Clinical trial NCT01575860
Conditions: Lymphoma
Keywords: biopsy-proven diagnosis completed at least 2 cycles of salvage chemotherapy showing PET positive residual lesions
Sponsor: Abramson Cancer Center at Penn Medicine
Start date: 2012-04-01; Completion date: 2022-10-31
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being conducted to evaluate the overall safety of lenalidomide (also known as Revlimid) in patients with lymphoma, and to determine whether it is effective in preventing this disease from returning after stem cell transplant. This study will also determine the dose of lenalidomide that can be given without causing severe side effects. Lenalidomide has not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of lymphoma. At least 28 people will be enrolled on this study at the University of Pennsylvania.

Detailed description:
Describe succinctly and clearly the past findings which justify the plan for this project. A summary of the relevant literature in the area of interest and reports of previous studies should be included.

For majority of lymphoma patients who relapse after complete response or who are primary refractory to initial treatment, a combination of salvage chemotherapy followed by high dose chemotherapy and ASCT is considered the standard of care. Sensitivity to salvage chemotherapy affects the outcome after ASCT. Traditionally, the response to salvage chemotherapy prior ASCT was determined by conventional computed tomography (CT) scans using size criteria. In the past several years, it has been shown that functional imaging with PET scans using fluorodeoxyglucose (FDG) provides additional information to anatomic imaging with CTs. Recently, PET scans have been incorporated into the response assessment as published by the Imaging Subcommittee of International Harmonization Project in Lymphoma. These days, most institutions use PET/CT scans which incorporate functional imaging with PET scan fused with low dose non-contrast enhanced CT scan.

We have previously reported the outcome of patients with relapsed/refractory lymphomas who continued to have residual FDG avid PET (positive) lesions after salvage chemotherapy and prior to ASCT. This group of patients included those who had excellent anatomic response by size criteria, but continued to have persistent hypermetabolic FDG activity within the residual lesions. We found that PET positive patients have an extremely poor chance of durable remission after ASCT. In the PET negative group, the median PFS was 19 months with 54% of patients without progression at 12 months after ASCT. In the PET positive group, the median PFS was 5 months with only 7% of patients without progression at 12 months after ASCT. We concluded that, for patients with PET positive residual disease after salvage chemotherapy and prior to ASCT, novel therapeutic approaches and agents need to be investigated.

Lenalidomide is a proprietary IMiD® compound of Celgene Corporation. IMiD® compounds have both immunomodulatory and anti-angiogenic properties which could confer antitumor and antimetastatic effects. Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of mechanisms are postulated to be responsible for lenalidomides activity against hematological malignancies. Lenalidomide has been demonstrated to possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation response to bFGF. In addition, lenalidomide has a variety of immunomodulatory effects. Lenalidomide stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 production. Up-regulation of T cell derived IL-2 production is achieved at least in part through increased AP-1 activity. The increased levels of circulating cytokines augment natural killer cell number and function, and enhance natural killer cell activity.

Clinical activity of lenalidomide in various lymphoma subtypes has been documented in several phase II trials. In patients with relapsed/refractory mantle cell lymphoma, the overall response rate (ORR) was 53% with PFS at 12 month 40%. In patients with aggressive lymphoma (mostly diffuse large B-cell subtype), the ORR was 35% with PFS at 12 months about 25%. There also have been many case reports of patients who achieved durable complete response to lenalidomide after failing multiple cytotoxic chemotherapy regimens.

Most clinical studies of lenalidomide in patients with active lymphoma used dose of 25 mg daily on days 1-21 in 28 day cycle which is the dosing recommended for active multiple myeloma. While lenalidomide was well tolerated in the lymphoma studies, the dose of 25 mg is associated with high risk of developing cytopenias including grade 3 neutropenia in 25-40% of patients and thrombocytopenia in 12-20%. Our group reported that low dose lenalidomide at 10 mg daily (continuous dosing) in combination with weekly dexamethasone can be effective in patients with active relapsed/refractory low grade and mantle cell lymphomas. The continuous dose of 10 mg daily has also been used in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

Lenalidomide has been used as maintenance therapy in multiple myeloma, but there is limited experience with maintenance lenalidomide in lymphoma patients. Two large clinical trials of maintenance lenalidomide in patients with multiple myeloma after ASCT have shown benefit in PFS over observation. These studies used daily dosing of lenalidomide at 10 mg or 15 mg which were well tolerated over long term administration.

Revlimid® (lenalidomide) is currently indicated for the treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Revlimid® is also approved in combination with dexamethasone for the treatment of patients with multiple myeloma that have received at least one prior therapy.

The most frequently reported adverse events reported during clinical studies with lenalidomide in oncologic and non-oncologic indications, regardless of presumed relationship to study medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, disease progression, death not specified and fractures.

Complete and updated adverse events are available in the Investigational Drug Brochure and the IND Safety Letters.

Rationale for Treatment in this Setting:

Our previously reported data and similar studies from other institutions indicate that patients with PET positive lesions after salvage chemotherapy and prior ASCT do very poorly. In our study, patients with residual PET positive lesions before ASCT had median PFS of 5 months with only 7% of patients without progression at 12 months after ASCT. It can be speculated that patients with PET positive lesions prior ASCT harbor chemotherapy resistant lymphoma cells in their tumors. Since the mechanism of action of lenalidomide differs from traditional cytotoxic chemotherapy, the use of this novel agent in this group of patients is an attractive concept. The immunomodulary properties of lenalidomide over the maintenance period of 24 months could improve the overall outcome of patients following ASCT. Since there is a valid concern that lenalidomide could cause severe cytopenias when used early after ASCT, we proposed to administer dose 10 mg of lenalidomide daily with an option of dose modification to 5 mg daily according to previously defined toxicity criteria. The daily maintenance dosing of lenalidomide at 10 mg has been used in patients with multiple myeloma after ASCT and improved PFS in two large randomized trials.

Arms: arm 1: Total of 24 cycles of lenalidomide. Subjects received a starting daily dose of 10mg lenalidomide on days 1 through 28 of each 28 day cycle. Subjects initiated lenalidomide 28-100 days post-ASCT.
Interventions: intervention 1: Lenalidomide
Intervention descriptions: intervention 1: Lenalidomide, 10mg, oral tablets, daily

Protocol documents:
Prot_SAP_000.pdf: 
UPCC#11411 
Confidential 
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Version:  09/27/2016 
Protocol Title: Maintenance Lenalidomide Therapy after 
Autologous Stem Cell Transplant in Patients with 
 High Risk Relapsed/Refractory Lymphomas 
 
Regulatory Sponsor  University of Pennsylvania 
Funding Sponsor  Celgene Corporation 
Celgene Tracking #:  RV-NHL 0623 
Principal Investigator:  Jakub Svoboda, MD 
Sub-Investigators:  Alison Loren, MD 
Sunita Nasta, MD 
Stephen Schuster, MD 
Edward Stadtmauer, MD 
Donald Tsai, MD, PhD 
Anthony Mato, MD 
Daniel Landsburg, MD 
 
Medical Monitor: 
 
 Amy Clark, MD 
IND#  EXEMPT 
 
Initial Version:  
 
06.16.2011 
Protocol Amendment: 
04.25.2012 
Protocol Amendment: 
10.28.2013 
Protocol Amendment: 
05.21.2014 
Protocol Amendment: 
07.07.2014 
Protocol Amendment: 
09.27.2016 
 
 
CONFIDENTIAL 
 
The information contained in this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to another party unless law or regulations 
require such disclosure.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
 
 


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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Principal Investigator: 
 
Jakub Svoboda, MD 
Perelman Center for Advanced Medicine 
3400 Civic Center Blvd. 
Philadelphia, PA 19104 
Tel: 215 614 1846 
Fax: 215 615 5888 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY PERSONNEL 
 
Supporter:  
Celgene Corporation 
86 Morris Ave 
Summit,  NJ   07901 
1-800-742-3107 
Study Location:  
University of Pennsylvania 
Principal Investigator:  
Jakub Svoboda, MD 
Sub-Investigators:  
Alison Loren, MD 
Sunita Nasta, MD 
Stephen Schuster, MD 
Edward Stadtmauer, MD 
Donald Tsai, MD 
Dan Vogl, MD 
Anthony Mato, MD 
Daniel Landsburg, MD 
Biostatistician:  
Rosemarie Mick, MS 
Medical Monitor:  
Amy Clark, MD 
 
 
 


UPCC#11411 
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Version:  09/27/2016 
 
TABLE OF CONTENTS 
 
1.0 Protocol Synopsis………………………………………………...……………….................7 
2.0 Schedule of Study Assessments………………………………...….......................................9 
3.0 Background and Rationale……………………………………….…………….….............11 
3.1 Introduction…………………………………………………........…………………….11 
 
3.1.1 Indications and Usage………………………………………..……………………12 
3.2 Adverse Events……………………………………………………..……….…………..12 
3.3 Rationale for Treatment in this Setting….....................................................................12 
4.0 Study Objectives and Endpoints……………………………………..………..…………...13 
       4.1 Objectives……………………………………………………………..………………...13 
 
4.1.1 Primary Objectives…………………………………………………………….......13 
 
4.1.2 Secondary Objectives………………………………………………………...........13 
       4.2 Endpoints………………………………………………………………………...……...13 
 
4.2.1 Primary Endpoints……………………………………………………………...….13 
 
4.2.2 Secondary Endpoints………………………………………………………...…….13 
5.0  Investigational Plan………………………………………………………….......................13 
        5.1 Overall Design………………………………………………………………………….13 
 
5.1.1 Protocol Therapy…………………………………………………...………………14 
 
    5.1.1.1 Lenalidomide Description……………………………………………………..14 
 
    5.1.1.2 Clinical Pharmacology…………………………………………………...……15 
 
    5.1.1.3 Pharmacokinetics and Drug Metabolism………………………………...……15 
 
    5.1.1.4 Supplier………………………………………………………………………..16 
 
    5.1.1.5 Dosage Form…………………………………………………………………..16 
 
    5.1.1.6 Packaging………………………………………………………………...……16 
 
    5.1.1.7 Storage……………………………………………………...............................16 
 
    5.1.1.8 Prescribing Information…………………………………………………….....16 
        5.2 Screening and Eligibility……………………………………………………………....16 
 
5.2.1 Inclusion Criteria………………………………………………..............................17 
 
5.2.2 Exclusion Criteria………………………………………………………………….18 
        5.3 Visit Schedule and Assessments…………………………………………………….....19 
 
5.3.1 Screening …………………………………………………………...……………..19 
 
5.3.3 Cycle 1 of Lenalidomide Therapy…………………….………...............................19 
 
5.3.4 Cycles 2-24……………………………………………………………………...…20 
 
5.3.5 Radiographic Evaluations…………………………………………………...…….21 
 
5.3.6 Study Discontinuation………………………………………………………..……21 
 
5.3.7 Safety Assessment………………………………………………………………....21 
 
5.3.8 Follow Up……………………………………………………………………….....21 
        5.4 Drug Administration………………………………………………………………..…22 
 
5.4.1 Dosing Regimen…………..……………………………………………………….22 
 
5.4.2 Special Handling Instructions……………………..................................................24 
 
5.4.3 Record of Administration…………………………………………...……………..24 
        5.5 Dose Continuation, Modification and Interruption………………………………….24 
 
