. Thus, it is 
unlikely that substrates or inhibitors of these transporters would affect 
lenalidomide disposition in humans. 
 
Lenalidomide is not an inhibitor of BSEP, BCRP, MRP2, OAT1, OAT3, 
OATP1B1, OATP1B3, or OCT2. Thus, lenalidomide is not anticipated to cause 
any significant drug-drug interactions due to inhibition of these transporters. 
 
Lenalidomide is not an inhibitor of UGT1A1 and is not anticipated to cause any 
significant drug-drug interactions due to UGT1A1 inhibition. 
 
In vitro, lenalidomide is a weak substrate, but not an inhibitor of P-glycoprotein 
(P-gp). 
 
Erythropoietic agents or other agents that may increase the risk of thrombosis, 
such as hormone replacement therapy and oral contraceptives, should be used 
with caution in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
 
 
Periodic monitoring of digoxin plasma levels is recommended due to increased 
Cmax and AUC with concomitant lenalidomide therapy.  Close monitoring of PT 
and INR is recommended in multiple myeloma patients taking concomitant 
warfarin. 


MC078E 
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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
 
15.17 Known potential toxicities:   
 
Pregnancy Warning: Lenalidomide, a thalidomide analogue, caused limb 
abnormalities in a developmental monkey study similar to birth defects caused by 
thalidomide in humans. If lenalidomide is used during pregnancy, a teratogenic 
effect of Lenalidomide in humans cannot be ruled out.  Pregnancy must be 
excluded before start of treatment. Prevent pregnancy during treatment by the use 
of two reliable methods of contraception. 
 
Very Common AEs (≥ 10%): anemia, febrile neutropenia, leukopenia, 
neutropenia, thrombocytopenia, cataracts, blurred vision, abdominal pain, 
constipation, diarrhea, dyspepsia, nausea, vomiting, asthenia, chills, edema 
including peripheral, fatigue, pyrexia, abnormal liver function tests, bronchitis, 
gastroenteritis, influenza, nasopharyngitis, sinusitis, pneumonia, rhinitis, upper 
respiratory tract infection, urinary tract infection, weight decreased, decreased 
appetite, hyperglycemia, hypocalcemia, hypokalemia, arthralgia, back pain, bone 
pain, muscle spasms, musculoskeletal pain, myalgia, pain in extremity, dizziness, 
dysgeusia, headache, hypoesthesia, neuropathy peripheral, neuropathy, tremor, 
depression, insomnia, renal failure, cough, dyspnea, epistaxis, pharyngitis, 
pulmonary embolism, dry skin, pruritus, rash, and deep vein thrombosis. 
 
Common (≥ 1% and < 10%):, granulocytopenia, hemolytic anemia, 
lymphopenia, pancytopenia, acute myocardial infarction, atrial fibrillation, 
cardiac failure, congestive heart failure, myocardial ischemia, tachycardia, 
vertigo, upper abdominal pain dry mouth, toothache, chest pain, fall, cholestasis, 
arthritis infective, bacteremia, cellulitis, erysipelas, herpes simplex, herpes zoster, 
infection, lower respiratory infection, respiratory infection, lung infection, 
meningitis, ophthalmic herpes zoster, sepsis, contusion, alanine aminotransferase 
increased, c-reactive protein increased, gamma-glutamyltransferase increased, 
dehydration, diabetes mellitus, gout, hypercalcemia, hyperuricemia, 
hypophosphatemia, hypomagnesemia, hyponatremia, iron overload, muscular 
weakness, acute myeloid leukemia, basal cell carcinoma, Myelodysplastic 
syndrome, squamous cell carcinoma of skin, T-cell type acute leukemia, tumor 
flare, tumor lysis syndrome, cerebrovascular accident, lethargy, paresthesia, 
peripheral sensory neuropathy, syncope, mood altered, respiratory distress, 
erythema, hyperhidrosis, night sweats, hematoma, hypertension, hypotension, 
peripheral ischemia, thrombosis, and vasculitis. 
 
Uncommon, limited to important or life-threatening (< 1%): appendicitis, 
bursitis infective, airways disease, pyelonephritis, hypersensitivity, Graft vs. Host 
Disease, viral reactivation (such as hepatitis B virus or herpes zoster), DRESS. 
 
The following additional adverse reactions have been reported in Celgene-
sponsored clinical studies and are considered by the company to be at least 
possibly related to the administration of lenalidomide: pneumonitis, transient 
abnormal liver laboratory tests, hyperthyroidism, , TLS, TFR, rhabdomyolysis, 
and allergic conditions, including angioedema, SJS, and toxic epidermal 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
necrolysis.  These reactions are reported voluntarily from a population of 
uncertain size, so it is not possible to reliably estimate their frequency. 
 
Lenalidomide may have minor or moderate influence on the ability to drive and 
use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have 
been reported with the use of lenalidomide. Therefore, caution is recommended 
when driving or operating machines. 
 
Please refer to the Investigator Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
 
15.18 Drug procurement:  Lenalidomide (Revlimid®) will be provided directly to 
research subjects for the duration of their participation in this trial at no charge to 
them or their insurance providers in accordance with the REVLIMID REMS™  
program.  Per standard 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 
Celgene  REVLIMID REMS™  program.  Prescriptions must be filled within 7 
days.  Only enough lenalidomide for one cycle of therapy will be supplied to 
the patient each cycle. 
 
 
Any unused lenalidomide should be returned for disposition in accordance with 
the REVLIMID REMS™   program. 
 
 
15.19 Nursing Guidelines:  
 
15.191 Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. 
Instruct patient to report any unusual bruising or bleeding 
(thrombocytopenia); signs and symptoms of infection (neutropenia); and 
energy conserving lifestyle (anemia). 
 
15.192 Lenalidomide can have thrombotic adverse events (i.e DVT and PE). 
Instruct patient to report any limb swelling or pain, and to seek medical 
attention for shortness of breath or chest pain. 
 
15.193 Because of the potential for birth defects patients should be instructed in 
effective methods of birth control. Female patients should use 2 forms of 
birth control during treatment and for 4 weeks after discontinuing 
therapy. Males must be instructed to use a latex condom during any 
sexual contact with a woman of child bearing potential (even if they have 
had a vasectomy), because it is unknown if lenalidomide is present in 
semen. 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
 
15.194 Patents may experience pruritus, rash and dry skin. Because of the rare 
risk of Steven’s Johnson Syndrome, patients should immediately report 
any rash to their provider. 
 
15.195 Drug may cause hyperglycemia. Patients with diabetes or impaired 
fasting glucose may need to have their glucose levels monitored more 
closely. 
 
15.196 Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patent symptomatically and 
monitor for effectiveness. 
 
15.197 Patients may experience myalgias, arthralgias, and other generalized 
pain. Administer analgesics as ordered and monitor for their 
effectiveness. 
 
15.198 Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) can 
be seen. Manage symptomatically and monitor for effectiveness. 
 
15.199a Agent may cause fatigue, dizziness, vertigo or blurred vision. Instruct 
patients to use caution when driving or operating machines.  
 
15.199b Monitor LFT’s and report any elevations to the study team. Instruct 
patient to report abdominal pain and/or jaundice to the study team. 
 
