Long-term Follow-up and/or Continued Thalidomide (THALOMID®) Maintenance Therapy for Patients Enrolled on Clinical Trial 20030165
Phase: PHASE2
Conditions: Mantle Cell Lymphoma, Non-Hodgkin's Lymphoma
Sponsor: University of Miami

eProst # 20150402 
Long-term Follow-Up and/or Continued Thalidomide (THALOMID®) 
Maintenance Therapy for Patients Enrolled on Clinical Trial 20030165 
PRINCIPAL INVESTIGATOR: 
Izidore Lossos, MD* 
Professor  
Hematology/Oncology 
SUB-INVESTIGATOR(S): 
(N/A) 
VERSION #: 
1 
VERSION  DATE: 
15/APR/2015 
Confidentiality Statement: The information contained in this document, especially unpublished data, is 
confidential property.  The information in this document may not be disclosed to others unless federal or 
state law or regulations require such disclosure.  Subject to the foregoing, this information may be 
disclosed only to those persons involved in the study who have a need to know, with the obligation not to 
further disseminate this information.        
CLINICALTRIALS.GOV IDENTIFIER:  NCT02507336

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INVESTIGATOR AGREEMENT 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practices, and the applicable federal, state, and local 
laws, rules, and regulations relating to the conduct of the protocol.   
I have read and understand the information in the Investigators’ Brochure (and/or other such 
pertinent safety information) regarding the risks and potential benefits.   
I agree to inform all those who assist/collaborate with me in the conduct of this study of their 
responsibilities and obligations.  
Once the protocol has been reviewed and approved by the Institutional Review Board (IRB) I 
understand that any change(s) made during the course of the study must also (first) be approved 
by the IRB prior to implementation, except when such modification is made to remove any 
immediate hazard(s) to the subject(s).   
I certify that I and the study staff responsible, have received the requisite training to conduct this 
research protocol.   
I agree to maintain adequate and accurate records in accordance with the University of Miami 
policies, federal, state and local laws and regulations.   
I agree to maintain the confidentiality of all information received and/or developed in connection 
with this protocol. 
eProst Number: 
Protocol Version Number: 
Protocol Version Date: 
Signature of Investigator: 
Date: 
Name of Investigator (printed): 
Institution: 

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PROTOCOL REVISION HISTORY 
Version # 
Summary of Changes 
Version Date 

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TABLE OF CONTENTS 
CONTACT INFORMATION ......................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
PROTOCOL REVISION HISTORY ............................................................................................. 4 
TABLE OF CONTENTS ................................................................................................................ 5 
ABBREVIATIONS & DEFINITIONS .......................................................................................... 8 
PROTOCOL SYNOPSIS................................................................................................................ 9 
PROTOCOL SCHEMA ................................................................................................................ 11 
BACKGROUND ............................................................................................................... 12 
Study Disease ................................................................................................................. 12 
Study Agent .................................................................................................................... 12 
Rationale ......................................................................................................................... 13 
OBJECTIVES .................................................................................................................... 14 
Primary Objectives ......................................................................................................... 14 
Secondary Objectives ..................................................................................................... 14 
ENDPOINTS ..................................................................................................................... 14 
Primary endpoint ............................................................................................................ 14 
Secondary endpoints ...................................................................................................... 14 
SUBJECT SCREENING & RECRUITMENT .................................................................. 15 
PATIENT SELECTION .................................................................................................... 15 
Inclusion Criteria ............................................................................................................ 15 
Exclusion Criteria ........................................................................................................... 15 
Enrollment Procedures ....................................................................................................... 16 
Cancellation Guidelines ................................................................................................. 16 
Emergency Registration ................................................................................................. 16 
STUDY DESIGN............................................................................................................... 16 
TREATMENT PLAN ........................................................................................................ 17 
Thalidomide (THALOMID®) for Group A ................................................................... 17 
Treatment Dispensation, Compliance and Accountability of thalidomide 
(THALOMID®) for Group A ................................................................................................... 17 
Supportive Care Guidelines ........................................................................................... 17 
Drug Interactions and Precautions ................................................................................. 17 

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Duration of Treatment .................................................................................................... 17 
Duration of Follow-Up ................................................................................................... 18 
AGENTS (DRUG FORMULATION AND PROCUREMENT) ...................................... 18 
Thalidomide (THALOMID®) ....................................................................................... 18 
TREATMENT/ DOSE MODIFICATIONS ...................................................................... 31 
Unacceptable Toxicity .................................................................................................... 31 
Dose Modification Guidelines for Thalidomide (THALOMID®) ................................ 31 
STUDY/TREATMENT DISCONTINUATION ............................................................... 31 
SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS ............................... 31 
Pre-Treatment Evaluations (Screening) ......................................................................... 31 
Evaluations on Treatment for Group A .......................................................................... 31 
Evaluations on Study for Group B ................................................................................. 32 
Off-Treatment Evaluations (End of Treatment or EOT) for Group A ........................... 32 
Follow-up Evaluations for All Patients .......................................................................... 33 
Calendar of Clinical and Laboratory Evaluations .......................................................... 33 
MEASUREMENT OF EFFECT........................................................................................ 33 
Definitions ...................................................................................................................... 33 
Response Criteria ........................................................................................................... 34 
(Duration of Overall Response) ..................................................................................... 35 
(Duration of Stable Disease) .......................................................................................... 35 
Progression-Free Survival (PFS) .................................................................................... 35 
Overall Survival (OS)..................................................................................................... 35 
ADVERSE EVENTS ......................................................................................................... 36 
Purpose ........................................................................................................................... 36 
Adverse Event ................................................................................................................ 36 
Serious Adverse Events (see also Appendix A) ............................................................. 37 
Adverse Event Collection Period ................................................................................... 38 
Targeted Adverse Event Collection ............................................................................... 38 
Adverse Event Reporting Requirements ........................................................................ 38 
Expedited Adverse Event Reporting Requirements ....................................................... 39 
STATISTICAL CONSIDERATIONS............................................................................... 39 
DATA REPORTING ......................................................................................................... 40 

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Data and Safety Monitoring ........................................................................................... 40 
INVESTIGATOR RESPONSIBILITIES .......................................................................... 40 
Investigator Responsibility/Performance ....................................................................... 40 
Confidentiality ................................................................................................................ 40 
Informed Consent and Permission to Use Protected Health Information ...................... 40 
Source Documentation and Investigator Files ............................................................... 41 
Recording and Processing of Data ................................................................................. 41 
Non-Protocol Research .................................................................................................. 42 
Ethics .............................................................................................................................. 42 
Essential documents for the conduct of a clinical trial ................................................... 43 
REFERENCES .................................................................................................................. 44 
APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS ..... 46 
APPENDIX B: DATA SUBMISSION SCHEDULE ................................................................... 47 
APPENDIX C: PERFORMANCE STATUS SCALES ............................................................... 48 
APPENDIX D: NYHA CLASSIFICATION OF HEART DISEASE .......................................... 49 
APPENDIX E: INFORMATION ON THALOMID REMS™ .................................................... 50 
No table of figures entries found. 

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ABBREVIATIONS & DEFINITIONS 
Term 
Abbreviation Definition 
Overall Survival 
OS 
The length of time from either the date of 
diagnosis or the start of treatment for a disease, 
that patients diagnosed with the disease are still 
alive.   
Progression-Free Survival 
PFS 
The length of time during and after the 
treatment of a disease that a patient lives with 
the disease but it does not get worse.   
Time to Progression 
TTP 
The length of time from the date of diagnosis or 
the start of treatment for a disease until the 
disease starts to get worse or spread to other 
parts of the body.   
Reference: National Cancer Institute (NCI) Dictionary of Cancer Terms 
http://www.cancer.gov/dictionary   

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PROTOCOL SYNOPSIS 
Protocol Title 
Long-term Follow-Up and/or Continued Thalidomide 
(THALOMID®) Maintenance Therapy for Patients Enrolled 
on Clinical Trial 20030165 
Targeted Patient Population 
Patients enrolled on Clinical Trial 20030165. 
Study Design 
The study is designed to provide long-term follow-up and/or 
to offer continued maintenance thalidomide (THALOMID®) 
therapy to those patients enrolled in 20030165.  
Group A: Patients who achieved CR in 20030165 and 
continue to receive maintenance Thalidomide. 
Group B: Patients who achieved CR in 20030165, but are not 
receiving maintenance Thalidomide. 
Group C: All other patients enrolled in 20030165 who 
expired or experienced disease progression. 
Treatment Schema 
Thalidomide (THALOMID®) will be administered as per 
standard of care guidelines to Group A; in compliance with 
REMS™ program requirements. 
Study Duration 
Patients in Group A, B and C will be followed until 
withdrawal of consent, or death. 
Note: All other patients in Group C who expired on 
20030165 will also be included in all analyses.  
Follow-up Required 
All patients will be followed annually by telephone or in-
person visit(s), until death or withdrawal.  
Objectives 
Primary Objective: To provide long-term follow-up and/or 
offer continued maintenance thalidomide (THALOMID®) to 
patients enrolled in 20030165 .  
Secondary Objective: To continue to evaluate objectives 
specified for 20030165 (please refer to 20030165 for details). 
Expected Number of Patients 
Group A: 2  
Group B: 12 
Group C: 8 
Expected Number of Centers 
1-Sylvester Comprehensive Cancer Center (SCCC)
Note: SCCC is inclusive of the constituent satellite sites.