5.5.1 Dose Reduction Steps…………………………………………………………...…24 
 
5.5.2 Instructions for Initiation of a New Cycle…………………....................................24 
 
5.5.3 Instructions for Dose Modifications or Interruptions…………………………...…25 
 
5.5.4 Treatment Adherence……………………………………………………………....27 
        5.6 Concomitant Therapy………………………………………………………..............27 


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5.6.1 Recommended Concomitant Therapy……………………………………………27 
 
    5.6.1.1 Anticoagulation……………………………………………………………...28 
 
5.6.2 Prohibited Concomitant Therapy………………………………………………...28 
    5.7 Discontinuation of Study Treatment………………………………..............................28 
    5.8 Follow Up………………………………………………………………………………..28 
6.0 Adverse Events……………………………………………………………………...……..28 
    6.1 Serious Adverse Event Definition……………………………………………………...28 
    6.2 Adverse Event Reporting……………………………………………………………….29 
        6.2.1 Pregnancies…………………………………………………………………………..30 
        6.2.2 Celgene Drug Safety Contact Information………………………………………......30 
    6.3 Investigator Reporting Responsibilities………………………………………………..31 
        6.3.1 Expedited Reporting by Investigator to Celgene………………………………….....31 
        6.3.2 Investigator Reporting to IRB/DSMC/Medical Monitor...……………………….….31 
    6.4 Adverse Event Updates/IND Safety Reports…………………………………………..33 
7.0 Response Assessments…………………………………………………………….……….34 
8.0 Study Amendments and Deviations…………………………………………….……..….34 
    8.1 Protocol Amendments…………………………………………………………………..34 
    8.2 Protocol Deviations…………………………………………………...............................34 
9.0 Data Management…………………………………………………………………….……35 
    9.1 Analyses and Reporting……....………………………………………………………....35 
    9.2 Data Monitoring Committee………….………………………………………………...35 
    9.3 Study Auditing…………………………….……………………………………………..36 
        9.3.1 Investigator Responsibilities…………………………................................................36 
10.0 Statistical Considerations……………………………………….......................................36 
    10.1 Design………………………………………………………….………………………..36 
    10.2 Objectives…………………………………………………….…………………………36 
    10.3 Endpoints…………………………………………………..……………………………37 
    10.4 Phase I Design……………………….………………………………………………….38 
    10.5 Rules for Early Termination for DLT during Phase I……………………………….38 
    10.6 Plans for Data Analysis………………………………………………………………...39 
    10.7 Sample Size…………………………………………………………………………..….39 
    10.8 Study Duration……………………………………………………………………….....39 
11.0 Regulatory Considerations…………………………………………………......................40 
    11.1 Institutional Review Board/Ethics Committee Approval………….………………....40 
    11.2 Informed Consent……..…………………………………………………………….…..40 
    11.3 Subject Confidentiality………………………………………………..………………...40 
    11.4 Study Records Requirements……………………..……….............................................41 
    11.5 Premature Discontinuation of Study………………………………...............................41 
Appendices 
Appendix A: Risks of Fetal Exposure, Pregnancy Test Guidelines and Acceptable Birth 
Control       
Methods…………………..………………………....................................................................42 
    Appendix B: ECOG Performance Status……………..……………………………………….45 
    Appendix C: IWRC for Non-Hodgkins Lymphoma……………………………………..……46 
References………………………………………………………………………..........................48 
 
 
 


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Version:  09/27/2016 
1  Protocol Synopsis 
PROTOCOL TITLE: Maintenance Lenalidomide Therapy after Autologous Stem Cell 
Transplant (ASCT) in Patients with High Risk Relapsed/Refractory Lymphomas 
 
DATE PROTOCOL FINAL: 
September 27, 2016 
INDICATION: 
Relapsed/refractory lymphomas (diffuse large B-cell, 
mantle cell, follicular, marginal zone, peripheral T-cell, 
small lymphocytic with large cell transformation, and 
Hodgkin lymphomas)  
STUDY PHASE: 
Phase I/II 
BACKGROUND AND RATIONALE: 
 
Lenalidomide (Revlimid®, CC-5013) is an oral immunomodulatory drug which has activity in 
several hematologic malignancies.  Patients with relapsed/refractory lymphomas who failed 
multiple cytotoxic chemotherapy regimens were found to have encouraging overall response rates 
(over 30%) and duration of response (over 10 months) when treated with lenalidomide as a single 
agent. 
 
We have previously reported the outcome of patients with relapsed/refractory lymphomas who 
continued to have residual hypermetabolic lesions on positron emission tomography (PET) scans 
after salvage chemotherapy and prior to ASCT (Svoboda et al. 2006, 211-216).  We concluded 
that these patients have an extremely poor chance of durable remission after ASCT and should be 
considered for novel therapeutic approaches.  Using lenalidomide maintenance therapy after 
ASCT in this setting is a novel concept which might improve the historically poor outcomes in 
this population. 
 
STUDY OBJECTIVES: 
Primary: 
Determine the safety of lenalidomide maintenance therapy implemented early after ASCT and the 
appropriate dose for further studies. 
Secondary: 
Determine the progression free survival (PFS) and overall survival (OS) after ASCT in this high 
risk group with relapsed/refractory lymphomas treated with lenalidomide maintenance.  We will 
compare these findings to our historical controls with PET positive disease prior to ASCT. 
 
STUDY DESIGN: 
We propose a phase I/II trial of lenalidomide maintenance therapy after ASCT in high risk 
patients with relapsed/refractory lymphomas.  We define this group of patients by the presence of 
residual hypermetabolic lesion(s) on PET scans (PET positive disease) after salvage 
chemotherapy and prior to ASCT.  This will be a non-randomized, single institution study. 
 
Patients will be identified and undergo screening activity to determine eligibility within 28-100 
days after ASCT following positive PET scan.  Patients will be registered if determined to be 
eligible.  Eligible patients will proceed with lenalidomide maintenance therapy. 
 


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Patients will continue on lenalidomide maintenance for 24 months unless they develop 
progressive disease or unacceptable toxicity.  The initial dose of maintenance therapy will be 10 
mg of lenalidomide daily.  We plan to adjust the dose according to specific dose modification 
criteria.  To monitor response during lenalidomide maintenance, we will obtain post-ASCT 
imaging scan prior to starting lenalidomide and then every three months during the first year and 
every 4 months during the second year. 
 
STUDY ENDPOINTS 
Primary: 
Dose limiting toxicity (DLT) as assessed by NCI CTCAE version 4.0 
Secondary: 
Progression free survival 
Overall survival 
 
STUDY DURATION: 60 months 
 
DOSING REGIMEN:  The initial dose of lenalidomide will be 10 mg daily.  We will use a 3+3 
design to determine tolerability of this dose in these heavily pretreated patients.  We will allow 
decreasing lenalidomide to 5 mg daily according to specific dose modification criteria.  We will 
stop the study if there are 2 subjects with DLTs at the 5 mg dose level. 
 
TOTAL SAMPLE SIZE: We plan to enroll 24 evaluable patients with relapsed/refractory 
lymphoma who will initiate lenalidomide maintenance after ASCT during the initial 3 years of 
the study.  It is likely that at least 28 patients may be enrolled to provide 24 evaluable patients. 
 
DRUG SUPPLIES:  Celgene Corporation will provide lenalidomide at no charge through the 
Revlimid REMS® program for study participants. 
 
 


 
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2 Schedule of Study Assessments 
 
 
Procedure 
 
Screening 
 
Cycle 1 
Cycles 
2-24* 
Discontinuation 
From Protocol 
Therapy 
Follow-
Up Phase 
On day 28-100 after ASCT at 
hematological recovery (<28 days 
before starting maintenance)  
Day 
1^ 
 
Day 
15 
Day 
22 
Day 
1 
 
Every 3 
months8 
Informed Consent 
X 
 
 
 
 
 
 
Record lymphoma diagnosis, current 
medications 
X 
 
 
 
 
 
 
Record prior anti-cancer therapies 
X 
 
 
 
 
 
 
Physical examination, vital signs, weight 
X 
X6 
X 
 
X 
X 
 
ECOG performance status 
X 
X6 
X 
 
X 
X 
 
Imaging (PET/CT or CT scan) 
X 
 
 
 
X4 
 
 
ECG 
X 
 
 
 
 
 
 
CBC 
X 
X6 
X 
X 
X 
X 
 
Serum chemistries1 
X 
X6 
X 
 
X 
 
 
Pregnancy testing2,3 
X 
X6 
 
 
X 
X 
 
Register patient into Revlimid REMS® 
program 
X 
 
 
 
 
 
 
Baseline lesion assessment 
X 
 
 
 
 
 
 
Prescribe lenalidomide via Revlimid REMS® 7 
X 
 
 
 
X 
 
 
Response assessment4 
 
 
 
 
X4 
X4 
 
Record adverse events 
 
 
X 
 
X 
X5 
 
Record concomitant therapies/procedures 
 
X 
 
 
X 
X 
 
Assess drug compliance/patient’s study 
calendar 
 
 
 
 
X 
X 
 
Follow-up anti-cancer treatments 
 
 
 
 
 
 
X 
Follow-up progression and survival information 
 
 
 
 
 
 
X 
 
*   Variations of ± 7 days of scheduled visits are permitted; in rare circumstances, the study calendar may be recalculated to accommodate for a change in 
study visits out of this window (due to transportation issues, weather events, etc.) at the discretion of the treating physician. 
^ To be performed within 7 days of day 1 of lenalidomide therapy.  If Screening physical examination, vital signs, weight, labs and ECOG performance 
status were done within 7 days of Day 1, they do not need to be repeated at this timepoint. 
An unscheduled visit can occur at any time during the study.  Source must be maintained for these unscheduled visits. The date for the visit and any data 
generated must be recorded on the appropriate CRF.  Source documents for these unscheduled visits must also be maintained. 


