Clinical trial NCT00799513
Conditions: Diffuse Large B-cell Lymphoma
Keywords: Lenalidomide revlimid large B-cell lymphoma relapse
Sponsor: IRCCS San Raffaele
Start date: 2009-03-01; Completion date: 2021-08-01
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II multi-institutional trial will explore the safety and efficacy of lenalidomide monotherapy given as maintenance therapy following salvage chemo-immunotherapy in patients with relapsed or refractory chemosensitive diffuse large B-cell lymphoma

Detailed description:
Patients older than 65 years or younger but not eligible to high-dose chemotherapy and autologous stem cell transplantation with biopsy-proven diffuse large B-cell lymphoma relapsed to previous combination chemotherapy regimen ± rituximab, who achieved at least a partial response to second-line chemotherapy (ICE or DHAP/DHAOx ((D)examethasone (H)igh-dose (A)ra-C - cytarabine (P)latinol (cisplatin)) or MINE (Mesna Ifosfamide Mitoxantrone Etoposide) regimen) + rituximab will receive single-agent lenalidomide 25 mg once daily for 21 days out of 28, as maintenance treatment until progression of disease. Dose reductions of study drug will be made in case of adverse events when reported as correlated and when clinically appropriate.

One-year progression free survival (PFS) will be the primary endpoint and overall survival, response rate and toxicity will be the secondary endpoints. With the null hypothesis (P0) of 1-year PFS of 30%, this study will consider a satisfactory efficacy of lenalidomide worth of further investigation a P1 corresponding to a 1-yr PFS of 50% (that is an absolute increase of 20% in terms of 1-yr progression-free survival). Considering a standard type I error (α) of 0,05 and a power of 80% (Type 2 error of 20%) 47 patients will be necessary for the trial.

Arms: arm 1: single-agent lenalidomide 25 mg once daily for 21 days out of 28, as maintenance treatment after the end of second-line chemotherapy until progression of disease.
Interventions: intervention 1: Lenalidomide
Intervention descriptions: intervention 1: single-agent lenalidomide 25 mg once daily for 21 days out of 28, as maintenance treatment after the end of second-line chemotherapy until progression of disease.

Protocol documents:
Prot_SAP_000.pdf: 
San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
Page 1 of 39  
 
 
Lenalidomide and DLBCL, version n. 4 errata corrige – December 01,2015 
 
 
STUDY PROTOCOL 
 
A phase II trial to evaluate the safety and activity of single-agent 
lenalidomide given as maintenance therapy after response to salvage 
treatment in patients with relapsed diffuse large B cell lymphoma 
[Lenalidomide and DLBCL] 
 
 
Principal investigator 
Andrés J. M. Ferreri, M.D.  
Unit of Lymphoid Malignancies 
Unit of OncoHematological Medicine 
Dept. of OncoHematology 
San Raffaele Scientific Institute 
I-20132 Milan 
Tel: 0039-02-2643 7649 
Fax: 0039-02-2643 7625 
E-mail: andres.ferreri@hsr.it 
 
Co-investigators 
Marianna Carolina Sassone M.D. 
Unit of Lymphoid Malignancies 
Division of OncoHematological Medicine 
Dept. of OncoHematology 
San Raffaele Scientific Institute 
I-20132 Milan 
 
 
SPONSOR OF THE STUDY: 
Ospedale San Raffaele 
Via Olgettina 60 
20132 Milan  
 
 
Date of the Protocol: 
version n. 4 errata corrige- December 01, 2015 
 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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STUDY SYNOPSIS /FLOW CHART 
 
 
STUDY TITLE 
A phase II trial to evaluate the safety and activity of single-
agent lenalidomide given as maintenance therapy after 
response to salvage treatment in patients with relapsed diffuse 
large B cell lymphoma (DLBCL) 
 
COORDINATOR STUDY 
SITE 
Unit of Lymphoid Malignancies 
Division of OncoHematological Medicine 
Department of OncoHematology 
San Raffaele Scientific Institute 
Via Olgettina 60-20132 Milan 
 
PRINCIPAL 
INVESTIGATOR 
Andrés J. M. Ferreri, M.D. 
Unit of Lymphoid Malignancies 
Division of OncoHematological Medicine 
Department of OncoHematologySan Raffaele Scientific 
Institute 
Via Olgettina 60 -20132 Milan 
Tel: 0039-02-2643 7649 
Fax: 0039-02-2643 7625 
E-mail: andres.ferreri@hsr.it 
 
STUDY OBJECTIVES 
 
 
Primary objective: 
- To explore the efficacy of lenalidomide monotherapy given 
as maintenance therapy following salvage chemotherapy in 
patients with relapsed or refractory DLBCL  
 
Secondary objectives: 
- To evaluate the safety of Lenalidomide maintenance therapy 
in this setting. 
 
 
 
 
  
 
 
Primary Endpoint: 
 
Secondary Endpoints: 
- To provide data about the three DLBCL subgroups 
according to immunohistochemical profile.  
- To investigate whether specific genetic alterations amenable 
to distinct DLBCL subtypes add prognostic information on 
DLBCL patients survival.  
 
 
One-year progression free survival   
 
Overall survival (OS), response rate (RR), Adverse Event  


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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(AE) and Serious AE reporting 
 
 
 
 
 
 
 
 
 
INCLUSION 
CRITERIA 
- 
Age  18 years  
- 
Biopsy-proven DLBCL at first or second relapse 
following 
previous 
combination 
chemotherapy 
regimen 
± 
rituximab, 
including 
high-dose 
chemotherapy supported by autologous stem cell 
transplantation  
- 
Partial response or complete remission to second- or 
third-line chemotherapy (ICE or DHAP/DHAOx or 
MINE regimen) + rituximab 
- 
ECOG performance status score  3 
- 
Female of childbearing potential (FCBP) must 
demonstrate to practice a proper contraception to 
avoid any pregnancy risk during the study and at least 
28 days after the discontinuation of the study 
- 
Male subjects must agree to practice a proper 
contraception during any sexual contact with females  
childbearing potential  
- 
 
EXCLUSION 
CRITERIA 
- 
CNS involvement  
- 
TTP <3 months after previous line of treatment 
- 
Use 
of 
experimental 
drugs 
during 
salvage 
chemotherapy 
- 
Severe concomitant illnesses / medical conditions 
(e.g. impaired respiratory and/or cardiac function, 
uncontrolled diabetes mellitus ) 
- 
Active infectious disease  
- 
HIV positivity 
- 
HBV-DNA or HCV-RNA positivity  
- 
Impaired liver function (Bilirubin >2 x upper normal 
limit; ALT/AST/GGT > 3 x upper normal limit) at 
one month from salvage chemotherapy conclusion 
- 
Impaired renal function (creatinine clearance <50 
ml/min) at one month from salvage chemotherapy 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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conclusion 
- 
Absolute neutrophil count (ANC) <1000/L  
- 
Platelet count <75.000 /mm3  
- 
Hemoglobin <9 g/dL 
- 
Non-co-operative behaviour or non-compliance  
- 
Psychiatric diseases or conditions that might impair 
the ability to give informed consent 
- 
Pregnant or lactating females 
- 
 
STUDY 
MEDICATION  
 
Patients, eligible for the study, will enter the treatment phase 
and receive single-agent lenalidomide 25 mg once daily for 
21 days out of 28, as maintenance treatment after the end of 
salvagechemotherapy for 24 cycles, unless treatment is 
discontinued 
earlier 
due 
to 
disease 
progression 
or 
unacceptable toxicity.. 
Dose reductions of study drug will be made in case of adverse 
events when reported as correlated and when clinical 
appropriate. 
 
 
 
 
 
STATISTICS/DESIGN 
 
 
Design: 
 
Simon's two-stage optimal design will be used. The null hypothesis 
that the true 1-year PFS is 30% will be tested against a one-sided 
alternative. In the first stage, 15 patients will be accrued. If there are 5 
or fewer patients progression-free at one year in these 15 patients, the 
study will be stopped. Otherwise, 32 additional patients will be 
accrued for a total of 47. The null hypothesis will be rejected if 19 or 
more patients progression-free at one year are observed in 47 patients. 
This design yields a type I error rate of 5% and power of 80% when 
the true 1-year PFS is 50%. 
 