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Expected Duration of the 
Protocol 
At least 5 years. 
Inclusion Criteria 
1. Enrolled on the 20030165 clinical trial.
2. Ability to understand and willingness to sign a written
informed consent document.
Exclusion Criteria 
1. Patients who were discontinued from 20030165 for any
reason prior to the completion of protocol-specified
treatment (e.g. withdrawal of consent).
2. Uncontrolled, intercurrent serious illness including but
not limited to ongoing or active infection, symptomatic
congestive heart failure, unstable angina pectoris, and/or
cardiac arrhythmia.
3. Psychiatric illness/condition likely in the judgment of the
Principal Investigator (PI) to limit compliance with
clinical study requirements.

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PROTOCOL SCHEMA  
Eligible: Enrolled in SCCC clinical trial 
20030165 and completed or continuing 
protocol-specified therapy  
Group B 
Patients in complete 
remission (CR), but not 
receiving maintenance 
therapy  
Group A 
Patients in complete 
remission (CR) and 
continuing on maintenance 
thalidomide 
Patients to continue to 
receive long-term 
thalidomide maintenance 
therapy (until disease 
progression or intolerable) 
Patients to be followed for 
progression-free survival 
(PFS) and overall survival 
(OS) 
Patients to be followed for 
progression-free survival 
(PFS) and overall survival 
(OS) 
Informed Consent process 
Group C 
All other patients (death or 
disease progression on 
20030165)  
Patients who remain alive 
are to be followed for 
overall survival (OS) 

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BACKGROUND 
Study Disease 
Mantle cell lymphoma (MCL), a subtype of non-Hodgkin’s lymphoma (NHL) that 
represents a distinct disease entity.  The term MCL was proposed in 1992 to unify 
previously defined subtypes of NHL, such as diffuse poorly differentiated lymphocytic 
lymphoma, intermediate differentiated lymphocytic lymphoma, centrocytic lymphoma, 
and diffuse small cleaved cell lymphoma, into a single disease entity (1).  According to 
the International Lymphoma Study Group (ILSG), MCL represents 6% of all NHLs (2).  
MCL is derived from a subset of naive pre-germinal center cells, and may present with 
two cytological variants: typical (lymphocytic) or blastic (3-4).  In addition, there are 
three possible patterns of involvement:  mantle-zone, nodular or diffuse (4).  It has been 
suggested that the treatment response and survival of the diffuse and nodular patterns 
are worse than those involving the mantle cell zone.  Majlis et al reported 3-year 
survival rates for mantle-zone, nodular, and diffuse type of 100%, 50%, and 55% 
respectively (5).  The monoclonal B-cells express CD19, CD20, CD22, HLA-DR, CD5, 
surface IgM and, in most cases, surface IgD.  They are negative for CD23 and CD10 
(CALLA) antigens (6). 
The characteristic cytogenetic abnormality in MCL is the t(11;14) (q13;q32) 
translocation.  Band 11q23 includes the BCL-1 locus, which is the site of the PRAD1 
(CCND1) gene encoding for cyclin D1.  This rearrangement results in translocation of 
the BCL-1 locus to the immunoglobulin heavy chain gene enhancer region located at 
14q32, causing cyclin D1 over-expression.  Cyclin D1 interacts with cyclin dependent 
kinases 4 and 6 to facilitate the progression of cell through G1 into S phase of 
proliferation (7). 
MCL is one of the worst types of NHL since it incorporates some of the undesirable 
features of both low-grade and high-grade lymphomas, namely incurability and rapid 
course respectively (7).  Most of the patients present with advanced stage, high 
international prognostic index (IPI), and extranodal involvement.  The incidence of 
Stage III and IV varies between 75 to 90% of the patients (2, 4, 6-8).  In addition, there 
is a high incidence of extranodal involvement, the most common sites being bone 
marrow (61-79%), spleen (31-60%), liver (13-30%), peripheral blood (12-30%), and 
gastrointestinal tract (18-20%) (6-9).  Central nervous system (CNS) involvement 
occurs in about 4% of the patients and is associated with poor prognosis (10). 
The long-term survival for patients with MCL is generally poor, with only about 27% 
of the patients surviving 5 years after diagnosis and 11% of the patients being disease-
free after 5 years.  In addition, the ILSG found no 5-year survivors with IPI index 4/5, 
placing MCL among the lymphomas with worse overall prognosis (2).  Despite 
response rates of 50% to 70% to different regimens, all patients eventually develop 
disease progression after chemotherapy, with the mean survival around 3 years (11). 
Study Agent 

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Patients in Group A will receive daily oral thalidomide (THALOMID®) as per standard 
of care and THALOMID® REMS™ guidelines (formerly known as S.T.E.P.S.).   
Rationale 
Several studies using combination chemotherapy with or without anthracyclines (CHOP 
or COP) showed responses between 56% and 90%, with CR rates ranging from 9% to 
58%.  However, relapse-free survival was relatively short with average of 15 to 20 
months.  Median survival in most studies ranged from 28 to 52 months (12).  Therapy 
with fludarabine alone or in combination with other chemotherapeutic agents has been 
tested in small trials.  In a recent study, Cohen et al obtained response rates of 66% (30% 
CR) in a study involving 30 patients treated with fludarabine and cyclophosphamide. 
The overall survival for patients receiving this combination as first line therapy has not 
been reached at 43 months, although failure- free survival was 28 months (13).  In another 
study involving 29 patients, Zinzani et al achieved a 63% overall response (28% CR) 
using fludarabine alone or in combination with idarubicin (14).  Rituximab has also been 
tested in MCL.  Igarashi et al treated 21 patients with refractory or relapsed MCL, 
achieving a 31% response rate (no CR observed) (15).  Howard et al obtained a 96% 
response rate (48%n CR) in 25 patients with MCL, using a combination of CHOP and 
rituximab.  25 patients were evaluated for molecular remission, which was seen in 9 of 
them.  However, the achievement of CR or molecular remission did not translate into a 
prolonged progression-free survival, which was 16.6 months (16).  Khouri et al, treated 
patients 
with 
Hyper-CVAD, 
an 
aggressive 
regimen 
alternating 
cycles of 
cyclophosphamide, doxorubicin, vincristine, and dexamethasone and high-dose 
methotrexate and cytarabine.  This regimen induced a 93% response rate with 82% CR.  
This therapy was followed by stem cell transplantation and 93% of previously untreated 
patients were alive at 3 years post-transplant, 73% of them disease-free (19).  
Although encouraging results have been reported for stem cell transplant (SCT), its role 
in the treatment of patients with MCL remains unknown.  Overall 3-year survival for 
MCL patients previously treated ranges between 24% to 59%, with one study, performed 
by Milpied et al, reporting 80% overall survival at 4 years (20- 22).  Event-free survival 
(EFS) or progression-free survival (PFS) at three years however, ranges between 17% to 
48% (19, 22).  Stewart et al, reported a 23% overall survival for SCT in MCL patients in 
first remission.  EFS/PFS however, was only 8% (23).  There have been few small studies 
on the use of allogeneic SCT in MCL.  The reported overall survival is 55% to 62% at 2 
years (24-25).  
Due to unsatisfactory results obtained with both conventional chemotherapy and SCT, it 
has become clear that new high-dose intense chemotherapeutic regimens are needed to 
improve the survival rates for patients with MCL.  Similar intensity protocols have been 
used for treatment of Burkitt’s lymphoma.  Magrath treated patients with Burkitt’s 
lymphoma using the CODOX-M protocol, which consisted of cyclophosphamide, 
doxorubicin, prednisone, vincristine, high-dose methotrexate and intrathecal 
methotrexate, alternating with IVAC (ifosfamide, etoposide, high-dose cytarabine and 
intrathecal methotrexate).  This regimen resulted in excellent disease control and was 

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relatively well tolerated in both children and adults (17).  Mead et al used this same 
regimen in 52 patients with Burkitt’s lymphoma.  All patients developed grade ¾ 
neutropenia and 64% of the patients developed grade ¾ thrombocytopenia.  The only 
other significant side effect was mucositis, observed in about 40% of the cases (18).  We 
have therefore developed a similar intense protocol combining most of the agents that 
demonstrated activity in MCL in an attempt to provide a better disease control with 
improved response rates and overall survival.Since a recent study has demonstrated a 
beneficial effect of thalidomide in patients with mantle cell lymphoma, patients were 
offered the option to receive maintenance thalidomide after the completion of the 
induction therapy as a consolidation to the aggressive chemotherapy (25a). 
OBJECTIVES 
Primary Objectives 
To provide long-term follow-up and/or offer continued maintenance thalidomide 
(THALOMID®) to patients enrolled in 20030165.  
Secondary Objectives 
To continue to evaluate objectives specified for 20030165 (please refer to 20030165 for 
details).  
ENDPOINTS 
Primary endpoint 
Progression-free survival (PFS): Patients will be evaluated at least annually and at the 
discretion of the treating Investigator.  PFS is defined as the time from 20030165 
enrollment until documented disease progression or death (by any cause, in the absence 
of progression).  In progression-free patients, PFS will be censored at the last evaluable 
tumor assessment (clinical, hematologic, and/or radiographic). 
Criteria for Evaluation 
•
Evaluable for PFS:  Any eligible subject enrolled into the SCCC 20030165
study, who received protocol-specified therapy.
Secondary endpoints 
Progression-free survival (PFS): Patients will be evaluated at least annually and at the 
discretion of the treating Investigator.  PFS is defined as the time from 20030165 
enrollment until documented disease progression or death (by any cause, in the absence 
of progression).  In progression-free patients, PFS will be censored at the last evaluable 
tumor assessment (clinical, hematologic, and radiographic). 

