Conditions: Anaplastic Large Cell Lymphoma, ALK-Negative Recurrent Anaplastic Large Cell Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma Recurrent Non-Hodgkin Lymphoma Recurrent Transformed Non-Hodgkin Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 74
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of lenalidomide when given after combination chemotherapy with or without rituximab and stem cell transplant and to see how well it works in treating patients with non-Hodgkin lymphoma that has not responded to treatment or has returned after a period of improvement and is resistant to chemotherapy. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as carmustine, etoposide, cytarabine, and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, may block cancer growth by targeting certain cells. Giving lenalidomide after combination chemotherapy with or without rituximab may work better in treating patients with non-Hodgkin lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) of lenalidomide given in the post-transplant setting for a 12 month maintenance period.

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of the 1-year response rate, event-free and overall survival using this regimen.

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

PRE-CONDITIONING (patients with cluster of differentiation \[CD\]20+ non-Hodgkin lymphoma): Patients receive rituximab intravenously (IV) per standard of care.

PREPARATIVE REGIMEN: Patients receive carmustine IV on day -6, etoposide IV twice daily (BID) and cytarabine IV BID on days -5 through -2, and melphalan IV on day -1.

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION: Patients undergo stem cell infusion on day 0.

MAINTENANCE THERAPY: Beginning approximately 100 days post-transplant, patients receive lenalidomide orally (PO) on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms:
arm 1: PRE-CONDITIONING (patients with CD20+ NHL): Patients receive rituximab IV per standard of care.

PREPARATIVE REGIMEN: Patients receive carmustine IV on day -6, etoposide IV BID and cytarabine IV BID on days -5 through -2, and melphalan IV on day -1.

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION: Patients undergo stem cell infusion on day 0.

MAINTENANCE THERAPY: Beginning approximately 100 days post-transplant, patients receive lenalidomide PO on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Autologous Hematopoietic Stem Cell Transplantation intervention 2: Carmustine intervention 3: Cytarabine intervention 4: Etoposide intervention 5: Lenalidomide intervention 6: Melphalan intervention 7: Rituximab
Intervention descriptions: intervention 1: Undergo autologous hematopoietic stem cell transplant intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given PO intervention 6: Given IV intervention 7: Given IV

Protocol document:
Prot_SAP_000.pdf: 
 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 1 of 75 
Protocol Title:  Phase I/II Study of Lenalidomide Maintenance Following BEAM (+/- 
Rituximab) for Chemo-Resistant or High Risk Non-Hodgkin’s Lymphoma 
 
Principal Investigator:  
 
Julie M. Vose, M.D., M.B.A.  
 
 
 
 
 
 
 
Neumann M. and Mildred E. Harris Professor  
Chief, Section of Hematology/Oncology  
Professor of Medicine  
987680 Nebraska Medical Center 
 
 
 
 
 
Omaha, NE 68198-7680  
 
 
 
 
 
Phone (402) 559-3848  
FAX (402) 559-6520 
 
 
 
 
 
e-mail: jmvose@unmc.edu 
 
Secondary Investigators: 
 
James O. Armitage, M.D. 
Philip J. Bierman, M.D. 
 
 
 
 
 
R. Gregory Bociek, M.D. 
 
 
 
 
 
Matthew Lunning, MD 
 
Multi-site Participation:  
 
IRB Approved Sites 
 
Collaborating Sites:  
 
Paolo F. Caimi, MD 
University Hospital Seidman Cancer Center 
 
 
 
 
 
Case Western Reserve University 
 
 
 
 
 
Cleveland, OH 
 
 
 
 
 
 
Siddhartha Ganguly, MD 
University of Kansas Cancer Center 
Westwood, KS 
 
 
 
 
 
 
 
 
Participating Personnel:  
 
UNMC Physicians - Pathology:  
 
 
 
 
 
 
Dennis Weisenburger, MD 
 
 
 
 
 
Kai Fu, MD, PhD 
 
 
 
 
 
Rakesh Singh, Ph.D. 
 
Biostatistician: 
 
 
Jane L. Meza, PhD 
 
 
Research Study Coordinator: 
Mary Mailliard, R.N., B.S.N., OCN 
 
 
 
 
 
Clinical Research Support 
UNMC Fred & Pamela Buffett Cancer Center, CPDMU 
Early Phase Therapeutic Clinical Trial Unit 
986805 Nebraska Medical Center 
 
 
 
 
 
Omaha, NE 68198-6805 
 
 
 
 
 
Phone (402) 559-5582         FAX (402) 559-8895 
 
 
 
 
 
e-mail: mjmailli@unmc.edu 
 
 
 
Lenalidomide: 
 
 
Celgene Corporation  
                                                       
Protocol Number  RV-LYM-PI-0328 
 
 
 
 
 
IND 103,802 EXEMPT 10-17-08 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 2 of 75 
Index: 
 
 
 
 
 
 
 
 
 
 
Page 
Abstract/Schema 
 
 
 
 
 
 
 
3 
 
1.0 – Objectives 
 
 
 
 
 
 
 
4 
 
 
2.0 - Background, Significance, and Preliminary Studies  
 
 
4 
 
3.0 - Eligibility Criteria  
 
 
 
 
 
 
15 
 
 
4.0 - Registration Procedures  
 
 
 
 
 
18 
 
5.0 – Treatment Plan  
 
 
 
 
 
 
21 
 
6.0 - Measurement of Effect 
 
 
 
 
 
 
27 
 
7.0 - Study Parameters 
 
 
 
 
 
            28 
 
8.0 - Drug Formulation and Procurement 
 
 
 
 
31 
 
9.0 - Toxicity Reporting Guidelines 
 
 
 
 
 
36 
 
10.0 - Statistical Considerations 
 
 
 
 
 
46 
 
11.0 - Records to be Kept 
 
 
 
 
 
 
48 
 
12.0 - Subject Consent form Statement 
 
 
 
 
48 
 
13.0 – References 
 
 
 
 
 
 
 
50 
 
14.0 - Data Forms 
 
 
 
 
 
 
 
53 
 
Appendix A – 
Karnofsky Performance Scale 
 
 
 
54 
Appendix B –  
Risks of Fetal Exposure, 
 
Pregnancy Testing Guidelines  
 
and Acceptable Birth Control Methods 
 
 
55 
Appendix C –      New York Heart Association Heart  
 
Disease Classification 
 
 
 
 
59 
Appendix D –   Response Criteria, International Harmonization  
 
Project’s update to the International Working  
 
Group guidelines  
 
 
 
 
 
60 
Appendix E –    NCI Common Toxicity Criteria Version 4.0 
 
 
64 
Appendix F –    Medwatch SAE Reporting Form 
 
 
 
64 
Appendix G –  
BSA and Creatinine Clearance Calculations  
            64 
Appendix H-    Eligibility Checklist                                               
 
65 
Appendix I-  “Oral, Sublingual, and/or Buccal Route Medication  
          Adherence Standard Procedure   
          Example:  Medication Diary       (Form A)                                   70 
Appendix J-     Blood and Tissue Sample Processing and Shipping 
                          for Cytokine Level Studies   
 
 
 
           72 
Appendix K-     International Prognastic Index (IPI)                                          74  
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 3 of 75 
Abstract:  This is a multi-center Phase I/II trial in which up to 16 evaluable subjects with 
persistent or relapsed non-Hodgkin’s lymphoma (NHL) (any histology) that is chemo-
resistant (< a PR), has received 3 or more prior chemotherapy regimens, or for subjects with 
lymphomas that have a high relapse rate following autologous or syngeneic stem cell 
transplantation (transformed NHL, peripheral T-cell lymphoma (PTCL), mantle cell 
lymphoma, ALK-negative  anaplastic large cell lymphoma (ALCL, alk neg), intermediate IPI 
or high risk IPI or subjects with a positive PET scan prior to transplant. Subjects that relapse 
within one year of diagnosis are also eligible. Subjects will receive the suggested transplant 
regimen of BEAM +/-Rituximab (Rituximab added for CD20+ NHL’s) treatment and 
Autologous Hematopoietic Stem Cell Transplantation (AHSCT) (Standard of Care) followed 
by lenalidomide maintenance. Lenalidomide Phase II maintenance therapy will be started 
day 100, or as close as possible by treating physician’s discretion and dependent on the 
subject’s travel conditions, etc., when the ANC is > 1000 and the plts are > 60K. 
Lenalidomide was administered to four subject dose cohorts, (10 mg, 15 mg, 20 mg and 25 
mg). Lenalidomide will be administered orally on days 1-21 followed by 7 days of rest (28 
day cycle) for 12 cycles maintenance. Three (3) subjects will be accrued in each 
Lenalidomide dose cohort with enrollment starting at dose cohort 1, (10 mg). These subjects 
will be evaluated to establish the maximum tolerated dose of Lenalidomide that can be 
tolerated 
in 
following 
Rituximab/BEAM 
autologous 
peripheral 
blood 
stem 
cell 
transplantation.  The Lenalidomide of 10 mg will be utilized for the Phase II cohort. Due to 
the high dropout rate of subjects and the counting of consented never treated subjects, up to 
114 subjects will be enrolled to achieve the 16 evaluable at the Phase II 10 mg dose level to 
estimate the 1 year event-free and overall survival. Data collected will be utilized to obtain a 
preliminary estimate of the response rate, event-free and overall survival using this regimen.   
 
 
Summary Schema: 
Stem cell collection per standard protocol 
Rituximab per standard care. 
 
 
 
 
 
Day – 6 
 
 Day - 5 
  Day - 4 
  Day - 3 
  Day - 2 
    Day - 1  
 
  Day 0  
 
 
Transplantation 
 
 
 
BCNU  
300mg/
m2 
 
Etoposide 
100mg/m2 
BID 
Cytarabine 
100mg/m2 
BID 
Etoposide 
100mg/m2 
BID 
Cytarabine 
100mg/m2 
BID 
Etoposide 
100mg/m2 
BID 
Cytarabine 
100mg/m2 
BID 
Etoposide 
100mg/m2 
BID 
Cytarabine 
100mg/m2 
BID 
Melphalan 
140mg/m2 
Stem 
Cell 
Infusion 
 
 
 
 
Day 100, or as close as possible by treating physician’s discretion and dependent on the subject’s travel conditions, etc., post-transplant* 
Phase I Cohort 
# Pts 
Days 1-21 of a 28 day cycle for 12 cycles after initiation of the therapy post- 
transplant. 
#-1 
 
Maintenance Lenalidomide 5 mg PO 
#1 
3 
Maintenance Lenalidomide 10 mg PO  
#2 
3 
Maintenance Lenalidomide 15mg PO  
#3 
3 
Maintenance Lenalidomide 20 mg PO  
#4 
3 
Maintenance Lenalidomide 25 mg PO 
Phase II Cohort  
 
Days 1-21 of a 28 day cycle for 12 cycles after initiation of the therapy post-
transplant 
 
Up to 24 
Maintenance Lenalidomide 10mg PO 
* the first cycle of Lenalidomide should be started day 100, or as close as possible by treating physician’s discretion and 
dependent on the subject’s travel conditions, insurance approval, primary/referral oncologist approval, consolidation radiation, 
which may delay day 100, etc., post-transplant when the ANC is > 1000 and the plts are > 60K. 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 4 of 75 
 
1.0    Objective 
 
1.1   
Primary Objective 
 
To establish the maximum tolerated dose (MTD) of Lenalidomide given in the 
post- transplant setting for a 12 month maintenance period  
. 
1.2 
Secondary Objective 
 
To obtain preliminary estimates of the 1-year response rate, event-free and 
overall survival using this regimen. 
 
2.0     Background, Significance, and Preliminary Studies 
 
 
Subjects with persistent or relapsed non-Hodgkin’s lymphoma that is 
 
chemotherapy resistant or have received 3 or more prior chemotherapy 
 
regimens have only a 15-30% long term disease-free survival following 
 
standard high-dose chemotherapy and autologous stem cell transplantation. 
 
The major cause for failure is progressive lymphoma.  However, the addition 
 
of other standard chemotherapy agents have not been found to improve the 
 
results in this difficult to treat subject population.  With this in mind, we have 
 
been adding agents to the transplant protocol that have a novel mechanism of 
 
action and have demonstrated some individual activity in NHL subjects. 
 
Lenalidomide has shown single agent activity in NHL.  The purpose of this 
 
proposed trial is to add on to this backbone of the BEAM (+/- Rituximab) with 
 
Lenalidomide maintenance therapy to decrease the post-transplant relapse of 
 
NHL. 
 
 
2.1 High-Dose Therapy in non-Hodgkin’s Lymphoma 
 
Subjects with relapsed non-Hodgkin’s lymphoma have a high complete 
response rate with Rituxan/BEAM and autologous stem cell transplantation.  
However, there are still a number of subjects who relapse following this 
procedure.  It is hoped the addition of maintenance therapies would improve 
the outcomes for subjects receiving high-dose chemotherapy and stem cell 
transplantation for treatment of relapsed non-Hodgkin’s lymphoma without 
excessive toxicity.  A Phase I study of the addition of Lenalidomide need to be 
carried out due to the lack of prior studies with this treatment used as 
maintenance in the post-transplant setting.   
 
 
Subjects who have transformed from a follicular to a diffuse large cell non-
 
Hodgkin’s are felt to have a poor prognosis with standard therapies.   
 
(Lerner and Burns, 2003; Martinez-Climent, Alizadeh, Segraves, 2003)     
However, if subjects have at least a partial response to salvage 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 5 of 75 
chemotherapy with respect to the large cell component and then go on to 
receive high-dose chemotherapy and autologous stem cell transplantation, 
they have been found to have a similar prognosis to subjects receiving a 
similar transplant for follicular NHL.  (Cao, Horning, Negrin, 2001; Andreadis, 
Schuster, Chong, 2005; Laudi, Arora, Burns, 2005)  In one study by Cao et al, 
17 subjects with transformed NHL who underwent autologous stem cell 
transplant had a 4 year estimate of overall survival of 50% (95% CI, 24% -
76%) and disease- free survival year survival of 49% (95% CI, 20% - 78%).  
This compares to a 4 year overall survival of 60% and a disease-free survival 
of 44% in subjects who were transplanted still having a follicular histology.   
Rituximab (IDEC-C2B8) is a chimeric monoclonal antibody directed against 
the CD20 antigen.  It contains human IgG1 antibody and kappa constant 
regions, complexed to murine variable regions.  This combination seems to 
maximize antitumor activity while minimizing autoimmunogenicity. In vitro 
rituximab mediates antibody-dependent cell-mediated cytotoxicity (ADCC) 
and complement-dependent cytotoxicity (CDC).  It appears to directly inhibit 
cellular proliferation and induces apoptosis.  Rituximab has also 
demonstrated an ability to sensitize drug-resistant lymphoma cell lines to the 
cytotoxic effects of chemotherapy.  In vivo, it is not clear which of these 
mechanisms of action predominate.  In subjects with large circulating tumor 
burdens, rapid tumor lysis has been observed, most likely as a result of 
activation of the complement system.  Toxicity is generally infusional, and 
related to acute host responses to a foreign protein (e.g., fever, chills, 
asthenia).  Other toxicities such as acute bronchospasm/hypotension have 
been observed rarely, and generally respond to the agents used to treat acute 
hypersensitivity reactions.  Such reactions tend to be minimized or detectable 
early by administering the drug at a controlled gradually escalating infusion 
rate.  Responses to rituximab are seen over 1-3 months, with duration of 
response varying by tumor type, bulk of disease, and amount and type of 
prior therapy.  Median durations of response in these trials were often in the 
range of 7-13 months.  Very rarely, life threatening allergic reactions has 
occurred with the use or rituximab. 
 
2.2 Early Trials of Rituximab 
 
Maloney et al. initially evaluated Rituximab for use in subjects with relapsed 
non-Hodgkin’s lymphoma in usual Phase I fashion, administering it as a 
single agent in doses ranging from 10 to 500 mg/m2.  Among 15 treated 
subjects, 7 responses (2 partial, 5 minimal) were seen.  Therapy was in 
general well tolerated and no dose-limiting toxicity was observed, although 
the higher dose levels required that subjects undergo prolonged infusion 
times because of infusion-related side effects.  Toxicity consisted generally of 
allergic/infusional symptoms, including fevers, asthenia, chills, rash and 
urticaria with bronchospasm, hypotension and angioedema seen less 
commonly.  Some subjects experienced brief, clinically insignificant 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 6 of 75 
hematologic nadirs. Infusion-related symptoms tended to be most severe 
during the first infusion and generally diminished with subsequent treatments. 
No increased rates of infection were observed.  This is presumably because 
serum immunoglobulin and T-cell levels did not change significantly post 
therapy.  The higher dose in the multi-dose study was selected as the test 
dose for subsequent Phase II trials.  As responses appeared to be more 
common in subjects with relapsed indolent lymphomas, subsequent Phase II 
trials focused primarily on this subject population.  (Maloney et al.) 
 
McLaughlin et al. published the results of a pivotal large multicenter Phase III 
trial in which 166 subjects with previously treated low-grade lymphoma were 
enrolled.  Subjects received rituximab 375 mg/m2 weekly for 4 weeks.  In the 
intent-to-treat analysis the response rate was 48% and the complete 
response rate was 6%.  Response rates of 60% were seen in those with 
follicular lymphoma, and subjects considered chemotherapy-resistant still 
demonstrated a response rate of 36%.  The median time to progression for 
responders was 13.2 months and median duration of response was 11.6 
months.  Again, the majority of adverse events occurred during the first 
infusion and was allergic/infusional in nature.  Only 1 grade 4 neutropenia 
was observed. On the basis of these studies, rituximab was approved by the 
Food and Drug Administration for use in subjects with relapsed low-
grade/follicular non-Hodgkin’s lymphoma.  Several further studies have been 
conducted with rituximab to evaluate other aspects of its therapeutic potential.  
A study by Piro and colleagues evaluated safety and efficacy of extending 
therapy to 8 weekly infusions.  Thirty seven subjects with relapsed/refractory 
low-grade or follicular B-cell NHL who had relapsed or had failed primary 
therapy were treated.  The majority of toxicity as expected was infusional, 
with events decreasing with subsequent infusions.  No host antibody (human 
anti-chimeric antibody) responses were seen.  Mean serum immunoglobulin 
levels remained within normal.  On an intent-to-treat basis, 5 subjects (14%) 
had a complete response and 16 subjects (43%) had a partial response for an 
overall response rate of 57%.  Among 35 evaluable subjects, the response 
rate was 60% (14% CR and 46% PR), and the median time to progression 
(TTP) and the median response duration have not been reached after 19.4+ 
months and 13.4+ months, respectively.  The authors concluded that the 
safety profile appeared to compare favorably with 4 weekly injections.  It is 
possible that the median time to progression, and median response duration 
with 8 weekly injections is superior to that seen with 4 weeks of treatment, but 
no such direct comparison has yet been carried out. 
 