Number of patients: 
47 
 
Timelines: 
Anticipated start: July 2009 
Recruitment period: July 2009 – December 2015  
Final report: December 2016 
 
 
 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS / DEFINITION OF TERMS 
 
ADR 
 
 
 
 
Adverse Drug Reaction  
AE  
 
 
 
 
Adverse Event 
ALT (SGPT)   
 
 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC   
 
 
 
Absolute neutrophil count 
ASCT   
 
 
 
Autologous stem cell transplantation 
AST (SGOT)   
 
 
Asparate transaminase (serum glutamic oxaloacetic transaminase) 
β-hCG   
 
 
 
Beta-human chorionic gonadotropin hormone 
β2M   
 
 
 
Beta-2 Microglobulin 
BUN   
 
 
 
Blood urea nitrogen 
CBC   
 
 
 
Complete blood count 
CR  
 
 
 
 
Complete remission 
CRF   
 
 
 
Case report form 
CT  
 
 
 
 
Computed tomography 
CTC   
 
 
 
Common toxicity criteria 
DLT   
 
 
 
Dose-limiting toxicity 
EC  
 
 
 
 
Ethics Committee 
ECG   
 
 
 
Electrocardiogram 
ECOG  
 
 
 
Eastern Cooperative Oncology Group 
EMEA  
 
 
 
European Agency for Evaluation of Medicinal Products 
FCBP   
 
 
 
Female of child bearing potential 
FDA   
 
 
 
Food and Drug Administration 
GCP   
 
 
 
Good Clinical Practice 
CC-5013  
 
 
 
(lenalidomide) 
ICH  
 
 
 
 
International Conference on Harmonization 
IDMC  
 
 
 
Independent Data Monitoring Committee 
IMiD   
 
 
 
Immunomodulatory drug 
IRB  
 
 
 
 
Institutional Review Board 
LDH   
 
 
 
Lactate dehydrogenase 
LLN 
 
 
 
 
Lower Limit of Normal 
MedDRA 
 
 
 
Medical Dictonary for RegulatoryActivities 
MITT   
 
 
 
Modified Intent-to-Treat 
MR 
 
 
 
 
Magnetic Resonance 
NCI  
 
 
 
 
National Cancer Institute 
OS  
 
 
 
 
Overall survival 
PD  
 
 
 
 
Progressive disease 
PFS  
 
 
 
 
Progression free survival 
PR  
 
 
 
 
Partial remission 
SAE  
 
 
 
 
Serious adverse event 
SD  
 
 
 
 
Stable disease 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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SOP  
 
 
 
 
Standard Operating Procedure 
TSH   
 
 
 
Thyroid stimulating hormone 
TTF  
 
 
 
 
Time to treatment failure 
TTP  
 
 
 
 
Time to progression 
ULN   
 
 
 
Upper limit of normal 
WBC   
 
 
 
White blood cell count 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
2.1 PRIMARY OBJECTIVE 
15 
2.2  SECONDARY OBJECTIVES 
15 
3.2 SCHEDULE AND TIMELINES 
16 
4. SELECTION OF STUDY POPULATION 
16 
4.1     INCLUSION CRITERIA 
16 
4.2 
EXCLUSION CRITERIA 
17 
4.3 
REMOVAL OF PATIENTS FROM THERAPY / STUDY 
19 
4.3.1 REGULAR TERMINATION OF STUDY PARTICIPATION 
19 
4.3.2 
PREMATURE TERMINATION OF STUDY PARTICIPATION 
19 
5 
TREATMENT PLAN 
20 
5.1 
TREATMENT 
20 
5.2 
IDENTITY OF INVESTIGATIONAL PRODUCT 
20 
6 
EFFICACY AND SAFETY VARIABLES 
21 
6.1 
EFFICACY MEASURES 
21 
6.1.1 
ASSESSMENT OF THE DISEASE STATUS 
21 
6.1.2 
SURVIVAL STATUS 
21 
6.1.3 
CENTRAL PHATOLOGY REVIEW AND CELL ORIGIN  CHARACTERIZATION(COO) 
21 
6.2 
SAFETY MEASURES 
23 
6.2.1 
ADVERSE EVENTS 
22 
 
6.2.1.1 ADVERSE EVENT DEFINITIONS AND CLASSIFICATION 
23 
 
6.2.1.2 IMMEDIATE REPORTING BY INVETIGATOR TO SPONSOR AND CELEGENE 
25 
6.2.2  
SAFETY BOARD  
 
 
 
 
 
 
 
28 
6.3 
MONITORING AND PROPHIYLACTIC TREATMENT FOR HEPATITIS B REACTIVATION 28 
6.4  
MONITORING FOR HEPATITIS C VIRUS REACTIVATION 
 
 
 
30 
6.5 
FLOW CHART 
31 
7 
DATA QUALITY ASSURANCE 
32 
7.1 
QUALITY CONTROL 
32 
7.2 
DEVIATION FROM STUDY PROTOCOL 
32 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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8 
STATISTICAL PROCEDURES 
32 
8.1 
SAMPLE SIZE AND POWER CONSIDERATION 
32 
8.2 
EFFICACY ENDPOINTS 
33 
8.2.1 
OVERALL SURVIVAL 
33 
8.2.2 
PROGRESSION-FREE SURVIVAL 
33 
8.2.3 
DURATION OF RESPONSE 
33 
8.3 
SAFETY ENDPOINTS 
33 
8.3.1 
  GRADE 3-4 NCI-CTC AES 
33 
8.4 
EFFICACY ANALYSIS 
33 
8.5 
SAFETY ANALYSIS 
34 
 
9 DATA HANDLING AND RECORD KEEPING 
34 
9.1 
DEFINITION OF SOURCE DOCUMENTS AND DATA 
34 
9.2  
PATIENT REGISTRATION 
35 
9.3  
DOCUMENTATION OF DATA IN THE CASE REPORT FORM (CRF) 
35 
9.4  
DATA MANAGEMENT 
35 
9.5 
RECORD KEEPING 
35 
10. 
STUDY DRUG MATERIAL AND MANAGEMENT 
36 
10.1 
SUPPLIER(S) 
36 
10.2 
DOSAGE FORM 
36 
10.3 
PACKAGING 
36 
10.4 
SPECIAL HANDLING INSTRUCTIONS 
36 
10.5 
LABELLING 
36 
10.6 
RECEIPT OF STUDY DRUG 
36 
10.7 
STORAGE 
36 
10.8 
UNUSED STUDY DRUG SUPPLIES 
37 
10.9 
RECORD OF ADMINISTRATION 
37 
11  
FORMALITIES / REGULATORY ASPECTS 
37 
11.1 LEGAL REGULATIONS AND GUIDELINES 
37 
11.2 PATIENT INSURANCE 
37 
11.3 ADDITIONS / AMENDMENTS TO THE STUDY PROTOCOL 
37 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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12. REFERENCES 
37 
 
 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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APPENDICES 
 
 
A Informed consent form and declaration of data privacy 
 
 
39 
B Informed consent about Rules for use of biological material for research and/or scope of 
experiments in genetic research 
 
 
 
 
 
 
52 
C Patient identification list 
 
 
 
 
 
 
64 
D Drug accountability form 
 
 
 
 
 
 
65 
E Response criteria (IWRC) 
 
 
 
 
 
 
66 
F Performance Status ECOG scale  
 
 
 
 
 
68 
G Declaration of Helsinki, Edinburgh 2000 incl. Note of Clarification 2002 
69 
H List of participating centers 
 
 
 
 
 
 
73  
I 
Study drug dose reduction schedule 
 
 
 
 
 
74 
 
 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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Lenalidomide and DLBCL, version n. 4 errata corrige – December 01,2015 
 
1. Introduction 
 
1.1 
Non Hodgkin’s Lymphoma and diffuse large B-cell lymphoma (DLBCL) 
The 
non-Hodgkin’s 
lymphomas 
(NHLs) 
comprise 
a 
heterogeneous 
collection 
of 
lymphoproliferative malignancies, which are most common in people aged over 55 years. 
DLBCL is the most common type of NHL, accounting for approximately 30% of all new 
patients. Follicular lymphoma (FL) is the second most common NHL sub-type, and accounts for 
a further 22% of cases. While the incidence of most other cancers is decreasing, that of NHL is 
increasing steadily. During the 1970’s and 1980’s, worldwide NHL incidence rose by 3–4% per 
year. This rise has slowed in the 1990s, but an annual increase of 1–2% is still being recorded1. 
NHL occurs more commonly in males, and whites are affected more often than blacks. The 
incidence of NHL increases with age. NHL is known to be associated with chronic 
inflammation diseases such as Sjögren syndrome, Celiac disease, and rheumatoid arthritis. 
Immune suppression has also been associated with an increased risk of developing lymphoma2 
Following a solid organ transplant, the risk of lymphoma is associated with the duration of 
immunosuppression and the drugs and dosages used. In addition, infections with the human 
immunodeficiency virus (HIV) have been associated with a significantly elevated risk of NHL.  
The correct diagnosis today for DLBCL is done following the World Health Organization 
(WHO) classification, considering that this is still a heterogenous group including lymphomas 
with a wide variety of morphologic appearances, protein-expression patterns, and gene-
expression patterns. For example, patients with DLBCL can be divided into at least 3 clinically 
relevant groups using gene-expression profiling. These include the germinal-center type, the 
activated B-cell type, and mediastinal large B-cell lymphoma. A few patients will not easily be 
classified into these categories. Mediastinal large B-cell lymphoma represents less than 10% of 
all large B-cell lymphomas, occurs primarily in young women, and always presents with a 
mediastinal mass. The gene-expression profile is similar to that seen in classical Hodgkin 
disease. The other 2 types of DLBCL, and those not easily classified, have a median age at 
presentation in the 60s, a male predominance, and can present at essentially any site in the body. 
DLBCL can be seen after histologic transformation of most other types of B-cell lymphoma. 
This is particularly frequent in patients with follicular lymphoma and is recognized clinically in 
up to 50% of patients. In general, patients with DLBCL seen after histological transformation 
have a poorer response to therapy and prognosis than those with a de novo appearance, 
particularly if the patient were treated for the preceding lymphoma3. 
 