15.199c All prescribers and patients must be enrolled into the REVLIMID 
REMS program. Only enough lenalidomide for one cycle of therapy 
will be supplied to the patient each cycle. 
 
15.199d Rarely secondary malignancies have been seen after lenolidamide 
therapy, including MDS, squamous/basal cell carcinomas of the skin, T-
cell type acute leukemia. 
 
 
15.2 
Cyclophosphamide (Cytoxan, CTX, Neosar®) 
 
15.21 Preparation and storage:  Injectable powder is stored at room temperature.  The 
temperature is not to exceed 90°F.  Reconstituted parenteral solutions are stable 
for 24 hours at room temperature or six days if refrigerated.  Dissolve the 100 
mg, 200 mg, 500 mg, 1 gm, and 2 gm vials in 5, 10, 25, 50, and 100 mL of sterile 
water, respectively, resulting in a solution of 20 mg/mL.  Shake vials vigorously 
and warm slightly in lukewarm water to facilitate the dissolving of crystals.  The 
lyophilized form is more easily solubilized. Cyclophosphamide should be 
administered according to standard R-CHOP regimen. 
 
15.22 Known potential toxicities:  Myelosuppression, hemorrhagic cystitis, alopecia, 
nausea, and vomiting are all common, SIADH is dose–related (more common 
with single doses > 2 gm/m2), cardiac (if dose level ≥2 gm/m2).  Secondary 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
leukemia, liver dysfunction, headaches, dizziness, interstitial pulmonary fibrosis, 
cardiac necrosis may occur.  Anaphylaxis is rare. 
 
15.23 Drug procurement:  Commercially available for injection in 100 mg, 200 mg, 500 
mg, 1 gm and 2 gm vials. 
 
15.24 Nursing guidelines 
 
15.241 Leukopenia nadir occurs 8-14 days after administration and recovery is 
usually 18-25 days.  Monitor CBC. 
 
15.242 Instruct patient to drink 2-3 liters of fluid per day for 2-3 days following 
treatment and to void frequently, not greater than every three hours to 
facilitate emptying the bladder of drug. 
 
15.243 Instruct patient to report any urinary urgency, frequency, dysuria, or 
hematuria. 
 
15.244 Advise patient of possible strong metallic taste associated with Cytoxan 
and suggest hard candy with a strong flavor (cinnamon, peppermint) to 
alleviate it. 
 
15.245 Administer antiemetics as necessary to minimize nausea and vomiting, 
which usually occurs 6-8 hours after administration. 
 
15.246 Report and record any complaint of lightheadedness, facial “heat 
sensation”, or diaphoresis during administration. 
 
15.247 Corticosteroids, phenothiazine, imipramine, and allopurinol may inhibit 
Cytoxan metabolism and modify its effect.  They may also increase bone 
marrow suppression. 
 
15.3 
Rituximab (Rituxan®, C2B8) 
 
15.31 Background: Rituximab is a monoclonal antibody directed against the CD20 
antigen on B-lymphocytes. CD20 regulates cell cycle initiation; and, possibly, 
functions as a calcium channel. Rituximab binds to the antigen on the cell 
surface, activating complement-dependent cytotoxicity; and to human Fc 
receptors, mediating cell killing through an antibody-dependent cellular toxicity.  
 
15.32 Formulation: Commercially available for injection, solution [preservative free]: 
10 mg/mL (10 mL, 50 mL) [contains Polysorbate 80]. 
 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store vials at refrigeration temperature, 
do not freeze or shake. Protect vials from direct sunlight. Withdraw the necessary 
amount of rituximab and dilute to a final concentration of 1-4 mg/mL with 0.9% 
NaCL or D5W. Gently invert the bag to mix the solution; do not shake. Solutions 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
for infusion are stable at 2ºC to 8ºC for 24 hours and at room temperature for an 
additional 24 hours. 
 
15.34 Administration:  Do not administer I.V. push or bolus. Refer to treatment 
section for specific infusion instructions. Suggested administration guidelines 
are: 
Initial infusion: Start rate of 50 mg/hour; if there is no reaction, increase the rate 
by 50 mg/hr every 30 minutes, to a maximum of 400 mg/hour. 
Subsequent infusions: If patient did not tolerate initial infusion follow initial 
infusion guidelines. If patient tolerated initial infusion, start at 100 mg/hour; if 
there is no reaction; increase the rate by 100 mg/hour every 30 minutes, to a 
maximum of 400 mg/hour.  
Note: If a reaction occurs, slow or stop the infusion. If the reaction abates, restart 
infusion at 50% of the previous rate. 
 
Accelerated infusion rate (90 minutes):  For patients with previously untreated 
follicular NHL and diffuse large B-cell NHL who are receiving a corticosteroid 
as part of their combination chemotherapy regimen, have a circulating 
lymphocyte count <5000/mm3, or have no significant cardiovascular disease. 
After tolerance has been established (no grade 3 or 4 infusion-related event) at 
the recommended infusion rate in cycle 1, a rapid infusion rate may be used 
beginning with cycle 2. The daily corticosteroid, acetaminophen, and 
diphenhydramine are administered prior to treatment, then the rituximab dose is 
administered over 90 minutes, with 20% of the dose administered over the first 
30 minutes and the remaining 80% is given over 60 minutes. If the 90-minute 
infusion in cycle 2 is tolerated, the same rate may be used for the remainder of 
the treatment regimen (through cycles 6 or 8). 
 
 
15.35 Pharmacokinetic information: 
Duration: Detectable in serum 3-6 months after completion of treatment; B-cell 
recover begins ~6 months following completion of treatment; median B-cell 
levels return to normal by 12 months following completion of treatment 
Distribution: RA:  3.1 L; GPA/MPA:  4.5 L 
Absorption:  Immediate and results in a rapid and sustained depletion of 
circulating and tissue-based B cells 
4.3 L 
Half-life elimination: Proportional to dose; wide ranges reflect variable tumor 
burden and changes in CD20 positive B-cell populations with repeated doses: 
Following first dose: Mean half-life: 3.2 days  
Following fourth dose: Mean half-life: 8.6 days 
CLL: Median terminal half-life: 32 days 
NHL: Median terminal half-life: 22 days 
RA: Mean terminal half-life: 18 days 
GPA/MPA:  23 days 
 
Excretion: Uncertain; may undergo phagocytosis and catabolism in the 
reticuloendothelial system  
 
 


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15.36 Potential Drug Interactions:   
Increased Effect/Toxicity: Monoclonal antibodies may increase the risk for 
allergic reactions to rituximab due to the presence of HAC antibody. 
Antihypertensive medications may exacerbate hypotension. 
Decreased Effect: Currently recommended not to administer live vaccines 
during rituximab treatment. 
 
Herb/Nutraceutical Interactions: Avoid hypoglycemic herbs, including alfalfa, 
bilberry, bitter melon, burdock, celery, domain, fenugreek, grainier, garlic, 
ginger, ginseng, gymnema, marshmallow, and stinging nettle (may enhance the 
hypoglycemic effect of rituximab). Monitor. 
 
Immunosuppressants:  Rituximab may enhance the adverse/toxic effects 
of pimecrolimus, tacrolimus and to a lesser extent of denosumab. 
 