 
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1 To include Thyroid Stimulating Hormone (TSH) at Screening B, at treatment discontinuation, and whenever clinically indicated.  T3 and T4 levels may 
be assessed as clinically indicated.  If HIV and Hepatitis B status are unknown (unlikely since all patients undergoing ASCT are screened), then these tests 
will be sent at Screening B. 
2 Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time 
in the preceding 24 consecutive months). 
3 Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled 
within 7 days).  FCBP with regular or no menstruation must have a pregnancy test every 28 days while on therapy (including breaks in therapy); at 
discontinuation of lenalidomide, and at Day 28 post the last dose of lenalidomide.  If menstrual cycles are irregular, the pregnancy testing must occur 
weekly every 14 days throughout the duration of lenalidomide treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 28 
following lenalidomide discontinuation (see Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
4 Progression will be determined by the treating physician as based on clinical picture and radiographic findings.  The initial imaging will be performed 
after ASCT, but prior to initiating maintenance lenalidomide therapy.  During the maintenance phase, imaging (PET/CT or CT scan) will be performed 
every 3 months during the first year and every 4 months during the second year of maintenance.  Imaging studies after the second year of maintenance will 
be at discretion of treating physician.  During the first cycle of maintenance therapy, there will be two visits with physical exam.  Then, participants will be 
seen on day 1 of each subsequent cycle.  It will not be required to document progression by tissue biopsy (it will be at discretion of treating physician). 
5 An additional safety assessment will be done 28 days (+/- 7 days) following the last dose of protocol therapy. 
6 If screening assessments were done within 7 days of Day 1, they do not need to be repeated at Study Day 1. 
7 Lenalidomide must be prescribed through and in compliance with Celgene’s Revlimid REMS® program.  Prescriptions must be filled within 14 days, 
unless the patient is a female of childbearing potential, in which case the prescription must be filled within 7 days.  Consideration should be given to 
prescribing lenalidomide 5 to 7 days in advance of Day 1 of each cycle to allow time for required patient and prescriber surveys, and drug shipment to 
patient.  Any unused Revlimid® (lenalidomide) should be returned to the patient for disposition in accordance with the Revlimid REMS® program. 
8 Subjects will be followed every 3 months for the first 3 years after discontinuation of protocol therapy, and then annually thereafter; those patients who 
did not achieve hematological recovery by Day 100 after ASCT and never started on lenalidomide maintenance will also be followed every 3 months for 
the first year and then annually for anti-cancer treatment and progression/survival information. 
 


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3 Background and Rationale 
3.1 Introduction 
For majority of lymphoma patients who relapse after complete response or who are primary 
refractory to initial treatment, a combination of salvage chemotherapy followed by high dose 
chemotherapy and ASCT is considered the standard of care.  Sensitivity to salvage chemotherapy 
affects the outcome after ASCT (Philip et al. 1987, 1493-1498).  Traditionally, the response to 
salvage chemotherapy prior ASCT was determined by conventional computed tomography (CT) 
scans using size criteria.  In the past several years, it has been shown that functional imaging with 
PET scans using fluorodeoxyglucose (FDG) provides additional information to anatomic imaging 
with CTs.  Recently, PET scans have been incorporated into the response assessment as published 
by the Imaging Subcommittee of International Harmonization Project in Lymphoma (Juweid et 
al. 2007, 571-578).  These days, most institutions use ‘PET/CT scans’ which incorporate 
functional imaging with PET scan fused with low dose non-contrast enhanced CT scan. 
We have previously reported the outcome of patients with relapsed/refractory lymphomas who 
continued to have residual FDG avid PET (‘positive’) lesions after salvage chemotherapy and 
prior to ASCT (Svoboda et al. 2006, 211-216).  This group of patients included those who had 
excellent anatomic response by size criteria, but continued to have persistent hypermetabolic 
FDG activity within the residual lesions.  We found that PET positive patients have an extremely 
poor chance of durable remission after ASCT.  In the PET negative group, the median PFS was 
19 months with 54% of patients without progression at 12 months after ASCT.  In the PET 
positive group, the median PFS was 5 months with only 7% of patients without progression at 12 
months after ASCT.  We concluded that, for patients with PET positive residual disease after 
salvage chemotherapy and prior to ASCT, novel therapeutic approaches and agents need to be 
investigated. 
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.  IMiD® compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
antimetastatic effects.  Although the exact antitumor mechanism of action of lenalidomide is 
unknown, a number of mechanisms are postulated to be responsible for lenalidomide’s activity 
against hematological malignancies.  Lenalidomide has been demonstrated to possess anti-
angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell 
migration, due at least in part to inhibition of Akt phosphorylation response to bFGF (Dredge et 
al. 2005, 56-63).  In addition, lenalidomide has a variety of immunomodulatory effects.  
Lenalidomide stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-gamma, 
inhibits IL-1 beta and IL-6 and modulates IL-12 production (Corral et al. 1999, 380-386).  Up-
regulation of T cell derived IL-2 production is achieved at least in part through increased AP-1 
activity (Schafer et al. 2003, 1222-1232).  The increased levels of circulating cytokines augment 
natural killer cell number and function, and enhance natural killer cell activity (Davies et al. 2001, 
210-216). 
Clinical activity of lenalidomide in various lymphoma subtypes has been documented in several 
phase II trials (Wiernik et al. 2008, 4952-4957; Witzig et al. 2009, 5404-5409; Habermann et al. 
2009, 344-349; Boll et al. 2010, 480-482).  In patients with relapsed/refractory mantle cell 
lymphoma, the overall response rate (ORR) was 53% with PFS at 12 month 40% (Habermann et 
al. 2009, 344-349).  In patients with aggressive lymphoma (mostly diffuse large B-cell subtype), 
the ORR was 35% with PFS at 12 months about 25% (Wiernik et al. 2008, 4952-4957).  There 


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also have been many case reports of patients who achieved durable complete response to 
lenalidomide after failing multiple cytotoxic chemotherapy regimens (Musuraca et al. 2010; 
Ivanov et al. 2010, 1758-1760). 
Most clinical studies of lenalidomide in patients with active lymphoma used dose of 25 mg daily 
on days 1-21 in 28 day cycle which is the dosing recommended for active multiple myeloma.  
While lenalidomide was well tolerated in the lymphoma studies, the dose of 25 mg is associated 
with high risk of developing cytopenias including grade 3 neutropenia in 25-40% of patients and 
thrombocytopenia in 12-20% (Habermann et al. 2009, 344-349; Wiernik et al. 2008, 4952-4957).  
Our group reported that low dose lenalidomide at 10 mg daily (continuous dosing) in combination 
with weekly dexamethasone can be effective in patients with active relapsed/refractory low grade 
and mantle cell lymphomas (Ahmadi et al. 2009, 1700).  The continuous dose of 10 mg daily has 
also been used in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma 
(Andritsos et al. 2008, 2519-2525). 
Lenalidomide has been used as maintenance therapy in multiple myeloma, but there is limited 
experience with maintenance lenalidomide in lymphoma patients.  Two large clinical trials of 
maintenance lenalidomide in patients with multiple myeloma after ASCT have shown benefit in 
PFS over observation.  These studies used daily dosing of lenalidomide at 10 mg or 15 mg which 
were well tolerated over long term administration (Attal et al. 2010; McCarthy et al. 2010). 
3.1.1 Indications and Usage: 
Revlimid® (lenalidomide) is currently indicated for the treatment of patients with transfusion-
dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with 
a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.  
Revlimid® is also approved in combination with dexamethasone for the treatment of patients 
with multiple myeloma that have received at least one prior therapy. 
3.2 Adverse Events 
The most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study medication 
include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, nausea, 
vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, Upper 
respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, 
weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, 
dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary 
embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, 
syncope, disease progression, death not specified and fractures. 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
 
 


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3.3 Rationale for Treatment in this Setting 
Our previously reported data and similar studies from other institutions indicate that patients with 
PET positive lesions after salvage chemotherapy and prior ASCT do very poorly (Svoboda et al. 
2006, 211-216; Spaepen et al. 2003, 53-59).  In our study, patients with residual PET positive 
lesions before ASCT had median PFS of 5 months with only 7% of patients without progression 
at 12 months after ASCT.  It can be speculated that patients with PET positive lesions prior 
ASCT harbor chemotherapy resistant lymphoma cells in their tumors.  Since the mechanism of 
action of lenalidomide differs from traditional cytotoxic chemotherapy, the use of this novel agent 
in this group of patients is an attractive concept. The immunomodulary properties of lenalidomide 
over the maintenance period of 24 months could improve the overall outcome of patients 
following ASCT.  Since there is a valid concern that lenalidomide could cause severe cytopenias 
when used early after ASCT, we proposed to administer dose 10 mg of lenalidomide daily with 
an option of dose modification to 5 mg daily according to previously defined toxicity criteria.  
The daily maintenance dosing of lenalidomide at 10 mg has been used in patients with multiple 
myeloma after ASCT and improved PFS in two large randomized trials (Attal et al. 2010; 
McCarthy et al. 2010). 
4 Study Objectives and Endpoints 
4.1 Objectives 
4.1.1 Primary Objectives 
 
Determine the safety and dose-limiting toxicity of lenalidomide maintenance therapy 
implemented early after ASCT and the appropriate dose for further studies. 
4.1.2 Secondary Objectives 
 
Determine the progression free survival and overall survival after ASCT in this high risk 
group with relapsed/refractory lymphomas treated with lenalidomide maintenance. We 
will compare these findings to our historical controls with PET positive disease prior to 
ASCT. 
4.2 Endpoints (see Section 10.3 for definitions) 
4.2.1 Primary Endpoints 
 
Dose limiting toxicity (DLT) as assessed by NCI version 4.0 
4.2.2 Secondary Endpoints 
 
Progression free survival (PFS) 
 
Overall survival (OS) 


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5 Investigational Plan 
5.1 Overall Design 
Patients with relapsed/refractory lymphoma will undergo screening after ASCT following 
positive PET/CT scan.  PET/CT scan results will be categorized as negative when no evidence of 
lymphoma is found by the radiologist at the time of the scan.  PET/CT results will be categorized 
as positive when the intensity of any non-physiological signal is over 2.5 SUV, which is the 
measurement of FDG uptake often used to differentiate between benign and malignant lesions 
(Elstrom et al. 2003, 3875-3876; Al-Sugair and Coleman 1998, 303-319).  Patients with diffuse 
bone marrow activity while on growth factors and with mild symmetric supraclavicular adipose 
tissue activity in the absence of focal lesions will be deemed as negative.  All studies will be 
reviewed by a University of Pennsylvania nuclear medicine radiologist. 
Patients with PET positive lesions who are candidates for ASCT as determined by their treating 
physician will undergo ASCT.  The conditioning regimen will be at the discretion of the treating 
physician.  Subsequent screening to determine eligibility will commence 28 to 100 days after 
ASCT at the time of count recovery defined as ANC ≥ 1,000 and platelets ≥ 60,000.  Those 
patients who will undergo consolidative radiation after ASCT can proceed with maintenance 
treatment, but completion of their radiation and hematological recovery must occur by day 100 
after ASCT. 
To monitor response to lenalidomide, we will obtain post-ASCT imaging with PET/CT or CT 
scan prior to starting lenalidomide.  During the lenalidomide maintenance, imaging (PET/CT or 
CT scan) will be performed at least every three months during the first year and at least every 4 
months during the second year which reflects general frequency of imaging in this setting outside 
of this trial.  Further imaging after 2 years of follow-up will be at discretion of the treating 
physician. 
Patients will continue on lenalidomide for 24 cycles unless they develop progressive disease or 
unacceptable toxicity. One cycle is defined as 28 day period. We will initiate maintenance 
therapy with 10 mg of lenalidomide daily. We will dose adjust or hold lenalidomide for 
hematologic toxicity according to specific dose modification criteria. 
The 3+3 design will be conducted as follows (see details in Section 10.4). The first 3 patients 
enrolled on our study must each be followed for 28 days on lenalidomide before enrolling the 
second group of 3 patients.  If there is zero or one episode of dose limiting toxicity (DLT) in the 
initial group of 3 patients, then the group will be expanded to 6 patients at the 10 mg dose.  If 
there are 2 or more DLTs in the initial group of 3 patients, then we will decrease the dose of 
lenalidomide to 5 mg daily and repeat the 3+3 design.  If there is a second DLT in the expanded 
group of 6 patients at the 10 mg dose, then we will also decrease the dose to 5 mg and repeat the 
3+3 design.  We will stop the study if there are 2 or more DLTs at the 5 mg dose. 
 