1.2 
Lenalidomide 
Lenalidomide (REVLIMID®; Celgene Corp., NJ, USA) is a member of a class of 
pharmaceutical compounds known as immunomodulatory drugs (IMiDs). It offers potential 
benefit over the first commercially available IMiD, thalidomide, in terms of both safety and 
efficacy in human subjects. The key to its therapeutic potential lies in the fact that it has 
multiple mechanisms of action, which act to produce both anti-inflammatory and anti-tumor 
effects. These effects are thought to be contextual in that they depend on both the cell type and 
the triggering stimulus. To date, lenalidomide has been associated with TNF-α inhibitory, T cell 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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Lenalidomide and DLBCL, version n. 4 errata corrige – December 01,2015 
 
costimulatory, and antiangiogenic activities4-6. Preclinical studies have documented that 
Lenalidomide has several immunomodulatory effects:   
- 
co-stimulation of T cells thus enhancing Th1 type cellular immunity and NK cell-
mediated cytotoxicity7 
- 
inhibition of regulatory T cells, thereby reducing the suppression of CD4+ T cell activity 
in NHL 
- 
enhancement of antibody-dependent cellular cytotoxicity in Rituximab-treated NHL cell 
lines8 
 
and have shown other mechanisms which could explain its effects in NHL: 
- 
Inhibition of NHL cell proliferation, possibly through the Akt cell-survival pathway9 
- 
Inhibition of angiogenesis, including reduction of endothelial cell migration10 
 
Lenalidomide is marketed in the United States for the treatment of patients with transfusion-
dependent anemia due to low- or intermediate-1-risk Myelodysplastic Syndrome (MDS) 
associated with a deletion 5q- cytogenetic abnormality with or without additional cytogenetic 
abnormalities and for patients with relapsed or refractory Multiple Myeloma (MM) in 
combination with dexamethasone11-13. Lenalidomide is also marketed in the European Union for 
use in combination with dexamethasone as a treatment for patients with MM who have received 
at least one prior therapy. 
Lenalidomide is being investigated as treatment for various oncology indications, including  
non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia (CLL)14 and solid tumors. It is also 
being explored as a treatment for inflammatory conditions, including chronic regional pain 
syndrome. While many of the studies are ongoing, results from controlled and uncontrolled 
studies in subjects with and MDS are available. 
In the MDS study 148 patients received lenalidomide, the most frequent Grade 1-4 adverse 
events reported were; thrombocytopenia (61.5%), neutropenia (58.8%), pruritus (41.9%), rash 
NOS (35.8%), and diarrhea NOS (48.6%). The most frequently observed Grade 3 and 4 adverse 
events regardless of relationship to study drug treatment were neutropenia (53.4%) and 
thrombocytopenia (50%)13. 
A total of 691 patients (346 patients in the lenalidomide/dexamethasone arms and 345 in the 
placebo/dexamethasone arms) were treated in the two pivotal MM studies11,12. Most adverse 
events and Grade 3/4 adverse events were more frequent in the patients who received the 
combination of lenalidomide/dexamethasone. The most common Grade 1-4 adverse events in 
the lenalidomide/dexamethasone treatment groups were constipation (38.7%), fatigue (38.4%), 
insomnia (32.1%), muscle cramps (30.1%), and diarrhea NOS (29.2%), The most frequently 
observed 
Grade 
3 
and 
4 
adverse 
events 
reported 
in 
patients 
treated 
with 
lenalidomide/dexamethasone groups were neutropenia Grade 3 (17.3%), Grade 4 (3.8%) and 
thrombocytopenia Grade 3 (9%), Grade 4 (1.2%). Thrombotic or thromboembolic events were 
reported more frequently in patients treated with lenalidomide/dexamethasone groups (13%) 
compared to the placebo/dexamethasone groups (3.8%). 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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Lenalidomide and DLBCL, version n. 4 errata corrige – December 01,2015 
 
Patients with relapsed/refractory CLL have limited therapeutic options and the addition of novel 
agents with alternative mechanisms of action is needed. Based on the encouraging data from 
Chanan-Khan et al.14, a multicenter study is validating the potential therapeutic role of 
lenalidomide in the treatment of CLL.  
 
1.3 
Lenalidomide and NHL 
Over the last five years, the anti-CD20 monoclonal antibody, Rituximab, has radically changed 
the treatment of B cell NHL, and has become a component of salvage therapy in the follicular 
lymphoma setting. Several large scale prospective randomized trials have demonstrated 
prolongation of remissions when Rituximab is added to first line CHOP therapy 
(cyclophosphamide, doxorubicin, vincristine and prednisone)15. Despite this major advance a 
high proportion of elderly patients with DLBCL still progress or relapse and eventually die of 
their disease2. The three-year EFS projection of the study from Coiffier et al15. suggests that this 
number still approaches 50%. The prognosis is even poorer for patients relapsing following 
treatment with standard chemotherapy for aggressive non-Hodgkin's lymphoma. High-dose 
chemotherapy and autologous stem cell transplantation is a potentially curative approach for 
these patients, but many patients are not eligible for this approach due to age and/or 
comorbidities. Salvage chemotherapy remains the mainstay of treatment, and is tailored 
according to disease and patient characteristics, goals of therapy, and patient preference. A 
number of strategies have been explored to improve the response rate to second-line regimens. 
Different chemotherapeutic schemes, like DHAP (dexamethasone, cisplatin, and cytarabine)16, 
ICE17 (Ifosfamide, carboplatin, and etoposide), or ESHAP (etoposide, methylprednisolone, 
high-dose cytarabine, and cisplatin) with or without addition of rituximab are currently used to 
re-induce remission, and none of them have demonstrated to be superior to the others. 
A recent multicentre open label single arm phase II study has shown lenalidomide to be active 
in patients with relapsed/refractory aggressive NHL18. In a series of 46 patients, mostly with 
DLBCL (n=29) or MCL (n=13), the use of lenalidomide at the dose of 25 mg PO, days 1-21, 
every 28 days for 52 weeks, until toxicity or progressive disease (same dose as the one used in 
patients with multiple myeloma), was associated with a tumor control rate of 50%, with 
acceptable toxicity. Grade 4 adverse events were rare; grade 3 events included neutropenia in 
14% of cases, thrombocytopenia in 10% and leukopenia in 8%. In the initial pilot studies, 
response to lenalidomide was associated with low tumor burden, long interval from prior 
rituximab and high absolute lymphocyte count19, 20.  
The above mentioned properties and the preliminary results, prompted us to investigate the 
effects of lenalidomide in the maintenance of response of patients with relapsed or refractory 
aggressive B-cell lymphoma, treated with second-line chemotherapy and older than 65 years or 
younger but not eligible for high-dose chemotherapy and autologous transplantation. These 
patients can achieve a rapid and complete lymphoma regression with second-line therapy but 
invariably experience relapse, which is the main unfavorable prognostic event.  
An active maintenance therapy with an oral drug, with an acceptable safety profile such as 
lenalidomide, could contribute to prolong significantly time to progression and, possibly, overall 
survival of this patient population. 


San Raffaele Scientific Institute 
Division of OncoHematological Medicine 
Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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Lenalidomide and DLBCL, version n. 4 errata corrige – December 01,2015 
 
 
 
2. Study objectives and endpoints 
2.1 Primary objective 
- 
To explore the efficacy of lenalidomide monotherapy given as maintenance after at least 
a partial response (PR) to a second- or third-line chemo-immunotherapy in patients with 
relapsed DLBCL  
 
2.2  Secondary objectives 
- 
To evaluate the safety of Lenalidomide maintenance therapy in this setting. 
 
- 
To explore the efficacy of lenalidomide in the different DLBCL prognostic 
subtypes (see item 6.1.3) 
 
- 
To investigate, when possible, whether the classification of DLBCL subtypes and 
the expression of specific candidate genes can provide prognostic information 
about the efficacy of lenalidomide in DLBCL subtype’s  
 
2.3 
Primary endpoint 
- One-year progression free survival (PFS) 
 
2.4 
Secondary endpoints 
- 
Overall survival (OS), response rate (RR), adverse events (AE) and serious adverse 
events (SAE) rate 
 
 
3 Overall study design 
 
3.1 Type of study 
 
This is an open label, single-arm, multicentre phase II trial evaluating the maintenance treatment 
of oral lenalidomide monotherapy given to patients  with relapsed DLBCL who presented at 
least a PR to a second- or third-line therapy.   
A total number of 47 eligible patients will be enrolled in the protocol and receive Lenalidomide 
25 mg for 21 days every 28 days, until clinical appropriate. These subjects will be continuously 
monitored for safety, disease status and survival. 
 