Finally, a Phase II study of 31 subjects with low grade/follicular lymphoma 
described response rates and duration in subjects with low grade/follicular 
lymphoma and bulky disease (defined as the presence of at least one tumor 
mass ≥ 10 cm).  This study demonstrated an overall response rate of 40% in 
28 evaluable subjects.  The median time to progression and duration of 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 7 of 75 
response were 8.1 months and 5.9 months, respectively.  The shorter time to 
progression compared with studies of subjects with non-bulky disease 
suggests perhaps decreased penetrance of antibody in bulky disease sites.  
(Davis et al.) 
 
2.3 Rituximab in Conjunction with CHOP in Subjects with Indolent non-
Hodgkin’s Lymphomas 
 
A Phase II study by Czuczman et al. published in 1999 looked at the 
combination of CHOP chemotherapy in conjunction with rituximab in 40 
subjects with low-grade/follicular non-Hodgkin’s lymphoma.  Subjects had to 
be anthracycline naïve, and had to have a WHO performance status of 0-2.  
Most subjects had follicular small cleaved or follicular mixed histology, and 
nearly 80% of subjects had received no prior therapy.  CHOP was given in 
standard doses, at 21 day intervals for six cycles.  Rituximab was given at the 
usual dose for six infusions.  Two infusions were given prior to the initiation of 
CHOP; one infusion was given at weeks 5 and 11 respectively, then finally as 
two infusions after the completion of CHOP.  The overall response rate in this 
group of subjects was 95%, and with a median follow-up duration of nearly 
two years, 75% of subjects have not experienced disease recurrence or 
progression.  Toxicity did not appear to be different than that associated with 
CHOP alone, with the exception of the expected first dose effect seen with 
rituximab. 
 
2.4 Rituximab in Aggressive Non-Hodgkin’s Lymphoma 
 
A prospective Phase II study by Coiffier et al. looked at the use of rituximab in 
54 subjects with aggressive subtypes of non-Hodgkin’s lymphoma and 
mantle-cell lymphoma.  Subjects received 8 weekly infusions of rituximab at a 
dose of either 375 mg/m2 or a dose of 375 mg/m2 once followed by 7 weekly 
infusions at a dose of 500 mg/m2.  Subjects were evaluated for response 2 
months after completion of therapy.  In an intent-to-treat analysis, the 
complete response rate was 9% and the partial response rate was 22% for an 
overall response rate of 31%.  The projected median time to progression was 
greater than 105 days for all subjects and greater than 246 days for 
responding subjects.  Taking into account the observation that many of these 
subjects had chemorefractory disease, these data were considered 
encouraging for a single agent. 
 
The potential for synergy with rituximab in conjunction with chemotherapy led 
to a Phase II study of CHOP (cyclophosphamide, doxorubicin, vincristine, 
prednisone) in combination with rituximab in subjects with advanced stage 
aggressive B-cell lymphomas.  Subjects received rituximab 375 mg/m2 on 
day one and CHOP on day 3 of each 21 day chemotherapy cycle.  Thirty-one 
subjects were treated.  The median age of subjects was 49 years.  All 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 8 of 75 
subjects received six cycles of therapy. The overall response rate was 94%.  
The complete response rate was 61%.  The median time to progression had 
not been reached after a median follow-up of 26 months.  Toxicity was 
predominantly hematologic, but did not appear to be different than that 
expected from CHOP alone. Expected side-effects associated with rituximab 
were seen. 
 
The conclusion of this pilot trial was that this regimen was tolerable with 
serious adverse events occurring at a rate and severity similar to that seen 
with conventional CHOP chemotherapy.  Response rates may have been 
higher than that with CHOP alone, but since this was a pilot Phase II trial, no 
control group was available for comparison.  (Vose et al.)   
 
Most recently, a randomized trial comparing CHOP to rituximab/CHOP (r-
CHOP) in elderly subjects (60-80 years of age) with aggressive B-cell  
lymphomas was conducted by the GELA (Groupe d’Etude de Lymphomes 
Adultes) and the first peer reviewed results on this study were recently 
published.  In this study 399 subjects were randomized to CHOP versus r-
CHOP.  For subjects receiving r-CHOP both therapies were given on day 1.  
Response rates were higher for r-CHOP compared with CHOP alone (86% vs 
71%, P=0.007).  Eighteen-month event-free survival (62% vs 43%; 
P=0.00012) and overall survival (73% vs 61%; P=0.0065) were superior in the 
r-CHOP group.  This is the first published randomized trial comparing CHOP 
to r-CHOP.  Although preliminary results of a second randomized trial are 
likely to be available within the next one to two years, many centers are now 
considering r-CHOP as standard therapy for newly diagnosed aggressive B-
cell non-Hodgkin’s lymphoma.  (Coffier et al.)   
 
2.5 Rituximab in Conjunction with High-Dose Therapy/Autologous 
Hematopoietic Stem Cell Transplantation 
 
Since relapse is the most common cause of treatment failure in subjects with 
chemotherapy refractory or relapsed lymphoma, the evaluation of this 
combination was clearly warranted.  The potential additive or synergistic 
benefit of rituximab in conjunction with chemotherapy led to the design and 
execution of three clinical trials at UNMC.  Rituximab was given in conjunction 
with BEAM (carmustine, etoposide, cytarabine, melphalan) followed by 
AHSCT.  The first study included subjects with chemotherapy sensitive 
indolent NHL receiving high-dose BEAM/PSCT.  In this study rituximab was 
given as a pre and post-transplant agent as a possible chemosensitized and 
for the treatment of post-transplant minimal residual disease.  This study 
produced a complete response rate of 88% and a 24-month failure-free 
survival of 84% and a 24-month overall survival of 94%.  Toxicity did not 
appear to be greater than that expected from the BEAM regimen alone.   
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 9 of 75 
 
A second trial was conducted which enrolled subjects with chemorefractory 
disease prior to transplantation.  This trial of BEAM in conjunction with 
rituximab was completed in subjects with refractory disease, multiple prior 
chemotherapy regimens, or mantle-cell lymphoma.  In this trial, rituximab was 
administered twice prior to peripheral blood stem cell mobilization (preliminary 
information had demonstrated that at least two doses of rituximab given two 
weeks prior to hematopoietic stem cell collection was necessary for adequate 
clearing of PCR positive cells in the product to provide further cytoreductive 
therapy pre-transplant, as well as to act as a potential in-vivo purge prior to 
peripheral blood progenitor cell collection.  One further dose of rituximab was 
administered prior to beginning conditioning with BEAM, and a fourth dose 
was administered post recovery from transplantation.  Preliminary results of 
this trial have demonstrated a complete response rate of 65%, a 24-month 
overall survival of 88% and a 24-month event-free survival of 76%.    
 
Investigators from Stanford presented results from a Phase II trial of rituximab 
as an adjuvant to high-dose therapy/AHSCT at the recent meeting of the 
American Society of Hematology. Subjects with relapsed/refractory B-cell 
lymphomas were eligible.  Thirty-two subjects received CBV 
(cyclophosphamide carmustine, etoposide) as their conditioning regimen and 
three received a total body irradiation-based regimen.  All subjects received a 
purged stem cell product.  Subjects received four weekly infusions of 
rituximab starting at day + 40 post-transplant. Toxicity appeared to be similar 
to that expected with high-dose chemotherapy/ AHSCT alone.  At a median 
follow-up of 18 months, projected two year freedom from progression is 86%, 
and overall survival is 85%.  This result was felt by the investigators to be an 
improvement over that seen with conventional conditioning/transplantation 
only (comparison made with historical controls), and as a result a randomized 
intergroup trial is under development to evaluate rituximab as an adjuvant 
therapy further in this setting.  However, for subjects with chemotherapy 
refractory NHL results with high-dose chemotherapy and peripheral stem cells 
(PSC) continue to need improvement with additional modalities to the 
regimen (Horowitz et al.). 
  
2.6 Lenalidomide  
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.   
IMiD® compounds have both immunomodulatory and anti-angiogenic 
properties which could confer antitumor and antimetastatic effects.  
Lenalidomide has been demonstrated to possess anti-angiogenic activity 
through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell 
migration, due at least in part to inhibition of Akt phosphorylation response to 
bFGF. (Dredge et al., 2005)  In addition, lenalidomide has a variety of 
immunomodulatory effects.  Lenalidomide stimulates T cell proliferation, and 
the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 10 of 75 
modulates IL-12 production. (Corral et al.,1993) Upregulation of T cell derived 
IL-2 production is achieved at least in part through increased AP-1 activity. 
(Schafer et al., 2003)  
 
Although the exact antitumor mechanism of action of lenalidomide is 
unknown, a number of mechanisms are postulated to be responsible for 
lenalidomide’s activity against multiple myeloma.  Lenalidomide has been 
shown to increase T cell proliferation, which leads to an increase in IL-2 and 
IFN-gamma secretion.  The increased level of these circulating cytokines 
augment natural killer cell number and function, and enhance natural killer 
cell activity to yield an increase in multiple myeloma cell lysis. (Davies et al., 
2001)  In addition, lenalidomide has direct activity against multiple myeloma 
and induces apoptosis or G1growth arrest in multiple myeloma cell lines and 
in multiple myeloma cells of subjects resistant to melphalan, doxorubicin and 
dexamethasone. (Hideshima et al., 2000)   
 
Clinical Experience in Solid Tumors with Lenalidomide 
Twenty subjects with varying types of solid tumors (13 with malignant 
melanoma, 2 each with carcinoma of the pancreas and non-small-cell lung 
cancer [NSCLC], 1 each with renal carcinoma, breast carcinoma, and 
carcinoid-unknown primary) were enrolled in a Phase 1 study of lenalidomide 
conducted at the St. George Hospital, London, UK.  This was a non-
randomized, open-label with-in subject dose-escalation design, where 
subjects started on 5 mg/day for 7 days and then increased their dose every 7 
days to 10 mg/day, 25 mg/day, and 50 mg/day for a total of 4 weeks on 
therapy. (Bartlett et al., 2004) 
 
Clinical Experience in Multiple Myeloma with Lenalidomide 
In two (2) Phase I studies in multiple myeloma, a total of 41 subjects have 
been treated with lenalidomide.  In one study at the University of Arkansas, 
15 subjects who relapsed or were refractory to high dose melphalan therapy 
with stem cell transplant were treated for 4 weeks in an open-label safety 
study and were permitted to continue therapy in an extension Phase of the 
trial.  Subject cohorts were treated at the following daily doses: 5mg, 10mg, 
25mg, and 50mg. (Zangari et al. 2001).  In a similar study at the Dana Farber 
Cancer Institute, 27 subjects with rapidly advancing refractory multiple 
myeloma were enrolled. (Richardson et al., 2002) 
   
Anti-myeloma activity was observed in each of these 2 Phase I studies.  
Decreases in neutrophil and platelet counts were the dose-limiting toxicities 
associated with lenalidomide.  The maximum tolerated dose (MTD) was not 
reached within 28 days.  Due to dose modifications associated with 
myelosuppression observed beyond Day 28 at the 25mg and 50mg daily 
dose levels, the dose schedule most widely used in future studies has been 
lenalidomide 25 mg on Days 1-21, repeated every 28 days.   


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 11 of 75 
 
Pharmacokinetic analyses were performed on 15 multiple myeloma subjects 
treated in the Phase I studies.  Absorption was found to be rapid on both Day 
1 and Day 28 with time to maximum blood levels ranging from 0.7 to 2.0 
hours at all dose levels (5mg, 10mg, 25mg, and 50mg).  Plasma lenalidomide 
declined in a monophasic manner with elimination half-life ranging from 2.8 to 
6.1 hours on both Day 1 and 28 at all 4 doses.  No plasma accumulation was 
observed with multiple daily dosing.  Peak and overall plasma concentrations 
were dose proportional over the dosing range of 5mg to 50mg. (Wu, 
Scheffler, 2004) 
 
A recent Phase II trial utilizing lenalidomide plus dexamethasone for newly 
diagnosed multiple myeloma subjects were reported by the Mayo Clinic. 
Lenalidomide was given orally 25 mg daily on days 1-21 of a 28-day cycle. 
Dexamethasone was given orally 40 mg daily on days 1-4, 9-12, 17-20 of 
each cycle.  Objective response was defined as a decrease in serum 
monoclonal protein by 50% or greater and a decrease in urine M protein by at 
least 90% or to a level less than 200 mg/24 hours, confirmed by two 
consecutive determinations at least 4 weeks apart.  Thirty-one of 34 subjects 
achieved an objective response, including 2 (6%) achieving complete 
response (CR), and 11 (32%) meeting criteria for both very good partial 
response and near complete response, resulting in an overall objective 
response rate of 91%.  Of the 3 remaining subjects not achieving an objective 
response, two had minor response (MR) and one stable disease.  Forty-
seven percent of subjects experienced grade 3 or higher non-hematologic 
toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), 
pneumonitis (6%) and rash (6%). Revlimid®/dexamethasone is a highly active 
regimen with manageable side-effects in the treatment of newly diagnosed 
myeloma. (Rajkumar et al., 2005) 
 
A Phase I/II trial of liposomal doxorubicin (Doxil®), vincristine, 
dexamethasone (DVd) and lenalidomide in heavily pretreated 
relapsed/refractory multiple myeloma subjects is ongoing.  The MTD of 
lenalidomide was 10mg on Days 1-21 in combination with Doxil® 40mg/m2 
IVPB on Day 1, vincristine 2mg IVP on Day 1 and dexamethasone 40mg PO 
on Days 1-4 cycled every 28 days.  All subjects received amoxicillin, acyclovir 
and aspirin 81mg prophylactically.  The dose limiting toxicity with lenalidomide 
15mg on Days 1-21 in combination with DVd was sepsis/septic shock. 
(Hussin etg al., 2004)  Additional Phase I trials of lenalidomide with 
chemotherapy in advanced malignancies are in progress. 
 
Celgene Corporation sponsored 2 multicenter, randomized, double-blinded, 
placebo-controlled Phase III trials [1 U.S. (MM-009) and 1 international (MM-
010)] in subjects with relapsed or refractory multiple myeloma. (Data file 
Celgene Corporation)  More than 350 subjects were enrolled into each of 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 12 of 75 
these studies.  All subjects had to be considered sensitive to dexamethasone 
and were treated with dexamethasone 40mg daily on Days 1-4, 9-12 and 17-
20.  In addition to receiving dexamethasone, subjects were randomized to 
lenalidomide 25mg or placebo each given daily on Days 1-21.  Cycles were 
repeated every 28 days.  After 4 cycles, there was a predetermined reduction 
of the dexamethasone dose to 40mg daily on Days 1-4 repeated every 28 
days.  In both studies, a pre-specified interim analysis conducted by an 
Independent Data Monitoring Committee demonstrated that subjects 
receiving the combination of lenalidomide (Len) plus dexamethasone (Dex) 
had significantly longer times to progression and higher response rates than 
those treated with single-agent dexamethasone.  These studies led to the 
FDA approval of lenalidomide in combination with dexamethasone for the 
treatment of multiple myeloma in subjects that have received at least one 
prior therapy.  
 
Clinical experience in Myelodysplastic Syndromes (MDS) with 
Lenalidomide 
An exploratory trial in 43 MDS subjects with transfusion dependent or 
symptomatic anemia was conducted at the University of Arizona. (List et al., 
2005)  Subjects received lenalidomide at doses of 25mg or 10mg per day, or 
of 10mg on Days 1-21, repeated every 28 days.  All subjects had had no 
response to erythropoietin or had a high endogenous erythropoietin level.  
Response rates were similar across the 3 dose schedules used.  Responses 
were observed in 24 subjects overall (56%) including 21 subjects with a major 
response and 20 subjects with sustained transfusion independence.  Subjects 
with a major response reached a median hemoglobin level of 13.2 grams per 
deciliter, with a corresponding 5.3 grams per deciliter median increase from 
baseline.  After a median follow-up of 81 weeks, the median duration of major 
response had not been reached and was more than 48 weeks.  Of 20 
subjects with karyotypic abnormalities, 10 (50%) subjects had a complete 
cytogenetic remission.  The response rate was highest in subjects with a 
clonal interstitial deletion involving chromosome 5q31.1 (10 out of 12, 83%).  
Neutropenia and thrombocytopenia were the most common adverse events, 
and resulted in dose delays or reductions in 25 subjects (58%). 
 
Celgene Corporation sponsored a multicenter trial (MDS-003) of 148 MDS 
subjects with a clonal interstitial deletion involving chromosome 5q31.1.  
Lenalidomide was given at a dose of 10mg on Days 1-21, repeated every 28 
days, to 44 subjects, and at a dose of 10mg daily to the other 104 subjects.  
Transfusion independence was achieved in 93 subjects (64%), with a median 
hemoglobin increase of 3.9g/dl.  Cytogenetic response was achieved in 76% 
of transfusion independent subjects with 55% achieving a cytogenetic 
complete response.  Pathologic complete response was documented in 32 
out of 110 (29%) evaluable subjects.  With a median follow-up of 9.3 months, 
the median response duration had not been reached.  Neutropenia (39%) and 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 13 of 75 
thrombocytopenia (35%) were the most common adverse events requiring 
dose delays or reductions. (List et al., 2005 
 
Another Celgene Corporation sponsored trial (MDS-002) in subjects with low 
to intermediate-1 risk MDS enrolled 215 subjects, of whom, 166 were 
documented to have low to intermediate-1 risk MDS.  Among the subjects 
with documented low to intermediate-1 risk MDS, 84 subjects (51%) 
responded to treatment.  Transfusion independence was achieved in 54 
subjects (33%) and 30 subjects (18%) achieved a minor response, defined as 
a 50% or greater decrease in blood transfusion requirement.  The median 
duration of transfusion-independence was 41 weeks.  The median baseline 
hemoglobin level was 8.0g/dl, which increased by 3.2g/dl in responding 
subjects.  Among 20 subjects evaluable for cytogenetic response, 9 subjects 
(45%) experienced a cytogenetic remission. 
 
Clinical Experience with Lenalidomide and Non-Hodgkin’s Lymphoma. 
Two Phase II studies have been performed for subjects with relapsed non-
Hodgkin’s lymphoma.  One was for subjects with indolent NHL and the other 
for subjects with aggressive NHL.  In the protocol treating indolent NHL, the 
overall response rate was 26% in subjects with multiply relapsed follicular 
lymphoma, small lymphocytic, and marginal zone lymphoma (Witzig et al., 
2007).  In the Phase II study for subjects with relapsed aggressive NHL, the 
overall response rate was 41% with a 50% response rate in mantle cell 
lymphoma and a 50% response rate in transformed lymphoma. (Wiernik et 
al., 2007).  
 
