Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) to Treatment With Lenalidomide (Revlimid®)) Alone and in Combination With Epoetin Alfa (Procrit®)) in Subjects With Low- or Intermediate-1 Risk MDS and Symptomatic Anemia
Phase: PHASE3
Conditions: Anemia, Chronic Myelomonocytic Leukemia, De Novo Myelodysplastic Syndrome, Myelodysplastic Syndrome
Sponsor: National Cancer Institute (NCI)

 
i 
28 State Street, Suite 1100, Boston, MA 02109 
p: 857.504.2900 
f: 617. 589.0914 
ecog-acrin.org 
 
 
November 7, 2019 
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office 
Quality Assurance Section 
CTEP, DCT, NCI 
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD   20892 
Dear Ms. Kruhm: 
Enclosed is Addendum #15 to E2905, Randomized Phase III Trial Comparing the Frequency of 
Major Erythroid Response (MER) to Treatment with Lenalidomide (Revlimid®) Alone and in 
Combination with Epoetin Alfa (Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and 
Symptomatic Anemia. 
This addendum is in response to the request for Amendment from Dr. Howard Streicher on 
August 13, 2019. 
There are no revisions to the case report forms as a result of this amendment. 
 
Please replace your current copy of the protocol and Informed Consent document (if ICD 
changed) with this (these) updated version(s).  We recommend that each institution maintain a 
file containing the original protocol, Informed Consent, and all subsequent revisions/versions. 
 
IRB Review Requirements: 
Full IRB review of this addendum is recommended, however, ECOG-ACRIN will accept the 
method of review determined by the standard operating procedures for the IRB of record for this 
protocol. It is the decision of the local IRB whether or not subjects are to be re-consented.. This 
addendum must be submitted and reviewed by your IRB within 90 days of receipt of this notice, 
unless your local IRB has different written SOPs, which must be available at future ECOG-
ACRIN audits. 
 
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form 
changes have been approved by the CIRB and must be activated within 30 days of the CIRB 
posting of this notice.  
 
Sites not using the NCI CIRB: Per CTMB Guidelines, the protocol updates and/or  
informed consent changes must be approved by local IRBs within 90  
days of distribution of this notice. If your local IRB has different SOPs, they must be available at 
future E-A audit. 

ii 
The following are ECOG-ACRIN’s responses to CTEP’s Review of Amendment #21 of Protocol 
#E2905: “Randomized Phase III Trial Comparing the Frequency of Major Erythroid 
Response (MER) to Treatment with Lenalidomide (Revlimid®) Alone and in Combination 
with Epoetin Alfa (Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and 
Symptomatic Anemia” dated October 07, 2019, from the disapproval of Addendum #15 
submission to CTEP. Please note that the Principal Investigator’s comments appear in bold 
below: 
I. Comments Requiring a Response– Administrative & Editorial Issues: 
# 
Section 
Comments 
1. 
5.4 
Please add the following that was not added as part of the updated CAEPR for 
lenalidomide under the first NOTE: 
NOTE: In a trial of first line treatment of patients with chronic lymphocytic leukemia 
(CLL), single agent lenalidomide (CC-5013) increased the risk of death as compared to 
control arm (chlorambucil). 
NOTE: In two randomized trials of patients with multiple myeloma (MM), the addition of 
MK-3475 (pembrolizumab) to a thalidomide analog plus dexamethasone, resulted in 
increased mortality.  Treatment of patients with MM with a PD-1 or PD-L1 blocking 
antibody, such as MK-3475 (pembrolizumab), in combination with a thalidomide 
analog, such as lenalidomide, is not recommended outside of controlled clinical trials. 
NOTE:  In a clinical trial in patients with Mantle cell lymphoma (MCL), there was an 
increase in early deaths (within 20 weeks); 12.9% in the lenalidomide (CC-5013) arm 
vs. 7.1% in the control arm. 
PI Response: This has been added.  
2. 
8 
In the first and third NOTE, please rephrase the paragraph to include that those 
patients who previously received Procrit from the NCI will be switched to the 
commercially supplied Procrit. 
Will all vial sizes be used for this study? Recommend moving the applicable vial sizes 
to 8.2.8.   
The second NOTE should be deleted as it is now a duplicate of the first NOTE. 
Under availability, please make the following deletion: 
Lenalidomide (NSC# 703813) and epoetin alfa (NSC# 628281) may be 
requested by the Principal Investigator (or their authorized designees) at each 
participating institution. 
The third NOTE should be rephrased to: As of the activation of Addendum#13, all 
patients will receive epoetin alfa (Procrit) through the commercial channels, or through 
the ESA Apprise Oncology program. 
PI Response: These edits have been applied.  
3. 
8 
Under availability, please update the weblinks: 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application 
< https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx 
https://ctepcore.nci.nih.gov/OAOP>. Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account < https://eapps-
ctep.nci.nih.gov/iam/ https://ctepcore.nci.nih.gov/iam/ > and the maintenance of an 
“active” account status, and a “current” password, and active person registration 
status. 
PI Response: This has been changed.  

iii 
# 
Section 
Comments 
4. 
8.2.4 
8.2.6 
Please update these sections if multiple vial sizes are available.  Currently only the 
multidose vial information is included. 
PI Response: We’ve updated Sections 8.2.4 and 8.2.6 to include information on 
the multiple vial sizes available.  
5. 
8.2.8 
In Availability, please remove “Epoetin alfa (Procrit) will be supplied by the National 
Cancer Institute as a 20,000 units/mL, multidose, preserved vials for patients 
registered to this study on or prior to December 31, 2012.” 
Add, “Those patients who had previously received Procrit from the NCI will be switched 
to the commercially supplied Procrit.” 
Please edit. 
As of Addendum#13, all patients will receive epoetin alfa (Procrit) through the 
commercial channels, or through the ESA Apprise Oncology program. 
PI Response: These edits have been applied.  
6. 
ICD – 
Page 2 
In the Note under During the study, please rephrase the paragraph to say that as of 
April 2017, epoetin alfa (Procrit) will be supplied through commercial channels, or 
through the ESA Apprise Oncology program.  
PI Response: This has been changed. 
7. 
ICD – 
Page 13 
Please change the following paragraph:   
“As of April 2017, epoetin alfa (Procrit) will be supplied through commercial channels, 
referred to as the ESA APPRISE Oncology program., for all patients. You or your 
insurance company will have to pay for the epoetin alfa (Procrit)”  
to  
“As of April 2017, all patient will receive epoetin alfa (Procrit) through commercial 
channels, or through the ESA Apprise Oncology program. You and/or your insurance 
will be responsible for the cost of epoetin alfa (Procrit).” 
PI Response:  This has been changed.  
The following revisions to E2905 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date. 
2. 
5.3.3 
In second paragraph, first bullet, updated the AE Team at ECOG – ACRIN 
telephone number.  
3. 
5.3.3 
In sub-section, “Supporting and follow up data” updated the NCI/CTEP fax 
number in the last sentence.  
4. 
5.3.4 
In second paragraph, first sentence updated ECOG –ACRIN telephone 
number.  
5. 
5.4 
Updated the CAEPR for Lenalidomide (CC-5013, NSC 703813) to Version 
2.8, June 27, 2019. 
6. 
Appendix XIV 
In sub-section, “Additional Required Forms”, updated NCI/CTEP fax 
number.   

iv 
The following revisions to E2905 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date. 
2. 
“What side effects or 
risks can I expect 
from being in the 
study” 
Updated the risk list for Lenalidomide (CC-5013, NSC 703813) to Version 
2.8, June 27, 2019. 
If you have any questions regarding this addendum, please contact aagu@ecog-acrin.org or 
857-504-2900. 
We request review and approval of this addendum to E2905 so ECOG-ACRIN may activate it 
promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director, Protocol Development 
Enclosure 
CC: 
Alan List, M.D. 
Amit Verma, M.D. 
Mark Litzow, M.D. 
Zhuoxin Sun, Ph.D. 
Martin S. Tallman, M.D. 
Andrew Artz, M.D. 
Charles A. Schiffer, M.D. 
Aaron Cumpston, PharmD, BCOP 
Gary Lewis, R.Ph 
Mike Fallon, PharmD  
Jennifer Kate Piccolo, PharmD, BCOP 
 
Carol Chami, R.N. 
Melinda Flood 
Bruce Giantonio, M.D. 
Peter O’Dwyer, MD 
Donna Marinucci 
Kerry Higgins 
Sarah Archambault 
Jean MacDonald 
Abuchi Agu 
Lauren Lambert 
Henry Baptista  
 
 

E2905 
 
1 
Randomized Phase III Trial Comparing the Frequency of 
Major Erythroid Response (MER) to Treatment with 
Lenalidomide (Revlimid®) Alone and in Combination with 
Epoetin Alfa (Procrit®) in Subjects with Low- or 
Intermediate-1 Risk MDS and Symptomatic Anemia 
STUDY CHAIR: 
Alan List, M.D. 
STUDY CO-CHAIRS: 
Amit Verma, M.D. 
PATHOLOGY CO-CHAIR: 
John Bennett, M.D. 
LABORATORY CO-CHAIR: 
Alan List, M.D. 
STUDY STATISTICIAN: 
Zhuoxin Sun, Ph.D. 
COMMITTEE CHAIR: 
Martin S. Tallman, M.D. 
CALGB CO-CHAIR: 
Andrew Artz, M.D. 
SWOG CO-CHAIR: 
Charles A. Schiffer, M.D. 
Version Date:  November 7, 2019 
NCI Update Date:  August 18, 2010 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
NRG / NRG Oncology Foundation, Inc  
SWOG / SWOG 
 
January 29, 2009 
ALLIANCE / Alliance for Clinical Trials in Oncology  
Update #1 – 1/09 – Incorporated Prior to Activation 
 
 
Addendum #1 – 10/09 
Addendum #2 – 1/10 
Addendum #3 – 3/10 
Update #2 – 8/10 
 
 
Addendum #4 – 6/11 
 
 
Addendum #5 – 7/11 
Addendum #6 – 10/11 
Addendum #7 – 6/13 
 
 
 
Addendum #8 –11/13 
 
 
 
Addendum #9 – 6/14 
 
 
 
Addendum #10 – 10/14 
 
 
 
Addendum #11 – 4/15 
 
 
 
Addendum #12 – 7/16 
 
 
 
Addendum #13 – 5/17 
 
 
 
Addendum #14 
 
 
 
Addendum #15 
 
Lenalidomide (Revlimid®) (NSC #703813) IND #70116 
Epoetin Alfa (Procrit®) (NSC #628281) 
Rev. 6/11 
Rev. 6/14 
Rev. 10/14 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
2 
Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 Hypothesis ................................................................................................. 8 
1.2 Rationale ................................................................................................... 8 
1.3 Toxicity Profile ........................................................................................... 9 
1.4 Pharmacologic Effects of Lenalidomide in MDS ..................................... 10 
2. Objectives ......................................................................................................... 12 
2.1 Primary Objective .................................................................................... 12 
2.2 Secondary Objectives .............................................................................. 12 
3. Selection of Patients ......................................................................................... 13 
3.1 Eligibility Criteria ..................................................................................... 13 
4. Registration Procedures.................................................................................... 20 
4.1 Step 1: Randomization ............................................................................ 22 
4.2 Eligibility Verification .............................................................................. 23 
4.3 Stratification Factors ............................................................................... 23 
4.4 Additional Requirements ........................................................................ 23 
4.5 Instructions for Patients who Do Not Start Assigned Protocol Treatment24 
4.6 Step 2: Cross-Over Registration .............................................................. 24 
4.7 Eligibility Verification .............................................................................. 25 
4.8 Instructions for Patients who Do Not Start Assigned Protocol Treatment25 
5. Treatment Plan ................................................................................................. 26 
5.1 Administration Schedule ......................................................................... 26 
5.2 Cross-Over Treatment ............................................................................. 27 
5.3 Adverse Event Reporting Requirements ................................................. 27 
5.4 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Lenalidomide (NSC #703813) .................................................................. 36 
5.5 Dose Modifications ................................................................................. 43 
5.6 Supportive Care ....................................................................................... 47 
5.7 Duration of Therapy ................................................................................ 48 
5.8 Duration of Follow-up ............................................................................. 48 
6. Measurement of Effect ..................................................................................... 49 
6.1 MDS Response Criteria: Modified International MDS Working Group 
(IWG) Criteria for Measurement of Response/Treatment Effect in MDS 
will be used to assess response. ............................................................. 49 
7. Study Parameters .............................................................................................. 53 
7.1 Therapeutic Parameters.......................................................................... 53 
7.2 Biological Sample Submissions ............................................................... 56 
7.3 Schedule for pregnancy testing, education and counseling, and 
dispensing schedule for lenalidomide. ................................................... 57 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
3 
8. Drug Formulation and Procurement ................................................................. 58 
8.1 Lenalidomide (NSC# 703813) .................................................................. 59 
8.2 Epoetin Alfa (NSC# 628281) .................................................................... 63 
9. Statistical Considerations .................................................................................. 69 
9.1 Accrual ..................................................................................................... 69 
9.2 Primary Endpoint .................................................................................... 69 
9.3 Secondary Objectives .............................................................................. 70 
9.4 Interim Analyses ...................................................................................... 71 
9.5 Statistical Analysis for Correlative Studies .............................................. 73 
9.6 Gender and Ethnicity .............................................................................. 75 
9.7 Study Monitoring .................................................................................... 76 
10. Pathology Review .............................................................................................. 77 
10.1 Pathology Submission ............................................................................. 77 
10.2 Materials required for this protocol: ...................................................... 77 
10.3 Shipping Procedures ............................................................................... 78 
10.4 ECOG-ACRIN Central Biorepository and Pathology Facility: Sample 
Processing and Routing ........................................................................... 79 
10.5 ECOG-ACRIN Sample Tracking System .................................................... 79 
10.6 Banking .................................................................................................... 80 
11. Correlative Studies ............................................................................................ 81 
11.1 Cytogenetic Review (Mandatory) ........................................................... 81 
11.2 Additional Laboratory Studies ................................................................. 82 
11.3 Banking .................................................................................................... 86 
11.4 Sample Inventory Submission Guidelines ............................................... 86 
11.5 Lab Data Transfer Guidelines .................................................................. 86 
12. Records to Be Kept ............................................................................................ 87 
12.1 Records Retention ................................................................................... 87 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
4 
13. Patient Consent and Peer Judgment ................................................................ 87 
14. References ........................................................................................................ 87 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [DELETED IN ADDENDUM #7] .......................................................... 90 
Appendix II  Pathology Submission Guidelines ....................................................... 91 
Appendix III  Patient Thank You Letter .................................................................... 96 
Appendix IV  World Health Organization (WHO) Diagnostic criteria for MDS ........ 97 
Appendix V  ECOG Performance Status Score ......................................................... 98 
Appendix VI  [DELETED IN ADDENDUM #4] ............................................................ 99 
Appendix VII  Cooperative Research and Development Agreement (CRADA) ...... 100 
NCI/ DCTD Standard Protocol Language ............................................................... 100 
Appendix VIII  Medication Diary ............................................................................ 102 
Appendix IX  Specimen Submission Instructions for Southwest Oncology Group 
Patients  [DELETED IN ADDENDUM #1] .......................................................... 104 
Appendix X  Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods .......................................................... 105 
Appendix XI  Lenalidomide Education and Counseling Guidance Document ....... 109 
Appendix XII  Lenalidomide Information Sheet..................................................... 112 
Appendix XIII  CPPCP Site Counselor Form ............................................................ 114 
Appendix XIV  Instructions for Reporting Pregnancies on a Clinical Trial ............. 115 
 
 
 
Rev. 11/13 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
5 
STUDY CHAIR 
 
STUDY CO-CHAIR 
Alan List, M.D. 
The H. Lee Moffitt Cancer Center  
and Research Institute 
12902 Magnolia Drive 
Tampa, FL 33612-9497 
Phone: 813-745-6086 
Fax: 813-975-3727 
E-mail: alan.list@moffitt.org  
 
 
Amit Verma, M.D. 
Albert Einstein College of Medicine 
Chanin 302 B, 1300 Morris Park Ave 
Bronx, NY 10461 
Phone: 718-430-8761 
Fax: 718-430-8702 
E-mail: averma@aecom.yu.edu 
 
  
STUDY CHAIR LIAISON (SCL) 
 
SWOG CO-CHAIR  
Lisa Nardelli 
The H. Lee Moffitt Cancer Center and 
Research Institute 
12902 Magnolia Drive 
3rd Floor FOB 
Tampa, FL 33612-9497 
Phone: 813-745-4731 
Fax: 813-745-5807 
E-mail: lisa.nardelli@moffitt.org  
 