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3.2 Schedule and timelines 
 Anticipated start of recruitment: July 2009 
 
 
 Anticipated stop of recruitment: July 2013 
 
 
 Final report: July 2014 
 
 
 
4. Selection of study population 
4.1     Inclusion criteria 
- 
Age  18 years  
- 
Patients affected by histologically-proven DLBCL at first or second relapse following 
previous combination chemotherapy regimen  rituximab, including high-dose 
chemotherapy supported by autologous stem cell transplantation  
- 
Partial response (PR) or complete remission (CR) to a second- or third-line salvage 
chemotherapy, including the following regimens: R-DHAP (rituximab, dexametasone, 
high-dose cytarabine, cisplatinum), R-DHAOx (rituximab, dexametasone, high-dose 
cytarabine, oxalyplatinum), R-ICE (rituximab, ifosfamide, carboplatin, etoposide), R-
MINE (rituximab, methotrexate, ifosfamide, vinorelbine, etoposide) 
- 
ECOG performance status score  3 
- 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment 
into the study: 
 
Female subjects of childbearing potential† must:  
1.1 Understand that the study medication could have a potential teratogenic risk  
1.2 Agree to use, and be able to comply with, effective contraception without 
interruption, 4 weeks before starting study drug, throughout study drug 
therapy (including dose interruptions) and for 4 weeks after the end of 
study drug therapy, even if she has amenorrhoea. This applies unless the 
subject commits to absolute and continued abstinence confirmed on a 
monthly basis. The following are effective methods of contraception* 
1.2.1 
Implant** 
1.2.2 
Levonorgestrel-releasing intrauterine system (IUS)** 
1.2.3 
Medroxyprogesterone acetate depot 
1.2.4 
Tubal sterilisation 
                                               
† A female subject or a female partner of a male subject is considered to have childbearing potential unless she meets at least one 
of the following criteria: Age ≥50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer therapy does not 
rule out childbearing potential), premature ovarian failure confirmed by a specialist gynaecologist, previous bilateral salpingo-
oophorectomy or hysterectomy, XY genotype, Turner’s syndrome or uterine agenesis.  


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1.2.5 
Sexual intercourse with a vasectomised male partner only; 
vasectomy must be confirmed by two negative semen analyses 
1.2.6 
Ovulation inhibitory progesterone-only pills (i.e., desogestrel) 
* Combined oral contraceptive pills are not recommended. If a subject was using combined oral 
contraception, she must switch to one of the methods above. The increased risk of VTE 
continues for 4 to 6 weeks after stopping combined oral contraception. 
**prophylactic antibiotics should be considered at the time of insertion particularly in patients 
with neutropenia due to risk of infection 
1.3 Agree to have a medically supervised pregnancy test with a minimum 
sensitivity of 25 IU/ml not more than 3 days from the start of study 
medication once the subject has been on effective contraception for at least 
4 weeks. This requirement also applies to women of childbearing potential 
who practice complete and continued abstinence. 
1.4 Agree to have a medically supervised pregnancy test every 4 weeks 
including 4 weeks after the end of study treatment, except in the case of 
confirmed tubal sterilization. These tests should be performed not more 
than 3 days before the start of next treatment. This requirement also applies 
to women of childbearing potential who practice complete and continued 
abstinence 
 
Male subjects must 
1.5 Agree to use condoms throughout study drug therapy, during any dose 
interruption and for one week after cessation of study therapy if their 
partner is of childbearing potential and has no contraception. 
1.6 Agree not to donate semen during study drug therapy and for one week 
after end of study drug therapy. 
 
 
 
All subjects must 
1.7 Agree to abstain from donating blood while taking study drug therapy and 
for one week following discontinuation of study drug therapy.   
1.8 Agree not to share study medication with another person and to return all 
unused study drug to the investigator  
4.2 
Exclusion criteria 
- 
CNS involvement 


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- 
Time to progression < 3 months after the previous line of treatment 
- 
Use of experimental drugs during salvage chemotherapy 
- 
Concomitant malignancies diagnosed in the last five years before patient’s registration 
- 
Severe concomitant illnesses / medical conditions (e.g. impaired respiratory and/or 
cardiac function, uncontrolled diabetes mellitus) 
- 
Active infectious disease  
- 
HIV positivity   
- 
HBV-DNA or HCV-RNA positivity 
- 
Impaired liver function (bilirubin >2 x upper normal limit; ALT/AST/GGT > 3 x upper 
normal limit) at one month from salvage chemotherapy conclusion 
- 
Absolute neutrophil count (ANC) <1000/L and/or platelet count <75.000 /mm3 and/or 
hemoglobin <9 g/dL 
- 
Pregnant or lactating females 
- 
Impaired renal function (creatinine clearance <50 ml/min) at one month from salvage 
chemotherapy conclusion 
- 
Non-co-operative behaviour or non-compliance 
- 
Psychiatric diseases or conditions that might impair the ability to give informed consent 
- 
Pregnant or lactating females: 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject or the female partner of a male subject occurring while the 
subject is on study drug, or within 30 days of the subject’s last dose of study drug, are 
considered immediately reportable events. Study drug is to be discontinued immediately and the 
subject instructed to return any unused portion of the study drug to the investigator(s). The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Celgene S.r.l., 
drugsafety-italy@celgene.com or Tel. +0039-02-91434340, Fax +0039-02-63471119 or 
Celgene Drug Safety Department in the US at: +1 800 640 7854 immediately by phone and fac-
simile using the Pregnancy Reporting Form. 
The female should be referred to a physician specialized or experienced in teratology for further 
evaluation and counseling. 
The Investigator(s) will follow the female subject until completion of the pregnancy, and must 
notify the Celgene S.r.l, drugsafety-italy@celgene.com or Tel. +39-02-91434340 or Fax +39-
02-63471119 of the outcome of the pregnancy as a follow-up to the initial report. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to 
be documented], stillbirth, neonatal death, or congenital anomaly [including that in an aborted 
fetus]), the Investigator(s) should follow the procedures for reporting SAEs (i.e., report the 
event to the Celgene  S.r.l, drugsafety-italy@celgene.com or Tel. +39-02-91434340 by 
telephone and  Fax +39-02-63471119 facsimile within 24 hours of the Investigator’s knowledge 
of the event). 


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In the case of a live “normal” birth, the Celgene  S.r.l, drugsafety-italy@celgene.com or Tel. 
+39-02-91434340 should be advised by telephone and Fax +39-02-63471119 fac-simile within 
24 hours of the Investigator’s knowledge of the event. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator(s) suspects 
is related to the in utero exposure to the study drug should also be reported to the Celgene  S.r.l, 
drugsafety-italy@celgene.com or Tel. 0039-02-91434340 by telephone and Fax +39-02-
63471119  facsimile within 24 hours of the Investigators’ knowledge of the event. 
- 
If the female is found not to be pregnant, any determination regarding the subject’s 
continued participation in the study will be determined by the Investigator(s). 
 
4.3 
Removal of patients from therapy / study 
 
4.3.1 Regular termination of study participation 
The participation of the patient in the study is regularly terminated: 
1. In case of death or in case of lymphoma failure 
2. Discontinuation of study drug due to toxicity or adverse event 
 
4.3.2 
Premature termination of study participation 
The patient may drop out of the clinical study at any time without stating reasons. This may not 
have any negative consequences for the patient’s further treatment. 
 
Possible reasons for withdrawal of the patient are: 
 
 Withdrawal of the patient’s consent 
 Further participation assessed by the investigator to be unacceptable / intolerable  
 Pregnancy 
 Lack of co-operation/compliance of the patient 
 Occurrence of new diseases that could influence the treatment efficacy, for which the study 
medication is contraindicated or that are treated with a medication that is not permitted as a 
concomitant medication. 
 Reconsideration of the risk/benefit ratio, in consensus with Ethical Committee and 
Independent Safety Monitoring Committee 
 
The reason for both regular and premature termination should be recorded in the CRF and in the 
subject’s medical records. 
 
 
 


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Department of OncoHematology 
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5 
Treatment Plan 
5.1 
  Treatment 
After the documentation of PR or CR after salvage chemo-immunotherapy, patients will receive 
lenalidomide 25 mg daily orally for 21 days every 28 days for 2 years (24 cycles). This 
maintenance therapy will start after one month from salvage chemotherapy conclusion. The 
duration of period between the end of chemotherapy and the beginning of maintenance 
treatment can be variable according to the achievement of the acceptable  haematological and 
biochemical parameters. This interval could be prolonged until the patient will be considered 
eligible for the trial, within 2 months.  
 