Updated Information for Phase I. (Protocol V.3.8, dated 09-06-2012) 
Results from Phase I with 3 subjects treated at dose level I (10mg), 1 subject 
with dose level toxicity which resulted in expanding to 6 subjects and all 6 
subjects completed 12 cycles. At dose level II (15mg), 3 subjects were 
treated; 1 subject completed 12 cycles and 2 subjects withdrew from study, 
and no dose level toxicity occurred at this level. Moving onto dose level IIl 
(20mg), 3 subjects were treated; 1 subject completed 12 cycles and 2 
subjects withdrew from study, and no dose level toxicity occurred at this level.  
During dose level IV (25mg), 4 subjects were treated; 2 subjects completed 
12 cycles, 1 subject was removed from the study after repeated delays and 1 
subject was put on hold post elective surgery.  Two dose level toxicities 
occurred at this level and level was expanded to dose level 3 with 3 additional 
subjects with 1 subject receiving treatment and 2 subjects withdrawn from 
study.  All 3 additional subjects had dose level toxicity which is an indicator 
that all subjects will be treated with dose level II (15mg) in Phase II of the 
study.     
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 14 of 75 
Indications and Usage 
Revlimid® (lenalidomide) is indicated for the treatment of subjects with 
transfusion-dependent anemia due to Low- or Intermediate-1-risk 
myelodysplastic syndromes associated with a deletion 5q cytogenetic 
abnormality with or without additional cytogenetic abnormalities.  Revlimid® is 
also approved in combination with dexamethasone for the treatment of 
subjects with multiple myeloma that have received at least one prior therapy.  
 
Adverse Events 
Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of 
presumed relationship to study medication include: anemia, neutropenia, 
thrombocytopenia and pancytopenia, abdominal pain, nausea, vomiting and 
diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, cellulites, atrial fibrillation, congestive heart 
failure, myocardial infarction, chest pain, weakness, hypotension, 
hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, 
dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, 
dizziness, spinal cord compression, syncope, disease progression, death not 
specified and fractures. 
 
Complete and updated adverse events are available in the Investigational 
Drug Brochure and the IND Safety Letters. 
 
2.7  Study Rationale 
 
The rationale for this trial is to build upon the preliminary results with the 
combination of BEAM (+/- Rituxan) for subjects with relapsed NHL.  The 
current trial will add maintenance therapy starting day 100 (+/- 7 days) when 
the ANC is > 1000 and the plts are > 60K with Lenalidomide (in four dose 
cohorts, 10 mg, 15 mg, 20 mg and 25 mg) administered orally on days 1-21 
followed by 7 days of rest (28 day cycle) for 12 cycles after initiation of the 
therapy post-transplant.  This trial will be in chemoresistant (< PR), subjects 
who have received multiple prior treatments (> 3 regimens), or have 
histologies that have a known higher post-transplant relapse such as 
transformed lymphoma, PTCL, MCL or ALCL, alk neg, intermediate IPI or 
high risk IPI or subjects with a positive PET scan prior to transplant. 
 
Phase II dose will be 10mg 1 day x 21 days of 28-day cycle.  
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 15 of 75 
3.0       Eligibility Criteria 
 
3.1 Inclusion Criteria 
3.1.1 Persistent, or relapsed non-Hodgkin’s lymphoma (NHL) (any 
histology) that is chemo-resistant (< a PR), subjects who have 
received >3 prior chemotherapy regimens, or subjects with  
lymphomas that have a high relapse rate following autologous or 
syngeneic stem cell transplantation (transformed NHL, peripheral T-
cell lymphoma (PTCL), mantle cell lymphoma, ALK-negative  
anaplastic large cell lymphoma (ALCL, alk neg), intermediate IPI or 
high risk IPI or subjects with a positive PET scan prior to transplant, 
and otherwise eligible for transplantation with adequate end-organ 
function. 
 
3.1.2 Subjects that relapse within one year of diagnosis.   
 
3.1.3 Able to collect > 1.5 X 106 CD34+/kg cell for transplantation.   
 
3.1.4 ANC > 1000 cells/mm3 and Platelet Count > 60K when maintenance 
Lenalidomide is started [as close to as feasible to day 100 post-
transplant].  
3.1.5   Subjects must have calculated creatinine clearance ≥ 30ml/min 
(Appendix H).  
 
3.1.6 Total bilirubin < 1.5 x ULN 
 
3.1.7 AST (SGOT) and ALT (SGPT) < 3 x ULN. 
 
3.1.8 Age >19 years.  
 
3.1.9   Subjects who are seropositive because of hepatitis B virus  vaccine 
 
3.1.10 Subjects must be willing to give written informed consent, and sign 
an institutionally approved consent form before performance of any 
study-related procedure not part of normal medical care, with the 
understanding that consent may be withdrawn by the subject at any 
time without prejudice to future medical care. 
 
3.1.11 Able to adhere to the study visit schedule and other protocol 
requirements. 
 
3.1.12 Expected survival duration of > six months. 
 
3.1.13 Karnofsky Performance Status > 70.  (Appendix A)  
 
3.1.14 Subjects > age 60 or with clinical signs of heart disease must have 
ejection fraction ≥ 45% LVEF pre-transplant. 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 16 of 75 
 
3.1.15 Subjects with clinical signs of pulmonary insufficiency must have 
DLCO to be measured at > 50% of predicted value prior to 
transplant. 
 
3.1.16 No serious disease or condition that, in the opinion of the 
investigator,   would compromise the subject’s ability to participate in 
the study. 
 
3.1.17 Disease free of prior malignancies for ≥ 2 years with exception of 
currently treated basal cell, squamous cell carcinoma of the skin, or 
carcinoma “insitu” of the cervix or breast or low risk prostate cancer 
after curative therapy. 
 
3.1.18 All study participants must be registered into the mandatory Revlimid 
REMS TM program, and be willing and able to comply with the 
requirements of Revlimid REMS TM program. 
 
3.1.19 Females of childbearing potential (FCBP)† must have a negative 
serum or urine pregnancy test with a sensitivity of at least 50 
mIU/mL within 10 – 14 days prior to and again within 24 hours of 
prescribing lenalidomide (prescriptions must be filled within 7 days) 
and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one 
highly effective method and one additional effective method AT THE 
SAME TIME, at least 28 days before she starts taking lenalidomide.  
FCBP must also agree to ongoing pregnancy testing.  Men must 
agree to use a latex condom during sexual contact with a FCBP 
even if they have had a successful vasectomy.  See Appendix B 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
 
3.1.20 Females of reproductive potential must adhere to the scheduled 
pregnancy testing as required in the Revlimid REMS TM program. 
 
3.1.21 Able to take aspirin (81 or 325 mg) daily as prophylactic 
anticoagulation (subjects intolerant to ASA may use warfarin or low 
molecular weight heparin). 
 
3.1.22 Male subject agrees to use an acceptable method for contraception 
for the duration of the study. 
 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
                     
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 17 of 75 
3.2  Exclusion Criteria 
3.2.1 Chemosensitive NHL, except subjects receiving > 3 prior 
chemotherapy regimens, or subjects having transformed NHL, 
PTCL, MCL, or ALCL, alk neg. 
 
3.2.2 End-organ function not appropriate for transplantation. 
 
3.2.3 Inability to collect adequate stem cells. 
 
3.2.4 Known positive for HIV or infectious hepatitis, type B (HBV) or C 
(HCV) or active Hepatitis.  
 
3.2.5 Any serious medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from signing the informed 
consent form. 
 
3.2.6 Pregnant or breast feeding females. (Lactating females must agree 
not to breast feed while taking lenalidomide). 
 
3.2.7 Known hypersensitivity to thalidomide or lenalidomide (if applicable). 
 
3.2.8 The development of erythema nodosum if characterized by a 
desquamating rash while taking thalidomide or similar drugs. 
 
3.2.9 Any prior use of lenalidomide. 
 
3.2.10 Concurrent use of other anti-cancer agents or treatments. 
 
3.2.11 Serum creatinine >2.0mg/dL or calculated creatinine clearance <  
30ml/min (Appendix H). 
 
3.2.12 Active infection at the start of Lenalidomide. 
 
3.2.13 Myocardial infarction within 6 months prior to enrollment or has New 
York Heart Association (NYHA) Class III or IV heart failure 
uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 
electrocardiographic 
evidence 
of 
acute 
ischemia 
or 
active 
conduction system abnormalities. (Appendix C)  Prior to study entry, 
any ECG abnormality at Screening has to be documented by the 
investigator as not medically relevant. 
 
3.2.14 History of life threatening or recurrent thrombosis/embolism.  
Subjects may participate if they are adequately anticoagulated 
during the treatment. 
 
3.2.15 Subject has >Grade 2 peripheral neuropathy within 14 days before 
enrollment 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 18 of 75 
4.0       Registration Procedures 
 
Subjects who are referred to the Nebraska Medical Center (NMC) / UNMC; 
University of Kansas Cancer Center-Westwood, KS; University Hospitals Seidman 
Cancer Center-Case Western Reserve University- Cleveland, OH; or other IRB 
approved sites, for autologous stem cell transplant with persistent, or relapsed non-
Hodgkin’s lymphoma (NHL) (any histology) that is chemoresistant (< a PR), has 
received 3 or more prior chemotherapy regimens, or for subjects with lymphomas 
that have a high relapse rate following autologous or syngeneic stem cell 
transplantation (transformed NHL, peripheral T-cell lymphoma (PTCL), mantle cell 
lymphoma, ALK-negative  anaplastic large cell lymphoma (ALCL, alk neg), 
intermediate IPI or high risk IPI or subjects with a positive PET scan prior to transplant 
may be eligible for this trial.   The pre-conditioning regimen will be at the discretion of 
the treating physician.  Screening eligibility will be performed by the treating 
physician at the time of encounter.  On initial presentation, a history and physical 
examination are performed, laboratory data obtained, and performance status is 
assessed. Imaging studies will be obtained as clinically indicated.  The subject’s 
primary oncologist will make the decision as to eligibility of the candidate based on 
the eligibility criteria listed above. 
 
If the subject is found eligible, he/she will then be offered the option to participate.  
An informed consent will be signed by the subject after thorough review of the study 
is completed with the physician and his/her designee. All study participants must be 
registered into the mandatory Revlimid REMS TM program. 
 
Some insurance carrier’s may decline to cover the costs of usual medical care if the 
subject is participating in a clinical trial.  The subject will be provided assistance by 
the research nurse coordinator in determining if the insurance carrier will decline 
coverage.  Insurance carriers may or may not pay for study related expenses.  The 
subject can then decide if they wish to participate.   
 
4.1 Eligibility Verification/Registration: 
Before subjects are enrolled into the study, an eligibility checklist (Appendix H) must 
be completed to verify the subject meets the eligibility criteria.  Date of enrollment is 
defined as the date of the start of study treatment / first protocol related intervention. 
 
Subjects will be registered through the UNMC Fred & Pamela Buffett Cancer Center 
Research Project Coordinator and the UNMC Fred & Pamela Buffett Cancer Center 
Protocol Review and Monitoring System Office (PRMS).   
 
Study personnel from non-UNMC IRB approved sites will contact the UNMC Fred & 
Pamela Buffett Cancer Center Research Project Coordinator if a non-UNMC subject 
appears to meet the eligibility criteria.  They will fax the completed eligibility checklist 
(Appendix H) and accompanying applicable de-identified source documents (i.e. 
laboratory, pathology, and radiology records) to the UNMC research study 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 19 of 75 
coordinator, at FAX: 402-559-8895 (ph:402-559-5582 or 402-559-5286) to verify the 
subject meets the eligibility criteria.  The eligibility check list and source documents 
will be maintained in the study file.  If the UNMC research study coordinator confirms 
that the non-UNMC subject meets criteria, and target accrual has not been met, 
approval for the non-UNMC subject will be given. A confirmation of registration will 
be forwarded by the UNMC research study coordinator. 
 
UNMC:  
Study personnel will provide the UNMC Fred & Pamela Buffett Cancer Center PRMS 
office (ZIP 6805) a copy of the signed and dated consent form for each UNMC 
subject registered to the protocol within one (1) week that includes the following 
information:  
• Protocol Number 
• Subject Identification: Subject’s name UNMC/NMC medical record number 
• Subject demographics: gender, birth date (mm/dd/yyyy), race, ethnicity 
• New CTRP reporting requirements: Subject zip code/country (if not USA) 
and primary method of payment information 
 
Collaborating Sites: 
Collaborating sites must have both local and UNMC IRB approval, and have met all 
other UNMC criteria to enroll. Study personnel from non-UNMC IRB approved sites 
will provide the UNMC Research Project Coordinator with: 
• Study Manual demographics fax/scan cover 
• Copy of the signed (subject signature obliterated with signature line and 
subject initials visible) and dated consent form 
• Signed eligibility checklist 
• De-identified source documents (with study assigned subject I.D. if known 
on each page) to support eligibility (i.e., H&P, Medical/Surgical Hx, lab, 
pathology, scans, etc.). 
 
UNMC Research Project Coordinator will register collaborating site subjects to 
the National Cancer Institute (NCI) Clinical Trials Reporting Program (CTRP) 
Accrual Registry.  Collaborating sites will utilize the Fax/Scan Cover provided in 
the Study Manual which includes demographics required for CTRP accrual 
reporting compliance.  
 
The information listed below for subjects enrolled at collaborating sites will be 
provided to the PRMS office by the UNMC Research Project Coordinator within 
one (1) week of enrollment as applicable:  
 
• UNMC and Collaborating Site Protocol Numbers 
• Investigator/Collaborating Site Identifier (ID) 
• Subject ID:  Assigned by UNMC [Site ID followed by subject number (##-
###)] 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 20 of 75 
• Consent Date: Date subject signed consent 
• Re-consent Date:  (If applicable) 
• Ineligibility Status: (If known) 
• Off Study Date: (If applicable) 
• CTRP Status (Entered/Not entered) 
 
University of Nebraska Medical Center 
Fred & Pamela Buffett Cancer Center PRMS Office 
Attn: Anna Grant, RRT, PRMS Administrator 
986805 Nebraska Medical Center 
Omaha, NE 68198-6805 
Ph: (402)-559-4232 
FAX: (402)-559-4970 
 
4.2 Requirements for Non-UNMC Sites/ Collaborating Institutions: 
 
Submitting Regulatory Documents 
Before a collaborating institution may enter subjects, protocol specific 
regulatory documents must be submitted to the UNMC Fred & Pamela Buffett 
Cancer Center  study Project Coordinator. 
 
4.3  Required Protocol Specific Regulatory Documents 
1. Confirmation that UNMC PI and Research Study Coordinator conducted an 
initial Site Visit/Teleconference prior to opening a protocol to accrual at 
collaborating sites. 
2. Copy of IRB Informed Consent Document. 
    NOTE: Any deletion or substantive modification of information concerning 
    risks or alternative procedures contained in the sample informed consent 
   document must be justified in writing by the investigator and approved by 
   the IRB. 
3. IRB Approval Letter 
    NOTE: The above submissions must include the following details: 
• Indicate all sites approved for the protocol under an assurance 
  number. 
• OHRP assurance number of reviewing IRB 
• Full protocol title and number 
• Version Date 
• Type of review (full board vs. expedited) 
• Date of review. 
• Signature of IRB official 
 
5.0     Treatment Plan  
 
Subjects will receive the suggested transplant regimen of R/BEAM treatment and 
AHSCT (Standard of Care) followed by lenalidomide maintenance.  For the 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 21 of 75 
lenalidomide maintenance portion of the study, a Phase I study design was needed 
to determine the maximum tolerated dose (MTD) of lenalidomide in this setting.  The 
dose of lenalidomide used for the Phase II maintenance portion will be 10 mg.  
 
 
              5.1   Administration of Lenalidomide Maintenance Regimen 
Visits in between day of dismissal from transplant, as close as feasible 
to day 100 and 1 year can be done at the subjects referring or home 
physician.  Disease re-evaluation at day 100 (+/- 7 days), and 1 year is 
preferred to be done at UNMC but if not possible can be done referring 
or home physician office.  
 
Phase II maintenance therapy (the first cycle should be started day 
100, or as close as possible by treating physician’s discretion and 
dependent on the subject’s travel conditions, etc., post-transplant, 
when the ANC is > 1000 and the plts are > 60K) with Lenalidomide 
(see Lenalidomide dosing cohorts section 5.8.1) administered orally on 
days 1-21 followed by 7 days of rest (28 day cycle) for 12 cycles. 
Prescriptions must be filled within 7 days.  
 
Females of childbearing potential should not handle or administer 
lenalidomide unless they are wearing gloves. 
 
Lenalidomide will be supplied as capsules for oral administration. 
 
If a dose of lenalidomide is missed, it should be taken as soon as 
possible on the same day.  If it is missed for the entire day, it should 
not be made up. 
 
Subjects who take more than the prescribed dose of lenalidomide 
should be instructed to seek emergency medical care if needed and 
contact study staff immediately. 
 
Subjects are required to take a daily dosing of aspirin (81 or 325 mg) 
beginning Day 1 of Lenalidamide.  Low molecular weight heparin may 
be utilized in subjects that are intolerant to ASA.  Coumadin should be 
used with caution and close monitoring of INR. 
 
Subjects experiencing adverse events may need study treatment 
modifications (See section 5.8.4). 
 
5.1.1 Lenalidomide dosing 
Based in Phase I data, the MTD was determined to be 15 
mg but, the MTD for the study was based on cycle 1 of 
the Lenalidomide maintenance.  However, there is 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 22 of 75 
cumulative toxicity of Lenalidomide, especially in the 
post-transplant setting which led to a need to lower the 
dose to 10 mg for the Phase II study.  At the 10 mg dose, 
a much higher percentage of subjects were able to 
complete > 6 months of maintenance therapy.  Therefore 
the dose for continued Phase II will be 10 mg. 
Lenalidomide capsules will be taken orally daily days 1-
21 of a 28 day cycle for 12 cycles post-transplant. 
 