Charles A. Schiffer, M.D. 
Karmanos Cancer Institute 
Wayne State University 
Division of Hematology/Oncology 
4100 John R, HWRB - 4th Floor 
Detroit, MI 48201 
Phone: 313-576-8737 
Fax: 313-576-8764 
E-mail: schiffer@karmanos.org 
CALGB CO-CHAIR 
Andrew Artz, M.D. 
University of Chicago Medical Center, Hematology/Oncology 
5841 S. Maryland Ave, 3rd Floor FOB 
Chicago, IL 60637 
Phone: 773-834-8980 
Fax: 773-702-3002 
Email: aartz@medicine.bsd.uchicago.edu 
 
Rev. 10/09 
Rev. 10/09 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
6 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site 
registration documents: 
For patient enrollments:  
Submit study data  directly to the 
Lead Cooperative Group unless 
otherwise specified in the protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 
1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coc
cg.org (for submitting 
regulatory documents only) 
Please refer to the patient 
enrollment section of the 
protocol for instructions on using 
the Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations Office - 
Boston, FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal mail. 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions.   
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.   
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev. 6/11, 
6/14 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
7 
Schema 
 
R
A
N
D
O
M
I
Z
E
Stratify
· Serum erythropoietin 
level (< 500 mU/mL 
vs. 
> 500 mU/mL)
· Prior EPO/DA vs. 
None
1. Patients with a pretreatment platelet count of 50,000-99,000/mcL or an ANC of 500-999/mcL will receive a lenalidomide dose of 5 mg/day x 21 days.
Accrual Goal = 252 patients
MER = Major Erythroid Response
NOTE: 1 cycle = 28 days
Step 2:
Step 1:
R
E
G
I
S
T
E
R
Step 2:
Relapse
R
E
G
I
S
T
E
R
R
E
G
I
S
T
E
R
Determine if 
patient is del 
5q 31.1
Do Not 
Achieve 
MER        
Achieve 
MER        
Arm A: Lenalidomide1 
10 mg po/day X 21 
days. Repeat cycle 
every 28 days for 4 
cycles (16 weeks).
Do Not 
Achieve 
MER        
Achieve 
MER        
Patients on Arm A who do not achieve 
MER will be offered to cross over to Arm B 
to receive the combined treatment.  If a 
patient chooses to not cross over, he/she 
will then discontinue study treatment.
Arm B: Lenalidomide1 
10 mg po/day X 21 
days and epoetin alfa 
60,000 units s.c. every 
week. Repeat cycle 
every 28 days for 
4 cycles (16 weeks).
Continue Arm 
A treatment 
until relapse/
progression
Patients on Arm A 
who relapse will be 
offered to cross over 
to Arm B to receive 
the combined 
treatment.  If a patient 
chooses to not cross 
over, he/she will then 
discontinue study 
treatment.
Continue Arm B 
treatment until relapse/
progression
Discontinue Study 
Treatment
del 5q 31.1
Not 
del 5q 31.1
Week:
0
16
4
8
12
Rev. 6/11

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
8 
1. 
Introduction 
1.1 
Hypothesis 
Combined treatment with epoetin alfa and lenalidomide potentiates erythroid 
response in patients that have failed prior treatment with rhu-erythropoietin or 
epoetin alfa or have low probability of response to erythropoietic growth factors. 
1.2 
Rationale 
Ineffective erythropoiesis remains the hallmark of myelodysplastic syndromes 
(MDS) for which few treatments offer sustained erythropoietic improvement (1). 
Treatment with rhu-erythropoietin either alone or in combination with myeloid 
growth factors ameliorates anemia in some patients.  However, for those patients 
with frequent red blood cell (RBC) transfusion needs (> 2 units/month) or 
elevated endogenous erythropoietin levels (erythropoietin > 500 mU/mL), 
cytokine therapy is generally ineffective (2-4). Lenalidomide (REVLIMID) is an 
oral 4-amino glutarimide derivative of thalidomide that lacks the neurological 
toxicities of the parent compound. (5-8). Lenalidomide is a potent modulator of 
ligand-induced cellular response with biological effects that range from 
potentiation of antigen-initiated immune response, to modulation of integrin 
affinity and suppression of trophic response to angiogenic molecules. In AML cell 
lines, lenalidomide suppresses VEGF transcription, whereas in normal and 
malignant erythroid progenitors, lenalidomide potentiates clonogenic response to 
rhu-erythropoietin. In the UT7 erythroid progenitor cell line and in MDS erythroid 
progenitors, lenalidomide potentiates clonogenic response to rhu-erythropoietin 
by augmenting ligand-induced activation of STAT5 (9), indicating that 
erythropoietic response to lenalidomide is erythropoietin-dependent. 
In a safety and efficacy study (MDS-001) investigating erythroid response to 
lenalidomide monotherapy in 43 patients with MDS, lenalidomide yielded a high 
frequency of major erythroid response (MER) in patients that had either failed 
prior treatment with erythropoietin or had high endogenous levels and high 
transfusion burden (6).  Patients received treatment with one of three 
lenalidomide dose schedules, 25 or 10 mg daily, or 10 mg/day x 21 days every 4 
weeks. Neutropenia (67%) and thrombocytopenia (57%) > grade 3 NCI-CTC 
version 2.0 were dose limiting, necessitating treatment interruption and dose-
reduction in 25 (61%) patients. Other adverse effects were infrequent and of mild 
to moderate severity including pruritus, fatigue, diarrhea, edema, thyroid 
dysfunction and joint discomfort.  Among the 36 patients completing more than 
one cycle of treatment, 24 (67%) experienced an erythroid response according to 
International Working Group (IWG) criteria (10). MER defined by sustained 
transfusion-independence (> 8 weeks) or a rise in hemoglobin >2 g/dl was 
achieved in 21 patients and 3 patients experienced a >50% reduction in red 
blood cell (RBC) transfusions. Response rate was highest among evaluable 
patients with a chromosome 5q31.1 deletion (91%) compared to those with a 
normal karyotype (68%) or other chromosome abnormality (17%) [P=0.009], and 
response rate was higher in patients with lower (Low-/Intermediate-1) 
International Prognostic Scoring System (IPSS) risk categories (72% vs. 25%) 
[P=0.098] (11). Eleven of 17 (65%) patients with karyotypic abnormalities had a 
50% or greater reduction in abnormal metaphases, including ten (57%) complete 
cytogenetic remissions. After a median follow-up of 109 weeks in November 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
9 
2004, median duration of transfusion-independence had not been reached (81+; 
range, 19 to > 128 weeks) with a median sustained hemoglobin (Hgb) of 13.4 
g/dL (range, 11.5-15.8 g/dL) and median Hgb rise of 5.6 g/dL. The results of this 
study indicate that lenalidomide has significant and sustained erythropoietic and 
cytogenetic remitting activity in patients with Low/Intermediate-1 IPSS risk MDS 
that have failed or are unlikely to benefit from conventional cytokine therapy. 
Two phase II multicenter trials were completed in the past year, evaluating the 
frequency of MER to lenalidomide in patients with transfusion-dependent Low/Int-
1 risk MDS with (MDS-003; N=148) or without a chromosome 5q31.1 deletion 
(MDS-002; N=215). Intent-to-treat analysis of the data confirm the high response 
rate in patients with del 5q31.1 (MER 66%, MER + Minor erythroid response 
75%, cytogenetic response 70%) compared to a MER rate of 27% and Minor + 
MER rate of 44% in the MDS-002 results (7,8). Grade 3 or greater neutropenia or 
thrombocytopenia was more frequent in the 5q- study (approximately 50% vs. 
25%) and was the principal reason for treatment interruption and dose-reduction. 
A pilot study tested the potential benefit of combination treatment (CT) with 
epoetin alfa and lenalidomide in 40 Low/INT-1 MDS patients who had failed 
primary rhu-erythropoietin treatment (12). Patients received 16 weeks of 
treatment with lenalidomide monotherapy (MT), followed by the addition of 
subcutaneous epoetin alfa at a dose of 40,000 units/week for 8 weeks in those 
patients who failed to achieve a MER or suboptimal response to MT. Overall, 
36% of patients achieved an erythroid response to lenalidomide MT, whereas 
among 18 MT failures who proceeded to CT, 5 (28%) achieved an erythroid 
response. CT was well tolerated with no thromboembolic events reported after up 
to 18 months of CT. This pilot study indicates that lenalidomide may restore rhu-
erythropoietin responsiveness in patients who failed primary cytokine therapy. 
Moreover, the addition of epoetin alfa to lenalidomide may increase the rate of 
erythroid response compared to lenalidomide MT alone. 
1.3 
Toxicity Profile 
Clinical trials performed to date indicate that lenalidomide has encouraging 
erythropoietic activity in lower risk MDS with poor rhu-erythropoietin response 
profile. Although response rate is moderate in patients with non-del 5q31 
karyotypes, erythropoietic activity may be improved by the addition of epoetin 
alfa, given the erythropoietin-dependence of lenalidomide action. Erythropoietic 
growth factors and immunomodulatory drugs are recognized to variably increase 
thrombotic potential. Indeed, when combined with dexamethasone or other 
antineoplastics, thrombo-embolic complications have been reported in up to 10-
15% of non-prophylaxed patients with multiple myeloma (13,14). The thrombotic 
potential of lenalidomide appears much lower than thalidomide despite greater 
pharmacologic activity. In two recently completed phase III trials involving 692 
patients with relapsed multiple myeloma, [MM-009, and MM-010] thrombotic 
events were reported in 2.9% of patients assigned to treatment with 
dexamethasone and placebo, compared to 11.9 and 4.7% of patients in the 
lenalidomide and dexamethasone arms (15,16). Thrombo-embolic complications 
were not observed in patients receiving aspirin prophylaxis.  Thrombo-embolic 
events were reported in 15 (3.4%) of the 408 MDS patients treated on the MDS-
001, -002, and –003 trials.  Among 873 patients with non-myeloid malignancy 
enrolled in 7 darbepoetin alfa (DA) registrational trials, thrombo-embolic events 
were reported in 7% of patients treated with DA, compared to 5.2% of patients 

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receiving epoetin alfa and 4.1% of placebo (17-20).  A multivariate analysis 
identified DA treatment, prior TE history and poor ECOG performance status to 
be significant predictors of thrombo-embolic (ref. Data on File, Amgen 003). For 
this reason, candidates with a history of thrombo-embolic events within 3 years of 
registration will be excluded from study participation. Although epoetin alfa 
appeared less thrombogenic, thrombo-embolic events will be monitored in this 
study with an interim safety analysis of event frequency planned after 30 patients 
have completed 16 weeks of combined therapy on both arms of the study.  Since 
platelet dysfunction is common in MDS and thrombocytopenia is a frequent 
adverse effect of CC-5013, aspirin prophylaxis will not be applied to this study. 
1.4 
Pharmacologic Effects of Lenalidomide in MDS 
The precise target of lenalidomide that is responsible for its erythroid and 
cytogenetic remitting activity is under investigation. Blinded morphologic review 
of the bone marrow (BM) aspirates and biopsies from study participants suggests 
that in select patient populations such as those harboring a chromosome 5q31.1 
deletion, lenalidomide may extinguish the dominant MDS clone and possibly 
influence autologous immune response within the BM microenvironment. 
Megakaryocytic dysplasia resolved after lenalidomide treatment in 64% of 
evaluable patients in the MDS-001 study and corresponded to hematologic 
response (10), and complete pathologic responses were reported in blinded 
central review in 36% of patients treated in the MDS-003 trial. Lymphoid 
aggregates composed of an admixture of B- and T-lymphocytes, emerged in 
36% of patients in the MDS-001 trial, suggesting potentiation of autologous 
immunity. 
Lenalidomide has broad pharmacologic properties that may contribute to its 
hematologic activity. Lenalidomide suppresses tumor necrosis factor-alpha 
(TNF) generation (14), however, investigations involving selective TNF 
antagonists have shown only modest activity both in vitro and in clinical trials. 
Similarly, BM plasma concentrations of TNF were not significantly changed 
after study treatment in responding patients in the lenalidomide trial. 
Lenalidomide enhances cell-mediated immune response by potentiating 
interleukin-2 and interferon- production and expanding cytolytic T- and NK-cell 
populations in experimental models. The appearance of mixed lineage lymphoid 
aggregates in the trephine biopsies of responders in the MDS-001 study raises 
consideration that lenalidomide potentiates autologous medullary immune 
response. Investigations reported by Noonan et al. have shown that in BM-based 
malignancies such as multiple myeloma, cytolytic T-cell response to autologous 
tumor is more than seven-fold greater in medullary lymphocytes compared to 
those derived from the peripheral blood (14). 
Our preclinical investigations indicate that the hematopoietic effects of 
lenalidomide in MDS are karyotype-dependent, with direct cytotoxicity to and 
suppression of clones bearing the chromosome 5q31 deletion, and 
erythropoietin-dependent , sensitization of non-deletion 5q erythroid progenitors 
to rhu-erythropoietin by potentiating ligand-induced activation of STAT5 (List et 
al, unpublished data). Using the UT-7 erythroid progenitor cell line, lenalidomide 
pretreatment yields supra-additive clonogenic response to rhu-erythropoietin, 
whereas in the absence of the cytokine, lenalidomide has minimal effect on 
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formation in MDS patient specimens. Upon ligand engagement, erythropoietin 
receptor signaling is mediated in part through constitutively associated Janus 
kinase-2 (Jak2), which phosphorylates the receptor cytoplasmic tail to permit 
recruitment and phosphorylation of the STAT5 transcription factor.  
Phosphorylation of STAT5 allows its homodimerization and translocation to the 
nucleus, where it activates genes involved in erythroid proliferation and survival.  
In the UT7 cell line, lenalidomide potentiates erythropoietin-induced STAT5 
phosphorylation associated with an increase in STAT5 DNA binding by relieving 
inhibition of Jak and lyn kinase activity. Similar findings were detected in CD71 
Bright erythroid precursors by flow cytometry in primary MDS bone marrow 
specimens.These findings indicate that lenalidomide’s ability to modulate ligand-
induced response extends to erythropoietin-R activation, and suggests that 
combined treatment with rhu-erythropoietin may potentiate erythropoietic 
response in those patients experiencing sub-optimal benefit from lenalidomide 
monotherapy. 
Serum erythropoietin concentrations were prospectively monitored in an on-going 
pharmacokinetic study of lenalidomide in 21 anemic patients with MDS 
(Unpublished data – List AF). Prior to study treatment, sEPO concentration was 
elevated >500 mU/ml in 12 (57%) patients, in 3 patients sEPO was <100 mU/ml, 
and in 6 patient - 100-500 mU/ml.  During lenalidomide treatment, sEPO 
concentration declined 41% to 94% in 6 of the 12 non-del 5q patients with 
intermediate or high sEPO levels pre-study despite persistence of anemia. No 
patient with low sEPO pre-study (<100 mU/ml) experienced a rise in serum 
concentration during lenalidomide treatment. These data, if confirmed, indicate 
that sup-optimal endogenous EPO concentration may limit erythropoietic 
response to lenalidomide monotherapy in approximately 60% of patients, and 
thereby suggests that combined therapy with a recombinant erythropoietin may 
improve erythroid response.