5.2 
Identity of investigational product 
Celgene Corporation will supply 10 mg, 5 mg and 25 mg lenalidomide capsules for oral 
administration in order to treat patients with the full dose of 25 mg and in case to adjust this 
dose if any drug related AEs occur.  
Lenalidomide will be packaged in bottles containing 21 days of study drug.  
 
5.3 
Dose Modification or Interruption 
 
Dose reduction levels are reported on Appendix I.  
Subjects will be evaluated for AEs at each visit following the NCI CTCAE (Version 3.0) and 
used as a guide for the grading of severity: 
 
• Thrombocytopenia will be graded as follows: 
− Grade 1 ≥ 75 x 109/L and < LLN 
− Grade 2 ≥ 50 and < 75 x 109/L  
− Grade 3 ≥ 25 and < 50 x 109/L 
− Grade 4 < 25 x 109/L 
 
• Hemoglobin will be graded as follows: 
− Grade 1 ≥ 10 g/dL  and < LLN 
− Grade 2 ≥ 8 and < 10 g/dL   
− Grade 3 ≥ 6.5 and < 8 g/dL   
− Grade 4 < 6.5 g/dL   
 
• Neutropenia will be graded as follows: (ANC/µL) 
− Grade 1 ≥ 1500 and < 2000 x 109/L 
− Grade 2 ≥1000 and < 1500 x 109/L 
− Grade 3 ≥ 500 and < 1000 x 109/L 
− Grade 4 < 500 x 109/L 


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Department of OncoHematology 
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5.4   Prior/Concomitant Medications 
All medications (prescription and non-prescription), treatments and therapies taken during the 
treatment with study drug must be recorded on the appropriate CRF. 
All the therapies considered necessary for the subject’s wellbeing may be administered at the 
discretion of the Investigator. These therapies may include antibiotics, analgesics, 
antihistamines, or other medications as well as growth factors and transfusions of red blood 
cells, platelets, or fresh frozen plasma given to assist in the management of complications 
associated with NHL or its therapy. To date, no data on a higher risk of thromboembolic 
complications with lenlidomide in lymphoma patients have been reported. However, 
antithrombotic prophylaxis could be indicated according to the Institutional guidelines of each 
center and o the individual risk of the registered patient considering that patients entering into 
this trial will be older than 65 years and lenalidomide treatment will be long-lasting.   
 
5.5   Prohibited Concomitant Therapy 
Concomitant use of other lymphoma therapy or experimental therapies while the subject is on 
study drug is prohibited.  
6 Efficacy and safety variables 
6.1 
Efficacy measures 
6.1.1 
Assessment of the disease status 
Response to treatment is defined on the basis of International Workshop Response Criteria for 
non-Hodgkin’s Lymphoma (Appendix E).  
 
6.1.2 
Survival status  
Patient survival status will be determined every four weeks during the study treatment, every 
four months for three years after, every six months for the following two years and every year 
after there, until 10-year follow-up completion, progression or death.  
In addition to reporting the serious adverse events, patient‘s deaths must be recorded 
continuously throughout the study. 
Evaluation and documentation of the cause of death must be entered in the CRF. 
  
6.1.3 
Central pathology review and cell of origin (COO) characterization 
All the registered cases will undergo central pathology review.  


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Efficacy of the experimental therapy will be analysed stratifying registered patients according to their 
COO, namely “germinal-centre B cell type” and “activated B-cell type” subgroups. COO will be defined 
according immunohistochemical results of antibodies raised against CD20, CD3, CD10, bcl-6, MUM-
1/IRF4, and bcl-2 molecules, using the Hans algorithm. This is a surrogate practical tool in confirming 
data generated by gene-expression profiling and could be applied also to tissue microarrays obtained by 
formalin-fixed, paraffin-embedded (FFPE) clinical cases of DLBCL. The limits in detecting the precise 
COO by means of immunohistochemistry will be overcome by using a validated gene-expression-
profiling-based assay performed on NanoString’s nCounter® Analysis System, now available on FFPE 
pathological material. The correlation between COO in DLBCL subtypes and clinical efficacy will be 
studied in order to identify genetic predictors of successful response to therapy with lenalidomide.  
In order to identify cases of “double expressor lymphomas” and “double hit lymphomas”, MYC will be 
added to the previously mentioned bcl-6 and bcl-2 markers on FFPE samples by immunohistochemistry; 
these data will enable to select a subgroup of cases suitable for the assessment of MYC and BCL2 
genetic abnormalities through FISH technique.  
Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of 
lenalidomide. Expression of cereblon will be evaluated in diagnostic tissue samples by 
immunohistochemistry, through the use of a Celgene anti-CRBN rabbit monoclonal antibody CRBN65. 
The prognostic value of the expression of CRBN will be assessed on the clinical data from registered 
patients.  
In order to fulfil these aims, diagnostic tissue blocks (tissue block from biopsy performed at relapse is 
also requested if available) and all the diagnostic, already stained specimens per case should be referred 
to: Dr. Maurilio Ponzoni, Pathology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina 60 - 
20132, Milano (tel: 02-26432544 – e-mail: ponzoni.maurilio@hsr.it). In the case the blocks will not be 
available, all stained specimens plus 30 unstained slides, prepared as to undergo antigen retrieval, will be 
referred for analyses; in the case stained slides and blocks will not be available, one Haematoxylin and 
eosin plus 40 unstained slides, prepared as to undergo antigen retrieval, will be referred.  
 
 


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Department of OncoHematology 
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6.2 
Safety measures 
6.2.1 
Adverse events 
6.2.1.1 
Adverse Event Definitions and Classifications 
  
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of subjects and investigators and are mandated by 
Regulatory Agencies worldwide. 
  
 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product. An adverse event does not necessarily have a causal 
relationship with the treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational  medicinal product, whether or not considered 
related to the investigational medicinal product (Definition per International Conference on 
Harmonization [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Note: The Investigator collect adverse events starting from the time of signing the informed 
consent through the end of the designated follow-up period. 
Abnormal laboratory values defined as adverse events 
An abnormal laboratory value is considered to be an AE if the laboratory abnormality is 
characterized by any of the following: 
-results in discontinuation from the study 
-requires treatment, modification/interruption of study drug dose, or any other therapeutic 
intervention 
-is judged by the Investigator to be significant clinical importance 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page of the CRF. If the abnormality was 
not part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the 
AE. 
 
 
Serious Adverse Event 
A serious adverse event (SAE) as defined by ICH is any untoward medical occurrence that at 
any dose:  
- results in death 
- is life-threatening (the subject was at risk of death at the time of the event. It does not refer to 
an event that hypothetically might have caused death if it were more severe). 
- results in persistent or significant disability/ incapacity, or 
- is a congenital anomaly/birth defect 


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Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in situations other than those listed above. For example, important 
medical events 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 outcomes listed in 
the definition above. Any adverse event is considered a serious adverse event it is associated 
with clinical signs or symptoms judged by the investigator to have a significant clinical impact. 
Events not considered to be SAEs are hospitalizations which: were planned before entry into the 
clinical study; are for elective treatment of a condition unrelated to the studied indication or its 
treatment; occur on an emergency outpatient basis and do not result in admission (unless 
fulfilling other criteria above); are part of the normal treatment or monitoring of the studied 
indication and are not associated with any deterioration in condition. 
If an AE is considered serious, both the AE pages of the CRF and the SAE Report form must be 
completed. 
For each SAE, the investigator will provide information on severity , start and stop dates, 
relationship to (investigational product) study drug, action taken regarding (investigational 
product) study drug and outcome. 
 
 
Classification of severity 
For both AEs and SAEs, the investigator(s) must assess the severity of the event. The severity of 
adverse events (AEs) will be graded on a scale of 1 to 5 according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE). 
The NCI CTCAE V3.0 can be viewed on-line at the following NCI web site: 
http://ctep.cancer.gov/reporting/ctc.html. If a specific event is not included in the NCI CTCAE 
toxicity scale, the following scale should be used to grade the event  
 
 
 
Grade Definition: 
1
 
Mild Awareness of sign, symptom, or event, usually transient, requiring no 
special treatment and generally not interfering with usual daily activities  
2
 
Moderate Discomfort that causes interference with usual activities; usually 
ameliorated by basic therapeutic manoeuvres  
3
 
Severe Incapacitating with inability to do usual activities or significantly 
affects clinical status and warrants intervention. Hospitalization may or may 
not be required  
4
 
Life-threatening Immediate risk of death; requires hospitalization and 
clinical intervention.  
5
Death  


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 
UnexpectedAdverse Event 
An adverse event, the nature or severity of which is not consistent with the applicable product 
information (for an investigational medicinal product, the Investigator’s Brochure). Associated 
With the Use of the Investigational medicinal  product 
An adverse event is considered associated with the use of the investigational product if the 
attribution is possible, probable, or very likely by the definitions listed in Section 10.1.2. 
 