Rituximab may enhance the adverse/toxic effects of abatacept, belimumab, 
clozapine, dipyrone and tofacitinib. 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information. Refer to the package insert pertaining to the 
following boxed warnings: Severe infusion reactions; Progressive multifocal 
leukoencephalopathy (PML); Tumor lysis syndrome leading to acute renal 
failure; and severe and sometimes fatal mucocutaneous reactions (lichenoid 
dermatitis, paraneoplastic pemphigus, Stevens-Johnson syndrome, toxic 
epidermal necrolysis and vesiculobullous dermatitis).  
Common known potential toxicities, > 10%:   
Cardiovascular:  Peripheral edema, hypertension 
Central nervous system: Fever, fatigue, chills, headache, insomnia, pain 
Dermatologic: Skin rash, pruritus, night sweats 
Endocrine & metabolic:  Weight gain 
Gastrointestinal: Nausea, diarrhea, abdominal pain 
Hematologic: Lymphopenia, anemia, leukopenia, neutropenia, 
thrombocytopenia, cytopenia, febrile neutropenia 
Hepatic:  ALT increased 
Hypersensitivity:  Angioedema 
Immunologic:  Antibody development 
Infection:  Infection, bacterial infection 
Neuromuscular & skeletal: Weakness, muscle spasm, arthralgia 
Respiratory: Cough, rhinitis, epistaxis 
Miscellaneous: Infusion-related reaction: fever 
 


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Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Hypotension, flushing 
Central nervous system: Dizziness, anxiety, migraine, paresthesia 
Dermatologic: Urticaria 
Endocrine & metabolic: Hyperglycemia, increased lactate dehydrogenase 
Gastrointestinal: Vomiting, dyspepsia 
Neuromuscular & skeletal: Back pain, myalgia  
Respiratory: Dyspnea, throat irritation, bronchospasm, upper respiratory tract 
infection, sinusitis 
 
Rare known potential toxicities, <1% (Postmarketing and/or case reports):  
Acute mucocutaneous toxicity, acute renal failure (associated with tumor lysis 
syndrome), acute respiratory distress, anaphylactoid reaction/anaphylaxis, angina 
pectoris, aplastic anemia, arthritis (polyarticular), bone marrow depression,  
bronchiolitis obliterans, cardiac arrhythmia, cardiac failure, cardiogenic shock, 
encephalitis, fulminant hepatitis, gastrointestinal perforation, hemolytic anemia, 
hepatic failure, hepatitis, hypogammaglobulinemia (prolonged), hypoxia, 
increased serum immunoglobulins (hyperciscosity syndrome in Waldenstrom’s 
macroglobulinemia, interstitial pneumonitis, intestinal obstruction, Kaposi’s 
sarcoma (progression), laryngeal edema, lichenoid dermatitis, lupus-like 
syndrome, mucositis, myelitis, MI, nephrotoxicity, optic neuritis, pancytopenia, 
paraneoplastic pemphigus, pleurisy, pneumonia, pneumonitis, polymyositis, 
progressive multifocal leukoencephalopathy, pure red cell aplasia, reactivated 
pure red cell aplasia, reactivated tuberculosis, reaction of HBV, reversible 
posterior leukoencephalopathy syndrome, serum sickness, Stevens-Johnson 
syndrome, supraventricular arrhythmia, toxic epidermal necrolysis, uveitis, 
vasculitis with rash, ventricular fibrillation, ventricular tachycardia, 
vesiculobullous dermatitis, viral reactivation (includes JC virus [PML], 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, 
West Nile virus, and hepatitis C), wheezing 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.39 Nursing guidelines: 
 
15.391 Do not administer as an IV push or bolus since it increases the risk of a 
hypersensitivity reaction. 
 


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15.392 Hypotension, bronchospasm, and angioedema have occurred in 
association with Rituxan infusion.  Stop infusion for severe reaction.  
Infusion may be restarted at 50% rate after resolution of symptoms.  It is 
recommended that diphenhydramine, acetaminophen, epinephrine, 
bronchodilators, IV saline, and corticosteroids be available for immediate 
use in the event of a hypersensitivity reaction during administration. 
 
15.393 Patients should be cautioned to withhold their anti-hypertensive 
medication for 12 hours prior to drug administration. 
 
15.394 Patients with preexisting cardiac conditions including arrhythmias and 
angina have had recurrences of these events during Rituxan therapy and 
should be monitored throughout the infusion and immediate post-
infusion period. 
 
15.395 It has been found that patients with bulky disease (lesion >10 cm in 
diameter) have an increased incidence of adverse events. 
 
15.396 An infusion-related symptom complex consisting of fever and 
chills/rigors occurs in the majority of patients during the first infusion.  
These reactions generally occur within 30 minutes to 2 hours of 
beginning the first infusion and resolve with slowing or stopping the 
infusion and giving supportive care.  The incidence of adverse reactions 
decreased from 80% to 40% with subsequent infusions. 
 
15.397 Cytopenias are common and can be long term.  Monitor CBC.  Instruct 
patient to report signs and symptoms of infection, excessive bruising 
and/or bleeding to the health care team. 
 
15.398 GI disturbances (Nausea, abdominal pain and less commonly diarrhea, 
vomiting, dyspepsia) headache, and weakness are common side effects.  
Treat as necessary.  Monitor for effectiveness. 
 
15.399a Adequate birth control measures should be used during therapy and for 
12 months following therapy.  Women should not breastfeed while drug 
is detectable in serum. 
 
15.399bEndocrine and metabolic disturbances can be seen (hyper/hypoglycemia, 
hypocalcemia, hypocholesterolemia, hyperphosphatemia, hyperuricemia. 
Monitor labs and for signs or symptoms of these conditions. Treat 
accordingly.  
 
15.399c There is the possibility of  reactivation of Hepatitis B (HBV).  Paitents 
who are at high risk of hepatitis B virus should be screened prior to 
initiation of therapy, carriers of hepatitis B should be closely monitored. 
 
 
15.4 
Doxorubicin (ADR) 


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15.41 
Preparation and storage:  Doxorubicin RDF intact vials are stable protected from 
light at room temperature.  Doxorubicin PFS vials must be refrigerated.  
Reconstituted solutions are stable for 24 hours at room temperature and 48 hours 
under refrigeration.  The doxorubicin RDF 150 mg multidose vial is stable after 
reconstitution for 7 days at room temperatures or 15 days if refrigerated and 
protected from sunlight.  It is not necessary to further dilute.  This avoids long 
infusion times and the risk of extravasation.  Dilution takes place when 
administered through a rapidly flowing IV line.  Doxorubicin should be 
administered according to standard R-CHOP regimen. 
 
15.42 Known potential toxicities: 
 
15.421 Hematologic:  Leukopenia (dose-limiting), also thrombocytopenia and 
anemia.  Nadir 10-14 days, recovery in 21 days.  
 
15.422 Dermatologic:  Alopecia, usually complete, hyperpigmentation of 
nailbeds and dermal creases, radiation recall.  
 
15.423 Gastrointestinal:  Nausea and vomiting, sometimes severe, anorexia, 
diarrhea, mucositis.  
 
15.424 Cardiovascular:  Arrhythmias, thrombosis/embolism, ECG changes, 
rarely sudden death.  Congestive heart failure due to cardiomyopathy 
related to total cumulative dose, risk is greater with doses greater than 
550 mg/m2, mediastinal irradiation, preexisting cardiac disease, advanced 
age, risk is reduced with weekly or continuous infusion regimens.   
 