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2. 
Objectives 
2.1 
Primary Objective 
To compare the rate of major erythroid response (MER) between lenalidomide 
monotherapy and combined treatment of lenalidomide and epoetin alfa in 
erythropoietin non-responsive Low/Int-1 risk MDS patients or erythropoietin-
treatment naïve patients with low probability of erythropoietin benefit. 
2.2 
Secondary Objectives 
2.2.1 
To compare the time to MER by treatment assignment. 
2.2.2 
To evaluate the duration of MER by treatment assignment. 
2.2.3 
To estimate the frequency of MER to salvage combination therapy in 
patients who fail to experience a MER with lenalidomide 
monotherapy. 
2.2.4 
To evaluate and compare the frequency of minor erythroid response 
by treatment assignment. 
2.2.5 
To investigate the mechanism and target of lenalidomide action in 
patients with chromosome 5q31.1 deletion. 
2.2.6 
To evaluate the frequency of cytogenetic response and progression, 
and the relation between cytogenetic pattern and erythroid response. 
2.2.7 
To evaluate the frequency of bone marrow response (CR+PR). 
2.2.8 
To evaluate the relationship between erythroid response and 
laboratory correlates outlined below: 
2.2.8.1 
Pretreatment and onstudy endogenous erythropoietin level 
(Arm A); 
2.2.8.2 
To evaluate the effect of CD45 isoform profile on 
lenalidomide enhancement of erythropoietin-induced 
STAT5 phosphorylation in CD71Hi erythroid precursors and 
the relationship to erythroid response. 
2.2.8.3 
To characterize molecular targets relevant to lenalidomide 
cytotoxicity in del5q31.1 cells. 
2.2.8.4 
To evaluate the frequency of cryptic chromosome 5q31.1 
deletions in patients with non-del5q31.1 MDS by array-
based genomic scan, and to determine the relationship to 
hematologic response.
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. Screening is considered to start the 
date that the consent is signed (Day Zero) up to 56 days later. Subjects can be 
registered anytime within the 56 days as long as they meet the below criteria. 
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
M.D. Signature _______________________________  Date _________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria 
NOTE: 
Results of the bone marrow biopsy and aspirate as well as 
Cytogenetics are mandatory to register subjects onto study, which are 
indispensable to determine IPSS category needed for eligibility (see 
Section 3.1.1.3). Please note that it is not necessary to wait for the 
week 16, week 32, or week bone marrow and cytogenetic results prior 
to starting the next cycle unless deemed necessary by the treating 
physician.  One example of this exception can include if the subject 
shows signs of progression, such as increased peripheral blood blast 
percentage.  At that juncture, the treating physician may prefer to 
await the results prior to starting a new cycle.  If a cycle is started, and 
based on the bone marrow results it is felt by the treating physician 
that the subject should not continue on treatment, please be sure to 
note this information on the case report forms at end of treatment 
3.1.1 
Step 1: Randomization to Arm A or Arm B 
3.1.1.1 
Age ≥ 18 years. 
3.1.1.2 
Patient must have documented diagnosis of MDS lasting at 
least three months (MDS duration ≥ 3 months) according 
to World Health Organization (WHO) criteria (see Appendix 
) or non-proliferative chronic myelomonocytic leukemia 
(CMML) (WBC < 12,000/mcL)). 
3.1.1.3 
Patient must have International Prognostic Scoring System 
(IPSS) categories of Low- or Intermediate-1-risk disease 
(see Section 6).  Patients must have IPSS score 
determined by cytogenetic analysis prior to randomization. 
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Patients must have cytogenetic analysis done (to calculate 
IPSS). If the current bone marrow biopsy is a dry tap, 
patients with cytogenetic failure and < 10% marrow blasts 
will be eligible. Subjects with cytogenetic failure must have 
previous cytogenetic results (FISH is not a substitute) 
within the last 6 months post last type of MDS treatment (in 
this case, not referring to growth factors as type of MDS 
treatment). 
IPSS score: _______________Date of test: ___________ 
3.1.1.4 
Patients must have symptomatic anemia untransfused with 
hemoglobin < 9.5 g/dL  
≤ 8 weeks prior to randomization or with RBC transfusion-
dependence (i.e., ≥ 2 units/month) confirmed for ≤ 8 weeks 
before randomization. 
NOTE: 
For non-transfusion dependent patients (i.e., 
receiving < 2 units/4 weeks x 8 weeks pre-
study) who receive periodic transfusions, the 
mean 8 week pre-transfusion hemoglobin 
should be used to determine protocol eligibility 
and response reference. 
For non-transfusion dependent patients, a 
minimum of 2 pre-transfusion or un-transfused 
hemoglobin values are required. 
3.1.1.4.1 
Untransfused hemoglobin: _____________ 
1st:______ Date of test:_______ 
2nd:______ Date of test:______ 
3.1.1.4.2 
RBC transfusion-dependence (i.e. ≥ 2 
units/month) 
Date of onset of dependence: ___________ 
3.1.1.5 
NOTE: 
Applies only for patients without the deletion 5q 
31.1. Patients must have failed treatment with 
an erythropoietic growth factor, or have a low 
probability of response to rhu-erythropoietin. 
Patients with Low Probability of Response to 
rhu-erythropoietin or prior erythropoietin failures 
are defined as follows: 
3.1.1.5.1 
Prior erythropoietin failure – requires a 
minimum trial of ≥ 40,000 Units epoetin 
alfa/week x 8 weeks or equivalent dose of 
darbepoetin alfa for 8 weeks with failure to 
achieve transfusion independence in 
dependent patients or a failure to achieve a 
≥ 2g rise in hemoglobin sustained for ≥ 4 
weeks in non-transfusion dependent 
patients. 
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Rev. 10/09 
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3.1.1.5.2 
Low erythropoietin Response Profile – rhu-
erythropoietin and epoetin alfa-naïve 
patients receiving ≥ 2U pRBC/month for a 
minimum of 8 weeks, and serum 
erythropoietin > 500mU/mL in the 8 weeks 
prior to randomization for a hemoglobin < 
9.5 g/dL. 
3.1.1.6 
Patients must be off all non-transfusion therapy for MDS 
for 28 days prior to initiation of study treatment, including 
all types of growth factors. Patients may receive 
hydrocortisone prophylactically to prevent transfusion 
reactions. 
3.1.1.7 
Patients must have a serum erythropoietin level 
documented before randomization and ≤ 56 days before 
Day 1 of study treatment. 
NOTE: 
Hemoglobin must be < 9.5 g/dL at time that 
serum erythropoietin is drawn. 
EPO:______ Date of test:_______ 
HGB:______ Date of test:______ 
3.1.1.8 
Patients must not have documented iron deficiency. All 
patients must have documented marrow iron stores.  If 
marrow iron stain is not available, the transferrin saturation 
must be > 20% or a serum ferritin > 100 ng/mL. 
Bone marrow iron stain available? ______(Yes or No) 
If no: Transferrin saturation:________OR Serum ferritin: 
________ 
3.1.1.9 
Women must not be pregnant or breastfeeding: 
Females of childbearing potential must have a negative 
serum or urine pregnancy test with a sensitivity of at least 
25 mIU/mL within 10 – 14 days and again within 24 hours 
prior to starting Cycle 1 of lenalidomide. A female of 
childbearing potential(FCBP) is any woman, regardless of 
sexual orientation or whether they have undergone tubal 
ligation, who meets the following criteria: 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. FCBP must also 
agree to ongoing pregnancy testing. 
Female of childbearing potential? ______  (Yes or No) 
Date of first blood test or urine pregnancy test: _________ 
Date of second blood test or urine pregnancy test: ______ 
3.1.1.10 
Effective contraception must be used by patients 
participating in lenalidomide therapy, and all patients must 
agree to counseling by a trained counselor every 28 days 
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about pregnancy precautions and risks of fetal exposure. 
(See Appendix X: Lenalidomide Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods, and also Appendix XI: Lenalidomide 
Education and Counseling Guidance Document): 
Females of childbearing potential (FCBP) must either 
commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth 
control: one highly effective method and one additional 
effective method AT THE SAME TIME, at least 28 days 
before starting lenalidomide, during lenalidomide therapy, 
during dose interruptions, and for at least 28 days following 
discontinuation of lenalidomide therapy. Females of 
childbearing potential should be referred to a qualified 
provider of contraceptive methods, if needed. 
Males receiving lenalidomide must agree to use a latex 
condom during any sexual contact with females of 
childbearing potential even if they have undergone a 
successful vasectomy 
3.1.1.11 
Patients must not have prior therapy with lenalidomide. 
3.1.1.12 
Patients must not have a diagnosis of uncontrolled seizure 
or uncontrolled hypertension 
3.1.1.13 
Patients must not have proliferative (WBC 12,000/mcL) 
chronic myelomonocytic leukemia (CMML). WBC must be 
< 12,000/mcL. See Section 3.1.2. 
1st WBC: _______ Date of test: _______  
2nd WBC: _______ Date of test:_______ 
3.1.1.14 
Patients must not have MDS secondary to treatment with 
radiotherapy, chemotherapy, and/or immunotherapy for 
malignant or autoimmune diseases. 
3.1.1.15 
Patients must meet the following criteria (documented on 2 
occasions within 56 days prior to randomization; the 2 
occasions must be separated by at least 7 days). At least 
one of the two CBC/Diffs and chemistry testing (including 
liver function tests) must be done within 7 days of 
registration. 
NOTE: 
Hematology and chemistry testing can be 
utilized within 56 days prior to randomization for 
Sections 3.1.15, 1 – 5. 
3.1.1.15.1 
Platelet count  50,000/mcL (50 x 109/L) 
without platelet transfusion. 
1st:_____ Date of test:______ 
2nd:_____ Date of test:_____ 
3.1.1.15.2 
Absolute neutrophil count (ANC)  500 
cells/mcL (0.5 x 109/L). Hence ANC must be 
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 500/mcL without myeloid growth factor 
support. 
1st:_____ Date of test:______ 
2nd:_____ Date of test:_____ 
Serum creatinine ≤ 1.5x upper limit of 
normal (ULN) 
1st:_____ Date of test:______ 
2nd:_____ Date of test:_____ 

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3.1.1.15.3 
Serum SGOT/AST or SGPT/ALT ≤ 2.0 x 
ULN 
SGOT/AST 1st:_____ Date of test:_____ 
2nd:_____ Date of test:_____ 
SGPT/ALT  1st:_____ Date of test:_____ 
2nd:_____ Date of test:_____ 
3.1.1.15.4 
Serum total bilirubin < 3.0 mg/dL 
1st:_____ Date of test:______  
2nd:_____ Date of test:_____ 
3.1.1.16 
Prior thalidomide therapy is allowed, however, patients 
must not have prior  grade-3 allergic reactions to 
thalidomide. 
3.1.1.17 
Patients must not have prior history of desquamating rash 
from thalidomide at time of study entry. 
3.1.1.18 
Patients must not have clinically significant anemia 
resulting from iron, B12 or folate deficiencies, autoimmune 
or hereditary hemolysis, or gastrointestinal bleeding. 
3.1.1.19 
Patients must not have used cytotoxic chemotherapeutic 
agents or experimental agents (agents that are not 
commercially available) for the treatment of MDS within 8 
weeks of randomization. 
3.1.1.20 
Patients must not have prior history of malignancy other 
than MDS (except basal cell or squamous skin cell 
carcinoma or carcinoma in situ of the cervix or breast) 
unless the subject has been confirmed free of disease for  
3 years. 
3.1.1.21 
Patients must not have any serious medical condition or 
any other unstable medical co-morbidity, or psychiatric 
illness that will prevent the subject from signing the 
informed consent form or will place the subject at 
unacceptable risk if he/she participates in the study. 
3.1.1.22 
Patients must not have a history of thrombo-embolic 
events within 3 years prior to study randomization. 
3.1.1.23 
Patients must not have known HIV-1 seropositivity 
because HIV can be an alternate cause of anemia. 
3.1.1.24 
Patients must not have a known allergic reaction to epoetin 
alfa (Procrit®) or human serum albumin. 
3.1.1.25 
[Deleted in Addendum #1] 
3.1.2 
Crossover Registration from Arm A (Lenalidomide Alone) to Arm 
B (Lenalidomide and Epoetin Alfa) 
3.1.2.1 
Patients must have completed 16 weeks of monotherapy 
with lenalidomide. 
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3.1.2.2 
Patients must show failure to achieve MER (major 
erythroid response) or have achieved MER but relapsed on 
Arm A. 
3.1.2.3 
Patients must not have a limiting unresolved grade 3 or 
greater toxicity from lenalidomide monotherapy or drug 
intolerance preventing continuation of lenalidomide 
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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
· 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
· 
a current Curriculum Vitae (CV) 
· 
a completed and signed Supplemental Investigator Data Form (IDF) 
· 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For 
questions, please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ web site by entering 
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credentials at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will 
automatically load to RSS. 
Downloading Site Registration Documents   
Site registration forms may be downloaded from the E2905 protocol page located on the 
CTSU members’ website.   
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
· 
Click on the Protocols tab in the upper left of your screen 
· 
Click on the ECOG-ACRIN link to expand, then select trial protocol E2905 
· 
Click on the Site Registration Documents link 
Requirements for E2905 site registration: 
· 
CTSU IRB Certification 
· 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS. 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
PHONE: 1-866-651-2878 
FAX: (215) 569-0206 
E-MAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission 
only) 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
3. 
A. CTSU IRB Certification Form. 
 
Or 
B.  
HHS 310 Form. 
 