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Overall survival (OS): Patients will be evaluated at least annually.  OS is defined as the 
elapsed time from 20030165 enrollment to death or date of censoring.  Patients alive or 
lost to follow-up will be censored at the last date of contact (or last date known to be 
alive).  
Response rate (RR): Patients will be evaluated at least annually or more frequently as 
clinically indicated and at the Investigator’s discretion.  Response rate is defined as the 
percentage of patients whose cancer shrinks or disappears after treatment. 
Toxicity: Monitoring of AEs including serious adverse events (SAEs).  AEs will be 
assessed in terms of nature, grade and attribution to treatment, using the National Cancer 
institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0.  
Patients on maintenance thalidomide (THALOMID®) will be evaluated for adverse 
events (AEs) continually while on study.   
 Criteria for Evaluation 
• Evaluable for PFS:  Any eligible subject enrolled into the SCCC 20030165 
study, who received protocol-specified therapy.  
• Evaluable for OS:  Any eligible subject enrolled into the SCCC 20030165 
study, who received protocol-specified therapy. 
• Evaluable for RR: Eligible patients enrolled into the SCCC 20030165 study, 
who receive protocol-specified therapy. 
• Evaluable for Toxicity: Eligible patients in Group A, enrolled into the SCCC 
20030165 study, who experience AEs while receiving thalidomide 
(THALOMID®). 
 
 SUBJECT SCREENING & RECRUITMENT  
Patients enrolled on the 20030165 clinical trial are eligible for this trial and will be offered 
enrollment to this study.   
 
 PATIENT SELECTION 
 Inclusion Criteria  
 Enrolled on the 20030165 clinical trial. 
 Ability to understand and willingness to sign a written informed consent 
document. 
 Exclusion Criteria 
 Patients who were discontinued from 20030165 for any reason prior to the 
completion of protocol-specified treatment (e.g. withdrawal of consent). 

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 Uncontrolled, intercurrent serious illness including but not limited to ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, 
and/or cardiac arrhythmia likely in the judgment of the PI to interfere with 
clinical study requirements.  
 Psychiatric illness/condition likely in the judgment of the PI to limit compliance 
with clinical study requirements.  
 
 Enrollment Procedures 
To enter a patient, the Investigator or Study Team will contact the Clinical Research 
Services’ (CRS) Representative.  All eligibility requirements must be reviewed prior to the 
patient entering the study.  The following information must be provided to the CRS 
Representative: 
1) Completed and signed protocol-specific eligibility checklist; 
2) All pages of the original signed informed consent form (ICF) including HIPAA Form 
B; 
3) Relevant source documents such as: subject medical history and physical exam, 
admission or discharge notes, diagnostic reports, pathologic confirmation of 
diagnosis, and relevant subject-specific written communication. 
 Cancellation Guidelines 
If a patient does not wish to receive protocol therapy (i.e. for those in Group A) or to be 
followed, the patient may withdraw.  Contact the CRS Representative, or e-mail the 
information including the reasons for withdrawal.  
 Emergency Registration 
If an emergency registration takes place after business hours, the items listed above 
must be submitted by the next business day.  
 
 STUDY DESIGN 
The study is designed to provide long-term follow-up, as well as to offer continued 
thalidomide (THALOMID®) maintenance therapy to patients enrolled in 20030165.  
There are 14 eligible patients in Groups A and B expected to rollover from 20030165.  An 
additional Group C consisting of all other patients who expired or experienced disease 
progression on 20030165, will also be included in all analyses. 
 
 

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 TREATMENT PLAN 
 Thalidomide (THALOMID®) for Group A 
Thalidomide (THALOMID®) will be administered as per standard of care guidelines, 
in compliance with THALOMID® REMS™ program requirements. 
For additional information on thalidomide (THALOMID®) including mechanism of 
action, drug metabolism, pharmacokinetics & toxicology, known side effects, 
composition, and storage recommendations, see [Section 9.1]. 
 Treatment Dispensation, Compliance and Accountability of thalidomide 
(THALOMID®) for Group A 
Thalidomide will be administered in the outpatient setting as per standard of care 
guidelines, in compliance with THALOMID® REMS™ program requirements.   
 Supportive Care Guidelines  
Appropriate supportive care as per institutional guidelines should be given, as 
necessary.  
 Drug Interactions and Precautions  
The use of opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS 
depressants concomitantly with THALOMID® may cause an additive sedative effect 
and should be avoided. 
Drugs which cause bradycardia or peripheral neuropathy may cause additive effects and 
should be used with caution. 
Hormonal contraceptives increase the risk of thromboembolism. 
Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, 
rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. 
John's Wort with hormonal contraceptive agents may reduce the effectiveness of the 
contraception up to one month after discontinuation of these concomitant therapies. 
 Concurrent Medications 
Concurrent medications will not be captured as part of this trial. 
 Duration of Treatment 
Group A: Patients will continue with thalidomide (THALOMID®) as per standard of 
care guidelines, until progression of disease, discontinuation due to toxicity, death or 
study withdrawal.  Patients who discontinue thalidomide for any reason other than 
death, or withdrawal of consent will continue to be followed as per Section 8.6.  
See Section 12.0 for evaluations. 

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 Duration of Follow-Up   
Patients will be followed annually until death or withdrawal from the study.  See 
Section 12.0 for evaluations.  
 
 AGENTS (DRUG FORMULATION AND PROCUREMENT) 
 Thalidomide (THALOMID®) 
[Refer to the FDA-approved package insert for more information (26).]   
 THALOMID®, thalidomide 
 Mechanism of Action 
The mechanism of action of THALOMID is not fully understood. THALOMID 
possesses immunomodulatory, antiinflammatory and antiangiogenic properties. 
Available data from in vitro studies and clinical trials suggest that the 
immunologic effects of this compound can vary substantially under different 
conditions, but may be related to suppression of excessive tumor necrosis factor-
alpha (TNF-α) production and down-modulation of selected cell surface 
adhesion molecules involved in leukocyte migration. For example, 
administration of thalidomide has been reported to decrease circulating levels of 
TNF-α in patients with erythema nodosum leprosum (ENL); however, it has also 
been shown to increase plasma TNF-α levels in HIV-seropositive patients. Other 
anti-inflammatory and immunomodulatory properties of thalidomide may 
include suppression of macrophage involvement in prostaglandin synthesis, and 
modulation of interleukin-10 and interleukin-12 production by peripheral blood 
mononuclear cells. Thalidomide treatment of multiple myeloma patients is 
accompanied by an increase in the number of circulating natural killer cells, and 
an increase in plasma levels of interleukin-2 and interferon-gamma (T cell-
derived cytokines associated with cytotoxic activity). Thalidomide was found to 
inhibit angiogenesis in a human umbilical artery explant model in vitro. The 
cellular processes of angiogenesis inhibited by thalidomide may include the 
proliferation of endothelial cells. 
 Drug Metabolism, Pharmacokinetics and Toxicology 
In a C-radiolabel ADME study in humans, unchanged drug is the predominant 
circulating component. Thalidomide is not a substrate of the cytochrome P450 
system. At therapeutic concentrations, thalidomide is not an inhibitor or inducer 
of human cytochrome P450 enzymes in vitro. Pharmacokinetic drug-drug 
interactions with substrates, inhibitors or inducers of CYP450 are not 
anticipated. 

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Nonclinical Toxicology: Two-year carcinogenicity studies were conducted in 
male and female rats and mice. No compound-related tumorigenic effects were 
observed at the highest dose levels of 3,000 mg/kg/day to male and female mice 
(38-fold greater than the highest recommended daily human dose of 400 mg 
based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold 
the maximum human dose based upon BSA), and 300 mg/kg/day to male rats 
(7.5-fold the maximum human dose based upon BSA).  
Thalidomide was neither mutagenic nor genotoxic in the following assays: the 
Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese 
hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse 
micronucleus test.  
Fertility studies were conducted in male and female rabbits; no compound-
related effects in mating and fertility indices were observed at any oral 
thalidomide dose level including the highest of 100 mg/kg/day to female rabbits 
and 500 mg/kg/day to male rabbits (approximately 5- and 25-18 fold the 
maximum human dose, respectively, based upon BSA). Testicular pathological 
and histopathological effects (classified as slight) were seen in male rabbits at 
dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose 
based upon BSA). 
 