15.425 Other:  Red discoloration of urine, fever, anaphylactoid reaction, may 
enhance cyclophosphamide cystitis or mercaptopurine hepatotoxicity, 
secondary AML/MDS (risk is uncommon, but may be increased when 
given in combination with an alkylating agent, especially if one or both 
are given at higher than standard doses.  
 
15.426 Local effects:  Vesicant if extravasated; flush along vein, facial flush.  
 
15.43 Availability:  Commercially available as powder for injection in 10, 20, 50, 100, 
150 mg vials, and as 2 mg/ml solution for injection in 10, 20, 50, and 200 mg 
vials.  
  
15.43 Nursing guidelines:  
 
15.441 Check CBC and platelet counts.  Monitor for signs of infection, bleeding, 
and anemia. 
 
15.442 Advise patient that their urine may turn pink in color for approximately 
24 hours after administration of the drug.  
 


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15.443 Doxorubicin is a vesicant.  Check IV potency before and frequently 
during administration.  If extravasation occurs, refer to institutional 
extravasation policy. 
 
15.444 Hair loss occurs 2-4 weeks after initial injection and can be complete.  
Regrowth begins 2-3 months after discontinuation. 
 
15.445 Beware of doxorubicin “flare” that can occur during administration.  The 
reaction consists of an erythematous streak up the vein receiving the 
infusion.  Adjacent veins may also demonstrate red streaks.  Urticaria 
and pruritus can be associated with the reaction.  The use of 
corticosteroids and/or antihistamines has been helpful. 
 
15.446 Administer antiemetics to minimize nausea and vomiting. 
 
15.447 Assess for alterations in mucous membranes.  Stomatitis occurs within 7-
10 days after injection.  It begins with burning sensation and can 
progress to ulceration, which can last 3 days.  Carafate slurry may be 
useful.  Adequate nutritional counseling is important.  Topical 
anesthetics such as viscous Xylocaine can be used symptomatically.   
 
15.448 Advise patient that there is often significant malaise and fatigue  
1-2 weeks after injection. 
 
 
 
 
15.449a Doxorubicin may potentiate toxicity of other antineoplastic therapies.  It 
has reportedly exacerbated Cyclophosphamide- (Cytoxan, CTX) induced 
hemorrhagic cystitis. 
 
 
 
 
15.449b Assess heart and lung sounds.  Monitor vital signs (resting pulse).  Be 
alert to early signs of cardiotoxicity, i.e., dyspnea, steady weight gain, 
nonproductive cough, arrhythmias, tachycardia, and pulmonary rales. 
 
15.449c Document cumulative dose, which should not exceed maximum 
cumulative dose.   
 
15.449d Advise patient of probable facial flushing for several hours after drug 
administration, especially if given quickly. 
 
 15.5 
Vincristine (VCR) 
 
15.51 
Preparation and storage:  Vincristine is stored in the refrigerator.  No preparation 
is required. Vincristine should be administered according to standard R-CHOP 
regimen. 
 
15.52 Known potential toxicities: 
 
15.521 Hematologic:  Rarely leukopenia (mild), rarely thrombocytopenia, and 
anemia. 


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15.522 Dermatologic:  Alopecia, skin and soft tissue damage if extravasated (the 
manufacturer recommends subcutaneous injection of hyaluronidase and 
application of heat to help disperse the drug), rash.  
 
15.523 Gastrointestinal:  Nausea, rarely vomiting, constipation, abdominal 
cramps, anorexia, and diarrhea.  Fatal ascending paralysis follows 
intrathecal administration.  
 
15.524 Hepatic:  Elevation of AST and ALT (mild and transient). 
 
15.525 Neurologic:  Peripheral neuropathy (loss of deep tendon reflexes, 
paresthesias, paralysis), autonomic neuropathy (constipation, paralytic 
ileus, urinary retention, orthostasis), ataxia, myalgias, cortical blindness, 
headache, seizures.  
 
15.526 Pulmonary:  Bronchospasm (acute shortness of breath), more common 
when administered with mitomycin.   
 
15.527 Ocular:  Diplopia, ptosis, photophobia, cortical blindness (see 
neurologic), and optic atrophy.   
 
15.528 Other:  Severe pain in the jaw, pharynx, bones, back, and limbs 
following injection, syndrome of inappropriate antidiuretic hormone 
(SIADH), fever, rarely pancreatitis.  
 
15.529 Cardiovascular:  Thrombosis/embolism. 
 
15.53 Availability:  Commercially available in a concentration of 1 mg/ml in  
1, 2, and 5 mg vials and 1 mg and 2 mg syringes.  
 
15.54 Nursing guidelines: 
 
15.541 Check IV patency before and frequently during administration.  
Vincristine is a vesicant.  If extravasation occurs, refer to agency 
extravasation policy. 
 
15.542 Evaluate the patient for numbness and tingling in fingertips and toes, 
clumsiness of hands, and difficulty walking. 
 
15.543 Monitor bowel function and encourage use of stool softeners. 
 
15.544 Symptoms of cranial nerve neuropathy may develop several weeks after 
drug administration and take 10–12 months to resolve.  


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15.6 
Name of drug:  Prednisone (PRED) 
 
15.61 
Preparation and storage:  The drug is stored at room temperature in a dry place. 
 
15.62 Known potential toxicities: 
 
15.621 Hematologic:  Leukocytosis. 
 
15.622 Gastrointestinal:  Nausea, vomiting, anorexia, increased appetite and 
weight gain, peptic ulcer. 
 
15.623 Dermatologic:  Rash, skin atrophy, facial hair growth, acne, facial 
erythema, and ecchymoses.  
 
15.624 Genitourinary:  Menstrual changes (amenorrhea, menstrual irregularities) 
 
15.625 Neurologic:  Insomnia, muscle weakness, euphoria, psychosis, 
depression, headache, vertigo, and seizures.  
 
15.626 Cardiovascular:  Fluid retention and edema, hypertension, hyperkalemia.  
 
15.627 Ocular:  Cataracts, increased intraocular pressure, and exophthalmos.  
 
15.628 Metabolic:  Hyperglycemia decreased glucose tolerance, aggravation or 
precipitation of diabetes mellitus, adrenal suppression, and cushingoid 
syndrome.  
 
15.629 Other:  Osteoporosis (and resulting back pain), serious infections 
including herpes zoster, varicella zoster, fungal infections, pneumocystis 
carinii, tuberculosis, muscle wasting.  
 
15.63 Availability:  Commercially available in 1, 2.5, 5, 10, 20, 25, and 50 mg tablets.  
Also available as 1 mg/ml oral solution and syrup, and as a 5 mg/ml oral 
solution. 
  
15.64 
Nursing guidelines:  
 
15.641 Instruct patient to report any abdominal pain, GI bleeding (i.e., tarry 
stools, vomiting coffee-ground material, etc.) to health care team 
immediately since active peptic ulceration is a toxicity that requires dose 
modification.  Antacid therapy may be employed. 
 