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5.1.1 Protocol Therapy 
5.1.1.1 
Lenalidomide Description 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure: 
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3. 
Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 
to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active 
forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero. 
5.1.1.2 
CLINICAL PHARMACOLOGY 
Mechanism of Action: 
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and antiangiogenic properties.  Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory 
cytokines from peripheral blood mononuclear cells.  Lenalidomide inhibited cell proliferation 
with varying effectiveness (IC50s) in some but not all cell lines.  Of cell lines tested, 
lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma cell 
line with a deletion of one chromosome 5) but was much less effective in inhibiting growth of 
KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and other 
cell lines without chromosome 5 deletions.  Lenalidomide inhibited the expression of 
cyclooxygenase-2 (COX-2) but not COX-1 in vitro. 
5.1.1.3 
Pharmacokinetics and Drug Metabolism: 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 
Co-administration with food does not alter the extent of absorption (AUC) but does reduce the 
maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of lenalidomide 
is linear. Cmax and AUC increase proportionately with increases in dose. Multiple dosing at the 
recommended dose-regimen does not result in drug accumulation. 


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Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the phase I 
studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to maximum 
blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 50mg).  No 
plasma accumulation was observed with multiple daily dosing.  Plasma lenalidomide declined in 
a monophasic manner with elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 
28 at all 4 doses.  Peak and overall plasma concentrations were dose proportional over the dosing 
range of 5mg to 50mg (Wu A. 2004, 2056).  Exposure (AUC) in multiple myeloma patients is 
57% higher than in healthy male volunteers. 
Pharmacokinetic Parameters: 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and Excretion: 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. The 
process exceeds the glomerular filtration rate and therefore is partially or entirely active.  
Half-life of elimination is approximately 3 hours. 
5.1.1.4 
Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through the Revlimid REMS® program. 
5.1.1.5 
Dosage Form 
Lenalidomide will be supplied as capsules for oral administration. 
5.1.1.6 
Packaging 
Lenalidomide will be shipped directly to patients.   Bottles will contain a sufficient number of 
capsules for one cycle of dosing. 
5.1.1.7 
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected from 
excessive heat and cold. 
5.1.1.8 
Prescribing Information 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide will be 
provided in accordance with Celgene Corporation’s Revlimid REMS® program.  Per standard 
Revlimid REMS® program requirements, all physicians who prescribe lenalidomide for research 
subjects enrolled into this trial, and all research subjects enrolled into this trial, must be registered 
in and must comply with all requirements of the Revlimid REMS® program.  Prescriptions must 
be filled within 14 days, unless the patient is a female of childbearing potential, in which case the 
prescription must be filled within 7 days.  Only enough lenalidomide for one cycle of therapy 
will be supplied to the patient each cycle. 


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5.2 Screening and Eligibility 
The Investigator is responsible for keeping a record of all subjects who sign an Informed Consent 
Form for entry into the study.  All subjects will be screened for eligibility.  Screening procedures 
are outlined in Section 2, Schedule of Study Assessments and unless otherwise specified, must 
take place within 28 days prior to initiation of therapy. 
Approximately 60 subjects with relapsed/refractory lymphoma undergoing ASCT in our 
institution will be screened for enrollment over a 36 month period.  We anticipate that at least 28 
patients will be categorized as having PET positive disease prior ASCT and be enrolled on study.  
Twenty four patients will proceed with the maintenance phase involving daily dosing with 
lenalidomide. 
5.2.1 
Inclusion Criteria 
Subjects must meet the following inclusion/exclusion criteria to be registered to this study. 
Inclusion criteria: 
1. Able to understand and voluntarily sign the informed consent form. 
2. Aged 18 years at the time of signing the informed consent form. 
3. Able to adhere to the study visit schedule and other protocol requirements. 
4. Biopsy-proven diagnosis of lymphoma (including diffuse large B-cell, mantle cell, 
follicular, marginal zone, peripheral T cell, small lymphocytic lymphoma with large cell 
transformation, and Hodgkin lymphomas). 
5. Completion of at least 2 cycles of salvage chemotherapy, with pre-ASCT PET/CT 
imaging showing PET positive residual lesion(s) (SUV > 2.5). 
6. Disease free of other malignancies for  2 years with exception of basal cell and 
squamous cell carcinomas of the skin, or carcinoma in situ of the cervix or breast. 
7. Completion of high-dose chemotherapy with ASCT. 
8. Hematologic recovery at 28-100 days after ASCT (defined as ANC ≥ 1,000 and platelet 
count ≥ 60,000). 
9. All study participants must be registered into the mandatory Revlimid REMS® program 
and be willing and able to comply with the requirements of the Revlimid REMS® 
program 
10. ECOG performance status of  2 at study entry (see Appendix B). 
11. Patients undergoing planned consolidative radiation therapy must be finished with the 
therapy by day 100 after ASCT. 
12. Laboratory test results within these ranges: 
 
Absolute neutrophil count (ANC) > 1,000/uL 
 
Platelet count > 60,000/uL 
 
Serum creatinine < 2.0 mg/dL 
 
Total bilirubin  1.5 x ULN.  Patients with known Gilbert’s disease (as confirmed by 
study doctor) may participate with elevated bilirubin (serum bilirubin < 2.0 x ULN) 
as long as their AST and ALT are within normal range. 
 
AST (SGOT) and ALT (SGPT)  3 x ULN. 


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13. Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days and again 
within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled 
within 7 days) and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE SAME TIME, at least 28 days 
before she starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy 
testing.  Men must agree to use a latex condom during sexual contact with a FCBP even 
if they have had a successful vasectomy.  See Appendix: Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and Acceptable Birth Control Methods. 
14. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (warfarin or low 
molecular weight heparin may be used for patients intolerant of aspirin or at the 
discretion of the treating physician). 
5.2.2 
Exclusion criteria: 
1. A PET/CT or CT scan post-ASCT which shows disease progression. 
2. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form. 
3. Pregnant or breast feeding females (lactating females must agree not to breast feed while 
taking lenalidomide). 
4. Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study or confounds the 
ability to interpret data from the study. 
5. Use of any other experimental drug or therapy within 28 days of initiating treatment with 
lenalidomide. 
6. Known hypersensitivity to thalidomide. 
7. The development of erythema nodosum, a blistering or desquamating rash, while taking 
thalidomide or similar drugs. 
8. Any prior use of lenalidomide. 
9. Concurrent use of other anti-cancer agents or therapies during study treatment. 
10. Known seropositive for or active viral infection with human immunodeficiency virus 
(HIV) or hepatitis B virus (HBV).  Patients who are seropositive because of hepatitis B 
virus vaccine are eligible. 
 
 
                                               
 
† A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 


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5.3 Visit Schedule and Assessments 
5.3.1 Screening/Enrollment - to take place at the time of hematologic recovery, between 
Days 28-100 post ASCT and within 28 days of initiation of treatment with 
lenalidomide: 
 Review and signing of the Informed Consent Form 
 Complete medical history, including prior and current medications, treatments, and 
anti-cancer therapies. 
 Physical Exam and evaluation of ECOG PS 
 Vital signs, including blood pressure, heart rate, oral temperature and weight 
 Imaging with PET/CT scan or CT scan 
 Electrocardiogram 
 Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, 
serum creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT and TSH 
 For women of childbearing potential, a serum pregnancy test must be performed 
10-14 days and then within 24 hours prior to initiating treatment with lenalidomide 
 Registration into Revlimid REMS® program 
5.3.3  Cycle 1 of lenalidomide therapy 
 
Within 7 days of initiating lenalidomide therapy 
 Physical Examination and evaluation of ECOG PS (does not need to be repeated 
if previously performed within 7 days of starting treatment with lenalidomide) 
 Vital signs: blood pressure, heart rate, temperature and weight (does not need to 
be repeated if previously performed within 7 days of starting treatment with 
lenalidomide) 
 CBC with differential and platelets (does not need to be repeated if previously 
performed within 7 days of starting treatment with lenalidomide) 
 Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, 
serum creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT (does 
not need to be repeated if previously performed within 7 days of starting 
treatment with lenalidomide) 
 For women of childbearing potential, a serum pregnancy test must be performed 
10-14 days and then within 24 hours prior to initiating treatment with lenalidomide 
 
Cycle 1, Day 15 (+/- 3 days) 
 Physical Examination and evaluation of ECOG PS 
 Vital signs: blood pressure, heart rate, temperature and weight 
 CBC with differential and platelets 
 Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, 
serum creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT 
 Serum pregnancy test (for women with irregular menses) 
 Review of interim adverse events and concomitant medications 
Cycle 1, Day 22 (+/- 3 days) 
 CBC with differential and platelets 


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5.3.4 
Cycles 2-24, Day 1 (+/- 7 days) 
 Physical Examination and evaluation of ECOG PS 
 Vital signs: blood pressure, heart rate, temperature and weight 
 CBC with differential and platelets 
 Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, 
serum creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT 
 Serum pregnancy test (for women of child-bearing potential) 
 Review of interim adverse events and concomitant medications 
5.3.5 
Radiographic Evaluations 
Subjects will undergo radiographic evaluations to assess disease status at the timepoints 
listed below.  Timing of radiographic evaluations may be altered based on clinical 
indication or the discretion of the treating physician. 
 PET/CT after at least 2 cycles of salvage chemotherapy, but prior ASCT (using 
separate PET scan and dedicated CT scan performed within one week is acceptable) 
 Imaging (PET/CT or CT scan) after ASCT, but prior Cycle 1 of lenalidomide 
therapy 
 Imaging (PET/CT or CT scan) every 3 cycles during the first year of lenalidomide 
maintenance therapy (near end of Cycles 3, 6, 9, 12) 
 Imaging (PET/CT or CT scan) every 4 cycles during second year of lenalidomide 
maintenance therapy (near end of Cycles 16, 20, 24) 
5.3.6 
Study Discontinuation 
The following will be performed at the time of study discontinuation, whether due to 
study completion or early withdrawal from study participation 
 Physical Exam and evaluation of ECOG PS 
 Vital signs (Blood pressure, heart rate, temperature, weight) 
 CBC with differential and platelets 
 Serum chemistry panel including sodium, potassium, chloride, CO2, calcium, serum 
creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT and TSH 
 Assessment of adverse events and concomitant medications 
5.3.7 
Safety Assessment (to be performed 28 Days (+/- 7 days) after study discontinuation) 
 Assessment of adverse events and concomitant medications 
 
5.3.8 
Follow-Up (to be performed every 3 months for the first 3 years after study 
discontinuation, and then yearly thereafter) 
 Review of anti-cancer treatments 
 Review of progression and survival information 
Assessments to be performed at screening and during scheduled study visits are also outlined in 
Section 2 Table of Study Assessments. 
At treatment discontinuation, subjects will undergo off study evaluations per the Schedule of 
Assessments, Section 2.   In addition, a safety assessment will be done approximately 28 days 
after the last dose of protocol therapy.  Follow-up contact with the subjects should occur at a 
minimum of 3 months during the first 3 years after finishing maintenance phase and annually 
after that. 