 Management of Agent-Specific Adverse Events 
Most patients taking thalidomide can be expected to experience adverse 
reactions. 
Teratogenicity: 
The most serious toxicity associated with thalidomide is its documented human 
teratogenicity. The risk of severe birth defects, primarily phocomelia or death to 
the fetus, is extremely high during the critical period of pregnancy. The critical 
period is estimated, depending on the source of information, to range from 35 to 
50 days after the last menstrual period. The risk of other potentially severe birth 
defects outside this critical period is unknown, but may be significant. Based on 
present knowledge, thalidomide must not be used at any time during pregnancy. 
Because thalidomide is present in the semen of patients receiving the drug, males 
receiving thalidomide must always use a latex or synthetic condom during any 
sexual contact with females of reproductive potential, even if he has undergone a 
successful vasectomy. 
Venous and Arterial Thromboembolism: 
An increased risk of venous thromboembolism (such as deep vein thrombosis 
and pulmonary embolism), ischemic heart disease (including myocardial 

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infarction), and stroke have been reported in patients with multiple myeloma 
treated with thalidomide [see Venous and Arterial Thromboembolism]. 
Peripheral Neuropathy: 
Peripheral neuropathy is a very common, potentially severe, adverse reaction of 
treatment with thalidomide that may result in irreversible damage. Peripheral 
neuropathy generally occurs following chronic use over a period of months. 
However, reports following relatively short-term use also exist. Incidence of 
neuropathy events leading to discontinuation, dose reduction or interruption 
increases with cumulative dose and duration of therapy. Symptoms may occur 
sometime after thalidomide treatment has been stopped and may resolve slowly 
or not at all.  
Somnolence, dizziness, and rash are the most commonly observed adverse 
reactions associated with the use of thalidomide. Adverse event profiles from 
clinical trials are summarized in the sections that follow. 
Adverse Reactions in Multiple Myeloma Controlled Clinical Trials 
The safety analyses were conducted in two controlled clinical studies (Study 1 
and Study 2). The safety analysis in Study 1 was conducted on 204 patients who 
received treatment. Table 1 lists the most common adverse drug reactions (≥ 
10%). The most frequently reported adverse reactions were fatigue, 
hypocalcemia, edema, constipation, sensory neuropathy, dyspnea, muscle 
weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, 
nausea, anxiety/agitation , tremor, fever, weight loss, thrombosis/embolism, 
neuropathy-motor, weight gain, dizziness, and dry skin.  
Twenty-three percent of patients (47/204) discontinued due to adverse reactions; 
30% (31/102) from the THALOMID/dexamethasone arm and 16% (16/102) 
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The safety analysis in Study 2 was conducted on 466 patients who received 
treatment. Table 2 lists the most common adverse drug reactions (≥ 10%) that 
were observed. Table 3 lists the most common Grade 3/4 adverse drug reactions 
(occurring at > 2%) that were observed. The adverse reactions most often 
reported by patients treated with THALOMID/dexamethasone were constipation, 
peripheral edema, tremor, asthenia, dizziness and fatigue. Adverse reactions with 
a frequency at least 2-fold higher in the THALOMID/dexamethasone group than 
in the placebo/dexamethasone group include constipation, tremor, deep vein 
thrombosis and peripheral sensory neuropathy. Twenty-six percent of patients 
(121/466) discontinued due to adverse events; 37% (86/234) from the 
THALOMID/dexamethasone arm and 15% (35/232) from the 
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Less Common Adverse Drug Reactions in Multiple Myeloma Controlled 
Clinical Trials 
In Study 2, THALOMID in combination with dexamethasone in patients with 
multiple myeloma, the following adverse drug reactions not described above 
were reported*: 
Gastrointestinal disorders: Vomiting NOS, dry mouth, peritonitis, diverticular 
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Nervous system disorders: Somnolence, hypoesthesia, polyneuropathy NOS, 
transient ischemic attack 
Respiratory, thoracic, and mediastinal disorders: Bronchitis NOS 
Psychiatric disorders: Mood alteration NOS 
Vascular disorders: Hypotension NOS, orthostatic hypotension 
Cardiac disorders: Bradycardia NOS 
Eye disorders: Blurred vision 
* All adverse reactions with ≥3% of patients in THALOMID/dexamethasone 
arm and with a ≥1% difference in proportion of patients between the 
THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm. 
All grade 3/4 and serious adverse reactions reported >2 patients in 
THALOMID/dexamethasone arm and with a percentage higher in the 
THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm 
have been considered for possible inclusion. In any cases medical judgment has 
been applied for consideration of causality assessment. 
Adverse Reactions in Erythema Nodosum Leprosum (ENL) Clinical Trials 
Table 4 lists treatment-emergent signs and symptoms that occurred in 
THALOMID-treated patients in clinical trials in ENL. The most common 
adverse reactions (≥10%) reported in patients with ENL were somnolence, rash, 
headache. Doses ranged from 50 to 300 mg/day. All adverse reactions were mild 
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Other Adverse Events Observed in ENL Patients 
THALOMID in doses up to 400 mg/day has been administered investigationally 
in the United States over a 19-year period in 1465 patients with ENL. The 
published literature describes the treatment of an additional 1678 patients. To 
provide a meaningful estimate of the proportion of the individuals having 
adverse events, similar types of events were grouped into a smaller number of 
standardized categories using a modified COSTART dictionary/terminology. 
These categories are used in the listing below. All reported events are included 
except those already listed in the previous table. Due to the fact that these data 
were collected from uncontrolled studies, the incidence rate cannot be 
determined. No causal relationship between THALOMID and these events can 
be conclusively determined at this time. These are reports of all adverse events 
noted by investigators in patients to whom they had administered thalidomide. 
Body as a Whole: Abdomen enlarged, fever, photosensitivity, upper extremity 
pain. 
Cardiovascular System: Bradycardia, hypertension, hypotension, peripheral 
vascular disorder, tachycardia, vasodilation. 
Digestive System: Anorexia, appetite increase/weight gain, dry mouth, 
dyspepsia, enlarged liver, eructation, flatulence, increased liver function tests, 
intestinal obstruction, vomiting. 
Hemic and Lymphatic: ESR decrease, eosinophilia, granulocytopenia, 
hypochromic anemia, leukemia, leukocytosis, leukopenia, MCV elevated, RBC 
abnormal, spleen palpable, thrombocytopenia. 
Metabolic and Endocrine: ADH inappropriate, amyloidosis, bilirubinemia, BUN 
increased, creatinine increased, cyanosis, diabetes, edema, electrolyte 
abnormalities, hyperglycemia, hyperkalemia, hyperuricemia, hypocalcemia, 
hypoproteinemia, LDH increased, phosphorus decreased, SGPT increased.  
Muscular Skeletal: Arthritis, bone tenderness, hypertonia, joint disorder, leg 
cramps, myalgia, myasthenia, periosteal disorder. 
Nervous System: Abnormal thinking, agitation, amnesia, anxiety, causalgia, 
circumoral paresthesia, confusion, depression, euphoria, hyperesthesia, 
insomnia, nervousness, neuralgia, neuritis, neuropathy, paresthesia, peripheral 
neuritis, psychosis. 
Respiratory System: Cough, emphysema, epistaxis, pulmonary embolus, rales, 
upper respiratory infection, voice alteration. 

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Skin and Appendages: Acne, alopecia, dry skin, eczematous rash, exfoliative 
dermatitis, ichthyosis, perifollicular thickening, skin necrosis, seborrhea, 
sweating, urticaria, vesiculobullous rash. 
Special Senses: Amblyopia, deafness, dry eye, eye pain, tinnitus. 
Urogenital: Decreased creatinine clearance, hematuria, orchitis, proteinuria, 
pyuria, urinary frequency. 
 
Other Adverse Events Observed in HIV-seropositive Patients 
In addition to controlled clinical trials, THALOMID has been used in 
uncontrolled studies in 145 patients. Less frequent adverse events that have been 
reported in these HIV-seropositive patients treated with THALOMID were 
grouped into a smaller number of standardized categories using modified 
COSTART dictionary/terminology and these categories are used in the listing 
below. Adverse events that have already been included in the tables and narrative 
above, or that are too general to be informative are not listed. 
Body as a Whole: Ascites, AIDS, allergic reaction, cellulitis, chest pain, chills 
and fever, cyst, decreased CD4 count, facial edema, flu syndrome, hernia, 
thyroid hormone level altered, moniliasis, photosensitivity reaction, sarcoma, 
sepsis, viral infection. 
Cardiovascular System: Angina pectoris, arrhythmia, atrial fibrillation, 
bradycardia, cerebral ischemia, cerebrovascular accident, congestive heart 
failure, deep thrombophlebitis, heart arrest, heart failure, hypertension, 
hypotension, murmur, myocardial infarct, palpitation, pericarditis, peripheral 
vascular disorder, postural hypotension, syncope, tachycardia, thrombophlebitis, 
thrombosis.  
Digestive System: Cholangitis, cholestatic jaundice, colitis, dyspepsia, 
dysphagia, esophagitis, gastroenteritis, gastrointestinal disorder, gastrointestinal 
hemorrhage, gum disorder, hepatitis, pancreatitis, parotid gland enlargement, 
periodontitis, stomatitis, tongue discoloration, tooth disorder. 
Hemic and Lymphatic: Aplastic anemia, macrocytic anemia, megaloblastic 
anemia, microcytic anemia. 
Metabolic and Endocrine: Avitaminosis, bilirubinemia, dehydration, 
hypercholesteremia, hypoglycemia, increased alkaline phosphatase, increased 
lipase, increased serum creatinine, peripheral edema. 
Muscular Skeletal: Myalgia, myasthenia. 