 Attribution Definitions 
 
 
Not related. 
An adverse event that is not related to the use of the investigational product. 
 
Doubtful. 
An AE for which an alternative explanation is more likely, e.g., concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
 
Possible. 
An AE that might be due to the use of the investigational product. An alternative explanation, 
e.g., concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded. 
 
Probable. 
An AE that might be due to the use of the investigational product. The relationship in time is 
suggestive (e.g., confirmed by dechallenge). An alternative explanation is less likely, e.g., 
concomitant drug(s), concomitant disease(s). 
 
Very likely. 
An AE that is listed as a possible adverse event reaction, and cannot be reasonably explained by 
an alternative explanation, e.g., concomitant investigational drug(s), concomitant disease(s). The 
relationship in time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge). 
 
Classification of Relationship/Causality of adverse events (SAE/AE) to study drug 
 
The Investigator(s) must determine the relationship between the administration of study drug 
and the occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
 
Not 
suspected: 
The temporal relationship of the adverse event to study 
drug administration makes a causal relationship unlikely or 
remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for 
the observed event 
Suspected: 
The temporal relationship of the adverse event to study 
drug administration makes a causal relationship possible, 
and other medications, therapeutic interventions, or 


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underlying conditions do not provide a sufficient 
explanation for the observed event. 
 
Treatment-related mortality 
If an adverse event considered associated with the study medication results in a patient’s death, 
then the event will be listed as a “treatment-related mortality”. 
 
Procedures 
 
All Adverse Events 
All AEs, with the exception of progression of systemic AL-amyloidosis, that occur between the 
first study-related procedures and for 30 days following the last dose of investigational product 
will be reported. Resolution information after 30 days should also be provided for grade 3 to 4 
drug related events. This subset should be followed up until resolution to a grade 1 or better. 
Adverse events occurring after 30 days should also be reported if considered related to 
investigational product. 
Clinically relevant changes in laboratory values must be recorded in the adverse event section of 
the CRF. 
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be 
recorded in the source document and the CRF. Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to the study therapy. All measures 
required for adverse event management must be recorded in the source document. 
The Principal Investigator assumes responsibility for appropriate reporting of adverse events to 
the regulatory authorities. The Principal Investigator must report these events to the appropriate 
Institutional Review Board (IRB) that approved the protocol unless otherwise required and 
documented by the IRB. 
 
Serious Adverse Event (SAE) Reporting Report of Adverse Events to Regulatory Authorities and 
the Ethics Committee 
 
The sponsor will inform relevant Regulatory Authorities and the Ethics Committee: 
- 
of all relevant information about serious unexpected adverse events suspected to 
be related to the study medication that are fatal or life  threatening as soon as 
possible, and in any case no later than seven days after knowledge of such a 
case. Relevant follow-up information for these cases will subsequently be 
submitted within an additional eight days. 
- 
of all other serious unexpected events suspected to be related to the study 
medication as soon as possible , but within a maximum of fifteen days of first 
knowledge by the investigator. 
 
 
6.2.1.2 Immediate reporting by Investigator to Sponsor and Celgene 


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The investigator will inform the sponsor and Celgene of any serious adverse event. This applies 
to all SAEs, regardless of relationship to the study medication, that occur during the study, those 
made known to the Investigator(s) within 30 days after a subject’s last dose of study drug, and 
those made known to the investigator(s) at any time that are suspected of being related to the 
study medication. This must be documented on an SAE form.  This form must be completed in 
English and supplied to Celgene Europe Drug Safety within 24 hours/1 business day or at the 
latest on the following working day.  The initial report must be as complete as possible, 
including details of the current illness and serious adverse event, and an assessment of the 
causal relationship between the event and the investigational product(s).  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 
values received after the report) must be documented on a follow-up SAE form. 
All adverse event reports must include the patient number, age, sex, weight, severity of reaction, 
relationship to study drug, date and time of administration of test medications and all 
concomitant medications, and medical treatment provided. 
 
Safety Contact Information 
 
Safety Phone Number 
Safety Fax/e-mail 
 Fondazione S. Raffaele Safety 
Desk 
+39 02 2643 4289 
+39 02 2643 4760 
stefania.trinca@hsr.it 
Celgene International Sarl 
 
Att. Drug Safety Department 
Route de Perreux 1 
2017 Boudry 
CH-NE 
24-H Emergency Contact 
Call Centre Direct Telephone 
+41 32729 8476 and follow the 
instructions in the recorded 
message 
+41 32 729 8476 
 
Fax : +41 32 729 8409 
drugsafetyeurope@celgene.com 
 
Celgene S.r.l. 
Dr. Roberta Di Menno Di 
Bucchianico 
+39 02 91434340 
+39 340/8369630 
 
Fax +39 02 63471119 
drugsafety-italy@celgene.com 
 
Sponsor Reporting to Celgene 
 
The sponsor will provide Celgene with a copy of the annual safety report at the time of the 
submission to the regulatory authority and the Ethics Committee. 
 
Pregnancies 
Pregnancies occurring while subjects are on study drug or within 4 weeks after a subject’s last 
dose of study drug are considered events to be reported immediately to Celgene.  If the subject 
is on study drug the study drug is to be discontinued immediately and the subject is to be 


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Division of OncoHematological Medicine 
Department of OncoHematology 
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instructed to return any unused portion of the study drug to the Investigator.  The pregnancy 
must be reported to Celgene within 24 hours of the Investigator’s knowledge of the pregnancy 
by phone and facsimile using the SAE Form. The pregnancy must also be reported to the 
sponsor. 
The Investigator will follow the subject until completion of the pregnancy, and must notify the 
sponsor and Celgene of the outcome within 5 days or as specified below.  The Investigator will 
provide this information as a follow-up to the initial pregnancy report. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted foetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), the Investigator should follow 
the procedures for reporting SAEs. All neonatal deaths that occur within 30 days of birth should 
be reported, without regard to causality, as SAEs.  In addition, any infant death after 30 days 
that the Investigator suspects is related to the in utero exposure to the study drug should also be 
reported. 
In the case of a live “normal” birth, Celgene should be advised as soon as the information is 
available. 
Any suspected foetal exposure to CC-5013 must be reported to Celgene within 24 hours of 
being made aware of the event.  The patient should be referred to an obstetrician/gynaecologist 
experienced in reproductive toxicity for further evaluation and counselling. 
Adverse event updates/IND safety reports 
Celgene shall notify the Investigators and the sponsor 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 AE associated with the use of any other drug in this study that is both serious and 
unexpected as per the Summary of Product Characteristics for cyclophosphamide and 
dexamethasone. 
 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
The sponsor shall notify the EC and the relevant regulatory authorities of any new significant 
risks to subjects as required. 
 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject’s participation in the study, must be followed until 
any of the following occurs: 
 
- 
the events resolves; 
- 
the event stabilizes; 
- 
the event returns to baseline, if a baseline value is available; 
- 
the event can be attributed to agents other than the investigational product or to factors 
unrelated to study conduct; 


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- 
when it becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts). 
 
Data protection 
Patient’s identity will stay anonymously. 
 
6.2.2 
Safety board 
An Independent Data Monitoring Committee (IDMC) will review ongoing safety and efficacy 
data and at the time of the planned analyses to assess benefit-to-risk considerations throughout 
the study. Additional safety reviews will occur at scheduled intervals agreed upon by the IDMC. 
6.3 
 Monitoring and prophylactic treatment for hepatitis B reactivation 
At screening patients will be tested for hepatitis B serologic markers, that is HBsAg, HBsAb, 
and HBcAb. Patients with positive serologic markers should be tested for viral load dosing 
HBV-DNA. Patients with detectable levels of HBV-DNA will be excluded. Patients with 
HBsAg positivity, independently from HBsAb and HBcAb titres, will receive prophylaxis with 
lamivudine 100 mg/d. It will be started 1-2 weeks before lenalidomide treatment. HBV-DNA 
will be assessed on day 1 of each course (±7 days of scheduled visit), at the end of lenalidomide 
(within 7 days after stopping drug), and at 28-day follow-up visit (± 7 days of scheduled visit). 
Patients with undetectable levels of HBV-DNA and/or with HBsAg negativity, independently 
from HBsAb and HBcAb titres, will not receive prophylaxis treatment; HBV-DNA will be 
assessed as above mentioned. Antiviral prophylaxis therapy should continue for at least 4 weeks 
after last dose of lenalidomide. For hepatitis B reactivation definition and management 
guidelines see following table. 
Guidelines for management of hepatitis B 
 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with positive HBsAg 
 
 
 
____________________________________ 
reactivation is defined as: 
new appearance of measurable HBV-DNA 
± ALT elevation x 5 ULN 
Treat: Start a second antiviral AND interrupt lenalidomide 
administration until resolution: 
• ≤ grade 1 ALT (or baseline ALT, if > grade 1) and 
• undetectable HBV-DNA levels 
 
If resolution occurs within ≤ 28 days: lenalidomide should 
be re-started at 10 mg/d. If the patient is already receiving 
10 mg/d of lenalidomide, according to the protocol, the 
patient should restart at the same dose after resolution. 
Both antiviral therapies should continue at least 4 weeks 
after last dose of lenalidomide. 
 