5.1.2 Instructions for Initiation of a New Cycle of Lenalidomide 
A new course of treatment may begin on the scheduled Day 1 of a new 
cycle if lab work is obtained prior to Day 1: 
• 
The ANC is ≥1000mm³;  
• 
The platelet count is ≥ 60K;  
• 
Any drug-related rash or neuropathy that may have occurred 
 
has resolved to ≤ grade 1 severity; 
• 
Any other drug-related adverse events that may have occurred 
 
have resolved to ≤ grade 2 severity.  
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated weekly and a new cycle of treatment will not be initiated until the 
toxicity has resolved as described above.  If lenalidomide dosing was 
halted during the previous cycle and was restarted with a one-level dose 
reduction without requiring an interruption for the remainder of the cycle, 
then that reduced dose level will be initiated on Day 1 of the new cycle. If 
lenalidomide dosing was omitted for the remainder of the previous 
cycle or if the new cycle is delayed due to toxicity newly encountered 
on the scheduled Day 1, then the new cycle will be started with a one-
level dose reduction of lenalidomide. 
 
5.1.3  Instructions for Dose Modifications or Interruption During a 
Cycle of Lenalidomide   
 
(See the following Table.) 
NCI CTC Toxicity Grade 
Dose Modification Instructions 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 23 of 75 
NCI CTC Toxicity Grade 
Dose Modification Instructions 
 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
 
• 
Hold (interrupt) lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ grade 2 prior to Day 21of the 
current cycle, restart lenalidomide at next lower dose level and 
continue through the scheduled Day 21 of the current cycle. 
Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide by 1 dose level at the start of the next cycle. Omitted 
doses are not made up.  If neutropenia is the only toxicity for which 
a dose reduction is required, G-CSF may be used and the 
lenalidomide dose maintained.  If G-CSF is needed in more than 
one consecutive cycle then that should be a DLT 
 
 
 
Thrombocytopenia 
≥Grade 3 (platelet count 
< 50,000/mm³) 
 
• 
Hold (interrupt) lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to ≤ grade 2 prior to Day 21 of the current 
cycle, restart lenalidomide at next lower dose level and continue through 
the scheduled Day 21 of the current cycle. Otherwise, omit for remainder of 
cycle and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle. Omitted doses are not made up. 
 
 
Platelet count < 50K 
• 
Hold prophylactic anti-coagulation/ASA for platelet <50K 
• 
Restart prophylactic anti-coagulation when platelet count is ≥60K 
 
Non-blistering rash 
1 
Grade 3 
2 
3 
4 
5 
             Grade 4 
 
• 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to Day 21 of the current cycle, 
restart lenalidomide at next lower dose level and continue through the 
scheduled Day 21 of the current cycle. Otherwise, omit for remainder of 
cycle and reduce dose of lenalidomide by 1 dose level at the start of the 
next cycle. Omitted doses are not made up. 
 
• 
If Grade 4, discontinue lenalidomide.  Remove subject from study. 
 
 
Desquamating 
(blistering) rash- any 
Grade  
 
• 
Discontinue lenalidomide.  Remove subject from study. 
 
 
Neuropathy 
when Lenalidomide is 
<3% 
Grade 3 
 
 
 
 
 
 
Grade 4 
 
• 
If Grade 3, hold (interrupt) lenalidomide dose.  Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to Day 21 of the current cycle, 
restart lenalidomide at next lower dose level and continue through the 
scheduled Day 21 of the current cycle. Otherwise, omit for remainder of 
cycle and reduce the dose of lenalidomide by 1 dose level at the start of the 
next cycle. Omitted doses are not made up. 
 
 
 
• 
If Grade 4, discontinue lenalidomide.  Remove subject from study. 
 
 
 
Venous 
thrombosis/embolism 
≥ Grade 3 
• 
Hold (interrupt) lenalidomide and start therapeutic anticoagulation, if 
appropriate 
• 
 Restart lenalidomide at investigator’s discretion (maintain dose level). 
• 
See Anticoagulation Section 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 24 of 75 
NCI CTC Toxicity Grade 
Dose Modification Instructions 
 
Hyperthyroidism or 
hypothyroidism 
 
• 
Omit lenalidomide for remainder of cycle, evaluate etiology, and initiate 
appropriate therapy.  
• 
See Instructions for Initiation of a New Cycle and reduce the dose of 
lenalidomide by 1 dose level. 
 
other non-hematologic 
toxicity ≥ Grade 3 
 
• 
Hold (interrupt) lenalidomide dose.  Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 2 prior to Day 21 of the current cycle, 
restart lenalidomide and continue through the scheduled Day 21 of the 
current cycle. Otherwise, omit for remainder of cycle. Omitted doses are not 
made up. For toxicity attributed to lenalidomide, reduce the lenalidomide 
dose by 1 dose level when restarting lenalidomide. 
• 
 
 
 
5.1.4 Treatment compliance for Lenalidomide Dosing 
Research center personnel will review the dosing instructions with subjects.  
Subjects will not receive study medication until they speak with the Revlimid 
REMS TM certified pharmacist.  To provide a means of ensuring oral route of 
medication adherence to subject while participating in this clinical trial, 
standard procedure for “Oral, Sublingual, and/or Buccal Route Medication 
Adherence Standard Procedure (V 1.0 11-25-2013)” will be followed. See 
Appendix I. All unused Revlimid® (lenalidomide) capsules should be returned 
as instructed through Revlimid REMS TM program.  If any study drug is lost or 
damaged, its disposition should be documented in the source documents. 
 
5.2 Duration of Therapy 
Subjects may be withdrawn from the study by the investigator or supporter for 
the following reasons: any adverse event or toxicity which compromises the 
subject’s ability to participate, disease progression, and discontinuation of 
lenalidomide for any reason, major violation of the study protocol, suspected 
pregnancy, any intercurrent illness or condition which in the opinion of the 
investigator would necessitate withdrawal from the study.  Additionally, the 
subject may decide to withdraw from the study and will be offered 
consultation with the investigator to discuss consequences and benefits of 
such withdrawal. 
 
Subjects, who discontinue treatment for any reason, will be followed for 
toxicity, relapse, and death as per any standard transplant subject.  
 
Subjects with stable disease will remain on study until disease progression. 
Lenalidomide will be discontinued after 12 cycles after initiation of the 
therapy.  All subjects will continue to be followed for survival following 
treatment on the study. 
 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 25 of 75 
 
5.3 
Supportive Care/Additional Therapy 
The subjects will be cared for as standard bone marrow transplant subjects. 
Subjects should receive full supportive care, including transfusions of blood 
and blood products, antibiotics, and antiemetics when appropriate.  
 
Subjects will be discharged from the hospital and followed on an outpatient 
basis as clinically indicated. 
 
Females of childbearing potential (FCBP)† must either commit to continued 
abstinence from heterosexual intercourse or begin TWO acceptable methods 
of birth control, one highly effective method and one additional effective 
method AT THE SAME TIME, pre or day 1 of  transplant and at least 28 days 
before she starts taking lenalidomide.  FCBP must also agree to ongoing 
pregnancy testing.  Men must agree to use a latex condom during sexual 
contact with a FCBP even if they have had a successful vasectomy.  See 
Appendix B Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
 
External beam radiation therapy will not be administered during the transplant 
course.  External beam radiation may, however be given following the 
transplant as felt to be clinically indicated for areas of bulky tumor prior to 
transplant. External beam radiation given post –transplant should be given 
prior to start of lenalidomide. 
 
The use of hematopoietic growth factors (GCSF or GMCSF) to stimulate 
blood cell production will be initiated post stem cell transplant as per existing 
institutional policy (ANC < 500 associated with neutropenic fever).   
  
 
 
Treatment with corticosteroids, other than transient administration to control 
or prevent nausea or vomiting, asthma, or allergic reactions, will not be 
permitted and may result in withdrawal of a subject from the study.  Non-
steroidal hormones administered for non-lymphoma-related conditions, e.g., 
insulin for diabetes, are acceptable. 
 
Anticoagulation   
Lenalidomide increases the risk of thrombotic events in subjects who are at 
high risk of thrombosis or with a history of thrombosis, in particular when 
combined with other drugs known to cause thrombosis.  When lenalidomide is 
                     
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 26 of 75 
combined with other agents such as steroids (e.g. dexamethasone, 
prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin the risk of 
thrombosis is increased.  
  
The use of daily dosing of aspirin (81 or 325 mg) will be required to start with 
Day 1 of Lenalidamide.  Low molecular weight heparin may be utilized in 
subjects that are intolerant to ASA. Coumadin should be used with caution 
and close monitoring of INR.  
 
 
5.4 Staging Re-Evaluations 
Subjects will be restaged and evaluated by radiographic tests that are 
disease appropriate, such as: CT scans, PET scans, MRI. A bone marrow 
biopsy (only if previously positive) and evaluated with labs (CBC, diff, plt, 
CMET, LDH, TSH) at Day 100 as close as feasible and one year post-
transplant evaluation.  If <CR at Day 100 (+/- 7 days) repeat staging 
evaluations at the treating physicians discretion. 
 
At yearly intervals for 5 years minimum after the first annual visit post-
transplant, the subjects will be clinically evaluated.  Yearly labs, chest x-ray, 
scans and other tests will be performed as clinically appropriate and more 
frequently for symptoms or problems.    
 
5.5  Biospecimens for Research Purposes 
1. 
Diagnostic Tissue Block: 
For DLBCL    -- immunostaining to distinguish between GBC and non-GBC, 
 
 
 
 
    Ki67 
For FL            -- CD20, 3, 68, 10, BCL2, Fox P3, PD-1 
For MCL        -- CD20, 3, 5, Ki67, cyclin D1 
For all tumors – CD34 for vascular density 
 
Shipping: Send frozen tissue overnight on dry ice Monday through Thursday 
only.  Do not send the day before a holiday. Tissue should be frozen in an 
OCT block, or a sample of tissue frozen (not embedded) and wrapped in foil 
and sent overnight on dry ice.  It is critical that the frozen tissue remains 
frozen, is well-packed and surrounded by dry ice.  
 
Please contact Chengfeng Bi or Xuan Zhang, Dept. of Pathology/ 
Microbiology at (402) 559-7753 AND the UNMC Research Project 
Coordinator to advise of planned shipments and to discuss appropriate 
procedures in the event a tissue sample must be sent on a Friday or before a 
holiday. 
 
If alternative methods require consideration, please contact Kai Fu M.D., 
Ph.D. for guidance on acceptable specifications. 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 27 of 75 
 
2. 
 Post PSCT: 
2- 10ml Na Heparin tubes, baseline before Lenalidomide, 6 months and 1 
year post-transplant on Lenalidomide (or end of study drug if off 
Lenalidomide before this time point) if the subject returns to site.   
 
1- 10ml Serum tubes, baseline before Lenalidomide, 6 months and 1 year 
post-transplant on Lenalidomide (or end of study drug if off Lenalidomide 
before this time point) if the subject returns to site.   
 
Serum to assay for VEGF, sIL2R, IL12, TNFa 
Flow analysis for total T-cells (Th1, Th2, Th17), B-cells, NK-cells, 
monocytes (subsets) 
 
Shipping: Send blood sample overnight at room temp Monday through 
Thursday only; do not send the day before a holiday.  
 
Please contact Michelle Varney, Dept. of Pathology/ Microbiology at (402) 
559-5580 AND the UNMC Research Project Coordinator to advise of planned 
shipments and to discuss appropriate procedures in the event a sample 
collection must be drawn on a Friday or before a holiday. 
 
If alternative methods require consideration, please contact Rakesh Singh, 
PhD for guidance on acceptable specifications. 
 
6.0 
Measurement of Effect 
Response to therapy will be classified as complete response (CR), complete 
response, partial response (PR), no response (NR), progressive disease (PD), early 
death, or not evaluable.  Response to therapy will be determined at Day 100.  For 
specific definitions of the International Harmonization Project’s update to the 
International Working Group guidelines, see Appendix D. 
 
Subjects will be analyzed with respect to overall survival and event-free survival.  
Overall survival is defined as time from the first chemotherapy administered on the 
transplant trial until death from any cause.  Event-free survival is defined as time 
from therapy until relapse, progression, or death from any cause.  Response will be 
determined by the principal investigator or the co-principal investigators. 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 28 of 75 
7.0 
Study Parameters  
Schedule of Study Assessments for Lenalidomide  
 
 
Procedure 
 
Transplant 
Related 
Procedures 
(Standard of 
Care)  
Cycle 1 of Revlimid® (lenalidomide) 
Day 100 
Subsequent  
Cycles  
 
28 days after 
therapy 
completed 12 
cycles 
Follow-
Up 
Phase3 
Day  
1 
 
Day  
8 
Day  
15 
Day   
22 
Day   
1 
 
Record prior medications, treatments 
 
X 
 
 
 
 
 
 
Record prior anti-cancer therapies 
 
X 
 
 
 
 
 
 
Physical exam, vital signs, weight, 
height9, as medically indicated9a 
 
X9 
 
 
 
X9a 
X 
x 
KS performance status 
 
X9 
 
 
 
 
X 
x 
CT , or PET or MRI  
Pre-transplant  
 
 
 
 
X7 11 
X 11 
 
Chest x-ray 1 
 
 
 
 
 
 
 
 
Bone Marrow Bx 2, 11 
Pre-transplant if 
positive previously 
 
 
 
 
X2, 11 
X2, 11 
 
ECG, PFTs, Echocardiogram 
Pre-transplant  
 
 
 
 
 
 
 
HIV testing pre-transplant 
Pre-transplant 
 
 
 
 
 
 
 
Hematology CBC diff, PLT 
 
X9, 12 
X 
X 
X 
X 
X 
 
C MET LDH 
 
X9,12 
 
X 
 
X 
X 
 
TSH4 
 
X4, 12 
 
 
 
X4, 
 
 
Pregnancy testing5 
 
X6 
X 
X 
X 
X6 
X6 
 
Research blood specimen Dr. Singh’s 
lab VEGF and cytokines (2-10ml NA 
Heparin green top tubes and 1-ml no 
additive red top at baseline, 6 months 
and 1 year post-transplant) 
 
X 
 
 
 
X 1yr post-
transplant 
 
 
Request Research tissue block for 
immunostaining  Dr. Fu’s lab (see 
Appendix J) 
 
X 
 
 
 
 
 
 
Register subject into Revlimid REMS TM 
program 
 
X 
 
 
 
 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 29 of 75 
Prescribe lenalidomide via Revlimid 
REMS TM  10 
 
X10 
 
 
 
X10 
 
 
Response assessment  
 
 
 
 
 
X7 
X 
 
Record adverse events8 
 
 
X 
X 
X 
X 
X8 
 
Record concomitant 
therapies/procedures 
 
 
X 
 
X 
X 
X 
 
Obtain Follow-Up anti-cancer 
treatments 
 
 
 
 
 
 
 
X 
Obtain Follow-Up survival information 
 
 
 
 
 
 
 
X 
* Variations of ± 3 days of the scheduled visit are permitted.   
If Physical examination, vital signs, weight, height and KS performance status were done within 7 days of Day 1, they do not need to be 
repeated at Study Day 1. 
An unscheduled visit can occur at any time during the study.  Source must be maintained for these unscheduled visits.  The date for the visit 
and any data generated must be recorded on the appropriate CRF.  Source documents for these unscheduled visits must also be maintained. 
1 Not needed if Chest CT scan has been obtained. 
2 If subject had previously positive bone marrow bx.scan or if symptoms suggest metastases. 
3 Follow-up day 100, and yearly at UNMC or Collaborating Site preferably. Otherwise for the first year every 3 months by local MD’s per SOC 
with CBC, B-met, exams.  Then once every 6 months for the second year then yearly. 
4 To include Thyroid Stimulating Hormone (TSH) at Screening and at treatment discontinuation.  T3 and T4 levels may be assessed as 
clinically indicated. 
5 Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive months). 
6 Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled 
within 7 days).  FCBP with regular or no menstruation must have a pregnancy test weekly for the first 28 days and then every 28 days while on 
therapy (including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with 
irregular menstruation must have a pregnancy test weekly for the first 28 days and then every 14 days while on therapy (including breaks in 
therapy), at discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix: Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).  See Revlimid REMS TM program requirements for FCBP 
and birth control 
7 As clinically indicated. 
8 An additional safety assessment will be done 30 days (+/- 2 days) following the last dose of study drug. 
9 If screening assessments were done within 7 days of Day 1, they do not need to be repeated at Study Day 1. 
9a Physical exam, vital signs, weight, height only as medically indicated. 
10 Lenalidomide must be prescribed through and in compliance with Celgene Corporation’s Revlimid REMS TM program.  Prescriptions must be 
filled within 7 days.  Any unused Revlimid® (lenalidomide) should be returned to the research center for disposition, in accordance with the 
Revlimid REMS TM program.  If any study drug is lost or damaged, its disposition should be documented in the source documents. 
11 Subjects will be restaged and evaluated by radiographic tests that are disease appropriate, such as: CT scans, PET scans, MRI.  A bone 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 30 of 75 
marrow biopsy (only if previously positive) and evaluated with labs (CBC, diff, plt, CMET, LDH, TSH) at Day 100 and yearly unless clinical 
suspicion of progression. If <CR at Day 100 repeat staging evaluations at the treating physicians discretion. 
12 Day 1 reference Day 1 of treatment.  Lab work to be obtained as close to Day 1 or within Day 1. 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 31 of 75 
8.0 
Drug Formulation and Procurement: 
 
8.1 Lenalidomide 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent 
with anti-angiogenic properties.  The Chemical Abstract Service (CAS) registry 
number and name for lenalidomide are 191732-72-6 and 3-(4-amino-1-oxo 1, 3-
dihydro-2H-isoindol-2-yl) piperidine-2, 6-dione, respectively. Lenalidomide is also 
known by the earlier clinical code names, CC-5013 and CDC-501. 
  