Or 
 
C.  
IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
· Indicate all sites approved for the protocol under an assurance 
number. 
· OHRP assurance number of reviewing IRB 
· Full protocol title and number 
· Version Date 
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· Type of review (full board vs. expedited) 
· Date of review. 
· Signature of IRB official 
Checking Your Site’s Registration Status 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
· 
Click on the Regulatory tab at the top of your screen 
· 
Click on the Site Registration tab 
· 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within three working days after registration. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
· 
All eligibility criteria have been met within the protocol stated timeframes.  
· 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Step 1: Randomization 
4.1.1 
Protocol Number 
4.1.1.1 
Investigator Identification 
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4.1.1.1.1 
Institution and affiliate name (Institution 
CTEP ID) 
4.1.1.1.2 
Investigator’s name (NCI number) 
4.1.1.1.3 
Cooperative Group Credit 
4.1.1.1.4 
Credit Investigator 
4.1.1.1.5 
Protocol specific contact information 
4.1.2 
Patient Identification 
4.1.2.1 
Patient’s initials (first and last) 
4.1.2.2 
Patient’s Hospital ID and/or Social Security number 
4.1.2.3 
Patient demographics 
4.1.2.3.1 
Gender 
4.1.2.3.2 
Birth date 
4.1.2.3.3 
Race 
4.1.2.3.4 
Ethnicity 
4.1.2.3.5 
Nine-digit ZIP code 
4.1.2.3.6 
Method of payment 
4.1.2.3.7 
Country of residence 
4.2 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 3.1. An 
eligibility checklist has been appended to the protocol.  A confirmation of 
registration will be forwarded by the ECOG-ACRIN Operations Office - 
Boston.Patient Identification  
4.3 
Stratification Factors 
4.3.1 
Serum erythropoietin level (≤ 500 mU/mL vs. > 500 mU/mL) 
4.3.2 
Prior Erythropoietic Growth Factor (Prior erythropoietin/DA vs. None) 
4.3.3 
All patients with del 5q31.1 karyotype will be assigned to treatment 
with lenalidomide monotherapy (Arm A). 
4.4 
Additional Requirements  
4.4.1 
Patients must provide a signed and dated, written informed consent 
form. 
4.4.2 
Karyotypes (Section 11.1) and pathologic materials (Section 10) must 
be submitted for review. 
[Note deleted in Addendum #1] 
4.4.3 
Bone marrow and blood should be submitted for correlative studies as 
outlined in Sections 10.2.2.2 and 11.2. 
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4.4.4 
Baseline materials submitted per E2905 Forms Packet. 
NOTE: 
ECOG-ACRIN requires that biological samples submitted from 
patients participating in E2905 be entered and tracked via the online 
ECOG-ACRIN Sample Tracking System (STS). See Section 10.5. 
NOTE: 
Copies of the consent are not collected by the ECOG-ACRIN 
Operations Office - Boston. 
4.5 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E2905 Forms Packet. Document the reason for not starting 
protocol treatment on one of the baseline forms. Also report the date and type of 
the first non-protocol treatment that the patient receives. 
4.6 
Step 2: Cross-Over Registration 
4.6.1 
Subjects who fail to achieve a MER or who achieve a MER but 
relapse on Arm A will be offered combined treatment on Arm B in the 
absence of unresolved grade 3 or greater toxicity or drug intolerance. 
4.6.2 
Protocol Number 
4.6.2.1 
Investigator Identification 
4.6.2.1.1 
Institution and affiliate name (Institution 
CTEP ID) 
4.6.2.1.2 
Investigator’s name (NCI number) 
4.6.2.1.3 
Cooperative Group Credit 
4.6.2.1.4 
Credit Investigator 
4.6.2.1.5 
Protocol specific contact information 
4.6.3 
Patient Identification 
4.6.3.1 
Patient’s initials (first and last) 
4.6.3.2 
Patient’s Hospital ID and/or Social Security number 
4.6.3.3 
Patient demographics 
4.6.3.3.1 
Gender 
4.6.3.3.2 
Birth date 
4.6.3.3.3 
Race 
4.6.3.3.4 
Ethnicity 
4.6.3.3.5 
Nine-digit ZIP code 
4.6.3.3.6 
Method of payment 
4.6.3.3.7 
Country of residence 
4.6.4 
Additional Requirements 
4.6.4.1 
Karyotypes (Section 11.1) and pathologic materials 
(Section 10) must be submitted for review. 
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[Note deleted in Addendum #1] 
4.6.4.2 
Bone marrow and blood are to be submitted for correlative 
studies as outlined in Sections 10.2.2.2 and 11.2. 
NOTE: 
ECOG-ACRIN requires that biological samples submitted 
from patients participating in E2905 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking 
System (STS). See Section 10.5. 
NOTE: 
Institutions outside of the United States and Canada must 
confer with the receiving laboratory and the ECOG-ACRIN 
Operations Office - Boston regarding logistics for 
submission of fresh samples. 
4.7 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 3.2. An 
eligibility checklist has been appended to the protocol. A confirmation of 
registration will be forwarded by the ECOG-ACRIN Operations Office - Boston. 
4.8 
Instructions for Patients who Do Not Start Assigned Protocol Treatment 
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E2905 Forms Packet. Document the reason for not starting 
protocol treatment on the off-treatment form. Also report the date and type of the 
first non-protocol treatment that the patient receives. 
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5. 
Treatment Plan 
NOTE: 
1 cycle = 28 days 
NOTE: 
The use of steroids to prevent transfusion reactions must be documented on 
the E2905 treatment form. 
5.1 
Administration Schedule 
5.1.1 
Arm A (Lenalidomide Monotherapy) 
Lenalidomide 10 mg po/day on days 1-21 followed by 7 days of no 
therapy. Repeat cycles every 28 days for a total of 4 cycles. (Refer to 
Section 5.1.3 for further treatment). 
Patients with a pretreatment platelet count of 50,000-99,000/mcL or 
an ANC of 500-999/mcL will receive a lenalidomide dose of 5 mg 
po/day on days 1-21. 
5.1.2 
Arm B (Lenalidomide + Epoetin Alfa) 
Lenalidomide 10 mg po/day on days 1-21 followed by 7 days of no 
therapy and epoetin alfa 60,000 units subcutaneously (s.c.) every 
week.  Repeat cycles every 28 days for a total of 4 cycles. (Refer to 
Section 5.1.3 for further treatment). 
Blood pressure and heart rate measurements will be assessed prior to 
each dose of epoetin alfa. 
Patients with a pretreatment platelet count of 50,000-99,000/mcL or 
an ANC of 500-999/mcL will receive a lenalidomide dose of 5 mg 
po/day on days 1-21. 
5.1.3 
Patients on Arm A or Arm B who achieve a Major Erythroid Response 
(MER) according to modified International Working Group (IWG) 
criteria described in Section 6 may continue the assigned treatment in 
the absence of limiting toxicity or disease progression. 
Patients on Arm A who do not achieve a MER will have the option to 
cross over to Arm B (see Section 5.2).  If they choose not to cross 
over, they will then discontinue protocol treatment. 
Patients on Arm B who do not achieve a MER will discontinue 
treatment.  
If the treating MD and/or PI feels that the subject is receiving benefit 
from study (in the way of decreasing RBC transfusion frequency 
and/or HGB increase outside RBC transfusion influence) but does not 
meet MER, subjects may remain on treatment if they have achieved a 
minor erythroid response until demonstrating signs of lack of 
continued response (example:  increase in RBC transfusion 
dependence, or decreased HGB on consistent basis outside of the 
influence of RBC transfusions). See Section 6.1.2.3 for reference. If 
there are questions regarding this item, please have the treating MD 
and/or PI email Dr. List for further discussion on a case by case basis. 
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Treatment with white cell growth factors is allowed for the 
management of neutropenia at the discretion of the treating 
investigator. 
5.2 
Cross-Over Treatment 
Patients who fail to achieve a MER on Arm A AND patients on Arm A who 
relapse will be offered to cross over to Arm B to receive combined treatment in 
the absence of limiting toxicity precluding continuation of lenalidomide treatment.  
The dose for Arm B crossover is the dose of lenalidomide that would otherwise 
be implemented for continuation of therapy according to Section 5.5.  If a patient 
does not choose to cross over, he/she will then discontinue study treatment. 
Response to cross-over treatment will be assessed after 16 weeks (4 cycles) of 
combined therapy (i.e., study week 32). Arm A patients that cross over to Arm B 
that do not achieve a MER after 16 weeks of combined treatment (i.e. week 32) 
will discontinue protocol treatment. 
5.3 
Adverse Event Reporting Requirements 
5.3.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E2905 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
5.3.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
An investigational agent is a protocol drug administered under an 
Investigational New Drug Application (IND). In some instances, the 
investigational agent may be available commercially, but is actually 
being tested for indications not included in the approved package 
label. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
When a study arm includes both investigational and commercial 
agents, the following rules apply. 
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· 
Concurrent administration: When an investigational agent(s) 
is used in combination with a commercial agent(s), the 
combination is considered to be investigational and 
expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: Identify the type of event: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0 will be utilized until September 30, 2010 
for AE reporting. CTCAE version 4.0 will be utilized beginning October 
1, 2010.  
UPDATE: CTEP has released CTCAE Version 5.0 and effective April 
1, 2018, all expedited adverse event reporting done through CTEP-
AERS will utilize version 5 of the CTCAE. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov). 
Step 2: Grade the event using the NCI CTCAE v 5.0. 
Step 3: Determine whether the adverse event is related to the protocol 
therapy (investigational or commercial). Attribution categories are as 
follows: Unrelated, Unlikely, Possible, Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is NOT listed in: 
· 
Arm A – the current NCI Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
· 
Arm B – the current NCI Specific Protocol Exceptions to 
Expedited Reporting (SPEER) for the investigational agent or 
package insert/protocol for the commercial agent. 
NOTE: 
The NCI SPEER (Specific Protocol Exceptions to 
Expedited Reporting) is included in Section 5.4 of the 
protocol.  FOR THIS PROTOCOL, events listed in the 
SPEER should be considered EXPECTED if the grade 
being reported is the same or lower than the grade 
noted in the parentheses next to the AE in the SPEER.  
Events listed in the SPEER column should be 
considered UNEXPECTED if the grade being reported 
exceeds the grade noted in parentheses next to the AE 
in the SPEER.  The SPEER is presented in the last 
column of the CAEPR and identified with bold and 
italicized text. 
Step 5: Review the ”Additional instructions, requirements, and 
exceptions for protocol E2905” table in Section 5.3.6 for protocol 
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and/or ECOG-ACRIN specific requirements for expedited reporting of 
specific adverse events that require special monitoring. 
NOTE: 
For general questions regarding expedited reporting 
requirements, please contact the NCI AdEERS Help Desk:  
301-897-7497. 
5.3.3 
Reporting methods 
This study requires that expedited adverse event reporting use the 
NCI’s Adverse Event Expedited Reporting System (CTEP-AERS). 
CTEP's guidelines for CTEP-AERS can be found at 
http://ctep.cancer.gov.  A CTEP-AERS report must be submitted 
electronically to ECOG-ACRIN and the appropriate regulatory 
agencies via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
· 
the AE Team at ECOG-ACRIN (857-504-2900) 
· 
the NCI (301-897-7497) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 897-7404) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.3.4 
When to report an event in an expedited manner 
Some adverse events require 24-hour notification (refer to Section 
5.3.6). Please complete a 24-Hour Notification Report via the NCl 
CTEP-AERS website (http://ctep.cancer.gov) within 24 hours of 
learning of the event.  The full CTEP-AERS report must be completed 
and submitted via CTEP-AERS within 5 calendar days. 
If the CTEP-AERS system is down, a 24-hour notification call must be 
made to ECOG-ACRIN (857-504-2900) and to NCI (301-897-7497). 
Once the system is restored, a 24-hour Notification Report must be 
entered into the CTEP-AERS system by the original submitter of the 
report at the site. 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.3.6. 
NOTE: 
Adverse events that meet the reporting requirements in 
Section 5.3.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
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adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
requirements in Section 5.3.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
5.3.5 
Other recipients of adverse event reports 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
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5.3.6 
Expedited reporting for investigational agents 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  CTEP-AERS Expedited Reporting 
Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of Investigational 
Agent Lenalidomide in this Study (Arm A and B) OR Within 30 Days of the Last Dose of Any 
Protocol Treatment. 
 
Attribution 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
with  
Hospitali-
zation 
without 
Hospitali-
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
10 Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of treatment with 
an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
· Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
· Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
· Grade 5 expected events 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in 
the table. See NOTE below regarding how to report a death due to progressive disease. 
Please see additional information below under section entitled “Additional instructions, requirements, and exceptions for protocol E2905” 
March 2005 
NOTE: 
All deaths on study require both routine and expedited reporting regardless of causality.  Attribution to treatment or other 
cause should be provided. 
 

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NOTE: 
A death due to progressive disease should be reported as a Grade 5 “Disease progression” under the System Organ 
Class (SOC) “General disorder and administration site conditions”.  Evidence that the death was a manifestation of 
underlying disease (e.g. radiological changes suggesting tumor growth or progression: clinical deterioration associated 
with a disease process) should be. 
NOTE: 
A death that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or definitely to the 
treatment must be reported within 10 calendar days of learning of the event. 
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· 
Expedited AE reporting timelines: 
➢ 24 Hours; 5 calendar days – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ 10 calendar days – A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event. 
· 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization* (or prolongation of existing hospitalization) must be 
reported regardless of attribution and designation as expected or unexpected 
with the exception of any events identified as protocol-specific expedited adverse 
event reporting exclusions. 
· 
Any event that results in persistent or significant disability/incapacity, 
congenital anomaly, or birth defect must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND 
· 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
* Hospitalizations are defined as lasting 24 hours or longer and these events 
must be reported via CTEP-AERS. 
Additional instructions, requirements and exceptions for protocol E2905 
1. 
Additional Instructions: 
➢ With respect to determining the specific day by which the event must be reported, 
the day the reporter learns of the adverse event constitutes “Day 0” 
➢ For grade 2 and 3 unexpected events, CTEP-AERS reporting is only required if 
the event is related to the investigational agent(s); it is not required if the event is 
related only to the commercial agent(s) included in the protocol treatment. 
NOTE: 
For grade 3 unexpected events with hospitalization lasting  24 hours 
(or prolonged hospitalization), an CTEP-AERS report is required even 
if the event is unrelated to the investigational agent(s). 
➢ For instructions on how to specifically report events that result in persistent or 
significant disability/incapacity, congenital anomaly, or birth defect events via 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 
301-897-7497. 
2. 
ECOG-ACRIN and Protocol Specific expedited reporting requirements: 
The adverse events listed below also require expedited reporting for this trial: 
ECOG-ACRIN specific expedited reporting requirements: 
➢ Hospitalizations:  Any grade 1 or 2 adverse event which precipitates a 
hospitalization lasting ≥ 24 hours (or prolongs hospitalization) must be reported 
via CTEP-AERS within 10 calendar days of learning of the event regardless of 
the attribution and designation as expected or unexpected. 
 
 

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Protocol specific expedited reporting requirements: 
➢ All grade 3 expected events with an attribution of definite, probable, or possible, 
regardless of whether the patient is hospitalized, must be reported via CTEP-
AERS within 10 calendar days or learning of the event. 
➢ All ≥ grade 3 thrombo-embolic events, regardless of the attribution and 
designation as expected or unexpected and whether the patient is hospitalized, 
must be reported via CTEP-AERS within 10 calendar days of learning of the 
event. 
➢ Pregnancies  
Pregnancies and suspected pregnancies (including a positive/inconclusive 
pregnancy test regardless of age or disease state) occurring while the subject is 
on Lenalidomide, or within 28 days of the subject’s last dose of Lenalidomide, are 
considered immediately reportable events. The pregnancy, suspected 
pregnancy, or positive/inconclusive pregnancy test must be reported via 
CTEP-AERS within 24 hours of the Investigator’s knowledge. Please refer to 
Appendix XIV for detailed instructions on how to report the occurrence of a 
pregnancy as well as the outcome of all pregnancies. 
All occurrences of primary red cell aplasia (PRCA) or a report of anti-
erythropoietin antibodies must be reported via CTEP-AERS within 10 calendar 
days of learning of the event. Report under ‘Blood/Bone Marrow - Bone Marrow 
Cellularity’ as grade 4 events. 
3. 
Protocol specific expedited reporting exceptions: 
For study arms A and B, the adverse events listed below do not require expedited 
reporting via CTEP-AERS: 
➢ Grade 4 expected myelosuppression (unless it results in a hospitalization, in 
which case, an CTEP-AERS report is required). 
5.3.7 
Reporting Second Primary Cancers 
All cases of second and secondary malignancies [including acute 
myeloid leukemia (AML) and myelodysplastic syndrome (MDS)], 
regardless of attribution, that occur following treatment on NCI-
sponsored trials must be reported as follows: 
1. 
Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at: 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. 
Report the diagnosis via CTEP-AERS, regardless of 
attribution, at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, c.) treatment 
related secondary malignancy, or d.) Neoplasm Other, 
malignant (grade 3 or 4) 
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3. 
Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. 
If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: 
All new malignant tumors must be reported through CTEP-
AERS whether or not they are thought to be related to 
either previous or current treatment.  All new malignancies 
should be reported including solid tumors (including non-
melanoma skin malignancies), hematologic malignancies, 
Myelodysplastic Syndrome (MDS)/Acute Myelogenous 
Leukemia (AML), and in situ tumors. 
Whenever possible, the CTEP-AERS report should include the 
following: 
· 
tumor pathology 
· 
history of prior tumors 
· 
prior treatment/current treatment including duration 
· 
any associated risk factors or evidence regarding how long the 
tumor may have been present 
· 
when and how the tumor was detected 
· 
molecular characterization or cytogenetics or the original tumor (if 
available) and of any new tumor 
· 
tumor treatment and outcome (if available). 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form.

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5.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Lenalidomide (NSC #703813) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. Frequency is provided based on 4081 patients. Below is the 
CAEPR for lenalidomide (CC-5013). 
NOTE: 
FOR THIS PROTOCOL, events listed in the SPEER column should 
be considered EXPECTED if the grade being reported is the same or 
lower than the grade noted in the parentheses next to the AE in the 
SPEER. Events listed in the SPEER column should be considered 
UNEXPECTED if the grade being reported exceeds the grade noted 
in parentheses next to the AE in the SPEER. 
Version 2.8, June 27, 20191 
 
Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Blood and lymphatic 
system disorders - 
Other (pancytopenia) 
 
  
 
Febrile neutropenia 
 
  
 
Hemolysis 
 
  
CARDIAC DISORDERS 
  
 
 
Atrial fibrillation 
  
 
 
Heart failure 
  
 
 
Myocardial infarction2 
  
EAR AND LABYRINTH DISORDERS 
  
 
Vertigo 
 
  
ENDOCRINE DISORDERS 
  
 
 
Hyperthyroidism 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 3) 
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Cataract 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
  
 
Dyspepsia 
 
  
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
Rev. 1/10, 
3/10, 10/11 
10/14 
Rev. 6/13 
Rev. 7/16 
Rev. Add14 
Rev. Add15 

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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 3) 
 
Generalized edema  
  
 
Non-cardiac chest 
pain 
 
  
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
 
 
Hepatobiliary disorders - 
Other (cholestasis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
 
 
Anaphylaxis 
  
 
 
Immune system disorders 
- Other (angioedema) 
  
 
 
Immune system disorders 
- Other (graft vs. host 
disease)3 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
  
 
Fall 
 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
  
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
  
 
Blood bilirubin 
increased 
 
  
 
GGT increased 
 
  
 
Investigations - Other 
(C-Reactive protein 
increased) 
 
  
 
 
Lipase increased 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count decreased 
(Gr 4) 
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased 
(Gr 4) 

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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
Platelet count 
decreased 
 
 
 Platelet count decreased  
(Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell 
decreased 
 
 White blood cell decreased 
(Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
Hyperuricemia 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
  
 
Hypophosphatemia  
  
 
Iron overload 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Bone pain 
 
  
 
Generalized muscle 
weakness 
 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
 
 
Rhabdomyolysis5 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) 
  
 
 
Leukemia secondary to 
oncology chemotherapy6 
  
 
 
Myelodysplastic 
syndrome6 
  
 
 
Neoplasms benign, 
malignant and unspecified 
(incl cysts and polyps) - 
Other (tumor flare)7 
  
 
 
Neoplasms benign, 
malignant and unspecified 
(incl cysts and polyps) - 
Other (second primary 
malignancies) 
  
 
 
Treatment related 
secondary malignancy6 
  

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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Depressed level of 
consciousness 
 
  
 
Dysesthesia 
 
  
 
Dysgeusia 
 
  
 
Headache 
 
  
 
Paresthesia 
 
  
 
Peripheral motor 
neuropathy 
 
  
 
Peripheral sensory 
neuropathy 
 
  
 
 
Stroke2 
  
 
Syncope 
 
  
 
Tremor 
 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Psychiatric disorders 
- Other (mood 
altered) 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
 
Erythema multiforme 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular  
 Rash maculo-papular (Gr 3) 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(drug reaction with 
eosinophilia and systemic 
symptoms [DRESS]) 
  
 
Skin and 
subcutaneous tissue 
disorders - Other 
(pyoderma 
gangrenosum) 
 
  

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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 5.0 Term) 
[n= 4081] 
 
 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
 
 
Stevens-Johnson 
syndrome 
  
 
 
Toxic epidermal necrolysis   
SURGICAL AND MEDICAL PROCEDURES 
  
 
 
Surgical and medical 
procedures - Other 
(impaired stem cell 
mobilization)8 
  
VASCULAR DISORDERS 
  
 
Hematoma 
 
  
 
Hypertension 
 
  
 
Hypotension 
 
  
 
Peripheral ischemia  
  
 
Thromboembolic 
event9 
 
 Thromboembolic event9 (Gr 
3) 
 