15.642 Instruct patient to take prednisone after and close to meals.  To prevent 
sleep disruption and restlessness, avoid taking prednisone at bedtime.   
A mild sedative may be needed. 
 
15.643 Monitor CBC and glucose levels. 


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15.644 Educate patient concerning potential mood changes. 
 
15.645 Gradual tapering of doses should be employed after long-term use.  
 
16.0 
Statistical Considerations and Methodology  
 
16.1 
Overview:  This is a phase I/II study in newly diagnosed diffuse large cell and follicular 
grade III A/B B-cell lymphoma patients treated with a combination of lenalidomide, 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R2CHOP).  The 
phase I portion of this study is designed to determine the maximum tolerated dose (MTD) 
of R2CHOP in this patient population.  The phase II portion of this study will use a one-
stage design to assess the efficacy of R2CHOP in this patient population. 
 
16.11 
Primary Endpoint:   The primary endpoint of the phase I portion of this trial is 
toxicity.  For the phase II portion of this trial, the primary endpoint is event-free 
survival at 12 months (EFS12).  An event will be defined as death due to any 
cause, tumor progression or relapse (by CT scan), or initiation of subsequent anti-
lymphoma therapy following R2CHOP study therapy.  A patient will be 
considered a success if they are event-free at 12 months. 
 
16.12 
Sample Size:  This phase I portion of this study is expected to require a minimum 
of 9 and a maximum of 18 patients.  The 6 patients treated at the MTD in the 
phase I portion will also be included in the phase II portion.  An additional 26 
evaluable patients will be accrued at the MTD dose level for a maximum of 32 
evaluable patients in the phase II portion of this study.  If a patient is found to be 
ineligible after enrollment due to central pathology review, they will be replaced. 
 We anticipate accruing maximum of 3 additional patients during the phase II 
portion of the trial to account for ineligibility, cancellation, major treatment 
violation, or other reasons.  Therefore, the phase II portion is expected to accrue 
a maximum of 35 patients and the overall sample size will be a maximum of 47 
patients. 
 
As of Addendum 6, it is estimated that approximately 60% of DLBCL patients 
accrued to this study will have non-GCB lymphoma.  Approximately 18 patients 
with non-GCB lymphoma have been accrued to date.  Therefore, 32 additional 
evaluable DLBCL patients will need to be accrued to have 37 evaluable patients 
with this subtype.  We anticipate accruing 5 additional patients (overaccrual of 
15%) to account for ineligibility, cancellation, major treatment violation, or other 
reasons for a total of 37 additional DLBCL patients.  With 65 patients already 
accrued to the phase II portion of this study, there will be a total of 102 patients 
in the phase II portion and 108 patients overall. 
 
As of Addendum 8, ECOG will open a study for DLBCL patients that will be a 
replacement for this study for patients with DLBCL.   DLBCL patients will no 
longer be accrued to this study.  To further explore the R2CHOP regimen, this 
study will now focus on other subtypes of lymphoma to evaluate efficacy and 
toxicity.   We anticipate accruing 35 evaluable patients with transformed or 


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composite follicular lymphoma.   We anticipate accruing 4 additional patients to 
account for ineligibility, cancellation, major treatment violation, or other reasons 
for a total of 39 additional patients.  As of July 10, 2013, 98 patients have been 
accrued to this study and a maximum of 7 additional patients with DLBCL may 
be accrued before activation of Addendum 8.  Therefore, a maximum of 144 may 
be accrued overall. 
 
16.13 
Accrual Rate and Study Duration:  The anticipated accrual rate is 2-3 evaluable 
patients per month.  At this rate, it will likely take about 2 months to enroll, treat, 
and evaluate each set of 3 patients in the phase I portion of this study.  The phase 
I portion is expected to take between 6 and 12 months.  The phase II portion of 
this study will accrue in the subsequent 12 months.   
 
As of Addendum 6, we expect the additional DLBCL patients will be accrued in 
approximately 2 years.  The total study duration is expected to be approximately 
8 years, or until the last patient accrued has been observed for at least 3 years.  
 
As of Addendum 8, we expect the additional patients will be accrued in 
approximately 1.5 years.  The study is expected to be completed 3.5 years after 
Addendum 8 is implemented, or until the last patient accrued has been observed 
for 2 years. 
  
Phase I Portion (Cohort I): 
This portion of the study is designed to determine the MTD and toxicity of R2CHOP in patients 
with newly diagnosed diffuse large cell and follicular grade III A/B B-cell lymphoma. 
 
16.2 
 Study Design:  This portion of the study will consist of a single-arm, phase I trial to 
determine the MTD of R2CHOP.    
 
16.21   MTD Determination:  MTD is defined as the dose level below the lowest dose 
that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a 
maximum of 6 new patients). See section 7.2 for the MTD determination 
algorithm and DLT definitions. 
 
16.22 Primary Outcome Analyses: 
 
16.221 Adverse Events Profile:  The number and severity of all adverse events 
will be tabulated and summarized in this patient population. The grade 
3+ adverse events will also be described and summarized in a similar 
fashion. This will provide an indication of the level of tolerance for this 
treatment combination in this patient group.  
 
16.222 Toxicity Profile:  As per NCI CTCAE v3.0, the term toxicity is defined 
as adverse events that are classified as either possibly, probably, or 
definitely related to study treatment.  Non-hematologic toxicities will be 
evaluated via the ordinal CTC standard toxicity grading. Hematologic 
toxicity measures of thrombocytopenia, neutropenia, and leukopenia will 
be assessed using continuous variables as the outcome measures 


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(primarily nadir) as well as categorization via CTC standard toxicity 
grading.  Overall toxicity incidence as well as toxicity profiles by dose 
level and patient will be explored and summarized. Frequency 
distributions, graphical techniques and other descriptive measures will 
form the basis of these analyses.  
 
Phase II Portion (Cohort II) 
 
16.3  
Statistical Design: 
 
16.31 Decision Rule:  The largest success proportion where the proposed treatment 
regimen would be considered ineffective in this population is 80%, and the 
smallest success proportion that would warrant subsequent studies with the 
proposed regimen in this patient population is 95%.  The following one-stage 
design uses 32 patients to test the null hypothesis that the true success proportion 
in a given patient population is at most 80%.  Success is defined as being event-
free at 12 months. 
 
16.311 Final Decision Rule:  If 28 or fewer successes are observed in the first 32 
evaluable patients, we will consider this regimen ineffective in this 
patient population.  If 29 or more successes are observed in the first 32 
evaluable patients, we may recommend further testing of this regimen in 
subsequent studies in this patient population. 
 
16.312 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients is discussed in Section 16.44. 
 
16.32 Power and Signficance Level:  Assuming that the number of successes is 
binomially distributed, the significance level is .09, i.e. there is a 9% chance of 
finding the drug to be effective when it truly is not.  The probability of declaring 
that this regimen warrants further study (i.e. statistical power) under various 
success proportions can be tabulated as a function of the true success proportion 
as shown in the following table. 
 