The chemical structure of lenalidomide is as follows: 
N
N
H
O
O
O
NH2
 
Lenalidomide has an empirical formula of C13H13N3O3 and a molecular weight of 
259.3.  It is an off-white to pale-yellow solid powder, with a melting point between 
265ºC to 270ºC. 
Lenalidomide has 1 chiral center and is prepared as a 50:50 racemic mixture of the 
R (+) and S (-) isomers. 
Mechanism of Action:  The mechanism of action of lenalidomide remains to be 
fully characterized. Lenalidomide possesses immunomodulatory and antiangiogenic 
properties.  Experiments have demonstrated that lenalidomide inhibits the growth of 
cells derived from subjects with multiple myeloma and del (5q) myelodysplastic 
syndromes in vitro.  Lenalidomide causes a delay in tumor growth in some in vivo 
nonclinical hematopoietic tumor models, including multiple myeloma.  Lenalidomide 
inhibits the secretion of pro-inflammatory cytokines such as tumor necrosis factor 
alpha (TNF-α), from peripheral blood mononuclear cells.  Lenalidomide also inhibited 
the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro. 
Absorption:  Lenalidomide, in healthy volunteers, is rapidly absorbed following oral 
administration with maximum plasma concentrations occurring between 0.625 and 
1.5 hours post-dose.  Co-administration with food does not alter the extent of 
absorption (AUC) but does reduce the maximal plasma concentration (Cmax) by 
36%.  The pharmacokinetic disposition of lenalidomide is linear.  Cmax and AUC 
increase proportionately with increases in dose.  Multiple dosing at the 
recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic sampling in myelodysplastic syndrome (MDS) subjects was not 
performed.  In multiple myeloma subjects treated in the Phase I studies, maximum 
plasma concentrations occurred between 0.5 and 4.0 hours post-dose both on Days 
1 and 28.  AUC and Cmax values increase proportionally with dose following single 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 32 of 75 
and multiple doses. Exposure (AUC) in multiple myeloma subjects is 57% higher 
than in healthy male volunteers.  
Pharmacokinetic Parameters Distribution:  In vitro (14C)-lenalidomide binding to 
plasma proteins is approximately 30%. 
Metabolism and Excretion:  The metabolic profile of lenalidomide in humans has 
not been studied.  In healthy volunteers, approximately two-thirds of lenalidomide is 
eliminated unchanged through urinary excretion.  The process exceeds the 
glomerular filtration rate and therefore is partially or entirely active.  Half-life of 
elimination is approximately 3 hours.  
Supplier(s)  
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no 
charge through the Revlimid Risk Evaluation and Mitigation Strategy TM (REMS) 
program (formerly known as RevAssist® Program).  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 
Celgene Corporation’s Revlimid REMS TM program. 
Dosage Form:  
For clinical study, lenalidomide is provided as 1.25-, 2.5-, 5-, 10-, 15-, 20-, and 25-
mg capsules for oral administration.  Each capsule of lenalidomide contains 1.25, 
2.5, 5, 10, 15, 20 or 25 mg of lenalidomide and the following inactive ingredients: 
anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate.  The 1.25-, and 2.5-mg dose of lenalidomide is contained in a 
size 4 hard gelatin capsule.  The 5-mg dose of lenalidomide is contained in a size 2 
hard gelatin capsule.  The 10-, 15-, 20-, and 25-mg doses of lenalidomide 
are contained in a size 0 hard gelatin capsules.  The lenalidomide capsules are 
supplied in push-through blister foil or tamperevident, child-resistant, opaque, high-
density polyethylene (HDPE) containers with HDPE caps. 
Packaging: Lenalidomide will be shipped directly to subjects.  Bottles will contain a 
sufficient number of capsules for one cycle of dosing.   
Labeling 
Lenalidomide supplies are dispensed in individual bottles of capsules.  Each bottle 
will identify the contents as study medication.  In addition, the label will bear 
Celgene’s name, quantity contained and the standard caution statement as follows:  
“Caution: New drug - Limited by Federal law to investigational use.” Lenalidomide 
should not be handled by FCBP unless wearing gloves.  
The study drug label must be clearly visible.  Additional labels must not cover the 
Celgene label. 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 33 of 75 
Storage:  
Subjects should store Lenalidomide in a locked, safe area, and out of the reach of 
children to prevent unauthorized access. 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold.     
 
Care should be exercised in the handling of REVLIMID ® (lenalidomide). REVLIMID 
capsules should not be opened or crushed.  If a powder from REVLIMID contacts 
the skin, wash the skin immediately and thoroughly with soap and water.  If 
REVLIMID contacts the mucous membranes, flush thoroughly with water. 
 
Procedures for the proper handling and disposal of anticancer drugs should be 
considered.  Several guidelines on the subject have been published. 
 
White opaque capsules imprinted “REV” on one half and “5 mg” on the other half in 
black ink: 
• 5 mg bottles of 28 (NDC 59572-405-28) 
• 5 mg bottles of 100 (NDC 59572-405-00) 
• Blue/green and pale yellow opaque capsules imprinted “REV” on one half and 
“10 mg” on the other half in black ink: 
• 10 mg bottles of 28 (NDC 59572-410-28) 
• 10 mg bottles of 100 (NDC 59572-410-00) 
 
Powder blue and white opaque capsules imprinted “REV” on one half and “15 mg”on 
the other half in black ink: 
• 15 mg bottles of 21 (NDC 59572-415-21) 
• 15 mg bottles of 100 (NDC 59572-415-00) 
 
White opaque capsules imprinted “REV” on one half and “25 mg” on the other half in 
black ink: 
• 25 mg bottles of 21 (NDC 59572-425-21) 
• 25 mg bottles of 100 (NDC 59572-425-00) 
• Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP 
Controlled Room Temperature]. 
• Dispense no more than a 28-day supply. 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 34 of 75 
Prescribing Information:  Lenalidomide (Revlimid®) will be provided to research 
subjects for the duration of their participation in this trial (12 cycles) at no charge to 
them or their insurance providers.  Lenalidomide will be provided in accordance with 
the Celgene Corporation Revlimid REMS TM program.  Per standard Revlimid REMS TM 
program requirements all physicians who prescribe lenalidomide for research 
subjects enrolled into this trial, and all research subjects enrolled into this trial, must 
be registered in and must comply with all requirements of the Revlimid REMS TM 
program.  Prescriptions must be filled within 7 days for females of childbearing 
potential and 14 days for all other risk categories.  Only enough lenalidomide for 
one cycle of therapy will be supplied to the subject each cycle. 
Adverse Events of Medical or Regulatory Interest: 
 
Blood and Lymphatic System Disorders 
Hematologic Toxicity 
Lenalidomide is associated with anemia, neutropenia, febrile neutropenia, 
thrombocytopenia, and pancytopenia.  Grade 3/4 neutropenia and thrombocytopenia 
are the most common, doselimiting AEs associated with the administration of 
lenalidomide. 
 
Vascular Disorders 
Thromboembolic Events 
Lenalidomide, in combination with dexamethasone, has been associated with an 
increased incidence in thrombotic or thromboembolic events, including deep vein 
thrombosis (DVT), pulmonary embolism, thrombosis, and thromboembolism, 
particularly among MM subjects receiving concomitant therapy with an erythropoietic 
agent. DVT has been reported with both indications but is more frequent in MM than 
in MDS.  
 
Gastrointestinal Disorders 
Constipation, diarrhea, nausea, and vomiting were the most commonly reported 
gastrointestinal AEs during treatment with lenalidomide.  
 
Hepatic Disorders 
Cases of transient liver laboratory abnormalities (predominantly in transaminases) 
were reported in subjects treated with lenalomide. Successful rechallenge without 
recurrence of liver laboratory elevation was reported in some subjects. 
 
Cardiac Disorders 
Occasional TEAEs such as atrial fibrillation, myocardial infarction, and congestive 
heart failure have been reported with the use of lenalidomide from clinical studies 
and post-marketing. 
 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 35 of 75 
Infections and Infestations 
Treatment-emergent adverse events of infections specifically pneumonia (including 
MedDRA preferred terms of pneumonia NOS, bronchopneumonia NOS, lobar 
pneumonia, pneumocystis carinii pneumonia, pneumonia bacterial NOS, pneumonia 
cytomegaloviral, pneumonia legionella, pneumococcal pneumonia, pneumonia 
primary atypical, and pneumonia staphylococcal) are commonly seen with 
lenalidomide.  
 
Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) 
Cases of AML have been reported in some MDS and MM studies. In addition, cases 
of MDS have been reported in some MM trials.  It is thought that AML and MDS may 
be part of the natural course of MM.  Furthermore, certain treatments for MM, such 
as alkylating agents (eg, melphalan) are known to be associated with the increased 
incidence of AML.  It is unknown at this time if the use of lenalidomide increases the 
risk of AML or MDS; any potential causal relationship is under investigation. 
 
Tumor Lysis Syndrome and Tumor Flare Reaction 
Tumor lysis syndrome (TLS) and tumor flare reaction (TFR) have commonly been 
observed in subjects with CLL, and uncommonly in subjects with other lymphomas, 
who were treated with lenalidomide.  Subjects at risk for TLS and TFR are those with 
high tumor burden prior to treatment.  Fatal instances of TLS have been reported 
during treatment with lenalidomide.  Caution should be practiced when introducing 
these subjects to lenalidomide.  There have been rare reports of TLS in subjects 
with MM treated with lenalidomide, and no reports in subjects with MDS treated with 
lenalidomide. 
 
Musculoskeletal and Connective Tissue Disorders 
The rare TEAE of rhabdomyolysis has been observed with lenalidomide. 
 
Allergic Reactions  
Rare TEAEs of angioedema, pneumonitis, and serious dermatologic reactions 
including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 
have been reported with lenalidomide during commercial use. These events have 
the potential to be fatal.  
 
Mortality and Morbidity 
The results from Study E4A03 provide supportive data that the combination of 
lenalidomide and dexamethasone is safe and effective for the treatment of newly 
diagnosed MM. Study E4A03 further demonstrates that reducing the dose of 
dexamethasone in this combination results in an overall early survival advantage 
and has less toxicity with an improved safety profile than the standard 
examethasone regimen in subjects with newly diagnosed MM. A greater clinical 
benefit was observed in the older subject population (> 65 years). In addition, the 
treatment difference in improved mortality was maintained with continued 
observation (> 30 days after the last dose of protocol therapy). In this trial the 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 36 of 75 
combination of lenalidomide plus low dose dexamethasone demonstrated an 
improved safety profile and reduced mortality resulting in a clinically significant 
survival advantage.  Both the reduced mortality and morbidity are 
considered meaningful improvements in subject benefit as well as a significant 
reduction in risk when compared with the standard dose dexamethasone 
combination for subjects with newly diagnosed MM. 
Review of current post marketing data, which consists of thousands of subject 
exposure, did not identify any additional significant safety signal.  Cross-sensitivity 
with thalidomide has been reported in the literature.  
 
The safety of Lenolidomide will be assessed through collection and analyses of 
adverse events (AEs), baseline medical conditions, laboratory tests, and vital sign 
data. 
 
9.0 
Toxicity Reporting Guidelines 
This protocol will comply with monitoring and adverse event reporting requirements 
of the UNMC/Fred & Pamela Buffett Cancer Center Data Monitoring plan Celgene 
Corporation guidelines will also be adhered to for toxicity reporting. The protocol will 
adhere to the institutional, FDA, and Celgene Corporation guidelines for the toxicity 
reporting.    
All adverse events will be followed to a satisfactory conclusion.  Serious adverse 
events should be followed until resolution, death, or until no further improvement is 
reasonably expected.  Deaths occurring within 100 days of study treatment 
regardless of relationship will be reported to the UNMC IRB and UNMC DSMC.  
 
In addition to complying with all applicable regulatory reporting laws and regulations, 
all serious adverse events and toxicities for all subjects at all collaborating sites 
will be reported to the University of Nebraska Medical Center, Institutional Review 
Board (IRB) and Fred & Pamela Buffett  Cancer Center Data and Safety Monitoring 
Committee (DSMC), FDA, and Celgene Corporation Drug Safety.  
  
9.1 Adverse Experiences Definitions 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not the event is considered causally 
related to the use of the product.  
 
An elective surgery or procedure that is scheduled to occur during a study will not be 
considered an adverse event if the surgery or procedure is being performed for a 
pre-existing condition and the surgery or procedure has been planned before study 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 37 of 75 
entry.  However, if the pre-existing condition deteriorates unexpectedly during the 
study (e.g., the surgery is performed earlier than planned), then the deterioration of 
the condition for which the elective surgery or procedure is being done will be 
considered an adverse event.  
 
An adverse event can result from use of the drug as stipulated in the protocol or 
labeling, as well as from accidental or intentional overdose, drug abuse, or drug 
withdrawal.  Any worsening of a pre-existing condition or illness is considered an 
adverse event.  Laboratory abnormalities and changes in vital signs are considered 
to be adverse events if they result in discontinuation from the study, necessitate 
therapeutic medical intervention, meet protocol specific criteria (see Section 5.0, 
Treatment Plan) and/or if the investigator considers them to be adverse events. In 
general, if a laboratory abnormality or change in vital sign is associated with a 
specific diagnosis that is being reported concurrently as an adverse event (e.g. 
elevated creatinine with renal failure or sinus tachycardia in febrile neutropenia) the 
findings that support the diagnosis do not need to be reported as separate adverse 
events unless the investigator feels it is appropriate. 
 
Treatment-emergent Adverse Event  
Treatment-emergent adverse event is defined as any adverse event with 
onset or worsening from the time that the first dose of study drug is 
administered until 30 days after the final dose of study drug is administered.  
 
Unexpected Adverse Event 
An unexpected adverse event is any adverse drug event that is not listed in 
the current labeling (e.g. Lenalidomide Investigator’s Brochure).  This 
includes events that may be symptomatically and pathophysiologically related 
to an event listed in the labeling, but differ from the labeled event because of 
greater severity or specificity.  For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the labeling 
only referred to elevated hepatic enzymes or hepatitis.  Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the labeling only listed cerebral vascular accidents. 
“Unexpected,” as used in this definition, refers to an adverse drug experience 
that has not been previously observed (i.e., included in the labeling) rather 
than from the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product. 
 
Serious Adverse Event 
A serious adverse event is one that at any dose (including overdose) and 
regardless of causality that: 
 
Results in death 
 
Is life-threatening1 
 
Requires inpatient hospitalization or prolongation of existing 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 38 of 75 
hospitalization 
 
Results in persistent or significant disability or incapacity2 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event3 
 
Pregnancy 
 1“Life-threatening” means that the subject was at immediate risk of death at the time of the 
serious adverse event; it does not refer to a serious adverse event that hypothetically might 
have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption 
of a person’s ability to carry out normal life functions. 
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 subject 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 subject 
hospitalization, or the development of drug dependency or drug abuse.  A new diagnosis of 
cancer during the course of a treatment should be considered as medically important. 
 
9.2 Adverse Event Reporting  
 
Toxicity will be scored using CTCAE version 4.0 for toxicity and adverse 
event reporting. (Appendix E)  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP homepage (http://ctep.info.nih.gov).  All 
appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0.  All adverse clinical experiences, whether observed by the 
investigator or reported by the subject, must be recorded, with details about 
the duration and intensity of each episode, the action taken with respect to 
the test drug, and the subject’s outcome.  The investigator must evaluate 
each adverse experience for its relationship to the test drug and for its 
seriousness. 
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically 
significant, the investigator must provide details about the action taken with 
respect to the test drug and about the subject’s outcome 
Pregnancies and Male Subjects 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking lenalidomide should notify the Investigator, and 
the pregnant female partner should be advised to call their healthcare provider 
immediately. 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 39 of 75 
regardless of age or disease state) of a female subject or the female partner of a 
male subject occurring while the subject is on lenalidomide or within 4 weeks (28 
days) after the subject’s last dose of lenalidomide are considered immediately 
reportable events.  If the subject is on lenalidomide, it is to be discontinued 
immediately and the subject is to be instructed to return any unused portion of 
lenalidomide to the Investigator or designee.  The pregnancy, suspected pregnancy, 
or positive pregnancy test must be reported to Celgene Corporation Drug Safety 
immediately following the Investigator’s knowledge of the pregnancy,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 pregnant female until completion of the 
pregnancy, and must notify Celgene Corporation Drug Safety immediately of 
the outcome of the pregnancy (either normal or abnormal outcome).  The 
Investigator will provide this information using the Pregnancy Follow-up 
Report Form. 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the 
abnormal outcome meets any of the serious criteria, it must be reported as an SAE 
to Celgene Drug Safety immediately by facsimile, or other appropriate method, 
within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form.  
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking lenalidomide should notify the Investigator, 
and the pregnant female partner should be advised to call their healthcare 
provider immediately.. 
 
 
Celgene Corporation Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management  
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, NJ 07922 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 40 of 75 
Toll Free:   (800)-640-7854 
Phone:  
(908) 673-9667 
Fax:  
(908) 673-9115 
e-mail:  
drugsafety@celgene.com 
 
Adverse Event Causality 
The investigator will use the following definitions to assess the relationship of 
the adverse event to the use of study drug:  
 
Related  An adverse event has a strong temporal relationship to study drug, 
recurs on re-challenge or is known to be an effect of the study drug.  Another 
reasonable etiology either doesn’t exist or is unlikely.             
 
Possibly Related An adverse event has a strong temporal relationship to 
the study drug and an alternative etiology is either equally or less likely when 
compared to the potential relationship to study drug. 
 
Not Related    An adverse event is due to an underlying or concurrent illness 
or effect of another drug and is not related to the study drug (e.g., has little or 
no temporal relationship to study drug or has a much more likely alternative 
etiology).  
  
If an investigator’s opinion of not related to study drug is given, an alternate 
etiology (underlying disease, co morbid condition, other drug) must be 
provided for the adverse event.  
 
All subjects will be followed for adverse experiences (AEs) (serious and 
nonserious), regardless of relationship to study drug starting first day of study 
treatment (day 100 (+/- 7 days) post-transplant when the ANC is > 1000 and 
the plts are > 60K) and will be followed for determination of DLTs.  See 
Section 5.8.2 for determination of DLT and MTD for this trial. 
 
All grade 3 or greater toxicities (expected and unexpected, regardless of 
attribution) will be reported to the UNMC/Fred & Pamela Buffett Cancer 
Center Data and Safety Monitoring Committee (DSMC).   
 
Transplant related Adverse Experiences (AE’s) or Serious Adverse 
Experiences (SAE’s) will NOT be collected. However, all AE’s and SAE’s 
irrespective of attribution, when occurring after the start of Lenalidomide 
maintenance therapy.  Will need to be reported to the UNMC/Fred & Pamela 
Buffett Cancer Center Data and Safety Monitoring Committee (DSMC).   
 
Any subject withdrawn prior to completion of the planned therapy on this 
protocol will be followed at a minimum for 30 days following the last dose of 
the conditioning chemotherapy or Lenalidomide maintenance regardless of 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 41 of 75 
disease progression or discontinuation of planned therapy.  Adverse 
experiences will no longer be followed for this protocol if other disease related 
treatment is initiated within this 30 day timeframe.  
 
  
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting 
requirements.   
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, 
that an annual report is provided to the FDA within 60-days of the IND 
anniversary date.  21 CRF 312.33 provides the data elements that are to be 
submitted in the report.   The Annual Report should be filed in the study's 
Regulatory Binder, and a copy provided to Celgene Corporation as a 
supporter of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Affairs Operations 
 
Connell Corporate Park  
 
400 Connell Drive Suite 700 
 
Berkeley Heights, NJ  07922 
Tel: (908) 673-9000 
 
All adverse experience reports must include the subject number, age, sex, 
weight, severity of reaction (mild, moderate, severe), relationship to study 
drug (probably related, unknown relationship, definitely not related), date and 
time of administration of test medications and all concomitant medications, 
and medical treatment provided.  The investigator is responsible for 
evaluating all adverse events to determine whether criteria for “serious” and 
as defined above are present.  The investigator is responsible for reporting 
adverse events to Celgene Corporation as described below. 
 