Vasculitis 
 
  
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Myocardial infarction and cerebrovascular accident (stroke) have been observed in multiple myeloma 
patients treated with lenalidomde and dexamethasone. 
3 Graft vs. host disease has been observed in subjects who have received lenalidomide in the setting of 
allo-transplantation. 
4 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
5 The rare adverse event of rhabdomyolysis has been observed with lenalidomide. The reports of 
rhabdomyolysis were confounded by concurrent use of statins and dexamethasone, concurrent viral 
and bacterial infections, trauma, and serotonin syndrome. Statins, infections, trauma, and serotonin 
syndrome are known risk factors for rhabdomyolysis. 
6 There has been an increased frequency of secondary malignancies (SPM) including ALL, AML, and 
MDS, and certain other types of cancers of the skin and other organs in multiple myeloma (MM) 
patients being treated with melphalan, prednisone, and lenalidomide post bone marrow transplant. The 
use of lenalidomide in cancers other than MM, shows that invasive SPMs occurred in a small number of 
patients.  Patients treated with lenalidomide should be closely followed for the occurance of SPMs. 
7 Serious tumor flare reactions have been observed in patients with chronic lymphocytic leukemia (CLL) 
and lymphoma. 
8 A decrease in the number of stem cells (CD34+ cells) collected from patients treated with >4 cycles of 
lenalidomide has been reported. 
9 Significantly increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial 
thrombosis has been observed in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
10 Gastrointestinal hemorrhage includes: Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 

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hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the 
GASTROINTESTINAL DISORDERS SOC. 
11 Gastrointestinal obstruction includes:  Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small 
intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC. 
12 Osteonecrosis of the jaw has been seen with increased frequency when lenalidomide is used in 
combination with bevacizumab, docetaxel (Taxotere®), prednisone, and zolendronic acid (Zometa®). 
NOTE: 
While not observed in human subjects, lenalidomide, a thalidomide analogue, 
caused limb abnormalities in a developmental monkey study similar to birth defects 
caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may 
cause birth defects or embryo-fetal death. Pregnancy must be excluded before start 
of treatment. Prevent pregnancy during treatment by the use of two reliable methods 
of contraception. 
NOTE: 
In a trial of first line treatment of patients with chronic lymphocytic leukemia (CLL), 
single agent lenalidomide (CC-5013) increased the risk of death as compared to 
control arm (chlorambucil). 
NOTE: 
In two randomized trials of patients with multiple myeloma (MM), the addition of MK-
3475 (pembrolizumab) to a thalidomide analog plus dexamethasone, resulted in 
increased mortality.  Treatment of patients with MM with a PD-1 or PD-L1 blocking 
antibody, such as MK-3475 (pembrolizumab), in combination with a thalidomide 
analog, such as lenalidomide, is not recommended outside of controlled clinical 
trials. 
NOTE: 
In a clinical trial in patients with Mantle cell lymphoma (MCL), there was an increase 
in early deaths (within 20 weeks); 12.9% in the lenalidomide (CC-5013) arm vs. 7.1% 
in the control arm. 
Adverse events reported on lenalidomide (CC-5013) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that lenalidomide 
(CC-5013) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (monocytosis); Disseminated intravascular coagulation; Eosinophilia 
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block first degree; Cardiac arrest; 
Cardiac disorders - Other (cardiovascular edema); Cardiac disorders - Other (ECG 
abnormalities); Chest pain - cardiac; Left ventricular systolic dysfunction; Palpitations; 
Pericarditis; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Cushingoid 
EYE DISORDERS - Dry eye; Flashing lights; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Ascites; Colonic 
perforation; Dysphagia; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders 
- Other (Crohn's disease aggravated); Gastrointestinal disorders - Other (diverticulitis); 
Gastrointestinal disorders - Other (pale feces); Gastrointestinal hemorrhage10; Gastrointestinal 
obstruction11; Ileus; Mucositis oral; Pancreatitis; Rectal mucositis; Small intestinal mucositis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Multi-organ 
failure 
HEPATOBILIARY DISORDERS - Cholecystitis 

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INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other 
(opportunistic infection associated with >=Grade 2 Lymphopenia); Myelitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Hip fracture; 
Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Cholesterol high; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; INR increased; 
Investigations - Other (hemochromatosis) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypoglycemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; 
Joint effusion; Muscle weakness lower limb; Neck pain; Osteonecrosis of jaw12 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dysphasia; Edema cerebral; 
Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Leukoencephalopathy; 
Memory impairment; Nervous system disorders - Other (hyporeflexia); Spinal cord compression; 
Seizure; Somnolence; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Psychosis 
RENAL AND URINARY DISORDERS - Urinary frequency; Urinary incontinence; Urinary tract 
pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast 
disorders - Other (hypogonadism); Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Atelectasis; Bronchopulmonary hemorrhage; Hypoxia; Laryngeal 
mucositis; Pharyngeal mucositis; Pleural effusion; Pulmonary hypertension; Respiratory failure; 
Tracheal mucositis; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Nail loss; Photosensitivity; 
Rash acneiform; Skin and subcutaneous tissue disorders - Other (Sweet’s Syndrome); Urticaria 
VASCULAR DISORDERS - Hot flashes; Phlebitis; Vascular disorders - Other (hemorrhage 
NOS) 
NOTE: 
Lenalidomide (CC-5013) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 

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5.5 
Dose Modifications  
NOTE: 
Although effective April 1, 2018, expedited adverse event 
reporting done via CTEP-AERS (see Section 5.3) will use CTCAE 
version 5.0 terminology and grading, routine adverse event 
reporting and dose modifications outlined below will continue to 
be based on CTCAE version 4.0 terminology and grading. 
The toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov/). 
5.5.1 
Subjects will be evaluated for adverse events (AEs) at each visit. 
5.5.2 
Dose Reductions for Lenalidomide 
Table 1 gives the dose levels for the dose reduction steps for adverse 
events. 
Table 1 
Dose 
reductions for 
Lenalidomide 
Pre-treatment ANC>/= 1,000 
And PLT >/= 100,000 
Pre-treatment ANC >/= 500-999 
And PLT >/= 50,000-99,000 
Starting dose 
10 mg po/day on days 1-21, 
followed by 7 days of no 
therapy  
5 mg po/day, days 1-21, followed 
by 7 days of no therapy  
Dose level   -1 
5 mg po/day on days 1-21, 
followed by 7 days of no 
therapy 
5 mg po every other day for 28 
days 
Dose level   -2  
5 mg po every other day for 28 
days 
2.5 mg po every other day for 28 
days 
Patients who experience limiting cytopenias after prolonged treatment 
with 2.5 mg every other day may resume treatment at the same dose 
upon hematologic recovery. 
5.5.3 
Dose Modifications for Neutropenia 
Hold lenalidomide for a decline in neutrophil count to < 500/mcL that 
is not supported by myeloid growth factor administration. 
Lenalidomide should be resumed at the next dose reduction step 
when neutrophil count is > 500/mcL. Patients who do not experience 
neutrophil recovery within 8 weeks should be removed from study 
treatment and complete all off-study evaluations. 
5.5.4 
Dose Modifications for Thrombocytopenia 
Some MDS patients may develop thrombocytopenia precipitously 
within the first month of lenalidomide therapy. Therefore, weekly 
CBCs are assessed during the first eight weeks of the study. 
The following are dose interruption/modification guidelines for 
subjects who develop thrombocytopenia. 
Rev. 10/09, 
        8/10 
Rev. 6/11 
Rev. Add14 

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5.5.4.1 
For patients with a baseline platelet count  
 100,000/mcL; 
5.5.4.1.1 
Hold lenalidomide when the platelet count 
falls to < 30,000/mcL. Lenalidomide should 
be resumed within eight weeks at the next 
dose reduction step when the platelet count 
recovers to  50,000/mcL. Subsequent 
cycles should continue at that dose 
reduction level. 
Patients who do not experience platelet 
recovery within 8 weeks should be removed 
from study treatment and complete all off-
study evaluations. 
5.5.4.2 
For patients with a baseline platelet count 
<100,000/mcL; 
5.5.4.2.1 
Hold lenalidomide for decline in the platelet 
count  50% of the baseline value. 
Lenalidomide treatment should be resumed 
at the next dose reduction step upon 
platelet count recovery to  50,000/mcL. 
Subsequent cycles should continue at that 
dose reduction level. 
Patients who do not experience platelet 
recovery within 8 weeks should be removed 
from study treatment and complete all off-
study evaluations. 
Baseline plt count 
Hold for counts of 
Must recover to* 
 100,000 
< 30,000 
 50,000 
 60,000 – 99,999 
50% of baseline 
 50,000 
< 60,000 
50% of baseline 
> 30,000 
* Then dose reduce for remainder of cycle. 
Maintain dose reduction for next cycles, as 
long as subject meets requirements to start 
next cycle. 
5.5.5 
Combined Treatment (Arm B): If, at any time, the Hgb level rises to 
> 12g/dL, regardless of Hgb rate of rise, the epoetin alfa dose will be 
withheld until the Hgb level decreases to < 11 g/dL and will be 
resumed at a decreased dose, as outlined below: 
· 
Epoetin alfa 60,000 U sc QW → 40,000 U sc QW 
· 
Epoetin alfa 40,000 U sc QW → 30,000 U sc QW 
· 
Epoetin alfa 30,000 U sc QW → 20,000 U sc QW 
· 
Epoetin alfa 20,000 U sc QW → 10,000 U sc QW 
NOTE: If the Hgb rises due to a transfusion, epoetin alfa will continue 
to be administered, and the dose level will not change. 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 6/11 

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If Hgb rate of rise is > 1 g/dL in the 1-week or 2-week period 
immediately preceding the next epoetin alfa dose or the Hgb level 
exceeds 11.5 g/dL (and the Hgb is ≤ 12 g/dL), the epoetin alfa dose 
will be decreased immediately, as described, but will not be withheld. 
For example, at the week 5 scheduled dosing visit, assess Hgb rate of 
rise between weeks 4 and 5 and weeks 3 and 5. 
NOTE: 
Dose re-escalation may be allowed in the event of an 
increased, and then decreased, Hgb. Follow the 
recommendations for Epoetin alfa adjustment when 
reinstituted for decline in Hgb. 
5.5.6 
Lenalidomide Monotherapy (Arm A): For those patients 
experiencing a rise in hemoglobin  14 g/dL on Arm A, lenalidomide 
should be withheld until the hemoglobin is ≤ 12 g/dL, at which time 
treatment can be resumed according to the dose adjustment 
recommendations in Table 1 of Section 5.5.2. For those patients 
previously adjusted to the lowest lenalidomide dose, the lenalidomide 
schedule should be changed to a 2 week treatment schedule every 4 
weeks. 
5.5.7 
Dose Modifications for Other Adverse Events 
Dose interruption and modification guidelines for other adverse events 
are in Table 2. Lenalidomide should be held for any  grade 3 adverse 
events with suspected drug association until resolution to < grade 2. 
For any patient who does not experience resolution to < grade 2 
within 6 weeks should be removed from protocol treatment and 
complete all off-study evaluations. For patients with thromboembolic 
events, both agents should be discontinued and not resumed until 
resolution with proper prophylaxis according to the discretion of the 
treating investigator. 
NOTE: 
Patients will be removed from study treatment if 
lenalidomide is held for > 6 weeks for treatment-related 
toxicity. 
NOTE:  
For patients on Arm B, epoetin alfa will continue while 
lenalidomide is being held for toxicity. 
5.5.8 
Dose Reduction for Patients with Renal Insufficiency 
Defined as creatinine >1.5 mg/dl that does not resolve to grade 1. 
[Deleted in Addendum #4] 
· 
Patients with CLcr <60 mL/min and >/= 30 mL/min should be 
monitored closely for possibly excess myelosuppression or other 
toxicity, and dose reduce by 50% upon recovery. 
[Deleted in Addendum #4] 
Rev. 1/10 
Rev. 6/11 
Rev. 6/11 
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Table 2: Dose Modifications for Lenalidomide 
System 
NCI CTCAE Grade 
Action 
Coagulation 
Venous thrombosis/embolism 
≥ Grade 3 
· Hold (interrupt) dose and start 
anticoagulation; resume lenalidomide at 
investigator’s discretion (maintain dose 
level). 
Skin 
Desquamating (blistering) rash  
· Discontinue study treatment. 
Non- desquamating rash 
Grade 2 
 
· If Grade 2, interrupt lenalidomide therapy. 
Resume lenalidomide when the rash 
resolves to ≤ Grade 1 (decrease one 
dose level). 
Grade > 3 
· Hold lenalidomide study drug. 
Neurology 
Neuropathy 
Grade 3 
· If Grade 3, interrupt lenalidomide 3 
therapy. Resume lenalidomide when the 
neuropathy resolves to ≤ Grade 1 
(decrease one dose level). 
Grade 4 
· Hold lenalidomide study drug. 
Allergy 
Allergic reaction  
Grade 2 
· 
If Grade 2, interrupt lenalidomide 
therapy. Resume lenalidomide when 
symptoms resolve to ≤ Grade 1 
(decrease one dose level). 
 Grade 3 
· 
Hold lenalidomide study drug. 
Gastrointestinal 
Constipation  
≥ Grade 3 
· 
Hold (interrupt) dose. Initiate bowel 
regimen, and resume lenalidomide 
when constipation resolves to  grade 2 
(decrease one dose level). 
Endocrine 
Hyperthyroidism or 
hypothyroidism 
· 
Interrupt lenalidomide and initiate 
appropriate medical therapy. Resume 
lenalidomide at investigator’s discretion 
(maintain dose level). 
Cardiac 
Arrhythmias 
Sinus bradycardia/other cardiac 
arrhythmia 
Grade 2 
· 
Hold (interrupt) dose.  Follow at least 
weekly. 
· 
If the toxicity resolves to ≤ grade 
1resume at next lower dose level. 
≥ Grade 3 
· 
Hold lenalidomide study drug. 
Other Toxicity 
Other non-hematologic toxicity 
assessed as lenalidomide-
related 
≥ Grade 3 
· 
Hold (interrupt) dose.  Follow at least 
weekly. 
· 
If the toxicity resolves to ≤ grade 2 
resume at next lower dose level. 