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Nervous System: Abnormal gait, ataxia, decreased libido, decreased reflexes, 
dementia, dysesthesia, dyskinesia, emotional lability, hostility, hypalgesia, 
hyperkinesia, incoordination, meningitis, neurologic disorder, tremor, vertigo. 
Respiratory System: Apnea, bronchitis, lung disorder, lung edema, pneumonia 
(including Pneumocystis carinii pneumonia), rhinitis. 
Skin and Appendages: Angioedema, benign skin neoplasm, eczema, herpes 
simplex, incomplete Stevens-Johnson syndrome, nail disorder, pruritus, 
psoriasis, skin discoloration, skin disorder. 
Special Senses: Conjunctivitis, eye disorder, lacrimation disorder, retinitis, taste 
perversion. 
Postmarketing Experience 
The following adverse reactions have been identified during post approval use of 
THALOMID. Because these reactions are reported voluntarily from a population 
of uncertain size, it is not always possible to reliably estimate their frequency or 
establish a causal relationship to drug exposure. 
Cardiovascular System: Cardiac arrhythmias including atrial fibrillation, 
bradycardia, tachycardia, sick sinus syndrome, EKG abnormalities, myocardial 
infarction. 
Digestive System: Intestinal perforation, gastrointestinal perforations, intestinal 
obstruction. 
Metabolic and Endocrine: Electrolyte imbalance including hypercalcemia or 
hypocalcemia, hyperkalemia and hypokalemia, hyponatremia, hypothyroidism, 
increased alkaline phosphatase, tumor lysis syndrome. 
Nervous System: Changes in mental status or mood including depression and 
suicide attempts, disturbances in consciousness including lethargy, syncope, loss 
of consciousness or stupor, seizures including grand mal convulsions and status 
epilepticus, Parkinson’s disease, stroke. 
Skin and Appendages: Erythema multiforme, toxic epidermal necrolysis. 
Hemic and Lymphatic: Decreased white blood cell counts including neutropenia 
and febrile neutropenia, changes in prothrombin time, pancytopenia. 
Respiratory System: Pleural effusion. 
Reproductive System and Breast Disorders: amenorrhea, sexual dysfunction. 
Immune System Disorders: Hypersensitivity, angioedema/urticaria. 

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Ear and Labyrinthine Disorders: Hearing impairment/deafness. 
Renal and Urinary Disorders: Renal failure. 
Other Adverse Events in the Published Literature or Reported from Other 
Sources 
The following additional events have been identified either in the published 
literature or from spontaneous reports from other sources: acute renal failure, 
amenorrhea, aphthous stomatitis, bile duct obstruction, carpal tunnel, chronic 
myelogenous leukemia, diplopia, dysesthesia, dyspnea, enuresis, erythema 
nodosum, erythroleukemia, foot drop, galactorrhea, gynecomastia, hangover 
effect, hypomagnesemia, hypothyroidism, lymphedema, lymphopenia, 
metrorrhagia, migraine, myxedema, nodular sclerosing Hodgkin’s disease, 
nystagmus, oliguria, pancytopenia, petechiae, purpura, Raynaud’s syndrome, 
stomach ulcer, suicide attempt, interstitial lung disease and severe infections 
(e.g., fatal sepsis including septic shock). 
Composition and Dosage Forms 
Dosage forms and composition 
Strength Color 
Imprint 
Non-medicinal ingredients 
50 mg 
White 
opaque 
Do Not Get 
Pregnant  
woman logo  
CELGENE 50 mg 
pregelatinized starch and 
magnesium stearate; capsule shell 
contains gelatin, titanium dioxide 
and black ink* 
100 mg 
Tan 
opaque 
Do Not Get 
Pregnant  
woman logo  
CELGENE 100 mg 
pregelatinized starch and 
magnesium stearate; capsule shell 
contains gelatin, black iron oxide, 
yellow iron oxide, titanium 
dioxide, and black ink* 
200 mg 
Blue 
opaque 
Do Not Get 
Pregnant  
woman logo  
CELGENE 200 mg 
pregelatinized starch and 
magnesium stearate; capsule shell 
contains gelatin, FD&C blue #2, 
titanium dioxide, and white ink 
* The 50 mg and 100 mg capsule shells have black ink which contains shellac
and black iron oxide.
Drug Substance: 
Proper name: thalidomide 
Chemical name: α-(N-phthalimido) glutarimide 
Molecular formula and molecular mass: C13H10N2O4, 258.2 g 

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Structural formula: 
 
 
 
Physicochemical properties: Thalidomide is an off-white to white, odorless, 
crystalline powder that is soluble at 25̊C in dimethyl sulfoxide and sparingly 
soluble in water and ethanol. The glutarimide moiety contains a single 
asymmetric center and, therefore, may exist in either of two optically active 
forms designated S-(-) or R-(+). Thalidomide used in THALOMID® contains an 
equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical 
rotation of zero. 
 Storage Recommendations  
Store at 15-30º C. Keep out of the reach of children.  
 Dispensation and Accountability 
THALOMID® is only available through a controlled distribution program called 
THALOMID® REMS™.  Under this program, only enrolled prescribers and 
program-certified pharmacists are able to prescribe and dispense the product.  In 
addition, THALOMID® can only be dispensed to patients who are registered 
and meet all the conditions of the REMS™ program.   
For more information, call the manufacturer (Celgene Customer Care Center) 
toll-free number at 1-888-423-5436 or log on to the 
www.CelgeneRiskManagement.com website. 
 SPECIAL HANDLING INSTRUCTIONS 
Currently, no published data are available regarding the cutaneous absorption of 
thalidomide. 
Most health care institutions recommend that latex gloves be worn while 
handling chemotherapeutic agents. Health care providers may consider wearing 
gloves when directly handling THALOMID® (thalidomide capsules), along with 
standard hand washing. Females who could become pregnant, or who plan to 
become pregnant can handle THALOMID® capsules if they are using latex 
gloves.  
Repackaging of THALOMID® must only be done on exceptional circumstances. 
This should only be done by pharmacists. 
 

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 TREATMENT/ DOSE MODIFICATIONS 
 Unacceptable Toxicity 
Development of grade 3-4 peripheral neuropathy that is considered to be related 
(possibly, probably or definitely) and unacceptable (because of severity and/or 
irreversibility) will require THALIDOMIDE discontinuation.   
 Dose Modification Guidelines for Thalidomide (THALOMID®) 
Thalidomide (THALOMID®) will be administered as per standard of care guidelines 
and in compliance with REMS™ program requirements. 
 
 STUDY/TREATMENT DISCONTINUATION 
Study participation/Treatment may be discontinued for any of the following reasons: 
• The patient withdraws consent from the study 
• (Group A): The patient experiences an adverse event that in the opinion of the 
Investigator makes continued study treatment an unacceptable risk 
• (Group A): The patient experiences unacceptable toxicity as described in Section 10.1 
• The patient is significantly noncompliant with the requirements of the protocol 
Should discontinuation of study therapy occur (for Group A patients), all efforts should be 
made to execute/ report End-of-Treatment and/or Follow-up Evaluations as completely as 
possible and to determine/ document the reason for discontinuation (unless the patient 
withdraws consent).  
If a patient wishes to withdraw consent from the study, the PI must be notified.  The 
information regarding withdrawal (i.e. subject identifiers and date of withdrawal) should be 
documented in the subject’s record and updated within any other research database(s).  
 
 SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS 
 Pre-Treatment Evaluations (Screening) 
Prior to performing any study-specific procedures or evaluations, written informed 
consent and authorization for the use of protected health information (HIPAA) must be 
obtained in accordance with all applicable policies, regulations and laws.   
 Evaluations on Treatment for Group A 
The following evaluations should be performed as described.  Additional tests are at the 
discretion of the Investigator. 
 Monthly (every 4 weeks, ±5 days)  

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•
Additional for Women of Childbearing Potential (WoCBP) receiving
thalidomide maintenance therapy (Group A): Serum pregnancy test:
(beta-HCG)
•
Adverse Events (AEs): Monitoring and collection of Adverse Events (AEs)
should occur throughout the study for patients in Group A.
 Annually (every 12 months, ±30 days) 
•
Physical exam (PE)
•
Complete Blood Count (CBC), including
o
Differential (diff) and
o
Platelet count (PLT)
•
Comprehensive Metabolic Panel (CMP)
•
Lactate dehydrogenase (LDH)
 Evaluations on Study for Group B 
The following evaluations should be performed as described.  Additional tests are at the 
discretion of the Investigator. 
 Annually (every 12 months, ±30 days) 
•
Physical exam (PE)
•
Complete Blood Count (CBC)
o
Differential (diff) and
o
Platelet count (PLT)
•
Comprehensive Metabolic Panel (CMP)
•
Lactate dehydrogenase (LDH)
 Evaluations on Study for Group C 
The following evaluation(s) should be performed as described until death or withdrawal 
of consent as described.  Additional tests are at the discretion of the Investigator. 
 Annually (every 12 months, ±30 days) 
•
Survival: contact by telephone or in-person visit; Methods used for attempted
contact must also be documented properly.
 Off-Treatment Evaluations (End of Treatment or EOT) for Group A 
The following assessments should be performed at the EOT visit and should occur 30-
days (± 5 days) after the last dose of thalidomide.  
•
Physical exam (PE)
•
Complete Blood Count (CBC), including
o
Differential (diff) and
o
Platelet count (PLT)

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• Comprehensive Metabolic Panel (CMP) 
• Lactate dehydrogenase (LDH) 
•  (Additional for WoCBP) Serum pregnancy test: (beta-HCG) 
 Follow-up Evaluations for All Patients 
The following evaluation should be performed at least annually, until death or 
withdrawal of consent as described for:   
• Survival: contact by telephone or in-person visit; Methods used for attempted 
contact must also be documented properly.  
(For Group A, contact should occur after end of treatment visit; for Group B, contact 
should occur prior to or after disease progression; survival contact for patients in Group 
C should continue until death or withdrawal of consent.) 
 Calendar of Clinical and Laboratory Evaluations 
 
Baseline 
Every 4 
weeks  
(±5 days) 
Every 12 
months  
(±30 days) 
Off-Treatment A 
Follow-up B  
(Group A) 
thalidomide 
(THALOMID®) 
 
Once daily A 
 
 
Informed consent 
X 
 
 
 
 
Eligibility 
X 
 
 
 