If the true success proportion is... 
.80 
.85 
.90 
.95 
Then the probability of declaring that the 
regimen warrants further study is… 
.09 
.27 
.60 
.93 
 
16.33 Other considerations:  Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study 
 
16.4   Analysis Plan 
 
16.41 Primary Outcome Analyses (Group 1): 


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16.411 Definition:  The primary endpoint for the phase II portion of this trial is 
event-free survival at 12 months.  An event will be defined as death due 
to any cause, tumor progression or relapse (by CT scan), or initiation of 
subsequent anti-lymphoma therapy following R2CHOP study therapy. 
A patient will be considered a success if they are event-free at 12 
months.  All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for event-free 
survival. 
 
16.412 Estimation:  The proportion of successes will be estimated by the 
number of successes divided by the total number of evaluable patients. 
Exact binomial 95% confidence intervals for the true rate of event-free 
survival at 12 months will be calculated. 
 
16.413 As of March 2012, the Kaplan-Meier estimate for event-free survival at 
12 months is 75% (95% CI: 61-92%) in the first 32 evaluable patients 
included in the phase II portion.  Although this estimate is lower than we 
anticipated, there are several factors that warrant continuation of the 
expanded cohort: 
• 
There were 4/32 patients (13%) with primary mediastinal large B-
cell lymphoma, a subtype known to have shorter time to progression. 
 In the 8 patients who experienced an event during the first year after 
registration, 2 of these occurred in patients with primary mediastinal 
disease.  Comparisons to RCHOP studies that did not include 
patients with primary mediastinal disease may be misleading. Of 
note, primary mediastinal large cell lymphoma patients are excluded 
from study extension and no longer eligible. 
• 
Significant percentage (35%) of patients accrued to study was over 
60 years old with high or high-intermediate risk score according to 
International prognostic index (IPI). Advanced age and high IPI  is 
associated with inferior outcome in patients with DLBCL largely due 
to more aggressive disease in this group with reported one-year EFS 
of 60% (Fuegier et al. J. of Clin. Oncol. 2005.23;18 pp-4117-4126).  
• 
Due to developments in imaging technology and the more frequent 
response evaluations that occur during observation (every 3 months 
for year 1 and every 4 months for year 2), it is possible that 
progressive disease is being discovered earlier than in studies where 
monitoring is done every 6 months or annually. This notion is further 
supported by earlier plateau in EFS curves in current study than 
observed in older studies. It is important to point out that as outlined 
in background section, that 2 year EFS is reported in previous studies 
of RCHOP is reported to be to be 55-60%.   
• 
RCHOP is the standard of care for DLBCL.  The addition of 
lenalidomide to RCHOP has not added significant toxicities so there 
are no safety concerns in giving more patients this combination 
• 
Molecular classification of DLBCL by immunohistochemistry is a 
potential prognostic factor that is emerging.  There is preliminary 


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evidence that the addition of lenalidomide to RCHOP may increase 
event-free survival in patients with the non-GCB subtype.  The 
expanded cohort will be used to investigate molecular classification. 
 
16.42 Secondary Outcome Analyses (to be evaluated in each group independently, 
unless specified otherwise) 
 
16.421   Overall response rate:  The overall response rate will be estimated by the 
number of patients with an objective status of CR or PR divided by 
the total number of evaluable patients. All evaluable patients will be 
used for this analysis. Exact binomial 95% confidence intervals for 
the true overall response rate will be calculated. 
 
16.422   Overall CR rate:   The proportion of patients who achieve a CR will be 
estimated.  The overall CR rate will be estimated by the number of 
patients who achieve a CR divided by the total number of evaluable 
patients. All evaluable patients will be used for this analysis. Exact 
binomial 95% confidence intervals for the true overall CR rate will 
be calculated. 
 
16.423   Event-free survival: The event-free survival (EFS) time is defined as the 
time from registration to progression, subsequent anti-lymphoma 
treatment, or death due to any cause. The distribution of EFS time 
will be estimated using the method of Kaplan-Meier (Kaplan and 
Meier 1958). 
 
16.424   
Overall survival:  Survival time is defined as the time from 
registration to death due to any cause. The distribution of survival 
time will be estimated using the method of Kaplan-Meier (Kaplan 
and Meier 1958). 
 
16.425  
Progression-free survival: The progression-free survival (PFS) time 
is defined as the time from registration to progression or death due to 
any cause.  The distribution of progression-free survival will be 
estimated using the method of Kaplan-Meier (Kaplan and Meier 
1958). 
 
16.426   
Duration of response is defined for all evaluable patients who have 
achieved an objective response as the date at which the patient’s 
objective status is first noted to be either a CR or PR to the earliest 
date progression is documented. The distribution of duration of 
response will be estimated using the method of Kaplan-Meier 
(Kaplan and Meier 1958).  
 
16.427   
Analyses of translational endpoints:  Immune function will be 
evaluated before and after treatment by assessing T, B, and NK cell 
quantification.  Changes in these values will be both graphically and 
quanitatively summarized and explored.  In addition, these values 


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Protocol Version Date:  30Nov2017 
will be explored in relation to clinical outcomes such as EFS and 
response (responder vs non-responder as well as by quality of 
response, i.e. CR vs PR). 
 
 
16.428   
R2CHOP in non-germinal center B-cell-like lymphoma (Group 1 
only) 
 
DLBCL patients will be profiled for gene expression using 
pretreatment samples. Patients will be categorized as germinal-center 
B-cell-like (GCB) vs. non-germinal center B-cell-like (non-GCB).   
 
In a previous study of large B-cell lymphoma treated with R-CHOP, 
patients with the non-GCB subtype had significantly worse overall 
survival and lower event-free survival than patients with the 
germinal-center B-cell-like subtype (Fu et al, 2008).  The 3-year 
event-free survival for the 63 patients with the non-GCB subtype 
was approximately 52%. Although event-free survival also includes 
initiation of subsequent anti-lymphoma therapy as an event for this 
study, it is rare to see a patient receive subsequent treatment before 
tumor progression or relapse.  A 3-year event-free survival of 50% 
would be a reasonable historical estimate for non-GCB subtype 
lymphoma treated with R-CHOP even where subsequent treatment is 
considered an event.  We are interesting in testing the null hypothesis 
that the 3-year event-free survival for R2CHOP is 50% for DLBCL 
patients with the activated B-cell-like subtype. 
 
Decision Rule for DLBCL patients with activated B-cell-like 
lymphoma: The largest success proportion where the proposed 
treatment regimen would be considered ineffective in this population 
is 50%, and the smallest success proportion that would warrant 
subsequent studies with the proposed regimen in this patient 
population is 70%. The following one-stage three-outcome design 
(Sargent et al, 2001) uses 37 evaluable patients to test the null 
hypothesis that the true success proportion in a given patient 
population is at most 50%. Success is defined as being event-free at 
3 years, where an event is defined as death due to any cause, tumor 
progression or relapse (by CT scan), or initiation of subsequent anti-
lymphoma therapy following R2CHOP study therapy.  Assuming the 
number of successes is binomially distributed, the significance level 
is 0.05. 
 
Final Decision Rule: The following decision criteria will be used in 
the evaluation of all 37 evaluable patients: 
• “Not promising”: This regimen will be classified as not promising 
with respect to the success rate in this patient population if at most 
21 successes are observed in 37 evaluable 
patients. 