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5.4 Drug Administration 
5.4.1 
Dosing Regimen 
Lenalidomide capsule will be given by mouth daily (on days 1-28 of each 28 day cycle). 
Lenalidomide starting dose will be determined as detailed below. 
First 3 enrolled patients: The starting dose of lenalidomide for the first 3 subjects enrolled will 
be 10 mg daily. Three subjects must complete a full 28-day cycle before further study enrollment 
can proceed. The next cohort of 3 patients must also complete a full 28 day cycle before further 
enrollment can proceed. The lenalidomide starting dose for the remaining subjects will depend on 
the observance of dose limiting toxicities in this first cohort of 6 patients. 
No DLTs observed:  If the first 3 patients complete the first full cycle of study treatment 
without experiencing a DLT, then 3 additional patients will be enrolled. If 0 or 1 of 6 
patients experience DLT, then 10 mg will be considered the appropriate dose and the 
remainder of enrolled subjects will also use a lenalidomide starting dose of 10 mg daily 
(on days 1-28 of each 28 day cycle).  If 2 patients from the second 3-person cohort 
experience a DLT during the first cycle of study treatment, then 3 patients will be treated 
with lenalidomide at a dose of 5 mg daily (days 1-28 of each 28 day cycle).  3+3 
assessment will be conducted at 5 mg. 
One DLT observed:  If 1 out of the first 3 patients experiences a dose limiting toxicity 
during the first cycle of study treatment, an additional 3 patients will be treated with a 
starting dose of 10 mg daily and must complete a full cycle of study treatment before 
study enrollment can resume.  If no additional patients experience a DLT after the first 
cycle of treatment, then 10 mg will be considered the appropriate dose and the remainder 
of study patients will begin treatment using a lenalidomide dose of 10 mg daily.  If 1 
patient in the second 3-person cohort experiences a DLT, then 3 patients will be treated 
with lenalidomide at a dose of 5 mg by mouth daily.  The 3+3 assessment will be 
conducted at 5 mg. 
Two DLT’s:  If 2 patients from the first 3-person cohort experience a DLT during the 
first cycle of study treatment, then 3 patients will be treated with  lenalidomide at a dose 
of 5 mg daily (days 1-28 of each 28 day cycle).  3+3 assessment will be conducted at 5 
mg. 
Two DLT’s at 5 mg dose level:  If the starting dose level is determined to be 5 mg daily and 2 or 
more patients experience DLT’s at this dose level, the study will be stopped. 
 


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Dosing will be at approximately the same time each day.  Prescriptions must be filled within 7 
days. 
See section 5.6.1.2 for concomitant anti-coagulation. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should not be made up. 
Patients who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
Subjects experiencing adverse events may need study treatment modifications (See section 5.5). 
5.4.2 
Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
5.4.3 
Record of Administration 
Accurate records will be kept in the source documents of all drug administration (including 
prescribing and dosing).  Subjects should also record lenalidomide dosing on the study calendar 
during each cycle. 
 
 
Start first 3 
patients at10 mg 
daily 
days 1-28 (C1) 
No DLTs 
during C1 
1 DLT during 
C1 
2 or more 
DLTs during 
C1 
Enroll additional 
3 pts at 10 mg 
days 1-28 
No additional 
DLT’s during C1 
Starting dose is 
10 mg on days 
1-28 
1 additional DLT 
during C1 
Starting dose is 
5 mg on days  
1-28 
2 DLTs during 
C1 
Stop the study  
Enroll additional 
3 pts at 10 mg 
days 1-28 (C1) 
No additional 
DLTs or 1 DLT’ 
during C1 
2 additional DLT 
during C1 


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5.5 Dose Continuation, Modification and Interruption 
Subjects will be evaluated for AEs at each visit using the NCI CTCAE v4.0 as a guide for the 
grading of severity.   Sections below describe dose reduction steps, instructions for initiation of a 
new cycle of therapy and dose modifications during a cycle of therapy. 
5.5.1 
Dose Reduction Steps 
 
Table 1: Lenalidomide Dose Modification Steps 
Current Lenalidomide Dose 
One Level Dose Reduction 
10 mg daily (on days 1-28 of each 28 day cycle) 
5 mg daily (on days 1-28 of each 28 day cycle)* 
5 mg daily (on days 1-28 of each 28 day cycle)* 
See * below  
 
* Lenalidomide 5 mg daily (on days 1-28 of each 28 day cycle) is the minimum lenalidomide dose.  
Lenalidomide will be discontinued in patients who cannot tolerate this dose.  However, patients 
who experience toxicity requiring dose reduction while receiving lenalidomide 5 mg daily may, at 
the discretion of their physician, have their dose held until toxicity resolves as described in Sections 
5.5.2 and 5.5.3, and then restart lenalidomide 5 mg daily.  If the same toxicity recurs at 
lenalidomide 5 mg daily, consideration should be given to discontinuing lenalidomide. 
5.5.2 Instructions for Initiation of a New Cycle 
A new course of treatment may begin on the scheduled day 1 of a new cycle if: 
 The ANC is ≥ 1,000/uL 
 The platelet count is ≥ 50,000/uL 
 Any drug-related rash or neuropathy that may have occurred has resolved to ≤ 
grade 1 severity. 
 Any other drug-related adverse events that may have occurred have resolved to ≤ 
grade 2 severity. 
If these conditions are not met on day 1 of a new cycle, the subject will be evaluated 
weekly and a new cycle of treatment will not be initiated until the toxicity has resolved as 
described above. 
5.5.3 Instructions for Dose Modifications or Interruption During a Cycle 
Dose delay and dose reduction rules are as follows and in the table below. 
 Lenalidomide dose reduction steps are outlined in Section 5.5.1. 
 For treatment interruptions during a cycle, the 28-day schedule of each cycle will 
continue to be followed.  Missed doses of lenalidomide are not made up. 
 For treatment interruptions that delay the scheduled start of a new cycle, when 
toxicity has resolved as required to allow the start of a new cycle (Section 5.5.2), 
the restart day of therapy becomes day 1 of the next cycle. 


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Table 2: Dose Modifications : 
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
Grade 3 neutropenia 
associated with fever 
(T ≥ 38.5º C) or 
Grade 4 neutropenia 
 Hold (interrupt) lenalidomide dose. 
 Follow CBC weekly. 
 If neutropenia has resolved to ≤ grade 2 prior to Day 28 of the current 
cycle, restart lenalidomide at next lower dose level and continue 
through the scheduled Day 28 of the current cycle.  Otherwise, omit 
for remainder of cycle and reduce the dose of lenalidomide by 1 dose 
level at the start of the next cycle.  Omitted doses are not made up.  If 
neutropenia is the only toxicity for which a dose reduction is required, 
G-CSF may be used and the lenalidomide dose maintained. 
Thrombocytopenia 
≥Grade 3 (platelet 
count < 50,000/mm³) 
 Hold (interrupt) lenalidomide dose. 
 Follow CBC weekly. 
 If thrombocytopenia resolves to ≤ grade 2 prior to Day 28 of the current 
cycle, restart lenalidomide at next lower dose level and continue 
through the scheduled Day 28 of the current cycle.  Otherwise, omit 
for remainder of cycle and reduce the dose of lenalidomide by 1 dose 
level at the start of the next cycle.  Omitted doses are not made up. 
 Hold prophylactic anti-coagulation, if applicable. 
 Restart prophylactic anti-coagulation when platelet count is ≥ 
50,000/mm³. 
Non-blistering rash 
 
Grade 3 
 
 
 If Grade 3, hold (interrupt) lenalidomide dose.  Follow weekly. 
 If the toxicity resolves to ≤ grade 1 prior to Day 28 of the current cycle, 
restart lenalidomide at next lower dose level and continue through the 
scheduled Day 28 of the current cycle.  Otherwise, omit for remainder 
of cycle and reduce the dose of lenalidomide by 1 dose level at the 
start of the next cycle.  Omitted doses are not made up. 
               Grade 4 
 If Grade 4, discontinue lenalidomide.  Remove patient from study. 
Desquamating 
(blistering) rash- any 
Grade  
 Discontinue lenalidomide.  Remove patient from study. 
Lenalidomide-related 
neuropathy 
 
Grade 3 
 
 If Grade 3, hold (interrupt) lenalidomide dose.  Follow at least weekly. 
 If the toxicity resolves to ≤ grade 1 prior to Day 28 of the current cycle, 
restart lenalidomide at next lower dose level and continue through the 
scheduled Day 28 of the current cycle.  Otherwise, omit for remainder 
of cycle and reduce the dose of lenalidomide by 1 dose level at the 
start of the next cycle.  Omitted doses are not made up. 
Grade 4 
 If Grade 4, discontinue lenalidomide.  Remove patient from study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
 Hold (interrupt) lenalidomide and start therapeutic anticoagulation, if 
appropriate. 
 Restart lenalidomide at investigator’s discretion (maintain dose level). 
 See Anticoagulation Consideration (Section 5.6.1.2) 
Hyperthyroidism or 
hypothyroidism 
 
 Omit lenalidomide for remainder of cycle, evaluate etiology, and 
initiate appropriate therapy. 
 See Instructions for Initiation of a New Cycle and reduce the dose of 
lenalidomide by 1 dose level. 


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Table 2: Dose Modifications : 
NCI CTC Toxicity 
Grade 
Dose Modification Instructions 
(also see Instructions for Initiation of a New Cycle above) 
Creatinine ≥ Grade 2 
(>1.5 - 3.0 x baseline) 
 Hold lenalidomide dose until resolved to grade < 2. When re-starting, 
reduce lenalidomide by 1 dose level. Omitted doses are not made up.  
Other non-
hematologic toxicity 
≥ Grade 3 
 Hold (interrupt) lenalidomide dose.  Follow at least weekly. 
 If the toxicity resolves to ≤ grade 2 prior to Day 28 of the current cycle, 
restart lenalidomide and continue through the scheduled Day 28 of the 
current cycle.  Otherwise, omit for remainder of cycle.  Omitted doses 
are not made up.  For toxicity attributed to lenalidomide, reduce the 
lenalidomide dose by 1 dose level when restarting lenalidomide. 
 