 
Physical exam 
 
 
X 
X 
  
CBC w/diff, plts 
 
 
X 
X 
 
CMP 
 
 
X 
X 
 
Lactate 
dehydrogenase 
(LDH) 
 
 
X 
X 
 
Beta-HCG  
(WoCBP) 
 
X A 
X A 
X 
 
Adverse event 
evaluation 
 
X A 
 
Survival 
 
 
 
 
X B 
Footnote(s): 
A To be done only for patients in Group A  
B Contact by telephone or in-person visit until death or withdrawal of consent 
 
 MEASUREMENT OF EFFECT 
For the purposes of this study, patients should be evaluated for response every as per 
standard or care until documented disease progression or study withdrawal (for reasons 
including toxicity and/or death). 
 Definitions 

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Response 
Category 
Physical 
Exam 
Lymph Nodes 
Lymph Node 
Masses 
Bone Marrow 
CR 
Normal  
Normal  
Normal  
Normal  
CR (u) 
Normal  
Normal  
Normal or >75% 
decrease 
Normal 
indeterminate 
PR 
Normal  
Normal or ≥50% 
decrease 
Normal or ≥50% 
decrease 
Positive or 
irrelevant 
Relapse/ 
Progressive 
Disease 
Enlarging 
liver, spleen 
or other sites 
New or increased 
New or increased Reappearance 
Key: CR=Complete Response; CR(u)=Complete Response/unconfirmed; PR=Partial Response 
 Response Criteria 
 CR requires the following: 
1. Complete disappearance of all detectable clinical and radiographic evidence of 
disease and disappearance of all disease-related symptoms if present before 
therapy, and normalization of those biochemical abnormalities (e.g. LDH) 
definitely assignable to NHL. 
2. All lymph nodes and nodal masses must have regressed to normal size.  
Previously involved nodes that were between 1.1 to 1.5 cm in their greatest 
transverse diameter before treatment, must have decreased to ≤ 1 cm in their 
greatest transverse diameter after treatment, or by more than 75% in the sum of 
the products of the greatest diameters (SPD). 
3. The spleen, if considered to be enlarged before therapy on the basis of a CT 
scan, must have regressed in size and must not be palpable on physical exam.  
However, no normal size can be specified because of the difficulties in 
accurately evaluating splenic and hepatic sizes.   
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must be cleared on repeat bone marrow aspirate and biopsy on the same site. 
 CR/unconfirmed (CR (u)) requires the following: 
1. Residual lymph node mass greater than 1.5 cm in greatest transverse diameter 
that has regressed by more than 75% in the SPD.  Individual nodes that were 
previously confluent must have regressed by more than 75% in their SPD 
compared with the size of the original mass.  
2. Indeterminate bone marrow (increased number or size of aggregates without 
cytologic or architectural atypia).   
 PR requires the following: 
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2. No increase in the size of other nodes, liver, or spleen.
3. Splenic or hepatic nodules must regress by at least 50% in the SPD.
4. With the exception of splenic and hepatic nodules, involvement of other
organs is considered assessable and not measurable disease.
5. Bone marrow assessment is irrelevant for the determination of a PR because it
is assessable and not measurable disease.
6. No new sites of disease.
 Stable disease (SD) is defined as less than a PR but not progressive disease.
 Relapsed disease (PD requires the following:
1. Appearance of any new lesion or increase by ≥ 50% in the size of previously
involved sites.
2. ≥ 50% increase in greatest diameter of any previously identified node greater
than 1 cm in its short axis or in the SPD of more than one node.
 Progressive disease (PR or nonresponders) require the following: 
1. ≥50% increase from nadir in the SPD of any previously identified abnormal
node for PRs or nonresponders.
2. Appearance of any new lesion during the end of therapy.
 (Duration of Overall Response) 
(The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.) 
 (Duration of Stable Disease) 
(Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started.) 
 Progression-Free Survival (PFS) 
Patients will be followed at a minimum of annual intervals (every 12 months, ±30 days) 
or as clinically indicated and at the discretion of the Investigator to document the 
progression-free interval. 
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Patients will be followed at annual intervals to document the overall survival. 
 
 ADVERSE EVENTS 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for   Adverse Events (CTCAE) version 3.0 will be utilized for adverse event 
reporting. 
 Purpose 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies, as well as those 
who will enroll in future studies using similar agents.  Adverse events are reported in a 
routine manner at scheduled times during a trial.  Additionally, certain adverse events 
must be reported in an expedited manner for timelier monitoring of patient safety and 
care.  
 Adverse Event 
Adverse Event (AE): Can be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, 
medical treatment, or procedure without judgment about causality.  An adverse event 
can arise from any use and from any route of administration, formulation, or dose 
including an overdose. This includes any newly occurring event or a previous 
condition that has increased in severity or frequency since initiation of a drug, medical 
treatment, or procedure.  
Abnormal Findings 
In any clinical assessment, a value outside the normal or reference range (such as a 
clinical laboratory, vital sign, or ECG) will not be reported or assessed as an AE unless 
that value is considered to be of clinical significance by the investigator.  A value of 
clinical significance is one that leads to discontinuation or delay in protocol treatment, 
dose modification, therapeutic intervention*, or is considered to be a clinically 
significant new finding or change from baseline by the investigator.  
*Transfusion support administered to offset clinical symptoms of anemia or 
thrombocytopenia will not be considered therapeutic intervention. 
Signs and Symptoms 
Signs/symptoms resulting from an underlying clinical diagnosis should be documented 
as one comprehensive AE.  If no underlying clinical diagnosis can be identified, each 
sign/symptom should be reported as a separate independent event.  (A new or 
worsening event resulting from an underlying clinical diagnosis or a reaction to 
concurrent medications should be documented as a separate independent AE unless it 
is within the normal range of fluctuation for that patient.)   

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Grade Changes/Fluctuations 
AEs will be reported at the maximum grade/severity experienced for the duration of 
the event.  Should one particular event warrant further investigation, additional details 
may be collected at the discretion of the Principal Investigator.   
Progression of Disease 
Progression of disease, if documented in accordance to standard of care, should not be 
reported as an AE. 
Tests and Procedures 
Tests and procedures should not be reported as AEs.  The underlying clinical diagnosis 
(or sign/symptom in the event an underlying clinical diagnosis is not known) requiring 
testing or a procedure, should be reported as an adverse event if it meets criteria for 
reporting. 
 Serious Adverse Events (see also Appendix A) 
Serious AE (SAE) means any untoward medical occurrence that occurs at any dose: 
1. Results in death.  
2. Is life-threatening.  
The term "life-threatening" in the definition of "serious" refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe). 
3. Requires inpatient hospitalization or prolongation of present hospitalization.  
Elective hospitalization to simplify protocol treatment/evaluations or to treat a 
baseline condition that did not worsen from baseline will not be considered an SAE.    
4. Results in persistent or significant disability/incapacity.  
Disability is defined as a substantial disruption of a person’s ability to conduct 
normal life functions. 
5. Is a congenital anomaly/birth defect.  
6. Is a medically important event. 
A medically important event may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above, or involves 
suspected transmission via a medicinal product of an infectious agent.   Examples 
of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse; 
any organism, virus, or infectious particle (e.g., prion protein transmitting 
Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.  

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Clarification should be made between the terms serious and severe because they ARE 
NOT synonymous.  The term severe is often used to describe the intensity (severity) of 
a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, 
however, may be of relatively minor medical significance (such as a severe headache).  
This is NOT the same as serious, which is based on patient/event outcome or action 
criteria described above and is usually associated with events that pose a threat to a 
patient’s life or functioning.  A severe AE does not necessarily need to be considered 
serious.  For example, persistent nausea of several hours duration may be considered 
severe nausea but not an SAE.  On the other hand, a stroke resulting in only a minor 
degree of disability may be considered mild but would be defined as an SAE based on 
the above noted criteria.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations.   
 Adverse Event Collection Period 
In this protocol, adverse events include only treatment-emergent adverse events.  A 
treatment-emergent adverse event (TEAE) is defined as any event that begins or 
worsens after the start of protocol treatment.  All baseline-emergent adverse events, any 
event that begins or worsens after completion of the informed consent but prior to the 
start of protocol treatment, should be reported as a Baseline/Comorbid Condition.  
 