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5.6 
Supportive Care  
5.6.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.6.2 
Therapies considered necessary for the patient’s well being may be 
administered at the discretion of the Investigator. These therapies 
include antibiotics, analgesics, antihistamines, or other medications, 
and transfusions of red blood cells, platelets, or fresh frozen plasma 
given to assist in the management of complications associated with 
MDS or study treatment. 
5.6.3 
Packed RBCs: Transfusions of two units of packed RBCs should be 
considered for decline in hematocrit (HCT) to < 25% or symptoms of 
cardiovascular compromise.  The following transfusion thresholds 
and guidelines are recommended for study participants:  HCT < 
25%, two units of packed RBCs; HCT < 21%, three units of packed 
RBCs; HCT < 18%, four units of packed RBCs. 
5.6.4 
Platelets: Eight to ten units of random donor platelets or one 
cytopheresis unit of single donor platelets should be administered to 
all subjects with signs of hemostatic failure (i.e., bleeding or 
petechiae) or life threatening thrombocytopenia (i.e., platelet count < 
10,000/mcL). 
5.6.5 
Patients should not receive androgens or steroids for treatment of 
their anemia or thrombocytopenia as part of supportive therapy. 
5.6.6 
Patients may receive hydrocortisone prophylactically to prevent 
transfusion reactions. Steroids given for adrenal failure, hormones 
administered for non-cancer-related conditions (e.g. insulin for 
diabetes), and intermittent uses of dexamethasone as an antiemetic 
are permitted concomitantly with study drug. Short courses of steroids 
to treat study drug-induced skin rashes are also permitted. Use of 
steroids and reasons should be documented in the E2905 Forms 
Packet. 
5.6.7 
Each site must have two trained counselors available for counseling all 
patients receiving lenalidomide supplied by the Division of Cancer 
Treatment and Diagnosis.  Trained counselors must complete training 
using the online program provided free by the Celgene Pregnancy 
Prevention Counseling Program (CPPCP). Registration for CPPCP is 
done by completing the form found in Appendix XIII and following the 
directions provided in the email notification. After the training is 
complete, the counselors must generate a training certificate and 
provide it to the CTSU for documentation. Sites may not order 
lenalidomide until documentation for two trained counselors is provided 
to the appropriate office.” The CTSU operations office fax number for 
CPPCP training certificates: (1-888-691-8039). 
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5.7 
Duration of Therapy  
Patients will receive protocol therapy unless: 
5.7.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E2905 Forms Packet. 
5.7.2 
Patient withdraws consent. 
5.7.3 
Adverse event(s) (AEs) occur that, in the judgment of the Investigator, 
may cause severe or permanent harm or which rule out continuation 
of study drug. 
5.7.4 
Lack of therapeutic effect while on either Arm A (for those patients 
that are not eligible or do not wish to cross over to Arm B) or Arm B. 
5.7.5 
Patient’s disease converts to acute myeloid leukemia or disease 
progression. 
5.7.6 
Patient is lost to follow-up. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol treatment 
early, will be followed for response until relapse/progression, and for 6 months 
from end of protocol treatment. Arm A patients that cross over to Arm B that do 
not achieve a MER after 16 weeks of combined treatment (i.e. week 32) will 
discontinue protocol treatment. 
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6. 
Measurement of Effect 
6.1 
MDS Response Criteria: Modified International MDS Working Group (IWG) 
Criteria for Measurement of Response/Treatment Effect in MDS will be used to 
assess response. 
6.1.1 
International Prognostic Scoring System (IPSS) for MDS 
Prognostic Variable 
Survival and AML Evolution Score Value 
0 
0.5 
1.0 
1.5 
2.0 
Marrow Blasts (%) 
<5 
5 to 10 
N/a 
11 to 20 
21 to 30 
Karyotype 
Good 
Normal or any 1 
of: -Y (del(5q) 
del(20q) 
Intermed. 
Any other 
abnormality 
Poor 
chromosome 7 
anomalies; 
Complex: 
≥ 3 abnormalities 
n/a 
n/a 
Cytopenias 
Neutrophil Count < 1800/mcL 
Platelets < 100,000 mcL 
Hemoglobin < 10 g/dL 
0 or 1 
2 or 3 
n/a 
n/a 
n/a 
Low: total score = 0 
Int-1: total score 0.5-1.0 
Int-2: total score 1.5-2.0 
High: total score ≥ 2.5 
6.1.2 
MDS Response Criteria 
6.1.2.1 
Bone Marrow Response (CR or PR must last ≥ 8 weeks) 
1. 
Complete Remission (CR) 
Bone marrow evaluation: Bone marrow showing  
< 5% myeloblasts with normal maturation of all cell 
lines, with no evidence for dysplasia (see dysplasia 
qualifier under peripheral blood evaluation). When 
erythroid precursors constitute < 50% of bone 
marrow nucleated cells, the percent of blasts is 
based on all nucleated cells; when there are ≥ 50% 
erythroid cells, the percent blasts should be based 
on the non-erythroid cells. 
· 
Peripheral Blood Counts (Absolute values 
must last ≥ 8 weeks) 
o 
Hemoglobin greater than 11 g/dL. 
o 
Neutrophils 1500/mm3 or more (not 
on a myeloid growth factor) 
o 
Platelets 100 000/mm3 or more (not 
on a thrombopoetic agent) 
o 
Blasts – ≤ 5% 
o 
No dysplasia.  The presence of mild 
megaloblastoid changes may be 
permitted if they are thought to be 
consistent with treatment effect.  
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However, persistence of 
pretreatment abnormalities (e.g., 
pseudo-Pelger Huet cells, ringed 
sideroblasts, dysplastic 
megakaryocytes) is not consistent 
with CR. 
2. 
Partial Remission (PR) 
· 
All of the CR criteria (if abnormal prior to 
treatment), except 
o 
Bone marrow evaluation: Blasts 
decreased by 50% over 
pretreatment, or a less advanced 
MDS WHO classification than 
pretreatment.  Cellularity and 
morphology are not relevant. 
3. 
Stable Disease 
· 
Failure to achieve at least a PR, but with no 
evidence of progression for ≥ 2 months. 
4. 
Failure 
· 
Death during treatment or disease 
progression characterized by worsening of 
cytopenias, with increase in the percent of 
bone marrow blasts (as defined in Section 6 
below), and/or progression to an MDS FAB 
subtype more advanced than pretreatment. 
5. 
Relapse (following a CR or PR) 
· 
One or more of the following: 
o 
Return to pretreatment bone marrow 
blast percentage. 
o 
Decrement of > 50% from maximum 
remission response levels in 
neutrophils or platelets. 
o 
RBC transfusion dependence (≥ 2 
units RBC transfusions over an 8 
week period) or a reduction in 
hemoglobin concentration by ≥ 2 
g/dL in the absence of acute 
infection, gastrointestinal bleeding, 
hemolysis, treatment hiatus etc. 
6. 
Disease Progression 
· 
A 50 % increase in blasts, depending on 
baseline blast percent. 
o 
For patients with < 5% blasts: 
increase to ≥ 10% blasts 
o 
For patients with 5% to 10% blasts: 
≥ 50% increase to > 10% blasts 
o 
For patients with 10% to 20% blasts: 
≥ 50% increase to ≥ 20% blasts 
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7. 
Disease Transformation 
· 
Transformation to AML (≥ 20% blasts). 
6.1.2.2 
Cytogenetic Response 
Requires 20 analyzable metaphases when using 
conventional techniques.  Analysis of data will require 20 
metaphases before and after treatment, which must be 
done on bone marrow only (peripheral blood is not a 
substitute). Fluorescent in situ hybridization (FISH) may be 
used as a supplement to follow a specifically defined 
cytogenetic abnormality, but it is not a substitute for 
conventional cytogenetic studies. Cytogenetic response is 
defined as follows: 
Complete response: Restoration of a normal karyotype in 
patients with a documented pre-existing clonal (>2 
metaphases abnormal) chromosome abnormalities. 
Partial response: > 50% reduction in the percentage of 
bone marrow metaphases with only clonal abnormality. 
6.1.2.3 
Hematologic Improvement 
Improvements must last ≥ 8 consecutive weeks. 
1. 
Erythroid Response 
· 
Major Erythroid Response: Transfusion-
independence for ≥ 8 consecutive weeks for 
patients who were RBC transfusion-
dependent at baseline AND a ≥ 1 g/dL 
hemoglobin rise compared to mean pre-
transfusion baseline value; or a > 2 g/dL 
rise in hemoglobin without transfusion for 
non-transfusion dependent patients. 
· 
Minor Erythroid Response: The mean 
hemoglobin is sustained 1.0 to 2.0 g/dL 
above the baseline value for a minimum of 8 
weeks; or a 50% or greater decrease in 8-
week RBC transfusion requirements 
compared to baseline. 
2. 
Platelet Response 
· 
Major Platelet Response: For patients with a 
pretreatment count < 100,000/mm3, an 
absolute increase of ≥ 30,000/mm3; for 
platelet transfusion-dependent patients, 
stabilization of platelet counts and platelet 
transfusion independence. 
· 
Minor Platelet Response: For patients with a 
pretreatment platelet count < 100,000/mm3, 
a > 50% increase in platelet count with a net 
increase > 10,000/mm3 but < 30,000/mm3. 

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52 
3. 
Neutrophil Response 
· 
Major Neutrophil Response:  For 
pretreatment ANC < 1500/mm3, ≥ 100% 
increase, or an absolute increase of  
≥ 500/mm3, whichever is greater. 
· 
Minor Neutrophil Response: For ANC > 
1500/mm3 before therapy, ANC increase of 
at least 100%, but absolute increase less 
than 500/mm3, lasting greater than 8 weeks 
(56 days). 
4. 
Progression/Relapse Following Erythroid 
Hematologic Improvement 
· 
For patients who achieve RBC transfusion 
independence: requirement for ≥ 2 units 
RBC transfusion in an 8 week period or a 
reduction in hemoglobin concentration by  
≥ to 2 g/dL in the absence of acute infection, 
gastrointestinal bleeding, hemolysis, etc., 
reaching a hemoglobin < 9.5 g/dL. 
· 
For patients who achieve ≥ 50% decrease 
in RBC transfusions: return to pre-treatment 
RBC transfusion requirement over an 8 
week period. 
6.1.2.4 
Duration of Response 
Time to disease progression (as per Bone Marrow 
Responses above) or progression/relapse following 
hematologic improvement (as per Hematologic 
Improvement above). 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. 
All CBCs and RBC transfusion values for the eight weeks prior to 
randomization are required to establish transfusion-dependence and 
baseline hemoglobin. Transfusion number and dates must be 
documented for the eight weeks preceding initiation of study treatment. 
2. 
For non-transfusion dependent patients (i.e., receiving < 2 units/4 weeks 
x 8 weeks pre-study) who receive periodic transfusions, the mean pre-
transfusion hemoglobin should be used to determine protocol eligibility 
and response reference. 
NOTE: 
For non-transfusion dependent patients, a minimum of 2 pre-
transfusion or un-transfused hemoglobin values are required. 
3. 
[Deleted in Addendum #4] 
4. 
All required prestudy chemistries, as outlined in Section 3 (at least one 
set of the two required sets), should be done within 7 days before 
randomization. CBC/Diff and chemistries should also be performed on 
Day 1 of each cycle. 
5. 
Prestudy non-transfused Hgb, Hct, WBC, ANC, Plt should be 
documented on  
2 occasions over 56 days prior to randomization.  The 2 occasions must 
be separated by at least 7 days. 
Response Assessment 
Hematologic, pathologic and cytogenetic response will be assessed according to 
criteria outlined in Section 6.1.2. 
NOTE: 
When recording prestudy results on the ECOG-ACRIN forms, please 
make sure that ALL relevant dates are clearly given. Do not put all the 
results under the date for Day 1 of protocol treatment unless they 
were actually done that day. Record the actual dates. 
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Assessment 
Screening1 
(56 days prior to randomization 
unless otherwise noted) 
Weekly 
Day 1 of each 
cycle15 
Every  
8 
weeks15 
Week 16 and 
Treatment Discontinuation 
Follow-Up 
Medical History 
X 
 
 
 
 
 
Prior MDS Treatment 
X 
 
 
 
 
 
ECOG Performance Status 
X 
 
X 
 
X 
 
Pregnancy test2 
 X3 
 
 X4 
 
X 
 
Physical examination 
 X9 
 
X 
 
 
 
ECG 
X 
 
 
 
 
 
Thyroid function tests5 
X 
 
 
 
X 
  X11 
Serum erythropoietin (when 
Hgb  < 9.5 g/dL pre-study) 
X 
 
 
X 
X 
 
Serum chemistry6,7 
X 
 
X 
 
X 
  X11 
Hematology8 
X 
  X10 
 X9 
 
X 
  X11 
RBC Transfusion History8 
X 
 
 
 
 
 
Serum ferritin level 
 
 
 
X 
 
 
Response assessment13 
 
 
X 
X 
X 
  X11 
Toxicity assessment14 
 
X 
X 
X 
X 
  X11 
Bone marrow aspirate & 
biopsy12 
X 
 
 
 
X 
X 
NOTE: For patients receiving epoetin alfa (Procrit) through the ESA Apprise Oncology Program, please refer to the REMS 
requirements of the ESA Apprise Oncology Program for the guidelines for use, e.g, for hemoglobin testing, as they may 
differ from the protocol assessments requested in the Section 7 Assessment table above. 
NOTE: Results of the bone marrow biopsy and aspirate as well as Cytogenetics are mandatory to register subjects onto study, 
which are indispensable to determine IPSS category needed for eligibility (see Section 3.1.1.3). Please note that it is not 
necessary to wait for the week 16, week 32, or week bone marrow and cytogenetic results prior to starting the next cycle 
unless deemed necessary by the treating physician.  One example of this exception can include if the subject shows signs 
of progression, such as increased peripheral blood blast percentage.  At that juncture, the treating physician may prefer to 
await the results prior to starting a new cycle.  If a cycle is started, and based on the bone marrow results it is felt by the 
treating physician that the subject should not continue on treatment, please be sure to note this information on the case 
report forms at end of treatment. 
Rev. 10/09 
Rev. 4/15 
Rev. 6/13 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
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1. Pertains to subjects enrolled in arms A or B. 
2. Females of child bearing potential only. Serum or urine pregnancy testing for β-HCG with a sensitivity of at least 25 mIU/mL. For further 
requirements for pregnancy testing and birth control, please see Sections 3.1.9 and 3.1.10. See Section 7.3 for testing, counseling, and drug 
schedules. 
3. Within 10-14 days prior to the start of the study drug and again within 24 hours prior to the start of the study drug. 
4. Females of child bearing potential only. Weekly pregnancy testing during the first cycle of protocol treatment. Every 4 weeks while on study 
drug if menstrual cycles are regular.  Every 2 weeks if menstrual cycles are irregular. See Section 7.3 for testing, counseling, and drug 
schedules. 
5. TSH (thyroid-stimulating hormone), T3, and T4 levels should be done at screening, at 8 and 16 weeks, then every 3 months and at time of 
treatment failure and/or study discontinuation. 
6. Both sets of CBC/Diffs and chemistries should be collected after patient signs consent (see Section 3). 
7. Includes sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, blood urea nitrogen (BUN), creatinine, glucose, albumin, total 
protein, alkaline phosphatase, total bilirubin, aspartate transaminase (SGOT/AST) or glutamic pyruvic transaminase (SGPT/ALT), lactate 
dehydrogenase (LDH), and uric acid (at least one of the two required, see Section 3) to be done within 7 days prior to randomization. 
8. Red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count and differential, absolute neutrophil count (ANC), and 
platelet count required for protocol therapy must be done < 24 hours prior to the treatment cycle. Pre-study CBC with differential and 
chemistries (at least one of the 2 required, see Section 3) should be done within 7 days of randomization. 
9. Repeat on Day 1. 
10. Perform weekly for 8 weeks, then every 2 weeks until the completion of 16 weeks on study, and then every 4 weeks thereafter. 
11. Repeat every 3 months from last day of protocol treatment.  No specific requirements if patient is more than 6 months from last protocol 
treatment. There is a +/- 2 week window for follow-up visits. 
12.  Bone marrow aspirate and biopsy with cytogenetic analysis and iron stains performed pre-study, after 16 weeks of study treatment, at week 
32, and year 1 (if still receiving treatment) in addition to end of treatment or relapse or progression. The BMBx performed after 16 weeks of 
study treatment should be completed by the last week of the cycle 4 in order for the information from the results to be available for those 
considering crossing over to Arm B, whether to continue treatment, etc. If the subject has been on hold from starting a new cycle, then the 
BMBx should fall on the last week of cycle 4. Additional biological studies obtained with bone marrow aspiration are summarized in Section 
7.2. 
13. Hematologic, pathologic, and cytogenetic response will be assessed according to criteria outlined in Section 6.1.2. 
14. Toxicity assessment schedule will follow the hematology schedule. See schedule in Footnote 10. 
15. There is a +/- 5 business day window for all post-screening (on treatment) testing. 
 
 
 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
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Rev. 7/11 
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7.2 
Biological Sample Submissions  
1. 
Submission of karyotypes (Section 11.1) for cytogenetic review and 
pathologic materials (Section 10) for diagnostic review and classification 
is mandatory in order for the patient to be considered evaluable. Failure 
to submit the required materials may render the case unevaluable. 
2. 
Submission of bone marrow and blood for correlative studies should be 
submitted as outlined in Sections 10.2.2.2 and 11.2.  Collection of bone 
marrow and blood should be limited to those patients who have given 
written informed consent to participate in the correlative studies. 
NOTE: 
An informed consent MUST be signed prior to the submission of any 
samples for the mandatory diagnostic reviews and correlative studies. 
Samples for correlative studies should be submitted only from patients 
who have given written consent for the use of their samples for these 
purposes. 
NOTE: 
Institutions outside of the United States and Canada must confer with 
the receiving laboratory and the ECOG-ACRIN Operations Office - 
Boston regarding logistics for submission of fresh samples. 
NOTE: 
It is required that biological sample submissions be logged into the 
ECOG-ACRIN Sample Tracking System (STS) (see Section 10.5) for 
purposes of monitoring compliance. 
Rev. 10/09 
 
Baseline 
Week 
16 5 
Week 
32 
Year 1 
Relapse/Progression/
End of Treatment 
Rev. 10/09 
Diagnostic Slides/Smears*1 
X 
X 
X 
X 
X 
Rev. 10/09 
BM Biopsy Block +2, 6 
X 
X 
X 
X 
X 
Rev. 10/09 
Peripheral Blood (Sodium 
Heparin tubes) +3 
X 
X 
X 
X 
X 
Rev. 10/09,  
          7/11 
BM Aspirate (EDTA tube)+3,6 
X 
X 
X 
X 
X 
Rev. 10/09 
Karyotypes*4 
X 
X 
X 
X 
X 
*Mandatory 
+Submit per patient consent. 
1. 
Submit to the ECOG-ACRIN CBPF as outlined in Section 10 at baseline, week 16, week 
32, year 1 and progression. 
2. 
Submit to the ECOG-ACRIN CBPF per Section 10 from patients consenting to participate 
in the optional laboratory studies. If blocks cannot be submitted, please submit five (5) 
unstained bone marrow biopsy level slides. If you have questions please call Lynn 
Moscinski at (813) 979-3001. 
3. 
Submit to Dr. Alan List’s Laboratory as indicated in Section 11.2 from patients consenting 
to participate in the optional laboratory studies.  Direct questions to Kathy McGraw or 
Ashley Basiorka at (813) 745-8271. 
4. 
All study participants/cooperative groups must submit two original karyotypes to Mayo 
Clinic Cytogenetic Laboratory as indicated in Section 11.1. 
[Note deleted in Addendum #1] 
5. 
16 weeks after the first dose of drug. 
Rev. 10/09, 
        7/11 
Rev. 6/11 
Rev, 4/15 
Rev. 6/11 
Rev. 10/09  
Rev.4/15 
Rev. 10/09  
Rev.4/15 
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NCI Update Date: August 18, 2010 
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6. 
Patient must sign consent before collection of baseline bone marrow biopsy/aspirate and 
peripheral blood (collect Monday-Thursday only, do not collect on Fridays or the day 
before a holiday, and ship day of collection). Submit initial bone marrow aspirate to Dr. 
Alan List’s Laboratory using the Generic Specimen Submission Form (#2981) as outlined 
in Section 10.5.1. Please call Dr. List’s laboratory prior to shipping. Once the patient is 
randomized please call the receiving laboratories with the ECOG-ACRIN patient 
sequence number and enter the information into the ECOG-ACRIN STS. 
7.3 
Schedule for pregnancy testing, education and counseling, and dispensing 
schedule for lenalidomide. 
Procedure 
Screening 
Cycle 1 
Subsequent 
cycles 
Study drug 
discontinuation 
≤ 28 days from 
baseline (first day of 
study drug 
administration) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
3-4 weeks from 
the last of day of 
last cycle 
Pregnancy 
testing1 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Education 
and 
counseling3 
 