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Protocol Version Date:  30Nov2017 
• “Inconclusive”: The results of this study will be classified as 
inconclusive with respect to this regimen demonstrating an improved 
success rate if 22 or 23 successes are observed in 37 
evaluable patients. In this case, overall survival will be used in 
addition to event-free survival at 3 years to make the final decision 
as to whether or not this treatment is considered 
promising and worthy of further study in this patient population. 
• “Promising”: This regimen will be classified as promising with 
respect to increasing the success rate in this patient population if at 
least 24 successes are observed in 37 evaluable patients. Subsequent 
studies may be recommended. 
 
16.429   
R2CHOP in transformed and composite follicular lymphoma (Group 
2) 
 
In a previous study including 53 patients with transformed follicular 
lymphoma treated with a ritixumab-containing chemotherapy, the 2-
year progression-free survival estimate was approximately 60% 
(Villa et al, 2013).  We expect the addition of lenalidomide will 
increase the 2-year progression-free survival.  However, due to the 
heterogeneous nature of this patient population, the patients on this 
study may have a worse prognosis. Therefore, we are interesting in 
testing the null hypothesis that the 2-year progression-free survival 
for R2CHOP is 50% for patients with transformed or composite 
lymphoma. 
 
Decision rule for patients with transformed and composite 
lymphoma:  The largest success proportion where the proposed 
treatment regimen would be considered ineffective in this population 
is 50%, and the smallest success proportion that would warrant 
subsequent studies with the proposed regimen in this patient 
population is 70%.  The following one-stage binomial design uses 35 
patients to test the null hypothesis that the true success proportion in 
a given patient population is at most 50%.  Success is defined as 
being alive and progression-free at 24 months. 
 
Final Decision Rule:  If 21 or fewer successes are observed in the 
first 35 evaluable patients, we will consider this regimen ineffective 
in this patient population.  If 22 or more successes are observed in 
the first 35 evaluable patients, we may recommend further testing of 
this regimen in subsequent studies in this patient population. 
 
Assuming the number of successes is binomially distributed, this 
one-stage binomial design will have 87% power, with a 9% Type I 
error rate. 
 
16.43   Adverse Events:  All eligible patients that have intitiated treatment will be 
considered evaluable for assessing adverse event rates.  The maximum grade for 


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Protocol Version Date:  30Nov2017 
each type of adverse event will be recorded for each patient, and frequency tables 
will be reviewed to determine patterns.  Additionally, the relationship of the 
adverse events to the study treatment will be taken into consideration. 
 
16.44   Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final point 
estimates and confidence intervals. 
 
16.45    Data & Safety Monitoring: 
 
16.451  The principal investigator(s) and the study statistician will review the 
study at least twice a year to identify accrual, adverse event, and any 
endpoint problems that might be developing. The Mayo Clinic Cancer 
Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
 
16.452  Adverse Event Stopping Rules (These rules apply to all patients in this 
study treated at the MTD):   The stopping rules specified below are based 
on the knowledge available at study development.  We note that the 
Adverse Event Stopping Rule may be adjusted in the event of either (1) 
the study re-opening to accrual or (2) at any time during the conduct of 
the trial and in consideration of newly acquired information regarding the 
adverse event profile of the treatment(s) under investigation.  The study 
team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we 
observe adverse events considered at least possibly related to study 
treatment (i.e. an adverse event with attribute specified as  “possible”, 
“probable”, or “definite”) that satisfy either of the following: 


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Protocol Version Date:  30Nov2017 
If in the first 18 treated patients any of the following occur: 
• 
3 or more patients experience a grade 4 or higher non-hematologic 
adverse event at least possibly related to treatment with 
lenalidomide. 
• 
3 or more patients experience a grade 3 or higher 
thrombosis/embolism at least possibly related to treatment with 
lenalidomide.  
• 
3 or more patients experience a dose reduction or delay of over 7 
days of RCHOP at least possibly related to the addition of 
lenalidomide to RCHOP. The dose modifications of RCHOP based 
on known toxicity of RCHOP agents and thought to be unrelated or 
unlikely related to the addition of lenalidomide to study treatment 
will not be considered. 
 
If after the first 18 patients have been treated any of the following occur: 
• 
20% of all patients experience a grade 4 or higher non-hematologic 
adverse event at least possibly related to treatment with 
lenalidomide. 
• 
20% of all patients experience a grade 3 or higher 
thrombosis/embolism at least possibly related to treatment with 
lenalidomide.  
• 
20% of all patients experience a dose reduction or delay of over 7 
days of RCHOP at least possibly related to the addition of 
lenalidomide to RCHOP. The dose modifications of RCHOP based 
on known toxicity of RCHOP agents and thought to be unrelated or 
unlikely related to the addition of lenalidomide to study treatment 
will be not considered. 
 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
16.5 
Inclusion of Women and Minorities 
 
16.51 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.52 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
16.53 The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 7% of patients will be classified as minorities by 
race and about 40% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
1 
0 
2 
Not Hispanic or Latino 
57 
85 
0 
142 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all subjects 
58 
86 
0 
144 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
1 
1 
0 
2 
Black or African American 
1 
2 
0 
3 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
56 
83 
0 
139 
More than one race 
0 
0 
0 
0 
Unknown 
0 
0 
0 
0 
Racial Category: Total of all subjects 
58 
86 
0 
144 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, or 
other Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used 
in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original peoples 
of North, Central, or South America, and who maintains tribal affiliations or community 
attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, 
or the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, 
Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the 
Philippine Islands have been recorded as Pacific Islanders in previous data collection 
strategies.)  
Black or African American – a person having origins in any of the black racial groups of 
Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or African 
American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or 
North Africa. 
  


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Protocol Version Date:  30Nov2017 
 
17.0  
Pathology Considerations/Tissue Biospecimens   
 
17.1  
Tissue Biospecimen Submission.  
 
NOTE: Patients must have consented to submission of the optional tissue(s) listed in the 
following table.  
 
17.11 Summary Table of Tissue Biospecimens for this Protocol 
 Type of tissue to submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
Where to find 
specific details 
for  submission 
Formalin-fixed paraffin-
embedded (FFPE) tissue 
blocks/slides 
Mandatory 
≤ 42 days following 
registration 
Pathology review 
 
Immunohistochemistry 
for non-GCB vs. GCB 
subtype (DLBCL 
patients only) 
Section 17.2 
Formalin-fixed paraffin-
embedded (FFPE) tissue 
blocks/slides** 
Optional 
≤ 42 days following 
registration 
Correlative studies 
Section 17.3 
Frozen 
recurrent/refractory 
tumor tissue** 
Mandatory 
Anytime during 
study 
Correlative studies 
Section 17.4 
Frozen 
recurrent/refractory 
tumor tissue** 
Optional 
Anytime during 
study 
Correlative studies 
Section 17.4 
Tumor biopsy specimen  
Optional 
After registration, 
before treatment and 
prior to cycle 2 
Banking (Section 
17.54-17.55) 
Section 17.5 
Tumor biopsy specimen 
Optional 
After treatment – 
refractory/relapsed 
disease. 
Banking (Section 
17.56) 
Section 17.5 
**If an institution is not able to provide the tissue, it does not cause the patient to be ineligible; however, 
the collection of these tissues is strongly recommended. 
 