All adverse events that occur within ≤ 30 days of the last dose of study therapy will be 
reported and followed until resolution.  Resolution is defined as a return to baseline 
status or the stabilization of an event with the expectation that it will remain chronic.  
(Exception: If a patient begins an alternative therapy that confounds accurate 
assessment of AEs within ≤ 30 days of the last dose of study therapy, all adverse event 
collection will stop and any ongoing events will be left open.) 
 Targeted Adverse Event Collection 
The targeted collection of the following safety data is specified for this protocol: 
• 
Serious adverse events (unexpected or expected); see also Appendix A 
• 
Potentially serious adverse events, such as suicidality (suicidal ideation or 
thoughts) or suspected pregnancy in Group A patients  
• 
Adverse events that cause discontinuation of treatment/intervention (e.g. Section 
10.1) 
• 
Unexpected adverse events with reasonable causality (possible, probable or 
definite) to the treatment/intervention 
 Adverse Event Reporting Requirements 
The information to be reported in AEs will be assessed by and assigned severity using 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 3.0.   The NCI CTCAE provides descriptive terminology and a 
grading scale for each adverse event listed.  A copy of the NCI CTCAE v3.0 can be 

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downloaded from the CTEP home page 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).    
Information to be reported in the description of each adverse event may be included, 
but is not limited to: 
1. Clinical Diagnosis of the event as determined by NCI CTCAE, Version 3.0 
descriptive terminology.  If no clinical diagnosis can be identified, each 
sign/symptom should be reported as a separate independent event. 
2. Date of onset of the AE (start date). 
3. Date of resolution of the AE (end date).  
4. Severity of the event determined by NCI CTCAE, Version 3.0 grading scale.     
5. Relationship of the AE to study therapy.  Categorized as follows: 
Definite 
The adverse event is clearly related to the investigational agent(s) 
Probable 
The adverse event is likely related to the investigational agent(s) 
Possible 
The adverse event may be related to the investigational agent(s) 
Unlikely 
The adverse event is doubtfully related to the investigational agent(s) 
Unrelated 
The adverse event is clearly not related to the investigational agent(s) 
6. Whether or not the AE is Serious or Not Serious as defined in Section 14.3 Serious 
Adverse Events. 
7. Whether the AE is Suspected and/or Unexpected. 
Suspected 
Any AE for which there is a reasonable possibility that the drug caused 
the AE. For the purposes of expedited safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE. 
Unexpected 
Any AE for which the nature or severity of the event is not consistent 
with the applicable product information, e.g., the Investigator’s 
Brochure or Package Insert. 
8. Action taken as a result of the AE.  
9. Outcome. 
 Expedited Adverse Event Reporting Requirements 
All applicable AEs, regardless if serious or not, will be described in the source 
documents, reported on the applicable AE log, and entered into Velos.  However, 
certain adverse events must also be reported in an expedited manner for more timely 
monitoring of patient safety and care.  Appendix A provides information about these 
expedited reporting requirements. 
 
 STATISTICAL CONSIDERATIONS 

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At this time, no formal statistical analysis is planned for this long-term follow-up study.  If 
necessary, and as deemed by the Principal Investigator (PI), the results of this trial will be 
integrated with the 20030165 trial analyses.   
 
 DATA REPORTING 
Data must be submitted according to the protocol requirements for all patients registered.  
Patients for whom documentation is inadequate to determine eligibility will generally be 
deemed ineligible.  
 Data and Safety Monitoring  
The Sylvester Comprehensive Cancer Center (SCCC) Data and Safety Monitoring 
Committee (DSMC) will monitor this clinical trial according to the Cancer Center’s 
DSM Plan.  In its oversight capacity, the DSMC bears responsibility for suspending or 
terminating this study.  DSMC oversight of the conduct of this trial includes ongoing 
review of accrual and adverse event (AE) data, and periodic review of the study 
therapy.  The guidelines appearing in section 7.0 are offered for DSMC consideration 
in assessing AEs or other study endpoint(s).  In addition, the DSMC will review reports 
from all audits, site visits, or study reviews pertaining to this clinical trial and take 
appropriate action.  The SCCC DSM Plan to which this study is subject can also be 
found at www.sylvester.org.  
 
  
 INVESTIGATOR RESPONSIBILITIES 
 Investigator Responsibility/Performance 
The investigator will ensure that this study is conducted in accordance with all 
regulations governing the protection of human subjects. The investigator will ensure 
that all work and services described in or associated with this protocol will be 
conducted in accordance with the investigational plan, applicable regulations, and the 
highest standards of medical and clinical research practice. 
 Confidentiality 
The investigator must ensure that each subject’s anonymity will be maintained and each 
subject’s identity will be protected from unauthorized parties.  A number will be 
assigned to each subject upon study entry and the number and the subject’s initials will 
be used to identify the subject for the duration of the study.  The investigator will 
maintain all documents related to this study in strict confidence. 
 Informed Consent and Permission to Use Protected Health Information  

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It is the responsibility of the investigator to obtain written informed consent from each 
subject participating in this study after adequate explanation, in lay language, of the 
methods, objectives, anticipated benefits, and potential hazards of the study.  The 
investigator must also explain that the subject is completely free to refuse to enter the 
study or to discontinue participation at any time (for any reason) and receive alternative 
conventional therapy as indicated.  Prior to study participation, each subject will sign an 
IRB approved informed consent form and receive a copy of same (and information 
leaflet, if appropriate).  For subjects not qualified or able to give legal consent, consent 
must be obtained from a parent, legal guardian, or custodian. The investigator or 
designee must explain to the subject before enrollment into the study that for 
evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with the study sponsor, regulatory agencies, and the IRB.  It is 
the investigator’s (or designee’s) responsibility to obtain permission to use protected 
health information per HIPAA from each subject, or if appropriate, the subjects’ parent 
or legal guardian. 
 Source Documentation and Investigator Files 
The investigator must maintain adequate and accurate records to fully document the 
conduct of the study and to ensure that study data can be subsequently verified.  These 
documents should be classified into two separate categories:  (1) investigator study file 
and (2) subject clinical source documents that corroborate data collected on CRFs 
within Velos.  Subject clinical source documents may include hospital/clinic patient 
records; physician's and nurse's notes; appointment book; original laboratory, ECG, 
EEG, radiology, pathology, and special assessment reports; pharmacy dispensing 
records; subject diaries; signed informed consent forms; and consultant letters.  When 
the CRF or any form is used as the source document, this must be clearly stated in the 
investigator study file. Minimally, the following be documented in source documents: 
• Medical history/physical condition and diagnosis of the subject before involvement 
in the study sufficient to verify protocol entry criteria 
• Study number, assigned subject number, and verification that written informed 
consent was obtained (each recorded in dated and signed notes on the day of entry 
into the study) 
• Progress notes for each subject visit 
• Documentation of treatment 
• Laboratory test results 
• Adverse events (action taken and resolution) 
• Condition and response of subject upon completion of or early termination from 
the study 
 Recording and Processing of Data 
If using hard copies of CRF’s, study center personnel will complete individual CRF’s 
in black ink.  All corrections to entered data will be made by drawing a single line 

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through the information to be corrected without obscuring it.  All corrections will be 
initialed, dated and explained, if necessary.  The use of “white-out” or obscuring 
correction tape will be prohibited.  A CRF is required for every patient who received 
any amount of study treatment.  The investigator will ensure that the CRF’s are 
accurate, complete, legible and timely. Separate source records are required to support 
all CRF entries except those for which use of the CRF as source document is clearly 
allowed per note in the investigator study file. 
Data must be submitted according to the protocol requirements for ALL patients 
registered.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible.  
Data will be recorded in CRFs within Velos.  Monthly drug dispensing and annual 
reviews will be documented on electronic CRFs.     
CRFs will be captured within Velos.   
Basic forms should include: 
• On-Study information, including patient eligibility data; 
• Tumor/disease assessment forms or other forms for response assessment. 
• Specialty forms for pathology, radiation or surgery when required; 
• Off-Study summary sheet, including a final assessment by the treating 
physician; 
• Follow-up forms when required 
Data must be submitted according to the protocol requirements for ALL patients 
registered.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible.  
A list of forms to be submitted, as well as expectation dates may be found in Appendix 
B. 
 Non-Protocol Research 
No investigative procedures other than those described in this protocol will be 
undertaken on the enrolled subjects without the agreement of the IRB. 
 Ethics 
The investigator agrees to conduct the study in compliance with the protocol, current 
good clinical practices, and all applicable (local, FDA) regulatory guidelines and 
standard of ethics. 
UM Ethics Programs’ Research Ethics Consultation Service (RECS) is a free resource 
for UM Researchers.  See the website for further information: 
http://www.miami.edu/index.php/ethics/projects/recs/  

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 Essential documents for the conduct of a clinical trial 
Essential documents are those documents with individually and collectively permit 
evaluation of the conduct of a trial and the quality of the data produced. The following 
documents should be on file: 1) 1572 (for studies involving IND drugs or devices); 2) 
CV’s and license of all Investigators; 3) IRB documentation/correspondance and 4) 
Documentation of IRB certification 
 
 

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1. Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma. A proposal for unification 
of morphologic, immunologic, and molecular data. Am J Surg Pathol 1992 Jul;16(7):637-
640. 
2. The Non-Hodgkin’s lymphoma Classification Project. A clinical evaluation of the 
International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The 
Non-Hodgkin's Lymphoma Classification Project. Blood. 1997; 89:3909-18. 
3. Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. Semin Hematol 1999;36:115-
127. 
4. Weisenburger DD, Vose JM, Greiner TC, et al. Mantle cell lymphoma. A 
clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group. Am J 
Hematol 2000;64:190-196. 
5. Majlis A, Pugh WC, Rodriguez MA, Benedict WF. Mantle cell lymphoma: correlation of 
clinical outcome and biologic features with three histologic variants. J Clin Oncol 
1997;15:1664-1671. 
6. Weisenburger DD, Armitage JO. Mantle cell lymphoma-- an entity comes of age. Blood 
1996;87:4483-4494. 
7. Leonard JP, Schattner EJ, Coleman M. Biology and management of mantle cell 
lymphoma. Curr Opin Oncol 2001; 13 :342-327.  
8. Oinonen R, Franssila K, Teerenhovi L, et al. Mantle cell lymphoma: clinical features, 
treatment and prognosis of 94 patients. Eur J Cancer 1998;34: 329-36. 
9. Samaha H, Dumontet C, Ketterer N, et al. Mantle cell lymphoma: a retrospective study of 
121 cases. Leukemia 1998;12:1281-7. 
10. Oinonen R, Franssila K, Elonen E. Central nervous system involvement in patients with 
mantle cell lymphoma. Ann Hematol 1999;78: 145-149.  
11. Densmore JJ, Williams ME. Mantle cell lymphoma. Curr Treat Options Oncol 2000;1: 
281-285.  
12. Meusers P, Hense J. Management of mantle cell lymphoma. Ann Hematol 1999; 78:485-
494. 
13. Cohen BJ, Moskowitz C, Straus D, et al. Cyclophosphamide/fludarabine (CF) is active 
in the treatment of mantle cell lymphoma. Leuk Lymphoma 2001;42:1015-1022. 
14. Zinzani PL, Magagnoli M, Moretti L, et al. Fludarabine-based chemotherapy in 
untreated mantle cell lymphomas: an encouraging experience in 29 patients. 
Haematologica 1999;84:1002-1006.  
15. Igarashi T, Kobayashi Y, Ogura M et al. Factors affecting toxicity, response and 
progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle 