X3 
 
 
 
X3 
 
X3 
Dispense 
lenalidomide 
 
X4 
 
 
 
X4 
 
 
1Pregnancy tests for females of childbearing potential.  A female of childbearing potential 
(FCBP) is a female of childbearing potential is any woman, regardless of sexual orientation 
or whether they have undergone tubal ligation, who meets the following criteria: 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). 
2Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to 
initiation of lenalidomide.  FCBP with regular or no menstruation must have a pregnancy 
test weekly for the first 28 days and then every 28 days while on study treatment 
(including breaks in treatment); at discontinuation of lenalidomide and at day 28 post the 
last dose of lenalidomide.  Females with irregular menstruation must have a pregnancy 
test weekly for the first 28 days and then every 14 days while on study treatment 
(including breaks in treatment), at discontinuation of lenalidomide and at Day 14 and Day 
28 post the last dose of lenalidomide (see Appendix X: Lenalidomide Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods). 
3The Lenalidomide Education and Counseling Guidance Document (Appendix XI) must be 
completed and signed by a trained counselor at the participating site prior to each 
dispensing of lenalidomide treatment. A copy of this document must be maintained in the 
patient records. The Lenalidomide Information Sheet (Appendix XII) will be given to each 
patient receiving lenalidomide treatment. The patient must read this document prior to 
starting lenalidomide study treatment and each time they receive a new supply of study 
drug. 
4Only enough lenalidomide for 28 days or one cycle of study treatment (whichever is shorter) 
may be provided to the patient each cycle. 
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8. 
Drug Formulation and Procurement 
NOTE: As of Addendum #13, all patients who register to the study will use commercial 
supply of Procrit. Patients who previously received Procrit from the NCI will be 
switched to the commercially supplied Procrit. Sites will register to the REMS 
program, via the ESA APPRISE Oncology Program, for commercially supplied 
epoetin alfa (Procrit). In addition, each site should inform the hospital 
compliance group responsible for the ESA that the epoetin alfa (Procrit) is 
being used as part of an approved protocol.  Please contact the ESA APPRISE 
Oncology Program at 1-866-284-8089. Patients/insurance will be charged for 
the commercial supply of epotin alfa (Procrit). Only brand Procrit should be 
ordered through the REMS. Epogen may not be substituted for Procrit. 
Vial sizes available: 
Single-dose vial: 2000, 3000, 4000, 10,000, and 40,000 Units/1 mL (3). 
Multidose vial containing benzyl alcohol: 20,000 Units/2 mL and 20,000 Units/1 
mL (3). 
Overview of Steps - ESA Apprise Oncology Program: 
Steps for Hospitals and Hospital/Institution-affiliated Outpatient Facilities That 
Dispense ESAs to Patients With Cancer 
Select a Hospital Designee: This individual is designated by hospital 
management to assume authority and responsibility to internally coordinate and 
oversee the ESA APPRISE Oncology Program in the hospital (e.g., pharmacy 
director, Head of Hematology/Oncology Department). 
Complete Training: The Hospital Designee must complete the ESA APPRISE 
Oncology Program training for the Hospital Designee. 
Enroll:  The Hospital Designee must enroll in the ESA APPRISE Oncology 
Program by completing the ESA APPRISE Oncology Program Enrollment Form 
for Hospitals. 
Implement: The Hospital Designee must establish or oversee the establishment 
of a system, order sets, protocols, or other measures designed to ensure that 
ESAs are only dispensed to patients with cancer after verifying: 
· 
That the Healthcare Provider (HCP) who prescribed Procrit® for patients 
with cancer has enrolled in the ESA APPRISE Oncology Program. 
If an HCP who prescribes Procrit® is not enrolled in the ESA APPRISE 
Oncology Program, the prescriber will be notified that he/she is not able to 
prescribe Procrit® for patients with cancer. 
· 
That the discussion between the patient and ESA APPRISE Oncology 
Program-enrolled prescriber on the risks of Procrit® therapy is documented 
by patient and prescriber signatures on the ESA APPRISE Oncology 
Program Patient and Healthcare Professional (HCP) Acknowledgment 
Form prior to initiation of each new course of Procrit® therapy”. 
https://www.esa-
apprise.com/ESAAppriseUI/public/ESA_APPRISE_Oncology_Program_Ho
spital_Process_Overview_Flashcard.pdf  
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For complete details on the REMS for ESA Apprise please call 1-866-284-
8089. 
Availability 
Maintenance of NCI drug accountability records is required. Lenalidomide (NSC# 
703813) may be requested by the Principal Investigator (or their authorized designees) 
at each participating institution. Pharmaceutical Management Branch (PMB) policy 
requires that drug be shipped directly to the institution where the patient is to be treated. 
PMB does not permit the transfer of agents between institutions (unless prior approval 
from PMB is obtained – see general information). Completed Clinical Drug Requests 
(NIH-986): Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB Online 
Agent Order Processing (OAOP) application  
<https://ctepcore.nci.nih.gov/OAOP>. Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account 
<https://ctepcore.nci.nih.gov/iam/> and the maintenance of an “active” account status 
and a “current” password, and active person registration status. The NCI Clinical Drug 
Request form is available on the NCI home page (http://ctep.cancer.gov) or by calling 
the PMB at (240) 276-6575. 
NOTE: 
As of the activation of Addendum #13, all patients will receive epoetin alfa 
(Procrit) through the commercial channels, or through the ESA Apprise 
Oncology program. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling (240) 276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time, or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov) or by calling the PMB at (240) 276-6575. 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of all 
drugs received from the PMB using the NCI Investigational Agent Accountability Record 
available on the NCI home page (http://ctep.cancer.gov) or by calling the PMB at (240) 
276-6575. 
8.1 
Lenalidomide (NSC# 703813) 
NOTE: 
Before lenalidomide is dispensed, patients must 1) have a negative 
pregnancy test (if applicable) and 2) be counseled by a trained 
counselor. Pharmacists may be trained counselors (see Lenalidomide 
Counselor Program Site Counselor Identification Form in the 
protocol). The counseling requirements for investigational-use 
lenalidomide are separate from the RevAssist program. Only a 28-day 
supply may be dispensed to a patient at one time 
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8.1.1 
Other Names  
IMiD CC-5013, Revlimid® 
8.1.2 
Classification  
Immunomodulatory drug 
8.1.3 
Mode of Action  
Lenalidomide, a thalidomide analog, is an immunomodulatory agent 
with a spectrum of activity that is not fully characterized. In vitro, it 
inhibits secretion of the pro-inflammatory cytokines TNF-α, IL-1β, and 
IL-6 and increases secretion of the anti-inflammatory cytokine IL-10.  It 
also induces T-cell proliferation, IL-2 and IFN-γ production in vitro. 
8.1.4 
Storage and Stability  
How Supplied: Celgene supplies and CTEP, NCI, DCTD distributes 
lenalidomide 2.5 mg (size 4) and 5 mg (size 2) hard gelatin capsules in 
tamper-evident, child-resistant, opaque, high density polyethylene 
(HDPE) bottles with HDPE caps. Bottles contain 100 capsules per 
container. 
The capsules also contain anhydrous lactose, microcrystalline cellulose, 
croscarmellose sodium, and magnesium stearate. 
Storage: The capsules should be stored at room temperature (15-
30°C) away from moisture and direct sunlight. 
Stability: Refer to the package labeling for expiration date. Lenalidomide 
stability is adequate for at least 28 days after transferring to a pharmacy 
vial. 
8.1.5 
Dose Specifics  
Lenalidomide 10 mg po/day x 21 days (5 mg dose for moderate 
neutropenia or thrombocytopenia-see Section 5.1).  To be repeated 
every 28 days until relapse or progression. 
8.1.6 
Route of Administration  
Take lenalidomide by mouth with or without food. Do not crush, chew 
or open capsules. 
8.1.7 
Potential Drug Interactions 
In vitro, lenalidomide did not significantly inhibit marker enzyme 
activities for CYP1A2, CYP2C9, CYP2C19, CYP2E1, or CYP3A4.  In 
rats, no induction of any CYP450 enzymes was observed. These data 
suggest that lenalidomide is not likely to cause metabolic drug 
interactions in man. 
8.1.8 
Availability  
Lenalidomide is an investigational agent supplied by the National 
Cancer Institute. See Section 8 for ordering instructions. 
Available as both a 5 mg and a 2.5 mg hard gelatin capsule. 
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8.1.9 
Side Effects  
Please refer to Section 5.4. 
8.1.10 
Nursing/Patient Implications  
1. 
Effective contraception must be used by patients for at least 4 
weeks before beginning lenalidomide therapy, during 
lenalidomide therapy, during dose interruptions and for 4 
weeks following discontinuation of lenalidomide therapy.  
Reliable contraception is indicated even where there has been 
a history of infertility, unless due to hysterectomy or because 
the patient has been postmenopausal naturally for at least 24 
consecutive months. Two reliable forms of contraception must 
be used simultaneously, by females, unless continuous 
abstinence from heterosexual sexual contact is the chosen 
method.  Females of childbearing potential should be referred 
to a qualified provider of contraceptive methods, if needed. A 
female of childbearing potential is any woman, regardless of 
sexual orientation or whether they have undergone tubal 
ligation, who meets the following criteria: 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). 
Males receiving lenalidomide must always use a latex condom 
during any sexual contact with females of childbearing potential 
even if they have undergone a vasectomy. 
Before prescribing lenalidomide, females of childbearing 
potential should have 2 negative pregnancy tests (sensitivity of 
at least 25 mIU/mL). The first test should be performed within 
10 – 14 days, and the second test 24 hours prior to prescribing 
lenalidomide. A prescription for lenalidomide for a female of 
childbearing potential must not be issued by the prescriber until 
negative pregnancy tests have been verified by the prescriber.  
2. 
Caution patient not to drive or use hazardous machinery until 
the potential sedative effects of the drug are known in the 
patient. 
3. 
Caution patient to report leg swelling or shortness of breath, 
because of the risk of thrombosis/embolism 
4. 
Counsel patient to report abnormal sensations in hands or 
feet, such as decreased sensation or dysesthesia. 
Paresthesias are often noted early before neuropathy 
develops. 
5. 
Advise patient to immediately report rashes or fever. 
8.1.11 
Dispensing 
Only a 28-day supply may be dispensed at one time. Sites may not 
mail lenalidomide to patients. 
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8.1.12 
Patient Care Implications and Counseling 
Risks Associated with Pregnancy 
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. 
Definition of female of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as any 
woman, regardless of sexual orientation or whether they have 
undergone tubal ligation, who meets the following criteria: 1) has not 
undergone a hysterectomy or bilateral oophorectomy or 2) has not 
been naturally postmenopausal (amenorrhea following cancer therapy 
does not rule out childbearing potential) for at least 24 consecutive 
months (i.e., has had menses at any time in the preceding 24 
consecutive months). 
Before starting study drug: 
Female Subjects: 
· 
FCBP must have two negative pregnancy tests (minimum 
sensitivity of 25 mIU/mL) prior to starting study drug.  The first 
pregnancy test must be performed within 10-14 days prior to the 
start of study drug and the second pregnancy test must be 
performed within 24 hours prior to the start of study drug.  The 
subject may not receive study drug until the Investigator has 
verified that the results of these pregnancy tests are negative. 
Male Subjects:   
· 
Must agree to use a latex condom during sexual contact with 
females of childbearing potential while participating in the study 
and for at least 28 days following discontinuation from the study 
even if he has undergone a successful vasectomy.  
All Subjects: 
· 
Only enough lenalidomide for one cycle of therapy may be 
dispensed with each cycle of therapy. 
· 
If pregnancy or a positive pregnancy test does occur in a study 
subject or the partner of a male study subject during study 
participation, lenalidomide must be immediately discontinued. 
Counseling 
· 
In investigational studies where lenalidomide is supplied by the 
NCI, patients will be counseled by a qualified healthcare 
professional (including but not limited to, nurses, pharmacists and 
physicians). Two healthcare professionals at each site will be 
trained by Celgene in requirements specific to counseling of 
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subjects (investigators cannot counsel patients as part of this 
requirement). Refer to specific protocol sections for more 
information about training requirements. 
· 
Once trained, these healthcare staff will counsel subjects prior to 
medication being dispensed to ensure that the subject has 
complied with all requirements including use of birth control and 
pregnancy testing (FCBP) and that the subject understands the 
risks associated with lenalidomide. This step will be documented 
with a completed Lenalidomide Education and Counseling 
Guidance Document (Appendix XI) and no drug will be dispensed 
until this step occurs. Counseling includes verification with the 
female patient that required pregnancy testing was performed and 
results were negative. A Lenalidomide Information Sheet 
(Appendix XII) will be supplied with each medication dispense.” 
 