 
Expedited Reporting by Investigator to Celgene Corporation 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events of being related to lenalidomide based on the Investigator 
Brochure.  In the United States, all suspected unexpected serious adverse reactions 
(SUSARs) will be reported in an expedited manner in accordance with 21 CFR 
312.32. 
 
Serious adverse events (SAE) are defined above.  The investigator and 
collaborating site investigator must inform Celgene Corporation in writing 
using a Celgene SAE Form or MEDWATCH 3500A Form (Appendix F) of any 
SAE within 24 hours of being aware of the event.  The written report must be 
completed and supplied to Celgene Corporation by facsmile within 24 hours/1 
business day.  The initial report must be as complete as possible, including 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 42 of 75 
details of the current illness and (serious) adverse event, and an assessment 
of the causal relationship between the event and the investigational 
product(s) if available.  Information not available at the time of the initial report 
(e.g., an end date for the adverse event or laboratory values received after 
the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene Corporation 
tracking number (RV-LYM-PI-0328) and the institutional protocol number 
should be included on SAE reports (or on the fax cover letter) sent to Celgene 
Corporation.  A copy of the fax transmission confirmation of the SAE report 
sent to Celgene Corporation should be attached to the SAE and retained with 
the subject records. 
 
It is the responsibility of the collaborating site investigator to submit the Celgene 
SAE Form or MEDWATCH 3500A Form to UNMC within 24 hours of his/her 
knowledge of the SAE: Attn –Research Project/Data Coordinator: FAX 402-559-
5669, or email the UNMC Research Project/Data coordinator .  The SAE information 
will be routed to the UNMC Principal Investigator who will further evaluate the SAE. 
 
 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review 
Board (IRB) of a serious adverse event according to institutional policy.   
 
 
Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal 
Investigator and reviewed by Celgene Corporation.  Amendments should only 
be submitted to IRB/EC after consideration of Celgene Corporation review.  
Written verification of IRB/EC approval will be obtained before any 
amendment is implemented.   
 
 
Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a 
subject, a deviation will be made only for that subject.  A decision will be 
made as soon as possible to determine whether or not the subject (for whom 
the deviation from protocol was effected) is to continue in the study.  The 
subject’s medical records will completely describe the deviation from the 
protocol and state the reasons for such deviation.  In addition, the Investigator 
will notify the IRB/EC in writing of such deviation from protocol. 
Non-emergency minor deviations from the protocol will be permitted with 
approval of the Principal Investigator.  
 
 
Study Record Requirements 
The Investigator must ensure that the records and documents pertaining to 
the conduct of the study and the distribution of the study drug, that is copies 
of CRFs and source documents (original documents, data, and records [e.g., 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 43 of 75 
hospital records; clinical and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; SAE reports, pharmacy dispensing 
records; recorded data from automated instruments; copies or transcriptions 
certified after verification as being accurate copies; microfiches; photographic 
negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, 
etc.]) be retained by the Investigator for as long as needed to comply with 
national and international regulations (generally 2 years after discontinuing 
clinical development or after the last marketing approval).  The Investigator 
agrees to adhere to the document/records retention procedures by signing 
the protocol. 
 
 
Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least 
possibly associated to the drug, and that have not previously been reported 
in the Investigators brochure, or reference safety information document should 
be reported promptly to the Food and Drug Administration (FDA) by telephone 
or by fax.  Fatal or life threatening SAEs that meet the criteria for reporting to 
the FDA must be reported to the FDA within 7 calendar days after awareness 
of the event.  All other SAEs that meet the criteria for reporting to the FDA must 
be reported to the FDA within 15 calendar days after awareness of the event.  
A clear description of the suspected reaction should be provided along with an 
assessment as to whether the event is drug or disease related. 
 
Collaborating study sites should NOT report SAEs to the FDA.   The SAEs will be 
submitted to FDA if the UNMC sponsor-investigator, Julie Vose, M.D., determines 
21CRF312.32 criteria are met. 
 
 
 
 Adverse event updates/IND safety reports 
Celgene Corporation shall notify the Investigator via an IND Safety Report of 
the following information: 
• Any AE associated with the use of study drug in this study or in other studies 
that is both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
The Investigator shall notify his/her IRB/EC promptly of these new serious 
and unexpected AE(s) or significant risks to subjects. 
The Investigator must keep copies of all AE information, including 
correspondence with Celgene Corporation and the IRB/EC, on file. 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 44 of 75 
9.3 Adverse Event Reporting and Definitions Per University of Nebraska 
Medical Center, IRB and Fred & Pamela Buffett Cancer Center Data and Safety 
Monitoring Committee (DSMC) 
 
All internal serious adverse events (AE) must be reported to the IRB promptly 
through the electronic RSS system and in no case later than two (2) business days 
following PI notification that the event occurred if the principal investigator 
determines that conditions A, B, and C are met:  
 
a. The AE is unexpected, 
 
AND 
b. The AE is related to, or possibly related to, the drug, biologic, device, or other 
 
research  intervention, 
 
 
 
AND 
c. The AE is more than minor in nature which is defined as requiring treatment 
 
from a health professional.  
All unexpected, internal, fatal AEs must be reported promptly to the IRB, no later 
than 24 hours through the electronic RSS system following PI notification that the 
event occurred.  If documentation is still pending, the IRB office must be notified by a 
telephone call or e-mail. 
 
All expected, internal, fatal AEs (i.e., due to progressive disease or which reflect a 
risk currently found in the consent form) must be reported through the electronic 
RSS system no later than ten (10) business days following PI notification that the 
event occurred.   
The RSS system is accessed through a link on the UNMC IRB website 
(http://unmc.edu/irb).  
Data and Safety Monitoring Plan 
All grade 3 or greater toxicities (expected and unexpected, regardless of attribution) 
will be reported to the UNMC/Fred & Pamela Buffett Cancer Center Data and Safety 
Monitoring Committee (DSMC) in accordance with DSMC guidelines. Transplant 
related Adverse Experiences (AE’s) or Serious Adverse Experiences (SAE’s) will 
NOT be collected.  However, all AE’s and SAE’s irrespective of attribution, when 
occurring after the start of Lenalidomide maintenance therapy, will need to be 
reported to the UNMC/Fred & Pamela Buffett  Cancer Center Data and Safety 
Monitoring Committee (DSMC).   
 
The investigator will assign a causal relationship for all reportable AE’s, using the 
terminology of probably related (AE has strong temporal relationship to study drug or 
recurs on re-challenge, another etiology is unlikely or significantly less likely), 
possibly related (AE has strong temporal relationship to study drug, alternative 
etiology is equally or less likely), probably not related (AE has little or no temporal 
relationship to study drug and/or a more likely etiology exists), or not related (AE 
related to underlying or concurrent illness).  
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 45 of 75 
AEs will be collected from the time the subject starts Lenalidomide maintenance 
therapy and ending 4 weeks following the final Lenalidomide maintenance therapy. 
All AEs will be followed until resolution or a cause is identified. Prescription 
medication taken to relieve symptoms of the AE will be recorded in addition to the 
outcome. AEs judged by the investigator as not related or probably not related to the 
treatment will not be followed beyond the 4 weeks after the final chemotherapy.  
 
Severity of AE 
The severity of events reported on the AE case report form will be determined 
by the principal investigator according the NCI Common Toxicity Criteria.  
 
The likelihood of relationship of the AE to the study drugs will be determined 
by the investigator based on the following definitions: 
Unrelated:  The subject was not exposed to the study treatment or 
another cause is obvious. 
Unlikely related:  The AE is most likely explained by another cause, 
and the time of occurrence of the AE is not reasonably related to the 
study treatment. 
Possibly related:  Study treatment administration and AE occurrence 
reasonably related in time, and the AE is explained equally well by 
causes other than study treatment, or treatment administration and AE 
occurrence are not reasonably related in time, but the AE is not 
obviously a result of other causes. 
Probably related:  Study treatment administration and AE occurrence 
are reasonably related in time, and the AE is more likely explained by 
study treatment than by other mechanisms. 
Definitely related:  There occurrence and timing of the AE are clearly 
attributable to the study treatment.  
 
Copies of the AE report will be submitted to the IRB (when required), the Fred 
& Pamela Buffett Cancer Center’s Data Safety and Monitoring Committee and 
the Fred & Pamela Buffett Cancer Center Clinical Trials Office. 
 
It is the responsibility of the sponsor-investigator to submit to the FDA IND 
Safety Reports in accordance with 21 CFR 312.32.  In addition the sponsor-
investigator must notify the Ethics Review Committee/Institutional Review 
Board (EC/IRB) of a serious adverse event in writing in accordance with 
international and local laws and regulations. SAEs not meeting expedited 
criteria will be made available to FDA by the sponsor-investigator via the 
annual report. 
 
Monitoring:  The UNMC Fred & Pamela Buffett Cancer Center Scientific 
Review Committee (SRC) will review this protocol on at least an annual basis.  
This study will undergo audit on at least a quarterly basis by the UNMC Fred 
& Pamela Buffett Cancer Center Audit Committee for all collaborating sites.  


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 46 of 75 
All adverse events and toxicity reporting for all subjects at all collaborating 
sites will be reported to the UNMC Fred & Pamela Buffett Cancer Center 
Data and Safety Monitoring Committee (DSMC).  The DSMC will also monitor 
the protocol according to their evaluation of level of risk to subjects during 
regularly scheduled DSMC review processing and by request; the DSMC will 
be notified whenever a change in protocol dose is made (e.g., no DLT’s 
experienced at level 1; dose increased to dose level 2). Approved/applicable 
UNMC multi-site policies will be adhered to. 
 
The Principal Investigator will inform the DSMC when a dose escalation takes 
place or when the maximum tolerated dose level has been reached using the 
DSMC approved form. Celgene Corporation will simultaneously be provided a 
copy of the DSMC notification.  
 
10.0     Statistical Considerations 
 
 
10.1    Primary Objective 
 
 
To establish the MTD of lenalidomide given in the post-transplant setting for a 
12 month maintenance period. 
 
10.2    Secondary Objectives 
 
To obtain preliminary estimates of the 1-year response rate, 
event-free and overall survival using this regimen. 
 
10.3     Sample Size  
 
Phase I 3 +3 Sample Size Design  
The number of subjects enrolled in this study will vary depending on the dose 
escalation results.  The Maximum Tolerated Dose (MTD) is defined to be the 
dose cohort below which 3 out of 6 subjects experience dose limiting toxicities 
or the highest dose cohort of 25 mg, if 2 dose limiting toxicities are not 
observed at any dose cohort.  The maximum number of subjects for the 
Phase I portion is 24.  Three subjects will be enrolled at the initial dose level.  
If two of three subjects in Dose Cohort #1 have a dose-limiting toxicity, three 
additional subjects will be added to that dose level.  If 3 of these 6 subjects 
experience a dose limiting toxicity as defined as grade > 4 Hematologic or > 
grade 3 non-hematologic toxicity on the NCI Common Toxicity Criteria 
(version 4.0, see http://evs.nci.nih.gov/ftp1/CTCAE/About.html or APPENDIX 
E)  no further dose escalation wiIl take place.  If two of three subjects in Dose 
Cohort #2-#4 have a dose-limiting toxicity, three additional subjects will be 
added to that dose cohort.  If 2 of these 6 subjects experience a dose limiting 
toxicity as defined as grade > 4 Hematologic or > grade 3 non-hematologic 
toxicity 
on 
the 
NCI 
Common Toxicity 
Criteria 
(version 
4.0, 
see 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 47 of 75 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html or APPENDIX E) no further 
dose escalation will occur.   
 
Phase II Sample Size Design 
Due to the high dropout rate of subjects and the counting of consented never 
treated subjects, up to 114 subjects will be enrolled to achieve the 16 
evaluable at the 10 mg dose level to estimate the 1 year event-free and 
overall survival.  We will also estimate the response rate at one year.  Time 
point of 1 year is chosen since the regimen to be evaluated is one that is 
designed for maintenance treatment.  A sample of n=16 will provide a 
maximum width estimate of the 95% confidence interval at ±0.225.  The 1-y 
event-free survival estimate will be used to calculate sample requirements in 
future studies  
 
10.4 Stopping Rules 
During the Phase I portion of the protocol, the safety stopping rules are 
defined by the dose escalation plan.  An interim report for excessive toxicity 
after 3 subjects have completed 1 month of maintenance therapy at the dose 
level that is determined to be the MTD during the Phase I part of the trial will 
be performed.  Enrollment will continue during that time as Lenalidomide has 
been used extensively in subjects with multiple myeloma as maintenance in 
the post-transplant setting and has been found to be safe.   
   
Analysis of treatment-related mortality (TRM) at 90 days post initiation of 
treatment after accrual of 10 additional subjects will be performed.  If 1 of the 
first 10 (e.g. 5%) subjects experiences mortality due to the addition of the 
lenalidomide, the protocol will close.  If the death is related to other transplant 
related causes or progressive disease, accrual to the study will continue.   
 
10.5   Evaluable Subject  
Subjects are considered evaluable for DLT after they receive the first dose of 
chemotherapy.  Subjects evaluable for the secondary endpoints (Phase II) 
are those who complete 12 cycles of treatment or have developed disease 
progression during time of study.  
 
10.6   Analysis of Secondary Endpoints 
The complete response rate at 1 year will be estimated as the proportion of 
subjects who achieve a CR divided by the number of evaluable subjects.  The 
overall response rate will be estimated as the proportions of subjects who 
achieve a CR or PR divided by the number of evaluable subjects.  Each will 
be reported with their associated 95% confidence interval. 
 
The Kaplan-Meier method will be used to estimate the event-free and overall 
survival distributions. Disease progression or death will be considered events 
of interest for event-free survival.  We will also describe the gene expression 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 48 of 75 
profile of the different tissues, as well as studies on the microenvironment and 
immunomodulatory effects or changes over time post-lenalidomide using 
descriptive statistics.  When sample distribution allows, we will explore the 
correlation between biomarkers tested and response to Lenalidomide in able 
to assess if there are biomarkers that can predict subjects with better 
outcome of likely to stay in remission using Chi-square test.  
 
11.0 Records to be Kept 
 
The research data will be stored in the data managers work area and files.  The data 
will be secured behind locked doors during non-business hours.  The subjects' data 
information will be kept confidential and only number identifiers will be used.  Only 
the principal investigator, the subjects' primary physician, the research study 
coordinator, Celgene Corporation or their designee, UNMC/Fred & Pamela Buffett 
Cancer Center Scientific Review Committee, the UNMC/NHS IRB, and the Food and 
Drug Administration will have access to this information. 
 
Information regarding the actual treatments, adverse effects, radiographic and 
laboratory information, and pathology are to be recorded on appropriate forms. See 
attached Data forms.  Serious adverse events, when noted, will be recorded on site 
via the standard serious adverse effects form. 
 
11.1 Quality assurance:  
Complete records must be maintained in a research chart on each subject treated 
on the protocol.  These records should include primary documentation (e.g., lab, 
report slips, X-ray reports, scan reports, pathology reports, physician notes, etc.) 
which confirm that: 
 
- The subject met the eligibility criteria. 
- Signed informed consent was obtained prior to treatment. 
- Treatment was given according to protocol (dated notes about doses given 
& reasons for any dose modifications). 
- Toxicity was assessed according to protocol (laboratory report slips, etc.). 
- Response was assessed according to protocol (x-ray, scan, lab reports, 
dated notes on measurements & clinical assessment, as appropriate). 
 
12.0 Subject Consent 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 49 of 75 
The subject and their family will be placed in a consult room in the outpatient cancer 
center for their discussion of the protocol.  The study, risk/benefit ratio, side effects 
and possible outcomes are discussed with the subject by the primary investigator or 
the subject’s primary oncologist.  The consent form is reviewed in detail by the 
physician with the subject.  The subject and family are given the opportunity to ask 
questions at this time.  In addition, the subject is given the informed consent form to 
take with them and read in detail at their leisure.  They are seen back in a day or so 
to once again ask questions and to sign the informed consent form. 
 
When the process of informed consent has been completed, the subject will be 
asked to state in his/her own words all elements of the consent and protocol 
including, but not limited to, the purpose of the study, the procedures which will be 
carried out, the potential risks, the potential benefits to him/her, the alternatives and 
the right to withdraw from the study.  If there is any indication that a given subjects' 
comprehension of the study is anything less than accurate, the points of confusion 
will be discussed and clarified.  The subject will then be asked to explain these same 
points in his/her own words. 
No information will be purposely withheld from the subjects.  The consent form used 
in this study will include the adult consent form.   
  


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 50 of 75 
13.0  References  
 
Vose JM,  Tuscano JM ,  Justice G, Lossos IS,  Ervin-Haynes A, Takeshita K, 
Pietronigro D, Zeldis JB, Habermann TM: High Response Rate to Lenalidomide in 
Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma with Prior Stem Cell 
Transplant , Abstract 2570 2007 ASH Clinical Advances in Hematology & Oncology 6: 2 
Supp 4:  pg 8, 2008 
 
Lerner RE, Burns LJ:  Transformed lymphoma: an Achilles heel of non-Hodgkin’s 
lymphoma.  Bone Marrow Transplant 31: 531-537, 2003.   
 
Martinez-Climent, JA, Alizadeh AA, Segraves R. et al: Transformation of follicular 
lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA 
copy number and gene expression alternations.  Blood 101: 3109-3117, 2003.  
  
Cao TM, Horning S, Negrin RS, et al: High-dose therapy and autologous hematopoietic-
cell transplantation for follicular lymphoma beyond first remission:  the Stanford 
University experience.  Biol Blood Marrow Transplantation.  7:294-301, 2001.   
 
Andreadis C, Schuster SH, Chong EA, et al: Long-term event-free survivors after high-
dose therapy and autologous stem-cell transplantation for low-grade follicular lymphoma.  
Bone Marrow Transplant 36:955-961, 2005.   
 
Laudi N, Arora M, Burns LJ, et al: Long-term follow-up after autologous hematopoietic 
stem cell transplantation for low-grade non-Hodgkin’s lymphoma.  Biol Blood Marrow 
Transplant 11:129-135, 2005.  
  
Maloney DG, Liles TM, Czerwinski DK, et al.  Phase I clinical trial using escalating 
single-dose infusion of chimeric anti CD20 monoclonal antibody (IDEC-C2B8) in 
subjects with recurrent B-cell lymphoma.  Blood 1994;84:2457-2466. 
 