5.5.4 Treatment Adherence 
Study personnel will review the dosing compliance with subjects at each clinic visit, and 
make record of treatment adherence in the patient’s medical record. In addition, study 
diaries will be provided to subjects at the beginning of each cycle of lenalidomide 
therapy.  Subjects will be asked to record days on which lenalidomide is taken, and return 
the study diary at the end of each cycle.  These diaries will not be mandatory, but will 
serve as supplemental documentation to dosing information collected during each study 
visit. 
Any unused Revlimid® (lenalidomide) should be returned by the patient for disposition 
in accordance with the Revlimid REMS® program. 
5.6 Concomitant Therapy 
5.6.1 Recommended Concomitant Therapy 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, analgesics, and antiemetics when appropriate. 
5.6.1.2 Anticoagulation 
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or 
with a history a thrombosis, in particular when combined with other drugs known to 
cause thrombosis. When lenalidomide is combined with other agents such as steroids 
(e.g. dexamethasone, prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin 
the risk of thrombosis is increased.  For information on the risk of venous 
thromboembolism with combined oral contraception see Appendix: Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods. 
Study subjects will use aspirin (81 or 325 mg) or some other form of prophylaxis as 
deemed appropriate while taking lenalidomide. Low molecular weight heparin may be 
utilized in patients who are intolerant of aspirin. Coumadin should be used with caution 
and close monitoring of INR.  Patients who are intolerant of anti-coagulants due to 


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bleeding disorders or for whom anti-coagulation is contraindicated may participate in this 
study and receive daily dosing with lenalidomide with approval from the principal 
investigator. 
If prophylactic anti-coagulation is used, it should be held for platelet counts < 50,000/uL, 
and then restarted when platelet counts are at or above this level. 
5.6.2 Prohibited Concomitant Therapy 
Concomitant use of sargramostim (GM-CSF), anti-cancer therapies, including radiation, 
thalidomide, or other investigational agents is not permitted while subjects are receiving 
lenalidomide therapy during the maintenance treatment phase of the study. 
5.7 Discontinuation of Study Treatment 
Study treatment will continue until the completion of 24 cycles of lenalidomide 
maintenance therapy, or the occurrence of any of the following events: 
 Disease progression (See Appendix D) 
 Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of the treatment regimen. 
 Discontinuation or interruption in lenalidomide therapy for > 28 consecutive days. 
 Withdrawal of consent 
 Lost to follow up 
 Death 
 Pregnancy or a positive pregnancy test 
 
5.8 
Follow-Up 
Subjects who discontinue treatment for any reason will be followed for resolution of 
treatment-related adverse events and survival.  At treatment discontinuation, subjects will 
undergo a safety assessment approximately 28 days post the last dose of protocol therapy.  
In addition, off study evaluations per the Schedule of Assessments, Section 2, will be 
performed. 
 
Subjects 
will 
be 
followed 
for 
additional 
chemotherapy 
and 
progression/survival data every three months for the first three years after study 
discontinuation, and then yearly until death or withdrawal from study participation. 
 
 


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6 Adverse Events 
6.1 Serious Adverse Event (SAE) Definition 
A serious adverse event is one that at any dose (including overdose): 
 
Results in death 
 
Is life-threatening
1 
 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
 
Results in persistent or significant disability or incapacity
2 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event
3 
 
Pregnancy 
 
 1“Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred.  
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be considered 
serious.  Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
A new diagnosis of cancer during the course of a treatment should be considered as 
medically important. 
6.2 Adverse Event Reporting 
The adverse event recording and reporting period will begin with each subject’s first dose 
of lenalidomide and will end twenty-eight days after each patient’s last dose of 
lenalidomide, or upon resolution of any treatment-related adverse events, should their 
duration extend beyond the 28-day reporting period.  Pre-existing conditions (those 
events existing prior to each patient’s first dose of lenalidomide) will not be reported as 
adverse events unless they worsen in grade or severity. 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (HTTP://CTEP.INFO.NIH.GOV).  All appropriate treatment areas should have 
access to a copy of the CTCAE Version 4.0.  All adverse clinical experiences, whether 
observed by the investigator or reported by the patient, must be recorded, with details 
about the duration and intensity of each episode, the action taken with respect to the test 
drug, and the patient’s outcome.  The investigator must evaluate each adverse experience 
for its relationship to the test drug and for its seriousness. 


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The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and 
about the patient’s outcome on the adverse event CRF.  Lab abnormalities graded < grade 
2 in severity will not be reported as adverse events, unless deemed to be clinically 
significant by the treating physician. 
Lymphopenia of any grade will not be considered an adverse event. 
6.2.1 Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on lenalidomide, or 
within  28 days of the subject’s last dose of lenalidomide, are considered immediately 
reportable events. Lenalidomide  is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile or email using the Pregnancy Initial Report Form. The female 
subject should be referred to an obstetrician-gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and 
must notify Celgene Drug Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Pregnancy Follow-up Report Form.  If the 
outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome 
meets any of the serious criteria, it must be reported as an SAE to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 28 days that the Investigator 
suspects is related to the in utero exposure to the IP should also be reported to Celgene 
Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of 
the Investigator’s knowledge of the event using the SAE Report Form. 
 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking lenalidomide should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately. 
 
 
 
 
 
 
 


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6.2.2 Celgene Drug Safety Contact Information: 
Celgene Corporation 
Attn: Medical Affairs Operations 
Connell Corporate Park 
300 Connell Dr. Suite 6000 
Berkeley Heights, N.J. 07922 
 
Fax: 
 
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
6.3 Investigator Reporting Responsibilities 
6.3.1 Expedited reporting by investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500 form of any SAE within 24 
hours of being aware of the event.  The written report must be completed and supplied to 
Celgene by facsimile within 24 hours/1 business day.  The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (RV-NHL-PI-
0623) and the institutional protocol number should be included on SAE reports (or on the 
fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient records. 
6.3.2 Report of Adverse Events to the Institutional Review Board/Data Safety 
Monitoring Committee 
Institutional Review Board: 
Serious adverse events which in the opinion of the principal investigator are both 
unexpected and related to research procedures should be reported to the IRB within 10 
working days of investigator notification.  An event is considered “unexpected” when its 
specificity and severity are not accurately reflected in the protocol-related documents, 
such as the IRB-approved research protocol, any applicable investigator brochure, 
applicable package insert information, and/or the current IRB-approved informed consent 
document.  An event is considered “related to the research procedures” if the event is 
deemed probably or definitely related. 
 
Deaths occurring for patients on-study and within 30 days of study drug administration 
that are considered unforeseen and indicates participants or others are at increased risk of 
harm (i.e. unexpected and probably/definitely related), must be reported to the IRB 
within 24 hours of notification. 
 


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In addition, if other information becomes available that indicates a change to the risks or 
potential benefits of the research, in terms of severity or frequency, this should be 
reported within 3 days.  Examples of this include: 
 An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
 Safety monitoring indicates that a particular side effect is more sever, or more 
frequent than initially expected. 
 A paper is published from another study that shows that an arm of your research 
study is of no therapeutic value. 
 Any adverse event that represents a serious, unexpected problem that is rare in 
absence of drug exposure. 
 Withdrawal from marketing for safety of a drug, device, or biologic used in a 
research protocol. 
 Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
 Violation, meaning an accidental or unintentional change to the IRB approved 
protocol that placed one or more participants at increased risk, or has potential to 
occur again. 
 Breach of confidentiality. 
The IRB will accept other reports when the investigator is unsure whether the event 
should be reported, and the IRB will review such reports to determine whether the event 
meets the threshold for an unanticipated event presenting risk to the participant. 
Office of Regulatory Affairs, Institutional Review Board 
3624 Market Street, Suite 301S, Philadelphia, PA  19104-6006 
Phone: 215-573-2540 
Fax: 215-573-9438 
 
Abramson Cancer Center Data Safety Monitoring Committee (DSMC): 
Grade 3 or higher AEs for Penn Subjects, determined to be related to the study drug 
regardless of expectedness,  must  be submitted to the Abramson Cancer Center’s DSMC 
within 10 days of notification. Other events should be submitted if they may affect 
subject safety, if they are determined to be clinically significant, or if a relationship to the 
study drug cannot be ruled out.  All unexpected deaths or deaths related to the study drug 
should be reported within 24 hours of notification.  All other deaths should be reported 
within 30 days.  Onsite SAE reports should be sent to the DSMC for 90 days following 
the last date the last subject received study drug, and will not be accepted or processed 
after that time.   The AE recording period for this protocol is defined above in Section 
6.2. 
 


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The following events do not require reporting to the ACC DSMC. The treating 
investigator must clearly document the relationship of these events. 
 Grade 3 or 4 events that are probably or definitely related to the subjects’ 
underlying disease and/or other co-morbidity. 
 Grade 3 or 4 events that are probably or definitely related to an FDA approved 
drug based on the current labeling.  However if the toxicity is more severe or is 
occurring more frequently than the current labeling, the event would be reportable.  
If the drug is not being used in accordance with the current FDA approval (i.e. 
dose, disease, route) then standard reporting is required. 
 Grade 3 or 4 events that are obviously unrelated to the study drug (i.e. events 
related to a standard of care test/procedure). 
AEs will be submitted to the DSMC through the Velos Clinical Trial Management 
System. 
Medical Monitor: 
The medical monitor for this study will be Dr. Amy Clark from the University of 
Pennsylvania.  Dr. Clark is an Assistant Professor in the Department of Hematology-
Oncology at Penn, with extensive oncology and research experience. Dr. Clark has 
served as the Principal Investigator and as a Sub-Investigator on various other Oncology 
Studies at Penn. Dr. Clark is not directly involved in the trial and is not collaborating with 
the sponsor-investigator on any other trials. 
In the role, Dr. Clark will review all AEs including grading, toxicity assignments, all 
other safety data and activity data observed in the ongoing clinical trial. This will include 
a real-time review of safety data in the event of any unexpected/related SAE regardless of 
grade, and any on-study deaths. The Medical Monitor will also be consulted in the case 
of exception requests or the evaluation of deviations that may compromise subject safety 
or disrupt the design of the study. This information will be communicated to the Medical 
Monitor via email and filed in the Regulatory Binder/Subject Chart appropriately. As 
applicable, copies of this correspondence will be included in the corresponding IRB/ACC 
DSMC submission of these events. 
The Medical Monitor will also be asked to review study data and comprehensive adverse 
event data at least bi-annually (every 6 months) or more frequently depending on 
enrollment. This meeting will take place in person, and all study/safety information will 
be presented appropriately. This meeting will be clearly documented on a Medical 
Monitor Review Sheet, signed off on by the Medical Monitor.  At any point during the 
course of the study, the Medical Monitor may recommend reporting of adverse events 
and relevant safety data not previously reported and may recommend suspension or 
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6.4 Adverse Event Updates/IND Safety Reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
 Any AE that is possibly, probably or definitely associated with the use of drug in 
this study or in other studies that is both serious and unexpected. 
 Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
The Investigator shall notify the University of Pennsylvania IRB promptly of any new serious 
and unexpected AE(s) or significant risks to subjects that meet the local reporting policy. 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB on file (see Section 11.4 for records retention information). 
7 Response Assessment 
Baseline lesion assessments must occur within  28 days of protocol therapy initiation or as 
indicated in Section 2, Schedule of Study Assessments. 
Efficacy assessments are scheduled to occur within 28 days prior to starting lenalidomide 
therapy, every three cycles during the first year, and every four cycles during the second 
year of study participation.  Clinical assessments, including laboratory studies and physical 
exams, will occur monthly throughout study participation.  Follow-up contact with the subjects 
should occur at a minimum of 3 months during the three years after finishing maintenance phase and 
annually after that.  The frequency of follow-up imaging after completing 24 cycles of 
lenalidomide maintenance will be at discretion of the treating physician. 
8 Protocol Amendments and Deviations 
8.1 Protocol Amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed by Celgene.  Amendments should only be submitted to IRB/CTSRMC after 
consideration of Celgene review.  Written verification of IRB/CTSRMC approval will be 
obtained before any amendment is implemented. 
8.2 Protocol Deviations 
Reportable Events: 
An one-time accidental or unintentional deviation from the approved protocol, identified 
retrospectively, that in the opinion of the investigator or as defined by the protocol, 
placed one or more participants at increased risk, compromises the rights or welfare of 
subjects, and/or disrupts the study design, is considered a reportable event and must be 
reported to the Study Principal Investigator, Study Medical Monitor, IRB, and ACC 
DSMC within 10 working days of notification. Principal Investigator and Medical 
Monitor approval/acknowledgement must be received first and included in with the 
IRB/DSMC submission. 
Deviations to protect subjects from immediate harm/danger should be reported 
immediately following the event to the entities outlined above. 