C O N FI D E N TI A L  
 
Versi o n #: 1 
e Pr ost # 2 0 1 5 0 4 0 2  
 
Versi o n Date: 1 5 /A P R / 2 0 1 5  
Pa ge 4 5  of 5 0  
 
cell l y m p h o ma treate d wit h rit u xi ma b: a Ja pa nese p hase II st u d y. A n n O nc ol 
2 0 0 2; 1 3: 9 2 8- 9 4 3. 
1 6. H o war d O M, Gri b be n J G, Ne u ber g D S, et al. Rit u xi ma b a n d C H O P i n d ucti o n t hera p y 
f or ne wl y dia g n ose d ma ntle-cell l y m p h o ma: m olec ular c o m plete res p o nses are n ot 
pre dicti ve of pr o gressi o n-free s ur vi val. J Cli n O nc ol 2 0 0 2; 2 0: 1 2 8 8- 1 2 9 4. 
1 7. Ma grat h I, A d de M, S ha d A, et al. A d ults a n d c hil dre n wit h s mall n o n- clea ve d-cell 
l y m p h o ma ha ve a si milar e xcelle nt o utc o me w he n treate d wit h t he sa me c he m ot hera p y 
re gi me nJ Cli n O nc ol 1 9 9 6; 1 4: 9 2 5- 9 3 4. 
1 8. Mea d G M, S y des M R, Wale ws ki J, et al. A n i nter nati o nal e val uati o n of C O D O X- M a n d 
C O D O X -M alter nati n g wit h I V A C i n a d ult B ur kitt's l y m p h o ma: res ults of U nite d 
Ki n g d o m L y m p h o ma Gr o u p L Y 0 6 st u d y. A n n O nc ol 2 0 0 2; 1 3: 1 2 6 4- 1 2 7 4.  
1 9. K h o uri I F, R o ma g uera J, Ka ntarjia n H, et al. H y per- C V A D a n d hi g h- d ose 
met h otre xate/c ytara bi ne f oll o we d b y ste m -cell tra ns pla ntati o n: a n acti ve re gi me n f or 
a g gressi ve ma ntle -cell l y m p h o ma. J Cli n O nc ol 1 9 9 8; 1 6: 3 8 0 3- 3 8 0 9. 
2 0. S weete n ha m J W. Ste m cell tra ns pla ntati o n f or ma ntle cell l y m p h o ma: s h o ul d it e ver be 
use d o utsi de cli nical trials? B o ne Marr o w Tra ns pla nt 2 0 0 1; 2 8: 8 1 3- 2 0. 
2 1. Ketterer N, Salles G, Es pi n o use D et al. I nte nsi ve t hera p y wit h peri p heral ste m cell 
tra ns pla ntati o n i n 1 6 patie nts wit h ma ntle cell l y m p h o ma. A n n O nc ol 1 9 9 7; 8: 7 0 1- 7 0 4. 
2 2. Mil pie d N, Gaillar d F, M orea u P et al. Hi g h -d ose t hera p y wit h ste m cell tra ns pla ntati o n 
f or ma ntle cell l y m p h o ma: res ults a n d pr o g n ostic fact ors, a si n gle ce nter e x perie nce. 
B o ne Marr o w Tra ns pla nt 1 9 9 8; 2 2: 6 4 5 6 5 0. 
2 3. Ste wart D A, V ose J M, Weise n ber ger D D et al. T he r ole of hi g h -d ose t hera p y a n d 
a ut ol o g o us he mat o p oietic ste m cell tra ns pla ntati o n f or ma ntle cell l y m p h o ma. A n n O nc ol 
1 9 9 5; 6: 2 6 3- 2 6 6. 
2 4. K h o uri I F, Lee M- S, R o ma g uera J et al. All o ge neic he mat o p oietic tra ns pla ntati o n f or 
ma ntle cell l y m p h o ma: m olec ular re missi o ns a n d e vi de nce of graft -vers us - mali g na nc y. 
A n n O nc ol 1 9 9 9; 1 0: 1 2 9 3- 1 2 9 9. 
2 5. Va n de n ber g he E, R uiz de El vira C, Isaacs o n P et al. D oes tra ns pla ntati o n i m pr o ve 
o utc o me i n ma ntle cell l y m p h o ma ( M C L)? A st u d y fr o m t he E B M T. Bl o o d 2 0 0 0; 9 6: 
4 8 2a ( A bstr). 
2 5a. Drac h J, Kaf ma n n H, P ues p oe k A et al. Mar ke d A nti- T u m or Acti vit y of Rit u xi ma b 
Pl us T hali d o mi de i n Patie nts wit h Rela pse d/ Resista nt Ma ntle Cell L y m p h o ma.  Bl o o d 
1 1; 1 6 2a. 
2 6. T H A L O MI D ® (t hali d o mi de) ca ps ule [ Cel ge ne C or p orati o n]. D aily Me d . Cel ge ne 
C or p orati o n. N o ve m ber 2 0 1 3. Retrie ve d 2 0 Fe br uar y 2 0 1 5.  
 
 

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APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS 
For all AEs that meet criteria for expedited reporting, the Principal Investigator (PI) is obligated 
to pursue and provide follow-up reporting information until the event has resolved or until an 
acceptable medical endpoint has been reached (i.e. for the duration specified in the protocol), or 
the patient is lost to follow-up. 
 
The PI and all applicable research study team members should become familiar with the safety 
profile of the investigational agent(s) and/or intervention at the start of the study and for the 
duration of the research, e.g. by reviewing the Investigator’s Brochure (IB) and any Safety 
Reports released, (i.e. by the Sponsor) as applicable.   
 
 
A. FDA Expedited Reporting 
a. Adverse drug experiences that are suspected to be associated and any suspected 
pregnancy occurring during thalidomide (THALOMID) treatment.  
b. For more information regarding reporting to the FDA, please refer to the FDA 
website for REPORTING GUIDELINES:  
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
B. IRB Expedited Reporting 
a. All Investigators should also be aware of local Institutional requirements for AE 
reporting.  For more information regarding the IRB policy, please refer to the UM 
HSRO’s Investigator Manual: http://hsro.med.miami.edu/documents/HRP-103 -
INVESTIGATOR MANUAL 4.11.2014.docx and the UM HSRO SOP on New 
Information (HRP-024) 
https://eprost.med.miami.edu/eProst/Doc/0/HLJ5OTJVQEH419E0I6QPT3B199/HRP
-024%20-%20SOP%20-%20New%20Information.docx 
b. All AEs that are serious, unexpected and related or possibly related to the research 
and that indicate there are new or increased risks to subjects, shall be promptly 
reported to the IRB within ten (10) business days of the PI becoming aware of the 
event.   
C. Sponsor Expedited Reporting 
a. Please follow reporting methods outlined by the Celgene REMS program, as 
applicable.   
 

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APPENDIX B: DATA SUBMISSION SCHEDULE 
 
CASE REPORT FORM(S) 
TIMEPOINT TO BE COMPLETED 
ICF, including HIPAA signed/dated 
Prior to registration 
Eligibility Checklist  
SCCC Protocol Enrollment Form 
On-study Form 
Within 30 days of registration 
Treatment Form (Group A) 
Due every cycle  
Off Treatment Form (Group A) 
Within 14 days of discontinuation/completion of 
protocol therapy 
Follow-up Form 
Every 3 months if < 2 years from study entry; 
Every 6 months is 2-5 years from study entry; 
Every 12 months if more than 5 years from study 
entry 
Progression/Relapse 
Within 4 weeks of knowledge of progression/relapse 
Notice of Death Form 
Within 4 weeks of knowledge of death 
Subsequent Malignancy 
Within 4 weeks of knowledge of another malignancy 
 
 
 

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APPENDIX C: PERFORMANCE STATUS SCALES 
 
 
 
As published in Am J Clin Oncol: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, 
McFadden ET, Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655. The Eastern Cooperative Oncology Group, 
Robert Comis, MD, Group Chair.  
 
 

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APPENDIX E: INFORMATION ON THALOMID REMS™  
 
A known teratogen, THALOMID® (thalidomide) is approved for marketing only under a 
restricted distribution program approved by the Food and Drug Administration (FDA).  
This program is called the THALOMID Risk Evaluation and Mitigation Strategy (REMS) 
™ program (formerly known as the S.T.E.P.S® program). 
 
Please refer to the following website(s) for more information: 
www.CelgeneRiskManagement.com 
www.THALOMIDREMS.com 
 
Or call the Celgene Customer Care Center toll-free at 
1-888-423-5436 
 
 
 
 
 
 
 
 
 
 
 
Reference: Celgene Corporation. Risk Evaluation and Mitigation Strategy (REMS), 
THALOMID® (thalidomide). Modified: 9/2014.