If resolution occurs > 28 days. Patients should discontinue 


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* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 3.0 Metabolic 
Laboratory/Other: Viral Re-activation), unless considered life threatening by the investigator 
(grade 4 (CTCAE v 3.0 Metabolic Laboratory/Other: Viral Reactivation). 
 
lenalidomide but continue both antiviral therapies at least 
4 weeks after last dose of lenalidomide. 
For patients with baseline results: 
Negative HBsAg 
AND 
[Positive HBs Ab (with no prior vaccination 
against HBV), OR positive HBc Ab] 
___________________________________ 
reactivation is defined as: 
New appearance of measurable HBV-DNA 
Treat : Start first antiviral medication AND interrupt 
lenalidomide administration until resolution (undetectable 
HBV-DNA levels).  
 
If resolution occurs within ≤ 28 days: lenalidomide should 
be re-started at 10 mg/d. If the patient is already receiving 
10 mg/d of lenalidomide, according to the protocol, the 
patient should restart at the same dose after resolution. 
Antiviral therapy should continue at least 4 weeks after 
last dose of lenalidomide. 
 
If resolution occurs > 28 days: Patients should discontinue 
lenalidomide but continue antiviral therapy at least 4 
weeks after last dose of lenalidomide. 


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6.4  Monitoring for hepatitis C virus reactivation 
 
At screening, HCV-RNA will be tested using quantitative RNA-PCR in patients with HCV Ab 
positivity and in patients with known or suspected past hepatitis C virus infection (including 
patients with past interferon ‘curative’ treatment).  
Patients with detectable HCV RNA at baseline will be excluded. Patients known to have a 
history of HCV infection, despite a negative viral load test at screening (including those that 
were treated and are considered ‘cured’) will be monitored for HCV reactivation on Day 1 of 
every cycle, at end of lenalidomide (within 1 week after stopping study drug), and at 28-day 
follow-up visit (± 7 days of scheduled visit).  
In patients with known past hepatitis C infection with undetectable HCVRNA levels at baseline, 
reactivation will be defined by the new appearance of detectable HCV-RNA; in this case, 
lenalidomide must be discontinued.  
 
6.5 
 Flow chart 
6.5.1 
Screening 
All eligible patients will receive the following assessments: 
 
Medical history 
 
Clinical and laboratory evaluation 
 
Imaging documentation of therapy response (CT, MR, other) 
 
 
6.5.2 
Initial examinations 
 
Informed consent 
 
Medical history 
 
Concomitant medications 
 
Vital signs (pulse, blood pressure, weight and height) 
 
Physical examination including ECOG Performance Status 
 
CBC 
 
Biochemistry: creatinine, uricemia, AST, ALT, GGT, ALP, total and direct bilirubin, 
LDH, beta2-microglobulin, Nat, Kal, Ca  
 
HIV, HCV, HBV testing 
 
Pregnancy test (for FCBP only) 
 
6.5.3 
Interim examinations (every week for the first 8 weeks, then every 2 weeks) 
 
Concomitant medications 
 
Vital signs (pulse, blood pressure, weight and height) 
 
Physical examination including ECOG Performance Status 
 
CBC 


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 
Biochemistry 
 
Disease status evaluation (contrasted total body CT scan every 4 months) 
 
AE reports 
 
6.5.4 
Post-study surveillance evaluation (until 1 year after lenalidomide discontinuation) 
 
Concomitant medications 
 
Vital signs (pulse, blood pressure, weight and height) 
 
Physical examination including ECOG Performance Status 
 
CBC 
 
Biochemistry 
 
Disease status evaluation 
 
AE reports 
 
6.5.5 
Follow-up (every 4 months for the 2nd to the 4th year; every 6 months for the 5th and 6th , 
yearly afterward) 
 
Physical examination including ECOG Performance Status 
 
CBC 
 
Biochemistry 
 
Disease status evaluation (contrasted total body CT scan plus every procedure positive 
at first relapse (marrow biopsy according to clinical requirements)  
7 Data quality assurance 
7.1 
Quality control 
The investigators will assure the monitoring of the clinical study to assure conformance to 
protocol as well as the completeness, correctness and plausibility of the completed case report 
forms (CRF).  
7.2 
Deviation from study protocol 
Every deviation from the trial protocol must be specified and documented separately for each 
patient. The investigator is responsible of discussing the type and extent of deviation as well as 
the possible consequences for further participation of the patient in the study.  
8 Statistical procedures 
8.1 
Sample size and power consideration 
 


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Simon's two-stage optimal design will be used. The null hypothesis that the true 1-year PFS is 30% will 
be tested against a one-sided alternative. In the first stage, 15 patients will be accrued. If there are 5 or 
fewer patients progression-free at one year in these 15 patients, the study will be stopped. Otherwise, 32 
additional patients will be accrued for a total of 47. The null hypothesis will be rejected if 19 or more 
patients progression-free at one year are observed in 47 patients. This design yields a type I error rate of 
5% and power of 80% when the true 1-year PFS is 50%. 
 
 
8.2 
Efficacy endpoints 
8.2.1 
  Overall survival 
It is defined as the time from enrolment to death for any cause. Patients alive at last follow-up 
will be censored.  
 
8.2.2 
  Progression-free survival 
It is defined as the time from enrolment to progression or relapse of lymphoma (if post-
induction disease status was PR or CR, respectively). Patients alive at last follow-up will be 
censored.  
 
8.2.3 
  Duration of response 
It is defined as the time from induction therapy response documentation and progression or 
relapse of lymphoma.  
 
8.3 
Safety endpoints 
8.3.1 
  Grade 3-4 NCI-CTC AEs 
All NCI-CTCAE grade 3-4 will be recorded.  
 
8.4 
Efficacy analysis 
Efficacy analyses will be performed on the intention-to-treat population that includes all 
subjects enrolled. Response rate during and after lenalidomide treatment will be provided. 
Analyses will be performed to characterize PFS, TTP and OS. The Kaplan-Meier procedure will 
be used to characterize the time-to-event curves in the analyses where there is censoring. 
Otherwise, summary statistics (mean, standard deviation, median, minimum and maximum) will 
be provided. Parameters known to be potentially predictive of disease aggressiveness and 


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Department of OncoHematology 
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likelihood of response to lenalidomide in relapsed or refractory DLBCLs (tumour burden, LDH 
levels, time from last rituximab, etc) as well as  prognostic subtypes (namely “germinal-center B 
cell type” – GBC - and “activated B-cell type” – ABC) or specific gene expression 
patterns/genetic signatures amenable to DLBCL subtypes - where available - will be taken into 
consideration in post-hoc multivariate efficacy analysis. 
 
8.5 
Safety analysis 
All subjects who receive at least one week of study drug medication will be included in safety 
analysis. AEs, vital signs measurements, clinical laboratory information and concomitant 
medications will be tabulated and summarized. Subject incidence rates of all AEs and events 
requiring the discontinuation of study drug will be tabulated by system class, preferred term, 
and severity using MedDRA terms and NCI-CTCAE Version 3.0 severity grades. Time to first 
dose reduction will be summarized for each regimen. Death and clinically important AEs 
(including tumour lysis and thrombosis) will also be summarized.  
All other measurements will be summarized using means, standard deviations, medians, 
minimum and maximum. Graphical display will be provided where useful in the interpretation 
of results.   
9 Data handling and record keeping 
9.1 
Definition of source documents and data 
All parameters asked for in the case report form (CRF) should be documented in the source 
documents.  
 
Parameter 
Source document 
Medical history / patient’s eligibility 
- 
patients’ charts 
Therapy 
- 
patients’ charts 
Disease status 
- 
patients’ charts  
- 
histological / radiological / laboratory 
reports 
Adverse events 
- 
patients’ charts 
- 
laboratory reports 
- 
medical reports 
- 
nurses documentation 


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Department of OncoHematology 
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20132 – Milano 
 
 
 
 
 
 
 
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Physical examination 
- 
patients’ charts 
Disease response 
- 
patients’ charts  
- 
histological / radiological / laboratory 
reports 
Survival 
- 
patients’ charts, autopsy report if 
available 
 
For the following parameter, the CRF might be used as source document: 
- 
ECOG Performance Status 
 
9.2 Patient registration 
Registration of patients will be performed by responsible investigator of every participating 
center by sending a fulfilled Registration Form at the attention of the Principal Investigator by 
fax at +39 02 2643 4760. 
 