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Exceptions: 
An exception is defined as a one-time, unintentional action or process that departs from 
the IRB and CTSRMC approved study protocol, intended for one occurrence. AND this 
action disrupts the study progress, such that the study design or outcome (endpoints) may 
be compromised, or the action compromises the safety and welfare of study subjects (i.e. 
requests to enroll and/or treat subjects outside of the current protocol criteria). Exceptions 
that meet this criteria will not be allowed unless reviewed and approved first by the Study 
Medical Monitor and the Study Principal Investigator, and then subsequently by the ACC 
DSMC, and IRB prior to this subject being enrolled/treated.  Principal Investigator and 
Medical Monitor approval must be received first and included in with the IRB/DSMC 
submission. All entities should be given sufficient time to evaluate this request. 
Examples of Exceptions/Deviations that require submission include: 
 Violations of eligibility 
 Dose adjustments/stopping rules that were not completed per protocol 
 Other dosing errors 
Events not deemed reportable as outlined above will require a PI assessment regarding 
study and/or safety impact. 
9 Data Management 
9.1 Analyses and Reporting 
Data will be initially analyzed and reported on the 24 patients after the period of 12 
months from starting lenalidomide maintenance. All subsequent data collected will be 
analyzed and reported in a follow-up clinical report. 
9.2 Data Monitoring Committee 
Interim analyses of toxicity are to be performed after the first three patients finish one 
month of lenalidomide maintenance therapy, and then quarterly thereafter. 
This investigator initiated protocol is considered high risk as per the Abramson Cancer 
Center Data and Safety Monitoring Plan (DSMC). As such, high risk protocols are 
audited approximately three-six months from their first subject accrual and approximately 
every six month thereafter for the duration of the study by the ACC Department of 
Compliance and Monitoring (DOCM). However, this schedule may be changed at the 
discretion of the DSMC. High or quick enrolling studies may be audited more frequently 
as necessary. 
The PI will be notified in advance of the selection of their protocol for review and cases 
are randomly selected. Three randomly selected subjects or 10% of the total accrual (up 
to 10 subjects), whichever is higher, are audited. A formal report is written to the PI 
within about 5 business days of the audit. The committee may alter the frequency of re-
monitoring based on the audit findings and degree of deficiencies. 


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Upon review of inspection findings, the Committee designates the audit outcome as 
Minor, Moderate, or Major deficiencies.  The deficiency assigned by the Committee 
initiates specific follow-up actions. 
If an audit is unacceptable due to major deficiencies, representatives from the Department 
of Monitoring and Compliance (DOCM) meet with the PI to discuss the findings of the 
audit and review necessary corrective actions mandated by the DSMC. If the deficiencies 
involve subject safety or serious regulatory violations, the Cancer Center Director, 
DSMC Chair, and DSMC Administrative Director will meet to discuss necessary actions 
concerning study status. 
The PI is given five business days to respond to these finding. An evaluation of the 
deficiencies will be re-evaluated upon receiving the PI’s response. At this time, if the 
DSMC Chair and the Administrative Director do not find the response satisfactory, the 
IRB and OHR will be alerted of the actions taken by the ACC. The DSMC Director will 
update the IRB and OHR of the corrective actions being taken and progress being made. 
Quarterly team meetings will also be held throughout the course of this study in order to 
discuss the protocol, ongoing patients, toxicity data, and applicable recruitment issues. 
9.3 
Study Auditing 
9.3.1 Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice 
(GCP) and in the US Code of Federal Regulations. 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
ACC DOCM, the supporter (Celgene), government regulatory bodies, and University 
compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.). 
The Investigator will permit study-related audits by Celgene or its representatives 
providing direct access to the facilities where the study took place, to source documents, 
to CRFs, and to all other study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at 
some time during audits to review data and resolve any queries and to allow direct access 
to the subject’s records (e.g., medical records, office charts, hospital charts, and study 
related charts) for source data verification.  The data collection must be completed prior 
to each visit and be made available to the Celgene representative so that the accuracy and 
completeness may be checked. 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 


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10 Statistical Considerations 
10.1  Design 
This is a single arm phase I/II trial of lenalidomide maintenance for patients with high 
risk relapsed/refractory lymphomas who underwent high dose chemotherapy and ASCT. 
At 28-100 days post-ASCT, eligible patients will begin lenalidomide maintenance. The 
trial will be conducted in two stages. Phase I will evaluate the safety of lenalidomide 
implemented after ASCT by a 3+3 cohort design. Once the safety of a specific dose after 
ASCT is established, additional patients will be enrolled in phase II to evaluate the 
progression-free survival.  PFS is a relevant endpoint for lenalidomide maintenance since 
it is expected to delay progression of disease post-ASCT. A monitoring rule for 
unacceptable toxicity due to lenalidomide will be followed during phase II. 
10.2 Objectives 
The primary objective: 
-Dose-limiting toxicity due to lenalidomide 
 
The secondary objective is to determine: 
-Progression-free survival 
-Overall survival 
 
10.3 Endpoints 
Dose-limiting toxicity (DLT) is defined as any grade 3 toxicity or higher that occurs 
during the first 28 days of therapy and is possibly, probably or definitely related to 
lenalidomide maintenance.  Because certain levels of toxicity are considered acceptable 
in lymphoma therapy, the definition of DLT is limited to the following: 
-Any grade 3 or higher non-hematologic toxicity possibly, probably or definitely 
related to lenalidomide. 
-Grade 4 hematologic toxicity not attributable to progressive disease and that does 
not decrease to a grade 3 or less within 7 days of drug cessation. 
-Lymphopenia of any grade and anemia of any grade are not considered a DLT. 
-Nausea and vomiting are not considered DLTs unless they cannot be controlled 
with standard antiemetic therapy. 
-Diarrhea is not considered a DLT unless it cannot be controlled with standard 
anti-diarrheal therapy. 
-Nausea, vomiting, heartburn, anorexia, diarrhea, or constipation that improved to 
grade 1 or better within 2 days with the addition of symptom directed treatment 
will not be considered a DLT. 
NCI Common toxicity criteria (CTC Version 4.0) grades will be employed.  Toxicity 
unrelated to lenalidomide (i.e. clearly related to ASCT) will be scored separately. 


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Progression-free survival (PFS) is defined from date of ASCT (day 0) to first documented 
progression of disease, death due to any cause or last patient contact. Progression-free 
survival rate at 12 months (PFS12) is also of interest and is defined as the percentage of 
patients that are alive and progression-free at 12 months. Overall survival (OS) is defined 
as days from date of ASCT to death due to any cause or last patient contact. 
Patients are enrolled 28 to 100 days after ASCT (day 0).  Patients who complete one full 
cycle of lenalidomide maintenance or who experience DLT during the first cycle will be 
considered evaluable for DLT determination.  Patients who withdraw from the study 
prior to initiation of lenalidomide maintenance, or who initiate and discontinue 
lenalidomide maintenance before completing one full cycle and do not experience DLT, 
remain in the study population and are followed for PFS and OS but do not contribute to 
the determination of DLT.  These patients will be included in the estimation of PFS and 
OS, according to an intent-to-treat analysis plan.  A secondary analysis of PFS and OS 
will include only patients who complete at least one full cycle of lenalidomide or who 
experience DLT at any point during cycle 1 (“evaluable population”).  Patients who did 
not progress will be censored at the time of last contact. Evaluable patients contribute to 
determination of DLT, PFS and OS. Evaluable patient outcomes will be compared to 
historical rates for PFS12. 
10.4 Phase I Design 
A 3+3 design will be employed to determine the tolerability of lenalidomide maintenance 
at the dose of 10 mg daily in this setting. The dose will not be escalated, but in the event 
of 2 or more DLTs at 10 mg, the dose will be de-escalated to 5 mg. 
 
Dose Level 1: Three evaluable patients will be treated at 10 mg lenalidomide.  
 
If 2 or more of 3 evaluable patients have DLT, then the dose will be de-escalated to 5 
mg.  
If 0 or 1 of 3 evaluable patients has DLT, then 3 more evaluable patients will be treated 
at 10 mg daily. 
 
 
If 0 or 1 of 6 evaluable patients has DLT, then 10 mg will be declared the 
appropriate dose for phase II part of the trial. 18 additional evaluable patients will 
then be enrolled in phase II. 
If 2 or more of 6 evaluable patients have DLT, then the dose will be de-escalated 
to 5 mg daily. 
Dose Level -1: Three evaluable patients will be treated at 5 mg lenalidomide. 
 
If 2 or more of 3 evaluable patients have DLT, then the appropriate dose is not defined 
and the trial will be terminated. 
If 0 or 1 of 3 evaluable patients has DLT, then 3 more evaluable patients will be treated 
at 5 mg daily. 
 
 
If 0 or 1 of 6 evaluable patients has DLT, then 5 mg will be declared the 
appropriate dose. 
18 additional evaluable patients will then be enrolled in phase II. 
If 2 or more of 6 evaluable patients have DLT, then the appropriate dose is not 
defined and the trial will be terminated. 