Maloney DG, Grillo-Lopez AJ, Bodkin DJ, White CA, Liles T-M, Royston I, et al.   IDEC-
C2B8:  Results of a Phase I multiple-dose trial in subjects with relapsed non-Hodgkin's 
lymphoma.  Journal of Clinical Oncology 1997;15:3266-3274. 
 
Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al.   
IDEC-C2B8 (Rituximab) Anti-CD20 monoclonal antibody therapy in subjects with 
relapsed low-grade non-Hodgkin's lymphoma.  Blood 1997;90:2188-2195. 
 
McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Wiliams ME, et al.   
Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent 
lymphoma:  Half of subjects respond to a four-dose treatment program.  Journal of 
Clinical Oncology 1998;16:2825-2833. 
 
Piro LD, White CA, Grillo-Lopez AJ, Janakiraman N, Saven A, Beck TM, et al.   
Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory 
low-grade or follicular non-Hodgkin's lymphoma.  Ann Oncol 1999;10:655-661. 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 51 of 75 
Davis T, Levy R, White CA, Czuczman M, McLaughlin P, Link B, et al.   Rituximab:  
Phase II retreatment study in subjects with low-grade or follicular NHL.  Blood 
1998;92:414a. 
 
Davis TA, White CA, Grillo-Lopez AJ, Velasquez WS, Link B, Maloney DG, et al.   
Single-agent monoclonal antibody efficacy in bulky Non-Hodgkin's lymphoma:Results of 
a Phase II trial of rituximab.  J Clin Oncol 1999;17:1851-1857. 
 
Czuczman MS, Grillo-Lopez AJ, White CA, Saleh M, Gordin L, LoBuglio AF, et al.   
Treatment of subjects with low-grade B-cell lymphoma with the combination of chimeric 
anti-CD20 monoclonal antibody and CHOP chemotherapy.  J Clin Oncol 1999;17:268-
276. 
 
Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, et al.   Rituximab (anti-CD 20 
monoclonal antibody) for the treatment of subjects with relapsing or refractory 
aggressive lymphoma: A multicenter Phase II study.  Blood 1999;92:1927-1932. 
 
Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, et al.   Phase 
II study of rituximab in combination with CHOP chemotherapy in subjects with previously 
untreated, aggressive non-Hodgkin's lymphoma.  J Clin Oncol 2001;19:389-397. 
 
Coiffier B, Lepage E, Briere J, et al.  CHOP chemotherapy plus rituximab compared with 
CHOP alone in elderly subjects with diffuse large B-cell lymphoma. N Engl J Med 
2002;346:235-242. 
 
Horowitz SM, Negrin R, Stockerl-Goldstein KE, et al.  Phase II trial of rituximab as 
adjuvant therapy to high-dose chemotherapy and peripheral blood stem cell 
transplantation for relapsed and refractory aggressive non-Hodgkin's lymphomas.  Blood 
2001;98:862a.  
 
Dredge K, Horsfall R, Robinson S, Zhang L-H, Lu L, et al.  Orally administered 
lenalidomide (lenalidomide) is anti-angiogenic in vivo and inhibits endothelial cell 
migration and Akt phosphorylation in vitro.  Microvascular Research 69 (2005) 56-63. 
 
Corral LF, Haslett PAJ, Muller FW, Chen R, Wong LM, Ocampo CJ, Patterson RT, 
Stirling DI, Kaplan G.  Differential cytokine modulation and T cell activation by two 
distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.  J 
Immunol. 1993;163:380-386. 
 
Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man H-W, et al.  Enhancement of 
cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related 
immunomodulatory drugs.  J of Pharmacology and Exp Therapeutics, 305:1222-1232, 
2003. 
 
Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta 
D, Chauhan D, Treon SP, Richarson PG, Schlossman RL, Morgan GJ, Muller GW, 
Stirling DI, Anderson KC.  Thalidomide and immunomodulatory derivatives augment 
natural killer cell cytotoxicity in multiple myeloma.  Blood. 2001;98:210-216. 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 52 of 75 
Hideshima T, Chauhan D, Shima Y, Raje N, Davies F, Tai YT, Treon SP, Lin B, 
Schlossman RL, Richarson P, Muller G, Stirling DI, Anderson KC.  Thalidomide and its 
analogs overcome drug resistance of human multiple myeloma cells to conventional 
therapy.  Blood. 2000;96:2943-2950. 
 
Bartlett JB, Michael A, Clarke IA, Dredge K, Nicholson S, et al.  Phase I study to 
determine the safety, tolerability and immunostimulatory activity of thalidomide analog 
lenalidomide in subjects with metastatic malignant melanoma and other advanced 
cancers.  British J of Cancer (2004) 90, 955-961 
 
Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B.  Results of Phase I 
study of lenalidomide for the treatment of multiple myeloma (MM) subjects who relapse 
after high dose chemotherapy (HDCT). Blood 2001; 98:775a (Abstract #3226). 
 
Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, et al.  
Immunomodulatory drug (lenalidomide) overcomes drug resistance and is well tolerated 
in subjects with relapsed multiple myeloma.  Blood 2002; 100:3063-3067. 
 
Wu A, Scheffler MR.  Multiple-dose pharmacokinetics and safety of lenalidomide in 15 
multiple myeloma subjects.  Proc ASCO 2004, Abstract #2056. 
 
 
Rajkumar SV, Hayman SR, Lacy MQ et al. Combination therapy with lenalidomide plus 
dexamethasone (REV/DEX) for newly diagnosed myeloma. Blood 2005; 2005-2007. 
 
Hussein MA, Karam MA, Brand C, Pearce G, Reed J, et al.  Doxil (D), vincristine (V), 
reduced frequency dexamethasone (d) and Revlimid (R) (DVd-R) a Phase I/II trial in 
advanced relapsed/refractory multiple myeloma (Rmm) subjects.  Blood 2004, Abstract 
#208. 
 
Data on file.  Celgene Corporation 
 
List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, et al.  Efficacy of lenalidomide in 
myelodysplastic syndromes.  N Engl J Med 2005; 352:549-57. 
 
List AF, Dewald G, Bennett J, Giagounadis A, Raza A, et al.  Hematologic and 
cytogenetic (CTG) response to lenalidomide (lenalidomide) in subjects with transfusion-
independent (TD) myelodysplastic syndrome (MDS) and chromosome 5q31.1 deletion: 
Results of the multicenter MDS-003 study.  Proc ASCO 2005, abstract #5. 
 
Witzig TE, Vose J, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis J, Wiernik PH. 
Preliminary results from a Phase II study of lenalidomide oral monotherapy in 
relapsed/refractory indolent non-Hodgkin lymphoma. Proc ASCO 2007, abstract #8066 
 
Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE, McBride K, Wride K, 
Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Habermann TM. Lenalidomide 
Response in Relapsed/Refractory Aggressive Non-Hodgkin s Lymphoma Is Related to 
Tumor Burden and Time from Rituximab Treatment. Proc ASH 2007, abstract #2565. 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 53 of 75 
A predictive model for aggressive non-Hodgkin’s lymphoma.  The International Non-
Hodgkin’s Lymphoma Prognostic Factors Project.  N Engl J Med 1993;329(14):987-94 
Solal-Celigny, et al.  Follicular lymphoma international prognostic index.  Blood 
2004;104(5):12588-1265.  
 


 
 
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Data Forms  
See attached 


 
 
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Appendix A:  
 
Karnofsky Scale for Performance Status 
 
Scale (%) 
Description 
100 
 
Normal; no complaints  
 90 
 
Able to carry on normal activities; minor signs or symptoms of  
 
 
disease  
 80 
 
Normal activity with effort 
 70 
 
Cares for self.  Unable to carry on normal activity or to do active  
 
 
work  
 60 
 
Requires occasional assistance but able to care for most of needs 
 50 
 
Requires considerable assistance and frequent medical care 
 40 
 
Disabled; requires special care and assistance 
 30 
 
Severely disabled; hospitalization indicated though death not  
 
 
imminent  
 20 
 
Very sick.  Hospitalization necessary.  Active supportive treatment  
 
 
necessary 
 
 
 10 
 
Moribund  
  0 
 
Dead 
 
Reference: Karnofsky DA, et al. Cancer 1:634-656, 1948. 
 


 
 
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Appendix B: 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been 
studied nor has the effect of the lenalidomide on human eggs and sperm.   
Lenalidomide is structurally related to thalidomide.  Thalidomide is a known human 
teratogenic active substance that causes severe life-threatening birth defects.  An 
embryofetal development study in animals indicates that lenalidomide produced 
malformations in the offsprings of female monkeys who received the drug during 
pregnancy.  The teratogenic effect of lenalidomide in humans cannot be ruled out. 
Therefore, a risk minimization plan to prevent pregnancy must be observed.  
All study participants must be registered into the mandatory Revlimid REMS TM 
program, and be willing and able to comply with the requirements of Revlimid REMS 
TM program. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female 
who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not 
been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months).  
The investigator must ensure that: 
• Females of childbearing potential comply with the conditions for pregnancy 
risk minimization, including confirmation that she has an adequate level of 
understanding.  
• Females NOT of childbearing potential acknowledge that she understands the 
hazards and necessary precautions associated with the use of lenalidomide.  
• Male subjects taking lenalidomide acknowledge that he understands that 
traces of lenalidomide have been found in semen, that he understands the 
potential or pregnant female, if engaged in sexual activity with a female of 
childbearing potential or pregnant female, and that he understands the need 
for the use of a condom even if he has had a vasectomy, if engaged in sexual 
activity with a female of childbearing potential or pregnant female.  
 


 
 
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Contraception 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of 
contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at least 28 
days before starting lenalidomide; 2)throughout the entire duration of lenalidomide; 
and 3) for at least 28 days after lenalidomide discontinuation.  
The two methods of reliable contraception must include one highly effective method 
and one additional effective (barrier) method. FCBP must be referred to a qualified 
provider of contraceptive methods if needed.  The following are examples of highly 
effective and additional effective methods of contraception: 
• Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
• Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
 Because of the increased risk of venous thromboembolism in subjects with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills 
are not recommended.  If a subject is currently using combined oral contraception 
the subject should switch to one of the effective method listed above.  The risk of 
venous thromboembolism continues for 4-6 weeks after discontinuing combined oral 
contraception.  The efficacy of contraceptive steroids may be reduced during co-
treatment with dexamethasone.  
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
                     
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
 


 
 
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Prophylactic antibiotics should be considered particularly in subjects with 
neutropenia.  
Pregnancy testing 
 
Medically supervised pregnancy tests with a minimum sensitivity of 50mIU/mL must be 
performed for females of childbearing potential, including females of childbearing 
potential who commit to complete abstinence, as outlined below.                                          
 
Before starting study drug:   
Female Subjects   
• FCBP must have two (2) negative pregnancy tests (sensitivity of at least 50 
mIU/mL) prior to prescribing lenalidomide.  The first pregnancy test must be 
performed within 10-14 days prior to prescribing lenalidomide and the second 
pregnancy test must be performed within 24 hours prior to prescribing 
lenalidomide.  The subject may not receive lenalidomideuntil the Investigator 
has verified that the results of these pregnancy tests are negative. 
 
Male Subjects   
• Must agree to use a latex condom during sexual contact with females of 
childbearing potential while participating in the study and for at least 28 days 
following discontinuation from the study even if he has undergone a 
successful vasectomy.  
During study participation and for 28 days following discontinuation from the 
study: 
Female Subjects   
• FCBP with regular or no menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of lenalidomide treatment, including dose 
interruptions and then every 28 days throughout the remaining duration of 
lenalidomide treatment,including dose interruptions, at lenalidomide 
discontinuation,  and at day 28 following lenalidomide discontinuation.  If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for 
the first 28 days of lenalidomide treatment, including dose interruptions, and 
then every 14 days throughout the remaining duration of lenalidomide 
treatment, including dose interruptions, at lenalidomide discontinuation, and 
at Day 14 and Day 28 following lenalidomide discontinuation. 
• At each visit, the Investigator must confirm with the FCBP that she is 
continuing to use two reliable methods of birth control at each visit during the 
time that birth control is required.  


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 59 of 75 
• If pregnancy or a positive pregnancy test does occur in a study subject, 
lenalidomide must be immediately discontinued.  Pregnancy testing and 
counseling must be performed if a subject misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide 
treatment must be discontinued during this evaluation. 
• Female must agree to abstain from breastfeeding during study participation 
and for at least 28 days after lenalidomide discontinuation.  
Male Subjects 
• Must practice complete abstinence or use a condom during sexual contact 
with pregnant female or females of childbearing potential throughout the 
entire duration of lenalidomide treatment, during dose interruptions and for at 
least 28 days following lenalidomide discontinuation, even if he has 
undergone a successful vasectomy.  If pregnancy or a positive pregnancy test 
does occur in the partner of a male study subject during study participation, 
the investigator must be notified immediately.  
• Male subjects should not donate semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide.  
Additional precautions 
• Subjects should be instructed never to give lenalidomide to another person. 
• Subjects should not donate blood during therapy and for at least 28 days 
following discontinuation of lenalidomide. 
• Only enough lenalidomide for one cycle of therapy may be prescribed with 
each cycle of therapy. 
• Any unused lenalidomide must be returned as instructed through Revlimid 
REMS TM program.  
 
 
 


 
 
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Appendix C: 
 
NEW YORK HEART ASSOCIATION HEART DISEASE CLASSIFICATION 
 
Class 
 
Definition 
 
 
I. 
 
No limitation of physical activity.  Ordinary physical activity does 
not cause undue fatigue, or dyspnea. 
 
II. 
 
Slight limitation of physical activity.  Comfortable at rest, but 
ordinary physical activity results in fatigue, or dyspnea. 
 
 
III. 
 
Marked limitation of physical activity.  Comfortable at rest, but 
less than ordinary activity causes fatigue, or dyspnea. 
 
 
IV. 
 
Unable to carry on any physical activity without symptoms.  
Symptoms are present even at rest.  If any physical activity is 
undertaken, symptoms are increased. 
 
 


 
 
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Appendix D:    RESPONSE CRITERIA  
Response criteria (listed below) are the recommendations of the International Harmonization 
Project’s update to the International Working Group guidelines. 
 PET using [18F]fluorodeoxyglucose (FDG), has emerged as a powerful functional imaging 
tool for staging, restaging, and response assessment of lymphomas.  The advantage of PET 
over conventional imaging techniques such as computed tomography (CT) or magnetic 
resonance imaging is its ability to distinguish between viable tumor and necrosis or fibrosis 
in residual mass (es) often present after treatment. 
Complete Response (CR) The designation of CR requires the following (Table 1): 
1.  Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms if present before therapy. 
2a.  Typically FDG-avid lymphoma: in subjects 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. 
2b.  Variably FDG-avid lymphomas/FDG avidity unknown: in subjects without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on CT to normal size (<1.5 cm in their greatest transverse diameter for 
nodes > 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their 
long axis and more than 1.0 cm in their short axis before treatment must have decreased 
to<1.0cm in their short axis after treatment. 
3.  The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear.  However, determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen 
may reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, or 
causes other than lymphoma. 
4.  If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy.  The biopsy sample on which this determination is 
made must be 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 subject outcome. 
Partial Response (PR) The designation of PR requires all of the following: 
1.  At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the 
largest dominant nodes or nodal masses.  These nodes or masses should be selected 
according to all of the following: they should be clearly measurable in at least 2 
perpendicular dimensions; if possible they should be from disparate regions of the body; and 
they should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved. 
2.  No increase should be observed in the size of other nodes, liver, or spleen. 
3.  Splenic and hepatic nodules must regress by >50% in their SPD or, for single nodules, in 
the greatest transverse diameter. 
4.  With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
5.  Bone marrow assessment is irrelevant for determination of a PR if the sample was 


 
 
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positive before treatment.  However, if positive, the cell type should be specified (e.g., large-
cell lymphoma or small neoplastic B cells).  Subjects who achieve a CR by the above 
criteria, but who have persistent morphologic bone marrow involvement will be considered 
partial responders.  When the bone marrow was involved before therapy and a clinical CR 
was achieved, but with no bone marrow assessment after treatment, subjects should be 
considered partial responders. 
6.  No new sites of disease should be observed. 
7.  Typically FDG-avid lymphoma: for subjects 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. 
8.  Variably FDG-avid lymphomas/FDG-avidity unknown: for subjects without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, CT criteria should be used. In 
subjects with follicular lymphoma or mantle-cell lymphoma, a PET scan is only indicated with 
one or at most two residual masses that have regressed by more than 50% on CT; those 
with more than two residual lesions are unlikely to be PET negative and should be 
considered partial responders. 
Stable Disease (SD) Stable disease is defined as the following:  
1.  A subject is considered to have SD when he or she fails to attain the criteria needed for a 
CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]). 
2.  Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with 
no new areas of involvement on the post treatment CT or PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for subjects without a pretreatment 
PET scan or if the pretreatment PET was negative, there must be no change in the size of 
the previous lesions on the post-treatment CT scan. 
Relapsed Disease (RD) (after CR)/Progressive Disease (after PR, SD) 
1.  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. 
2.  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 subjects 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. 
3.. 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 (e.g., splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of less than 
1.0cm 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. 
4.  At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 
5.  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).  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 (e.g., pleural effusions, 


 
 
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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. In 
clinical trials where PET is unavailable to the vast majority of participants, or where PET is 
not deemed necessary or appropriate for use (eg, a trial in subjects with MALT lymphoma), 
response should be assessed as above, but only using CT scans.  However, residual 
masses should not be assigned CRu status, but should be considered partial responses.  
 
Table 1. Response Definitions for Clinical Trials 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
 
 
CR 
 
Disappearance of all 
evidence 
of disease 
 
 
(a) FDG-avid or PET 
positive prior to 
therapy; mass of any 
size permitted if PET 
negative 
 
(b) Variably FDG-avid 
or PET negative; 
regression to 
normal size on CT 
 
 
Not palpable, nodules 
disappeared 
 
 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate 
by morphology, 
immunohistochemistry 
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 
 
(a) FDG-avid or PET 
positive prior to 
therapy; one or 
more PET positive at 
previously involved 
site 
 
(b) Variably FDG-avid 
or PET negative; 
regression on 
CT 
 
 
> 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 
 
(a) FDG-avid or PET 
positive prior to 
therapy; PET 
positive at prior sites 
of disease and no new 
sites on CT or PET 
 
(b) Variably FDG-avid 
or PET negative; no 
change in 
size of previous 
lesions on CT 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 64 of 75 
 
Relapsed disease 
or PD 
 
 
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 in SPD of 
more than one node, 
or >50% increase in 
longest diameter of a 
previously identified 
node > 1 cm in short 
axis 
 
Lesions PET positive 
if FDG-avid lymphoma 
or PET positive prior 
to therapy 
 
 
> 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. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD,Specht L, Horning SJ, et al. 
Revised Resonse Criteria for Malignant Lymphoma. J Clin Oncol 2007; 25: 579-586. 
 