9.3 Documentation of data in the case report form (CRF) 
All relevant data collected during the study for all of the patients enrolled in the study shall be 
entered in the CRF by the responsible investigator or someone authorised by him in a timely 
manner so that they are clear and legible. The physician shall confirm the completeness, 
correctness and plausibility of the data by his signature with the date. The entries shall be made 
with black ball-point pen. 
The properly filled in CRF will remain in the trial centre.  
 
9.4 Data management 
The data will be recorded in the CRF designed for this study. All CRF will be checked for 
completeness, plausibility and compliance with the ICH guidelines and the institutional SOPs.  
 
9.5 
Record keeping 
The investigator shall arrange for the retention of the patient identification list, the signed 
informed consent forms and the signed data protection declaration for at least 15 years after the 
completion or discontinuation of the study. Patient files and other source data shall be kept  for 
the maximum period of time permitted by the hospital. 
The sponsor will keep essential documents according to ICH-GCP.  


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Lenalidomide and DLBCL, version n. 4 errata corrige – December 01,2015 
 
10.  Study drug material and management 
10.1 
Supplier(s) 
 
Celgene Corporation will supply lenalidomide.  
10.2 
 Dosage form 
 
Lenalidomide will be supplied as 5mg, 10mg and 25mg capsules for oral administration.  
10.3 
Packaging 
 
Lenalidomide will be shipped to the pharmacy at the study site in individual bottles 
each containing 21 capsules of lenalidomide 5mg, 10mg or 25mg. 
 
Patients will be treated for 24 cycles of therapy, unless treatment is discontinued 
earlier due to disease progression or unacceptable toxicity. At each cycle, patients 
will be provided with a number of bottles containing lenalidomide 5, 10 or 25mg 
sufficient to cover 21 days of treatment.   
10.4 
Special Handling Instructions 
Women of childbearing potential should not handle or administer the clinical dosage 
forms unless they are wearing gloves. 
10.5 
Labelling 
The label for study drug supplied by Celgene will detail Sponsor's name name and address, the 
protocol number, EudraCT number, product name, dosage form, and strength, medication 
identification/kit number, dosing instructions, storage conditions, the quantity of study drug 
contained, and required caution statements and/or regulatory statements as applicable. 
Additional information may be included on the label as needed an/or applicable. 
10.6 
Receipt of study drug 
The Investigator is responsible for taking an inventory of each shipment of study drug received, 
and comparing it with the accompanying study drug accountability form.  The Investigator will 
verify the accuracy of the information on the form, sign and date it, retain a copy in the study 
file, and return a copy to Celgene or its representative. 
10.7 
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
At the study site, all investigational study drugs will be stored in a double locked, safe area to 
prevent unauthorized access. 


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Lenalidomide and DLBCL, version n. 4 errata corrige – December 01,2015 
 
 
10.8 
Unused study drug supplies 
Patients will be instructed to return empty bottles or unused capsules.  Unused or returned study 
drug will be destroyed locally in compliance with local pharmacy destruction procedures and 
drug disposition must be appropriately documented in the study file.  If any study drug is lost or 
damaged, its disposition should be documented in the source documents. 
   
10.9 
Record of administration 
Accurate records will be kept of all study drug administration (including dispensing and dosing) 
in the study record files. 
11  
Formalities / regulatory aspects 
11.1 Legal regulations and guidelines 
This study will be conducted in conformance with the regulations of the latest versions of the 
applicable laws, the “Declaration of Helsinki” and the principles of good clinical practice (ICH-
GCP).  
 
11.2 Patient insurance 
In accordance with the drug regulations, all patients participating in the study have been insured for 
injury or death.  
 
11.3 Additions / amendments to the study protocol 
Substantial additions and changes to the trial protocol require a written amendment. Changes 
affecting the health of the patient will require another vote by the ethics committee and a new 
written consent by the patients affected. Celgene is to be notified of all amendments.  
Additions and changes made after the start of the trial will be communicated to all study 
participants in writing together with the date the change becomes effective. 
12. References 
1. Marcus R, Hagenbeek A. The therapeutic use of rituximab in non- Hodgkin’s 
lymphoma. 


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Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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Lenalidomide and DLBCL, version n. 4 errata corrige – December 01,2015 
 
Eur J Haematol 2007: 78 (Suppl. 67): 5–14 
 
2. Barners Rogers  Overview on non-Hodgking’s Lymphoma, Seminars in Oncology 
Nursing, Vol 22, No 2 (May), 2006: pp 67–72 
 
3. James O. Armitage, How I treat patients with diffuse large B-cell lymphoma. Blood 
First Edition paper, March 14, 2007; DOI 10.1182/blood- 2007–01-041871 
 
4. Galustian C, Labarthe MC, Bartlett JB, et al. Thalidomide-derived immunomodulatory 
drugs as therapeutic agents. Expert Opin Biol Ther. 2004 Dec;4(12):1963-70.  
 
5 
Knight R. IMiDs: a novel class of immunomodulators. Seminars in Oncology 2005 Aug 
32;4:S24-29.  
 
6 
Tohnya TM, Ng SS, Dahut WL, et al. A phase I study of oral CC-5013 (lenalidomide,     
Revlimid), a thalidomide derivative, in patients with refractory metastatic cancer. Clin 
Prostate Cancer. 2004 Mar;2(4):241-3.  
   
7 
Reddy N. Czuczman MS et al. Immunomodulatory drugs stimulate natural killer – cell 
function, alter cytokine production by dendritic cells, and inhibit angiogenesis 
enhancing the antitumor activity of Rituximab, BJH 2007  
 
8 
J. B. Bartlett et al. Lenalidomide and pomalidomide strongly enhance tumor cell killing  
in vitro during antibody-dependent cellular cytotoxicity (ADCC) mediated by 
trastuzumab, cetuximab and Rituximab Abstract #3023 Atlanta ASH 2007 
 
9 
Verhelle D., Chan KWH et al. Lenalidomide and CC-4047 inhibit proliferation of 
malignant B cells while expanding normal CD34+progenitor cells – Cancer Res 2007; 
67:( 2).Jan 15 2007 
 
10 Ling-Hua Zhang et al.  Lenalidomide displays direct anti-Non-Hodgkin’s Lymphoma 
(NHL) cell activity in association with enhanced SPARC expression but independent of 
its ability to strongly inhibit NHL cell VEGF production in vitro, Abstract # 3473 
Atlanta ASH 2007 
  
11 Donna M. Weber, Robert D. Knight, M.D., for the Multiple Myeloma (009) Study 
Investigators N Engl J Med 2007;357:2133-42. 
 
12 M. Dimopoulos, M.D., Jerome B. Zeldis, M.D., Ph.D., and Robert D. Knight, M.D., 
for the Multiple Myeloma (010) Study Investigators, N Engl J Med 2007;357:2123-32. 
 


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Department of OncoHematology 
Via Olgettina, 60 
 
20132 – Milano 
 
 
 
 
 
 
 
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13 List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. 
N Engl J Med. 2005 Feb 10;352(6):549-57.  
 
14 Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in 
patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II 
study. J Clin Oncol. 2006 Dec 1;24(34):5343-9.  
 
15 Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared 
with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J 
Med. 2002 Jan 24;346(4):235-42.  
 
16 Philip T, Chauvin F, Armitage J, et al. Parma international protocol: pilot study of 
DHAP followed by involved-field radiotherapy and BEAC with autologous bone 
marrow transplantation. Blood. 1991 Apr 1; 77(7):1587-92.  
 
17 van Besien K, Rodriguez A, Tomany S, et al. Phase II study of a high-dose ifosfamide-
based chemotherapy regimen with growth factor rescue in recurrent aggressive NHL. 
High response rates and limited toxicity, but limited impact on long-term survival. Bone 
Marrow Transplant. 2001 Feb;27(4):397-404.  
 
18 Czuczman M, Reeder CB, Polikoff J, et al. Initial results from an International Study in 
relapsed/refractory aggressive non-Hodgkin’s lymphoma to confirm the activity, safety, 
and criteria for predicting response to lenalidomide montherapy. Blood 2007 Dec; #762-
II (Abstract).  
 
 
19 T. E. Witzig et al. Initial results from an International Study in relapsed/Refractory 
Aggressive Non- Hodgkin s Lymphoma to Confirm the Activity, Safety and Criteria for 
Predicting Response to Lenalidomide Monotherapy - Abstract # 2572 ASH Atlanta 
2007 
 
20 P H. Wiernik et al Lenalidomide Response in Relapsed/Refractory Aggressive Non-
Hodgkin s Lymphoma is Related to Tumor Burden and Time from Rituximab 
Treatment. Abstract # 2565 ASH Atlanta 2007