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10.5 Rules for Early Termination for Dose Limiting Toxicity during Phase II 
Bayesian probability calculations will be employed to define rules for early termination. The table 
below indicates termination rules after groups of 6 evaluable patients have been treated. We will 
assume prior information equivalent to that of 6 treated patients which is commonly required to 
establish safety in a standard 3+3 phase I design. We will assume a beta(1,5) prior, which is 
information equivalent to DLT observed in 1 of 6 treated patients. A DLT rate <33% is 
considered acceptable. If the number of patients with DLT is greater than or equal to the number 
in the table below then termination will be considered as it is likely that the DLT rate is >33%, as 
noted by the Bayesian posterior probabilities. 
BAYESIAN TERMINATION RULE FOR DOSE LIMITING TOXICITY 
PATIENTS TREATED WITH LENALIDOMIDE 
12 
18 
24 
PATIENTS WHO EXPERIENCE DLT 
7 
9 
11 
POSTERIOR PROB [DLT RATE >33%] 
0.84 
0.80 
0.78 
ACTION  
TERMINATE ENROLLMENT 
 
10.6  Plans for Data Analysis 
All observed toxicities will be graded and tabled. The toxicities may be stratified as either related 
to lenalidomide or other medications (i.e. high dose chemotherapy and ASCT).  Progression-free 
survival and overall survival will be estimated by the method of Kaplan and Meier. A minimum 
of 12 months of observation time is required on all patients (or less if patient has failed), in order 
to estimate PFS12. The PFS12 rate and 95% confidence interval will be computed. In addition to 
the observed rate and 95% CI, evidence for success of lenalidomide will be assumed if >4 of 24 
evaluable patients are alive and progression-free at 12 months, based on operating characteristics 
defined by binomial probabilities. The probability of observing >4 patients alive and progression-
free in 24 patients when true rate is 10%, is 0.09 (false positive rate). The probability of observing 
<4 patients alive and progression-free when true rate is 30%, is 0.11 (false negative rate). 
10.7  Sample Size 
Twenty-four evaluable patients will be enrolled. If the rate of enrolled patients who underwent 
ASCT and do not receive lenalidomide is about 15% then at least 28 patients may need to be 
enrolled.  Regimens of high dose chemotherapy and ASCT for high risk (PET positive) 
lymphomas have historically produced a PFS12 of <10%.  Single agent lenalidomide in 
relapsed/refractory lymphomas has been shown to produce a PFS12 of approximately 30%.  The 
use of lenalidomide after high dose chemotherapy and ASCT will be considered worthy of further 
development if the PFS12 is 30% and will be considered not worthy of further development if the 
PFS12 is 10%. A total of 24 evaluable patients will provide 89% power for an exact test for a 
single proportion, with null rate of no interest (0) of 10%, alternative rate of interest (A) of 30%, 
at one-sided type I error () = 10%. A one-sided test is appropriate for early phase trials seeking 
to detect an improvement over historical rates. 
10.8  Study Duration 
Assuming that lenalidomide at 10 mg will be feasible and an accrual rate of 8-10 patients per 
year, accrual will continue for initial 36 months. PFS12 will be evaluated 12 months after end of 
accrual.  Lenalidomide maintenance will continue for up to 24 months after the end accrual.  The 
total duration of the study will be up to 60 months. 


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11 
Regulatory Considerations 
11.1 Institutional Review Board/Clinical Trials Scientific Review and 
Monitoring Committee Approval 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki.  The review of this protocol by the 
IRB/CTSRMC and the performance of all aspects of the study, including the methods 
used for obtaining informed consent, must also be in accordance with principles 
enunciated in the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal 
Regulations (CFR), Part 50 Protection of Human Subjects and Part 56 Institutional 
Review Boards. 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/CTSRMC and obtaining written approval for this study.  The approval will 
be obtained prior to the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of 
approval and version date. 
Any amendments to the protocol after receipt of IRB/CTSRMC approval must be 
submitted by the Investigator to the IRB/CTSRMC for approval. 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/CTSRMC prior to use. 
11.2 Informed Consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents.  
The original consent form signed and dated by the subject and by the person consenting 
the subject prior to the subject’s entry into the study, must be maintained in the 
Investigator’s study files. 
11.3 Subject Confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy.  In 
compliance with United States federal regulations, Celgene requires the Investigator to 
permit representatives of Celgene Corporation and, when necessary, representatives of 
the FDA or other regulatory authorities to review and/or copy any medical records 
relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual. 


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11.4 Study Records Requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the protocol therapy, that is copies of CRFs and source 
documents (original documents, data, and records [e.g., hospital records; clinical and 
office charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; 
SAE reports, pharmacy dispensing records; recorded data from automated instruments; 
copies or transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical study; documents regarding subject treatment and drug accountability; 
original signed informed consents, etc.]) be retained by the Investigator for as long as 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval).  The 
Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 
11.5 Premature Discontinuation of Study 
The Principal Investigator, institution and Celgene have the right to discontinue this study 
at any time for reasonable medical or administrative reasons.  Possible reasons for 
termination of the study could be but are not limited to: 
 Unsatisfactory enrollment with respect to quantity or quality. 
 Inaccurate or incomplete data collection. 
 Falsification of records. 
 Failure to adhere to the study protocol. 
Any possible premature discontinuation would be documented adequately with reasons 
being stated, and information would have to be issued according to local requirements 
(e.g., IRB/EC, regulatory authorities, etc.). 


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Appendices 
Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied 
nor has the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is 
structurally related to thalidomide.  Thalidomide is a known human teratogenic active 
substance that causes severe life-threatening birth defects.  An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of 
female monkeys who received the drug during pregnancy.  The teratogenic effect of 
lenalidomide in humans cannot be ruled out.  Therefore, a risk minimization plan to 
prevent pregnancy must be observed. 
All study participants must be registered into the mandatory Revlimid REMS® program, 
and be willing and able to comply with the requirements of Revlimid REMS®. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature female who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 
The investigator must ensure that: 
 Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of 
understanding 
 Females NOT of childbearing potential acknowledge that she understands the 
hazards and necessary precautions associated with the use of lenalidomide 
 Male patients taking lenalidomide acknowledge that he understands that traces of 
lenalidomide have been found in semen, that he understands the potential 
teratogenic risk if engaged in sexual activity with a female of childbearing 
potential, and that he understands the need for the use of a condom even if he has 
had a vasectomy, if engaged in sexual activity with a female of childbearing 
potential. 
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study: 1) for at 
least 28 days before starting lenalidomide; 2) throughout the entire duration of 
lenalidomide treatment; 3) during dose interruptions; and 4) for at least 28 days after 
lenalidomide discontinuation. 


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The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider 
of contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception: 
o Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
o Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended. If a patient is currently using combined oral contraception the patient 
should switch to one of the effective method listed above. The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-treatment 
with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with neutropenia. 
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing 
potential who commit to complete abstinence, as outlined below. 
Before Starting Lenalidomide 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
prescribing lenalidomide.  The first pregnancy test must be performed within 10-14 days 
prior to prescribing lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to prescribing lenalidomide.  The patient may not receive 
lenalidomide until the Investigator has verified that the results of these pregnancy tests 
are negative. 
Male Patients: 
Must agree to practice complete abstinence or agree to use a condom during sexual 
contact with pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 days 
following lenalidomide discontinuation, even if he has undergone a successful 
vasectomy. 


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During 
Study 
Participation 
and 
for 
28 
days 
Following 
Lenalidomide 
Discontinuation 
Female Patients: 
 FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
every 28 days throughout the duration of lenalidomide treatment, including dose 
interruptions, at lenalidomide discontinuation, and at Day 28 following 
lenalidomide discontinuation.  If menstrual cycles are irregular, the pregnancy 
testing must occur weekly every 14 days throughout the duration of lenalidomide 
treatment, including dose interruptions, at lenalidomide discontinuation, and at 
Day 28 following lenalidomide discontinuation. 
 At each visit, the Investigator must confirm with the FCBP that she is continuing 
to use two reliable methods of birth control at each visit during the time that birth 
control is required. 
 If pregnancy or a positive pregnancy test does occur in a study patient, 
lenalidomide must be immediately discontinued. 
 Pregnancy testing and counseling must be performed if a patient misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide 
treatment must be temporarily discontinued during this evaluation. 
 Females must agree to abstain from breastfeeding during study participation and 
for at least 28 days after lenalidomide discontinuation. 
Male Patients: 
 Must practice complete abstinence or use a condom during sexual contact with 
pregnant females or females of childbearing potential throughout the entire 
duration of lenalidomide treatment, during dose interruptions and for at least 28 
days following lenalidomide discontinuation, even if he has undergone a 
successful vasectomy. 
 If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
Additional precautions: 
 Patients should be instructed never to give lenalidomide to another person. 
 Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of lenalidomide. 
 Male patients should not donate blood, semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide. 
 Only enough lenalidomide for one cycle of therapy may be prescribed with each 
cycle of therapy. 


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


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Appendix C: International Workshop Response Criteria (IWRC) for Non-
Hodgkin Lymphoma 
 
Complete Response (CR) 
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., lactate dehydrogenase [LDH] 
definitely assignable to NHL. 
 
All lymph nodes and nodal masses must have regressed to normal size (< 1.5 cm in their 
greatest transverse diameter for nodes > 1.5 cm before therapy).  Previously involved 
nodes that were 1.1 to 1.5 cm in their 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). 
 
The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must 
have of the difficulties in accurately evaluating splenic and hepatic size.  For instance, 
spleens thought to be of normal size may contain lymphoma, whereas an enlarged spleen 
may not necessarily reflect the presence of lymphoma but variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or other causes.  The determination of 
splenic volume or splenic index by CT scan is cumbersome and not widely used.   Any 
macroscopic nodules in any organs detectable on imaging techniques should no longer be 
present.  Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have decreased in size. 
 
If the bone marrow was involved by lymphoma before treatment, the infiltrate must be 
cleared on repeat bone marrow aspirate and biopsy of the same site.  The sample on 
which this determination is made must be adequate (>20 mm biopsy core).   Flow 
cytometric, molecular, or cytogenetic studies are not considered part of routine 
assessment to document persistent disease at the present time. 
 
Complete Response/Unconfirmed (Cru) 
CR/unconfirmed (CRu) includes those subjects who fulfill criteria 1 and 3 above, but 
with one or more of the following features: 
 
A 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. 
Indeterminate bone marrow (increased number or size of aggregates without cytological 
or architectural atypia). 
 


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Partial Response (PR) 
>50% decrease in SPD of the six largest dominant nodes or nodal masses.  These nodes 
or masses should be selected according to the following features: (a) they should be 
clearly measurable in at least two perpendicular dimensions, (b) they should be from as 
disparate regions of the body as possible, and (c) they should also include mediastinal 
and retroperitoneal areas of disease whenever these sites are involved. 
 
No increase in the size of the other nodes, liver, or spleen. 
 
Splenic and hepatic nodules must regress by at least 50% in the SPD. 
 
With the exception of splenic and hepatic nodules, involvement of other organs is 
considered assessable and not measurable disease. 
 
Bone marrow assessment is irrelevant for determination of a PR because it is assessable 
and not measurable disease; however, if positive, the cell type should be specified in the 
report, e.g., large-cell lymphoma or low-grade lymphoma (i.e., small, lymphocytic small 
cleaved, or mixed small and large cells.) 
 
No new sites of disease. 
 
Stable Disease (SD) 
Stable disease is defined as less than a PR (see above) but is not progressive disease (see 
below). 
 
Relapsed Disease (RD) 
Appearance of any new lesion or increase by >50% in the size of previously involved 
sites (only applies to subjects that achieve a CR). 
 
>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 (PD) 
>50% increase from nadir in the SPD of any previously identified abnormal node for PRs 
or nonresponders. 
Appearance of any new lesion during or at the end of therapy which is >1.5 cm by 
radiologic evaluation or greater than 1 cm by physical examination 
 


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