 
 
 
 
 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 65 of 75 
Appendix E:  
NCI Common Toxicity Criteria Version 4.0 (CTCAE)  
Active Date: October 1, 2009 
 
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event 
reporting.  A copy of the NCI CTC Version 4.0 can be downloaded from the CTEP 
homepage: (http://ctep.info.nih.gov).  All appropriate treatment areas have access 
to a copy of the CTC Version 4.0. 
 
 
 
Appendix F:  
FDA 3500A MEDWATCH Form  
 
Available on-line at http://www.fda.gov/medwatch/SAFETY/3500.pdf 
 
 
 
Appendix G:   
Body Surface Area and Creatinine Clearance Calculations 
 
Body surface area (BSA) should be calculated using a standard nomogram that 
yields the following results in meters squared (m2): 
BSA = 
3131
)
(
)
(
lbs
Wt
inches
Ht
×
 
or 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht
×
 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl): 
(Cockcroft, 1976; Luke 
1990) 
 
 
CrCl (ml/min) =   
(140-age) x (actual wt in kg)               
 
(Males) 
 
   72 x (serum creatinine, mg/dL) 
 
CrCl (ml/min) =   
(140-age) x (actual wt in kg)       x 0.85        
 
(Females) 
 
   72 x (serum creatinine, mg/dL) 
Note:  In markedly obese subjects, the Cockroft-Gault formula will tend to 
overestimate the creatinine clearance. (Adipose tissue tends to contribute little 
creatinine requiring renal clearance.) 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 66 of 75 
Appendix H –   ELIGIBILITY CHECKLIST 
NCI/DCTC/CTMS CASE REPORT FORM 
 
Phase I/II Study of Lenalidomide Maintenance Following BEAM (+/- Rituximab) 
for Chemo-Resistant or High Risk Non-Hodgkin’s Lymphoma 
 
Date Completed: 
(dy/mth/yr) 
 
Protocol #:  446-08 
Institution: 
Subject ID: 
 
Checklist #: v4.7 
 
 
Effective Date   
 
 
 
Waiver #: 
Eligibility Checklist    
                             
1. Persistent, or relapsed non-Hodgkin’s lymphoma (NHL) (any histology) that is chemo-resistant 
(< a PR), subjects who have received >3 prior chemotherapy regimens, or subjects with  
lymphomas that have a high relapse rate following autologous or syngeneic stem cell 
transplantation (transformed NHL, peripheral T-cell lymphoma (PTCL), mantle cell lymphoma, 
ALK-negative  anaplastic large cell lymphoma (ALCL, alk neg), intermediate IPI or high risk 
IPI or subjects with a positive PET scan prior to transplant, and otherwise eligible for 
transplantation with adequate end-organ function.   
2. Subjects that relapse within one year of diagnosis.   
 
3. Able to collect > 1.5 X 106 CD34+/kg cell for transplantation.   
 
4. ANC > 1000 cells/mm3 and Platelet Count > 60K when maintenance Lenalidomide is started; as 
close as feasible to day 100 post-transplant.  
 
5. Age >19 years.  
 
6. Subjects must be willing to give written informed consent, and sign an institutionally approved 
consent form before performance of any study-related procedure not part of normal medical 
care, with the understanding that consent may be withdrawn by the subject at any time without 
prejudice to future medical care. 
 
7. Able to adhere to the study visit schedule and other protocol requirements. 
 
8. Expected survival duration of > six months. 
 
9. Karnofsky Performance Status > 70.  (Appendix A)  
 
10. Subjects > age 60 or with clinical signs of heart disease must have ejection fraction ≥ 45% 
LVEF pre-transplant. 
 
11. Subjects with clinical signs of pulmonary insufficiency must have DLCO to be measured at > 
50% of predicted value prior to transplant. 
Yes   No  N/A 
 
[   ]    [   ]1. 
 
 
 
 
 
 
[   ]    [   ]2. 
 
 
[   ]    [   ]3. 
 
[   ]    [   ]4. 
 
 
[   ]    [   ]5. 
 
[   ]    [   ]6. 
 
 
 
 
[   ]    [   ]7. 
 
[   ]    [   ]8. 
 
[   ]    [   ]9. 
 
[   ]    [   ]10. 
 
 
[   ]    [   ]11. 
 
 
. 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 67 of 75 
Appendix H ELIGIBILITY CHECKLIST 
NCI/DCTC/CTMS CASE REPORT FORM 
 
Phase I/II Study of Lenalidomide Maintenance Following BEAM (+/- Rituximab) 
for Chemo-Resistant or High Risk Non-Hodgkin’s Lymphoma 
 
Date Completed: 
(dy/mth/yr) 
 
Protocol #:  446-08 
Institution: 
Subject ID: 
 
Checklist #: v4.7 
 
 
Effective Date   
 
Waiver #: 
12 No serious disease or condition that, in the opinion of the investigator, would 
compromise the subject’s ability to participate in the study. 
 
13 Disease free of prior malignancies for ≥ 2 years with exception of currently treated 
basal cell, squamous cell carcinoma of the skin, or carcinoma “insitu” of the cervix 
or breast or low risk prostate cancer after curative therapy. 
 
14 All study participants must be registered into the mandatory Revlimid REMS TM 
Program, and be willing and able to comply with the requirements of Revlimid 
REMS TM Program. 
 
15 Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to 
and again within 24 hours of prescribing lenalidomide (prescriptions must be filled 
within 7 days) and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE SAME TIME, at least 28 days 
before she starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy 
testing.  Men must agree to use a latex condom during sexual contact with a FCBP 
even if they have had a successful vasectomy.  See Appendix B Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods. 
 
16 Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (subjects 
intolerant to ASA may use warfarin or low molecular weight heparin). 
 
17 Male subject agrees to use an acceptable method for contraception for the duration 
of the study. 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in 
the preceding 24 consecutive months). 
[   ]    [   ]12.  
 
 
[   ]    [   ]13. 
 
 
 
[   ]    [   ]14. 
 
 
 
[   ]    [   ]15. 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ]16. 
 
 
[   ]    [   ]17. 
 
 
 
 
 
 
 
                     
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 68 of 75 
Appendix H- ELIGIBILITY CHECKLIST 
NCI/DCTC/CTMS CASE REPORT FORM 
Phase I/II Study of Lenalidomide Maintenance Following BEAM (+/- Rituximab) 
for Chemo-Resistant or High Risk Non-Hodgkin’s Lymphoma 
Date Completed: 
(dy/mth/yr) 
 
Protocol #:  446-08 
Institution: 
Subject ID: 
 
Checklist #: v4.7 
 
 
Effective Date   
 
Waiver #: 
All of the above must be yes to be eligible.  
 
1. Chemosensitive NHL, except subjects receiving > 3 prior chemotherapy regimens, or 
subjects having transformed NHL, PTCL, MCL, or ALCL, alk neg. 
2. End-organ function not appropriate for transplantation. 
3. Inability to collect adequate stem cells. 
4. Known positive for HIV or infectious hepatitis, type A, B or C or active Hepatitis. 
5. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form. 
6. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while 
taking lenalidomide). 
7. Known hypersensitivity to thalidomide. 
8. The development of erythema nodosum if characterized by a desquamating rash while 
taking thalidomide or similar drugs. 
9. Any prior use of lenalidomide. 
10. Concurrent use of other anti-cancer agents or treatments. 
11. Serum creatinine >2.0mg/dL or calculated creatinine clearance < 30ml/min. 
12. Active infection at the start of Lenalidomide. 
13. Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure uncontrolled angina, severe uncontrolled 
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities. (Appendix C)  Prior to study entry, any ECG 
abnormality at Screening has to be documented by the investigator as not medically 
relevant. 
14. History of life threatening or recurrent thrombosis/embolism.  Subjects may participate if 
they are adequately anticoagulated during the treatment. 
15. Subject has >Grade 2 peripheral neuropathy within 14 days before enrollment. 
All of the above must be no to be eligible. 
 
 
[   ]    [   ]1. 
 
 
[   ]    [   ]2. 
 
[   ]    [   ]3. 
 
[   ]    [   ]4. 
 
[   ]    [   ]5. 
 
 
[   ]    [   ]6. 
 
 
[   ]    [   ]7. 
[   ]    [   ]8. 
 
 
[   ]    [   ]9 
 
[   ]    [   ]10. 
 
[   ]    [   ]11. 
[   ]    [   ]12. 
 
[   ]    [   ]13. 
 
 
 
 
 
 
 
[   ]    [   ]14. 
 
 
[   ]    [   ]15. 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 69 of 75 
Appendix H- ELIGIBILITY CHECKLIST 
NCI/DCTC/CTMS CASE REPORT FORM 
 
Phase I/II Study of Lenalidomide Maintenance Following BEAM (+/- Rituximab) 
for Chemo-Resistant or High Risk Non-Hodgkin’s Lymphoma 
 
Date Completed: 
(dy/mth/yr) 
 
Protocol #:  446-08 
Institution: 
Subject ID: 
 
Checklist #: v4.7 
 
 
Effective Date   
 
Waiver #: 
 
Eligibility:      [   ]   Subject satisfies all criteria.  
                     [    ]  Subject not formally eligible, but admitted to study because (state reason);  
 
 
 
 
 
Subject Initials:  __________MR or Study ID#______________DOB 
______________ 
   
ELIGIBILITY reviewed and confirmed  
Site Investigator Signature _______________________Date_____________   
             
__________________________________________________________________________________________ 
 
Date Completed: 
(dy/mth/yr) 
 
Protocol #: VOSE  446-08 
Institution:       
Subject ID: 
 
   
             
__________________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 70 of 75 
Appendix I: 
Oral, Sublingual, and/or Buccal Route  
Medication Adherence Standard Procedure 
 
PURPOSE 
To provide a means of ensuring oral, sublingual and/or buccal routes of medication 
adherence to subjects while participating in a clinical trial. 
1. A physician’s order will be completed by study subjects or representative for 
oral, sublingual and/or buccal administration per IRB approved protocol. 
2. To ensure the consistent and safe administration of medications not given 
under the direct supervision of study staff (at home), there will be a 
“Medication Information Sheet” and a diary to document times of drug 
administration. 
3. To record medication adherence Study staff will document results of 
medication reconciliation and or medication return in the subject’s chart. 
4. Maintain documentation of medications returned or sent to for destruction (if 
applicable).  
PROCEDURE 
1. Subjectss will be given a monthly “Medication Diary”.  The diary will have a 
place for the subject to record the time that the medication(s) were taken. 
(See Form A for example) 
 
2. The research nurse will review the subject’s “Medication Diary” for adherence 
to the study regimen for oral medication administration. Adherence will be 
noted in the subject’s chart.  All unused Revlimid® (lenalidomide) capsules 
should be returned to the research center for disposition in accordance with 
the Revlimid REMS TM program.  If any study drug is lost or damaged, its 
disposition should be documented in the source documents.   
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 71 of 75 
Medication Diary (Form A)  EXAMPLE Month 
 
~ September 2013 ~ 
Sun 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
1  
2  
Revlimid®  at: 
 
_______AM / PM 
 
3  
Revlimid®  at: 
 
_______AM / PM 
 
4  
Revlimid®  at: 
 
_______AM / PM 
 
5  
Revlimid®  at: 
 
_______AM / PM 
 
6  
Revlimid®  at: 
 
_______AM / PM 
 
7  
Revlimid®  at: 
 
_______AM / PM 
 
8  
Revlimid®  at: 
_______AM / PM 
9  
Revlimid®  at: 
 
_______AM / PM 
 
10  
Revlimid®  at: 
 
_______AM / PM 
 
 
11  
Revlimid®  at: 
 
_______AM / PM 
 
12  
Revlimid®  at: 
 
_______AM / PM 
 
13  
Revlimid®  at: 
 
_______AM / PM 
 
14  
Revlimid®  at: 
 
_______AM / PM 
 
15  
Revlimid®  at: 
_______AM / PM 
16  
Revlimid®  at: 
 
_______AM / PM 
 
17  
Revlimid®  at: 
 
_______AM / PM 
 
18  
Revlimid®  at: 
 
_______AM / PM 
 
19  
Revlimid®  at: 
 
_______AM / PM 
 
20  
Revlimid®  at: 
 
_______AM / PM 
 
21  
Revlimid®  at: 
 
_______AM / PM 
 
22  
Revlimid®  at: 
_______AM / PM 
 
 
 
 
 
 
 
Notes: 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 72 of 75 
Appendix J:   
 
Blood and Tissue Sample Processing and Shipping for Cytokine Level Studies  
(For research purposes only, to study factors that influences a subject’s response to a particular 
drug.) 
Description of Sample Collection: The proposed Cytokine Levels will be tested in the 
subject’s existing lymphoma specimen. Tissue samples for immunostaining  from either a 
baseline diagnostic or relapsed biopsy in either frozen or paraffin embedded tissue will be 
retrieved from all subjects and sent to the laboratory of Kai Fu, MD, PhD (a.k.a. Dr. Chan’s 
lab) at UNMC.  
Research blood specimens VEGF and cytokines will be obtained at baseline, 6 months and 
1 year post transplant (or at the end of taking lenalidomide if before these time points) and 
sent to the laboratory of Rakesh Singh, PhD at UNMC. 
No therapeutic intervention will be undertaken and the results of these studies will not have 
any influence on the medical management of the subjects.  
 
Facility 
Sample 
Contact 
Person(s) 
Date and Time 
Points 
Laboratory of Kai Fu, MD, 
PhD, Professor, 
Pathology/Microbiology, 
Director, Hematology 
Fellowship Program,  
Co-Director, Center for 
Lymphoma and Leukemia 
Research 
University of Nebraska 
Medical Center 
 
 
Tissue samples from 
either a baseline 
diagnostic or 
relapsed biopsy in 
either frozen or 
paraffin embedded 
tissue 
Xuan Zhan and 
Chengfeng Bi 
 
Dr. Kai Fu’s Lab   
Lied Bldg 11th Floor, 
Rm 11711 
Phone# 402-559-7753 
 
Shipping Address: 
Department of 
Pathology 
UMA Bldg, Rm 3528, 
Zip 3135 
University of Nebraska 
Medical Center 
668 S. 41st Street 
Omaha, NE 68105 
Phone# 402-559-7689 
Fax# 402-559-6018 
 
Baseline Tissue date: 
___/___/____ 
 
Check one: 
 
  Diagnostic   
         or  
  Relapsed biopsy  
          
Check one:   
  Frozen  
          or  
 Paraffin embedded  
 
Laboratory of Rakesh 
Singh, PhD, Professor, 
Department of Pathology/ 
Microbiology 
University of Nebraska 
Medical Center 
 
Research blood 
specimen for VEGF 
and cytokines. 
Two (2) -10ml NA 
Heparin green top 
tubes and one (1) 10 
ml no additive red top 
at baseline, 6 months 
and 1 year post 
transplant( or at the 
Michelle Varney 
 
Dr. Rakesh Singh’s 
Lab   
DRC2 Bldg, Rm 7072 
phone 402-559-5580 
  
Shipping Address: 
Michelle Varney 
DRC2 Bldg, Rm 70, 
Zip 5900 
Samples will need 
immediate handling in 
a research laboratory 
to evaluate the 
changes in the levels 
of various cytokines. 
 
Ship all specimens the 
day of collection.  
Please contact 
Michelle Varney to 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 73 of 75 
end of taking 
lenalidomide if before 
these time points). 
 
University of Nebraska 
Medical Center 
668 S. 41st Street 
Omaha, NE 68105 
ATTENTION: 
Dr. Rakesh Singh’s 
Phone# 402-559-5580 
 
advise of planned 
shipments.   
 
Whole blood tubes 
should be shipped with 
cold packs that are 
cold, but not frozen.  
 
Check one: 
 
 Baseline Sample: 
 
  Date:  _________ 
 
  Time:  _________ 
 
 
  Other Time Point: 
 
  Date:  _________ 
 
  Time:  _________ 
 
  
 
  
Research Nurse:  Mary Mailliard, RN, BSN, OCN  Office (402) 559-5582  pager (402) 888-
2123 Fax (402) 559-8895 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 74 of 75 
Appendix K: 
International Prognostic Index 
 
PURPOSE 
The International Prognostic Index (IPI) is a clinical tool developed by oncologists 
to aid in predicting the prognosis of subjects with aggressive non-Hodgkin's 
lymphoma. 
 
CATEGORIES 
International Prognostic Index 
One point is assigned for each of the following risk factors: 
• 
Age greater than 60 years 
• 
Stage III or IV disease 
• 
Elevated serum LDH (Lactic Acid Dehydrogenase) 
• 
ECOG/Zubrod performance status of 2, 3, or 4 
• 
More than 1 extranodal site 
The sum of the points allotted correlates with the following risk groups: 
• 
Low risk (0-1 points) - 5-year survival of 73% 
• 
Low-intermediate risk (2 points) - 5-year survival of 51% 
• 
High-intermediate risk (3 points) - 5-year survival of 43% 
• 
High risk (4-5 points) - 5-year survival of 26% 
Age-Adjusted IPI 
A simplified index can be used when comparing subjects within an age group (i.e. 60 
or younger, or over 60) and includes only 3 of the above factors: 
• 
Stage 
• 
LDH (Lactic Acid Dehydrogenase) 
• 
Performance status 
The sum of the points allotted correlates with the following risk groups: 
• 
Low risk (0 points) - 5-year survival of 83% 
• 
Low-intermediate risk (1 point) - 5-year survival of 69% 
• 
High-intermediate risk (2 points) - 5-year survival of 46% 
• 
High risk (3 points) - 5-year survival of 32% 


 
 
IRB # 446-08 Protocol Version 4.9, 01/24/17                                 Page 75 of 75 
 
Although the IPI has shown itself to be a useful clinical tool, widely used by 
oncologists and a mainstay of risk stratification in clinical trials for lymphoma, it 
should be kept in mind that it was developed prior to the use of rituximab, which is 
now included with anthracycline-based combination chemotherapy as of the 
standard of care in B-cell lymphomas (the majority of non-Hodgkin's lymphomas). 
Rituximab has dramatically improved the outcomes of lymphoma subjects, and its 
effect on the prognostic value of the IPI is uncertain.