17. 2    Central pathology review including and CD20 positivity will be performed for all patients 
participating in the study to confirm patient eligibility.  Immunohistochemistry will be 
performed for DLBCL patients to determine the molecular subtype (non-GCB vs. GCB) 
using the Hans method (Hans et al, 2004). Completion of central pathology review is not 
required prior to registration; however materials for central review must be reviewed 
within 42 days after registration. 
 
17.3     Tumor tissue from original diagnosis remaining after diagnostic studies and mandated 
archiving will be banked for future tissue microarray studies in order to identify tumor 
specific predictors of response and prolonged progression free survival (See section 
17.5).  
 




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Protocol Version Date:  30Nov2017 
events.  For TMAs, the donor block remains intact except for 6 small (0.6mm) 
holes where the cores were taken.  This process has minimal impact on the utility 
of the block for future clinical diagnostic needs.  
 
17.53 Fresh tissue obtained pre-treatment and at other timepoints in the study that were 
made into cell suspensions will be banked on 
in the SPORE 
Biospecimens repository and be available for future research.  
 
17.54 Paraffin-embedded primary biopsy material.  This material will be archived in 
hematopathology and will be available for future unspecified research at Mayo 
such as immunohistochemistry of new markers under the direction of the Mayo 
Hematopathology Group (Dr. W. Macon), see 17.5.  
 
17.55 Frozen pieces of primary biopsy material will be retained within 
Hematopathology or the diagnosis site and will be requested if needed for future 
unspecified research. 
 
17.56 Excess fresh tissue obtained at the time of the on-study biopsy (most likely 
consented under SPORE IRB 118-01) or if the patient consents to re-biopsy on 
this study per test schedule will be retained in the SPORE lab on 
  
Depending on size of tissue, some may be cryopreserved in the SPORE 
Biospecimens bank on 
 for future unspecified research. 
 
17.6 
Return of Genetic Testing Research Results. For this study, DNA and/or RNA specimens 
are only being banked and no specific genetic testing is being performed.  If, at any time, 
genetic results are obtained that may have clinical relevance, IRB review and approval 
will be sought regarding the most appropriate manner of disclosure and whether or not 
validation in a CLIA certified setting will be required.  Sharing of research data with 
individual patients should only occur when data have been validated by multiple studies 
and testing has been done in CLIA-approved laboratories. 
 


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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
18.0 
Records and Data Collection Procedures 
 
 
 
18.1 
Submission Timelines 
Forms 
Active-Monitoring Phase 
(Compliance with Test Schedule) 
Event-Monitoring Phase1 
(Completion of Active-Monitoring 
Phase) 
At Each Occurrence 
 
Initial 
Material 
 
Follow-up material 
 
 
≤2 weeks 
after 
registration 
At each 
evaluation 
At end  
of  
treatment 
q.6 
months 
until 
PROG  
At 
PROG  
 
 
After 
PROG  
q.6 mos. 
Death  
ADR/ 
AER 
New 
Primary 
Grade 4 or 5 
Non-AER 
Reportable 
Events/ 
Hospitalization 
Late 
Adverse 
Event 
On-Study Form 
X 
 
 
 
 
 
 
 
 
 
 
Baseline Adverse Events Form 
X 
 
 
 
 
 
 
 
 
 
 
Measurement Form  
X 
X  
X  
 
 
 
 
 
 
 
 
Blood Specimen Submission Form 
(Section 14.0) 
X 
X6 
X 
 
 
 
 
 
 
 
 
Tissue Specimen Submission Form 
(Section 17.0) 
X 
X6 
 
 
 
 
 
 
 
 
 
Evaluation/Treatment Form 
 
X3 
X 
 
 
 
 
 
 
 
 
Nadir/Adverse Event Form 
 
X 
X 
 
 
 
 
 
 
 
 
End of Active Treatment/Cancel 
Notification Form 
X4 
 
X 
 
 
 
 
 
 
 
 
Event Monitoring Form 
 
 
  
X 
X  
X 
X 
  
X 
 
X 
Evaluation/Observation Form 
 
X2 
  
 
 
 
 
 
 
 
 
ADR/AER (See Section 10.0) 
 
 
 
 
 
 
 
X 
 
 
 
NCI/CTEP Secondary  
AML/MDS 
Report Form (See Section 10.0) 
 
 
 
 
 
 
 
 
X5  
 
 
Grade 4 or 5 Non-AER  Reportable 
Events/ Hospitalization Form 
 
 
 
 
 
 
 
 
 
X 
 
Tumor Tissue Pathology Report 
X 
 
 
 
 
 
 
 
 
 
 
Pathology Reporting Form 
X7 
 
 
 
 
 
 
 
 
 
 
CT, PET, MRI reports 
X 
X 
 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy Report 
X 
X6 
 
 
 
 
 
 
 
 
 
Quantitative Flow Cytometry Form 
X 
X6 
 
 
 
 
 
 
 
 
 
Footnotes on following page. 


MC078E 
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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2. Complete at each evaluation during Observation (see Section 4.0). 
3. Complete at each evaluation during Active Treatment (see Section 4.0) 
4.     Submit if withdrawal/refusal prior to beginning protocol therapy occurs. 
5. Only applicable to new AML/MDS primaries, not for all new primaries. 
6. At timepoints required by Section 4.0. 
7. After the central review has been completed and materials have been returned, forward a copy of the Pathology Reporting Form to the QAS 
for documentation.  Send to:  QAS for MC078E, RO_FF_03_24-CC/NW Clinic. 


MC078E 
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MCCC Addendum 12 
 
Protocol Version Date:  30Nov2017 
 
19.0  
Budget 
  
 
19.1 
Costs charged to patient: All routine clinical care.  Lenalidomide will be provided by 
Celgene at no cost to the participant; however, standard charges will be assessed for all 
commercially available agents (RCHOP) and their administration. The participant will be 
billed for pharmacy charges and other ancillary expenses such as any oral medications 
prescribed at the time of discharge. 
 
 
19.2 
Tests to be research funded:  Lymphocyte panel by flow cytometry, tumor biopsy not 
required for clinical evaluation will be research funded. Specimen banking will be funded 
by Lymphoma SPORE CA97274.  
 
19.3 
Protocol administration, data management and statistical analysis efforts will be by 
funded by a grant from Celgene, according to the terms of the contract. 
 
20.0 
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Hussain, M.M., Klueppelberg, U., Norin, A.J., Akman, H.O., Ozcelik, T. & Batuman, O.A. 
(2005) Circulating endothelial progenitor cells in multiple myeloma: implications and 
significance. Blood, 105, 3286-3294. 
 
 


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Protocol Version Date:  30Nov2017 
Appendix I 
Ann Arbor NHL Staging System 
 
 
Stage I - disease in single lymph node or lymph node region.  
Stage II - disease in two or more lymph node regions on same  
side of diaphragm.   
Stage III - disease in lymph node regions on both sides of the diaphragm are affected.  
Stage IV - disease is wide spread, including multiple involvement at one or more extranodal 
(beyond the lymph node) sites, such as the bone marrow. 
 


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Protocol Version Date:  30Nov2017 
Appendix II 
ECOG Performance Status Scale 
 
SCORE  
DESCRIPTION  
0  
Fully active, able to carry on all pre-disease performance without 
restriction.  
1  
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work.  
2  
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.  
3  
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.  
4  
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.  
5  
Dead.