8.1.13 
References 
1. Richardson PG, Schlossman RL, Weller E, et al. 
Immunomodulatory drug CC-5013 overcomes drug resistance and 
is well tolerated in patients with relapsed multiple myeloma. Blood 
2002; 100:3063-7. 
2. Richardson P, Jagannath S, Schlossman R, et al. A Multi-center, 
Randomized, Phase 2 Study to Evaluate the Efficacy and Safety 
of 2 CDC-5013 Dose Regimens When Used Alone or in 
Combination with Dexamethasone (Dex) for the Treatment of 
Relapsed or Refractory Multiple Myeloma (MM). Blood 2003; 
102:235a. 
3. Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie 
B. Results of Phase I Study of CC-5013 for the Treatment of 
Multiple Myeloma (MM) Patients Who Relapse after High Dose 
Chemotherapy (HDCT). Blood 2001:775a (A3226). 
4. Davies FE, Raje N, Hideshima T, et al. Thalidomide and 
immunomodulatory derivatives augment natural killer cell 
cytotoxicity in multiple myeloma. Blood 2001; 98:210-6. 
8.2 
Epoetin Alfa (NSC# 628281) 
Experience in Subjects with Cancer 
A randomized controlled clinical study, previously summarized in the label and 
published in 2005, entitled, “Maintaining Normal Hemoglobin Levels With Epoetin 
Alfa in Mainly Nonanemic Patients With Metastatic Breast Cancer Receiving 
First-Line Chemotherapy: A Survival Study” (BEST) evaluated 939 women with 
metastatic breast cancer receiving chemotherapy. Patients received either 
weekly Epoetin alfa or placebo for up to a year. This study was designed to show 
that survival was superior when Epoetin alfa was administered to prevent anemia 
(maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% 
and 42%). The study was terminated prematurely when interim results 
demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher 
rate of fatal thrombotic events (1.1% Epoetin alfa vs. 0.2% placebo) in the first 4 
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months of the study were observed among patients treated with Epoetin alfa. 
Based on Kaplan-Meier estimates, at the time of study termination, the 12-month 
survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 
76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).6   
A multicenter, randomized, double-blind, placebo-controlled trial in which patients 
with advanced non-small cell lung cancer unsuitable for curative therapy were 
treated with Epoetin alfa targeting hemoglobin levels between 12 and 14 g/dL or 
placebo. Following an interim analysis of 70 of 300 patients planned, a significant 
difference in median survival in favor of patients in the placebo group was 
observed (63 vs. 129 days; HR 1.84; p = 0.04).7 
A preliminary report from a clinical study (DAHANCA) evaluated 522 patients 
with primary squamous cell carcinoma of the head and neck receiving radiation 
therapy. Patients were randomized to darbepoetin alfa (a different erythropoietin 
drug) or placebo. An interim analysis in 484 patients demonstrated a 10% 
increase in locoregional failure rate among darbepoetin alfa-treated patients (p = 
0.01). At the time of study termination, there was a trend toward worse survival in 
the darbepoetin alfa-treated arm (p = 0.08).8 
A recently completed phase 3, double-blind, randomized, placebo-controlled 16-
week clinical study evaluated 989 patients with active malignant disease not 
receiving chemotherapy or radiation therapy. There was no evidence of a 
statistically significant reduction in proportion of patients receiving RBC 
transfusions. In addition, there were more deaths in the darbepoetin alfa 
treatment group [26% (136/515)] than the placebo group [20% (94/470)] at 16 
weeks (completion of treatment phase). With a median survival follow up of 4.3 
months, the absolute number of deaths was greater in the darbepoetin alfa 
treatment group [49% (250/515)] compared with the placebo group [46% 
(216/470); HR 1.29, 95% CI: 1.08, 1.55].9 
NOTE: 
Refer to epoetin alfa package insert for more information. 
8.2.1 
Other Names 
Erythropoietin, rhu-erythropoietin, EPO, Epogen, Procrit. 
8.2.2 
Classification 
Colony stimulating factor; cytokine. 
8.2.3 
Mode of Action 
Stimulates red cell production.  It stimulates the division and 
differentiation of committed erythroid progenitors in the bone marrow. 
8.2.4 
Storage and Stability 
Epoetin alfa is stored in the refrigerator (2-8oC). Do not freeze or 
shake.  If the epoetin alfa solution freezes, it must not be used.  The 
solution should be brought to room temperature prior to injection. 
The 1 mL vial single-dose vial contains no preservative. Use one dose 
per vial. Do not re-enter vial; discard unused portions. 
The 1 mL or 2mL multidose vials contain preservative. Store at 2o to 
8o C after initial entry and between doses. Discard 21 days after initial 
entry. Epoetin alfa should be drawn up into a plastic syringe and 
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administered subcutaneously according to standard sterile 
techniques. 
8.2.5 
Dose Specifics 
60,000 subcutaneously weekly.  Repeated every 28 days for four 
cycles. 
8.2.6 
Preparation 
Usually single-dose vials are administered undiluted, although 
preservative-free solutions may be mixed with bacteriostatic NS 
containing benzyl alcohol 0.9% in a 1:1 ratio. 
Admixing is not necessary when using the multidose vials of epoetin 
alfa containing benzyl alcohol. Do not dilute or administer in 
conjunction with other drug solutions. 
8.2.7 
Route of Administration 
Subcutaneous 
8.2.8 
Availability 
Those patients who had previously received Procrit from the NCI will 
be switched to the commercially supplied Procrit. 
As of Addendum #13, all patients will receive epoetin alfa 
(Procrit) through the commercial channels, or  through the  ESA 
Apprise Oncology Program.  
Vial sizes available: 
Single-dose vial: 2000, 3000, 4000, 10,000, and 40,000 Units/1 mL 
(3). 
Multidose vial containing benzyl alcohol: 20,000 Units/2 mL and 
20,000 Units/1 mL (3). 
NOTE: 
See Section 8 for updated drug ordering instructions. 
8.2.9 
Incompatibilities 
Epoetin Alfa is contraindicated in subjects with the following: 
· 
Uncontrolled hypertension 
· 
Known hypersensitivity to the active substance or any of the 
excipients 
8.2.10 
Side Effects 
1. 
Fever (29%). 
2. 
Gastrointestinal: Diarrhea (21%), nausea (17%), vomiting 
(17%). 
3. 
Cardiovascular: Edema (17%), hypertension with dialysis 
patients. 
4. 
Neurologic: Paresthesia (11%); increased incidence of 
seizures in dialysis patients. 
4. 
Dermatologic: Local erythema; rash (mild, rare, and transient). 
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5. 
Thrombotic events: Pulmonary embolisom, cerevral vascular 
accident. 
6. 
Other:  Potential to increase tumor growth. 
Thrombovascular Events   
TVEs, such as myocardial ischemia, myocardial infarction, 
cerebrovascular accidents (cerebral hemorrhage and cerebral 
infarction), transient ischemic attacks, deep venous thrombosis, 
arterial thrombosis, pulmonary emboli, retinal thrombosis, and clotting 
of an artificial kidney or shunt have been associated with the use of 
erythropoietic agents as reflected in the labeling of all currently 
marketed products. Additionally, there is a potential for an increased 
rate of TVE occurrence when recombinant human erythropoietin is 
used in non-anemic subjects. Published findings from a study 
evaluating survival in subjects with cancer has indicated that there 
may be an increased risk of TVE associated with recombinant human 
erythropoietin treatment of non-anemic cancer subjects.10  
In summary, the occurrence of TVE is associated with epoetin alfa 
treatment whether used in anemic or non-anemic subjects. 
8.2.11 
Nursing Implications 
1. 
Monitor for central venous catheter occlusion or generalized 
thrombosis. 
2. 
Administer antipyretics, antiemetics and analgesics as 
needed.  Diphenhydramine PO may decrease erythema at the 
subcutaneous injection site. 
3. 
Inform patient of possible side effects. 
4. 
Encourage patient to keep scheduled laboratory visits, as 
frequent blood tests are needed to determine the correct dose 
of epoetin alfa. 
5. 
Monitor blood pressure and heart rate prior to each dose of 
epoetin alfa. 
6. 
Self-administration of epoetin alfa is not permitted for patients 
on protocol treatment. 
8.2.12 
Allergic Responses 
There may be a risk of developing an allergic reaction to rhu-
erythropoietin. Rare allergic symptoms following epoetin alfa 
treatment (e.g., skin rash, itching and hives) have been reported, It is 
possible for more serious allergic reactions to occur.  These possible 
reactions include a whole body rash, shortness of breath, wheezing, 
sudden drop in blood pressure, swelling around the mouth or eyes, 
rapid pulse or sweating.  If a serious allergic or anaphylactic reaction 
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8.2.13 
Antibodies 
Pure red cell aplasia (PRCA) in association with neutralizing 
antibodies to native erythropoietin has been observed in patients 
treated with recombinant erythropoietins. This has been reported 
predominately in patients with chronic renal failure. PRCA has been 
reported in a limited number of subjects exposed to other recombinant 
erythropoietin products prior to exposure to darbepoetin alfa; 
therefore, the contribution of epoetin alfa to the development of PRCA 
is unclear.  Any patient with loss of response to rhu-erythropoietin 
should be evaluated for the etiology of loss of effect.  Rhu-
erythropoietin should be discontinued in any patient with evidence of 
PRCA and the patient evaluated for the presence of binding and 
neutralizing antibodies to epoetin alfa, native erythropoietin, and any 
other recombinant erythropoietin administered to the patient. In 
patients with PRCA secondary to neutralizing antibodies to 
erythropoietin, epoetin alfa should be discontinued. (Source for 
reviewer: USPI) 
Serological screening to investigate the presence of neutralizing 
antibody to epoetin alfa can be arranged by contacting Janssen 
Products, LP, at 1-800-526-7736. 
All occurrences of PRCA, loss of effect (LOE) of epoetin alfa in the 
treatment of anemia and/or a report of the presence of antibodies to 
erythropoietin, will be defined as a SAE and reported and tracked as 
such. 
Any patient who develops a sudden loss of response to epoetin alfa 
therapy, (unexplained drop in Hb >2g/dL), accompanied by a low 
reticulocyte count should be appropriately evaluated for etiology (e.g. 
iron or vitamin deficiency, blood loss, hemolysis, infection or 
inflammation, progression of underlying malignancy, aluminum 
intoxication).  In the absence of another etiology, serum should be 
tested for the presence of antibodies to erythropoietin.   
In the event that erythropoietin testing is deemed necessary in the 
setting of PRCA, a consent form for the testing of erythropoietin 
antibodies is required. Refer to Appendix , Addendum 1. 
8.2.14 
Pregnancy and Lactation 
There are no adequate and well-controlled studies in pregnant women 
(pregnancy category C); therefore, epoetin alfa should not be used 
during pregnancy. In addition, it is not known if epoetin alfa is 
excreted in human milk, therefore, lactating mothers should stop 
nursing before participating in any epoetin alfa study. 
8.2.15 
Geriatric Use 
Please refer to the epoetin alfa drug insert for specific information on 
geriatric use. 
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8.2.16 
References 
Abels RI, et al.  Recombinant human erythropoetin (rhu-EPO) for the 
treatment of the anemia of cancer. Proc Beijing Symposium.  Murphy 
MJ, Jr. (ed.) Dayton, Ohio: Alpha Med Press, 1991. 
Nelson RA, et al. Long-term treatment of anemic cancer patients with 
recombinant human erythropoetin. American Society of Hematology 
34th Annual Meeting.  December, 1992. 
Case DC, et al.  Recombinant human erythropoetin therapy for 
anemic cancer patients on chemotherapy. J NCI 1993; 85. 
Leyland-Jones B, for BEST Investigators and Study Group. Breast 
cancer trial with erythropoietin terminated unexpectedly. Lancet 
Oncol. 2003, 4 (8): 459-460. (J & J sponsored EPREX [an epoetin alfa 
that is marketed outside the U.S.] study.) 
Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining Normal 
Hemoglobin Levels With Epoetin Alfa in Mainly Nonanemic Patients 
With Metastatic Breast Cancer Receiving First-Line Chemotherapy: A 
Survival Study. JCO. 2005; 23(25): 1-13. 
Wright JR, Ung YC, Julian JA, et al. Randomized, Double-Blind, 
Placebo-Controlled Trial of Erythropoietin in Non-Small-Cell Lung 
Cancer with Disease-Related Anemia. JCO. 2007; 25(9): 1-6. 
http://frejacms.au.dk/dahanca/get_media_file 
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9. 
Statistical Considerations 
The overall goal of this study is to improve the rate of MER through combined therapy of 
lenalidomide and epoetin alfa (arm B) by 20% over that of arm A of lenalidomide 
monotherapy, in which the rate of MER is estimated at 30%, in an MDS population 
without chromosome 5q31.1 deletion. The anticipated improvement in response is based 
upon the potentiation of erythroid colony-forming capacity in cell line models. MER will 
be evaluated at 16 weeks after start of study treatment. Patients without 5q31.1 deletion 
will be randomly assigned to one of two treatment arms, stratified by serum 
erythropoietin level (≤500 mU/mL vs. > 500 mU/mL) and prior erythropoietin/DA 
treatment (yes vs. no).  Patients with 5q31.1 deletion will be assigned to arm A only for 
correlative studies, and will not be included in the comparative analysis of the study. The 
original design required 236 total patients (212 to be randomized) in order to obtain 80% 
power for the primary comparison. Due to an interruption in drug supply, the study was 
suspended and epoetin alfa treatment was held on September 24, 2010. At that time, 67 
patients were enrolled. Among them, 57 were randomized (29 on arm A, 28 on arm B). 7 
patients on Arm B were still within 16 weeks treatment. New supply of epoetin alfa was 
available for arm B patients on October 27, 2010 and the study was reopened on 
February 4, 2011. Due to this unexpected drug supply issue, the comparison of the 
primary endpoint may lose some power. To minimize the potential effect on the primary 
endpoint, in the revised design, 14 patients (7 on arm A; 7 on arm B) randomized 
between May 19, 2010 and September 24, 2010 will be excluded from the primary 
analysis. The total accrual will be increased to 252 (226 to be randomized). This revised 
statistical considerations section is to incorporate this change. 
9.1 
Accrual 
This study requires 212 patients (226 to be randomized) without 5q31.1 deletion 
for the primary endpoint comparison. Assuming that 10% of patients in the MDS 
population as defined in this study have the 5q31.1 deletion, a total of 252 
patients will be entered. Accrual for E1996, a previous study in this patient 
population was lower than expected. However, since the proposed regimens 
(lenalidomide, lenalidomide + epoetin alfa) are different from the regimen used in 
E1996 (erythropoietin vs. supportive care) with promising activity in multi-center 
phase II trials, and this study will be an intergroup study, we anticipate no accrual 
impediment. In fact, based on the accrual to the study before its suspension, we 
anticipate that the accrual rate will be approximately 60 patients per year, and 
thus, the accrual will be completed in approximately five years, taking the 
suspension time into account. The feasibility of achieving the accrual goal will be 
monitored closely by the ECOG-ACRIN Data Monitoring Committee (DMC) and 
the NCI. According to NCI guidelines, if quarter 5-6 accrual (the number of 
patients enrolled on trial during quarters 5 and 6 after activation) is < 20% of 
projected rate, then the trial will be closed; If quarter 5-6 accrual is < 50% and > 
20% of projected rate, then the study team will be given 6 months to improve 
accrual. If the average accrual rate in quarter 8 is below 50% then the trial will 
have to be amended to reflect actual accrual. 
9.2 
Primary Endpoint 
The primary endpoint in this phase III study of previously erythropoietin/DA-
treated MDS patients or erythropoietin/DA-naïve patients but with high 
transfusion frequency or high endogenous erythropoietin level is major erythroid 
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response (MER), defined as sustained transfusion independence in transfusion-
dependent patients or a rise in hemoglobin > 2 g/dL in transfusion-independent 
patients with anemia for a minimum of eight consecutive weeks. The objective 
MER will be assessed 16 weeks after start of study treatment. At the time of 
objective MER assessment, patients who fail to achieve MER on Arm A will be 
allowed to crossover to Arm B. 
When patients were treated with lenalidomide alone in phase II trials, the MER 
rates were 25%-34% in patients without a chromosome 5q31.1 deletion and 67% 
with a chromosome 5q31.1 deletion. There is limited clinical information for the 
combination of lenalidomide with epoetin alfa. In a pilot study involving 40 
patients that had failed erythropoietin monotherapy, 5 of 18 patients who 
received the lenalidomide and epoetin alfa combination treatment achieved an 
erythroid response after failing to respond to lenalidomide alone, including 3 
MER (12). When UT7 erythroid progenitor cells are treated with lenalidomide and 
in vitro, clonogenic response and STAT5 activation is additive or greater. Thus, 
we anticipate that MER rate for the combination of lenalidomide with epoetin alfa 
will be even higher. Based on this information, we hypothesize that the MER rate 
in Arm A (lenalidomide) will be 30% and anticipate that the MER rate in Arm B 
(lenalidomide + epoetin alfa) will be at least 50%. Thus the study is designed to 
detect an improvement of 20% in the MER rate from 30% to 50%, comparing 
Arm A to Arm B.  Using the statistical package EaSt (Cytel Software Corporation, 
1993) to account for multiple interim looks in a sequential design for binomial 
distribution with continuity correction, a sample size of 212  cases will provide 
approximately 80% power to detect improvement in MER rate with an overall 
one-sided type I error rate of 0.025. The primary comparison of the MER rates 
will be performed on all patients randomized before May 19, 2010 and after 
September 24. The 14 patients (7 on arm A; 7 on arm B) randomized between 
May 19, 2010 and September 24, 2010 will be excluded. A secondary analysis 
will include all 226 patients randomized to this study. 
9.3 
Secondary Objectives 
All analyses on secondary endpoints will be performed on 212 patients 
randomized before May 19, 2010 and after September 24. The 14 patients (7 on 
arm A; 7 on arm B) randomized between May 19, 2010 and September 24, 2010 
will be excluded. 
Time to MER is defined in responders as the time from randomization to the 
documented date of MER.  For transfusion independent patients, the date of 
MER is the first date of the elevation in hemoglobin level of more than 2 g/dL that 
has been sustained for at least 8 weeks.  For transfusion dependent patients, the 
date of MER is the beginning date of the time interval of transfusion 
independence that has been sustained for at least eight weeks. 
Time to MER will be compared between lenalidomide monotherapy and 
combined treatment of lenalidomide and epoetin alfa in MER responders, using a 
one-sided log-rank test at the significance level of 0.025. Data from a prior study, 
MDS-001, of patients with MDS show that the median to MER is 11.5 weeks for 
patients on the lenalidomide schedule of 10 mg/day for 21 days (10).  Under the 
assumption that the proportions of major erythroid responders are 30% for the 
monotherapy and 50% for the combined therapy, the log-rank test will have 80% 
power to detect a hazard ratio of 1.88 of the combined therapy over the 

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monotherapy. If time to MER follows an exponential distribution, this difference 
corresponds to an improvement in median time to MER from 11.5 weeks to 6.1 
weeks. 
Duration of MER response is defined as the time interval between the 
documented date of MER and the earliest date of resumption of RBC 
transfusions ≥ 2 units in an 8 week period, a reduction in hemoglobin 
concentration ≥ 2 g/dL in the absence of acute infection, gastrointestinal bleeding 
and hemolysis, or death. 
Duration of MER response will be summarized by Kaplan-Meier method for 
patients who achieve MER by treatment arms. A secondary analysis will be done 
on duration of MER response by excluding all patients on arm B whose epoetin 
alfa treatment was interrupted by the drug supply issue occurred in September 
2010. 
The 90% confidence interval of the rate of MER to salvage combination therapy 
will be computed in patients who fail to achieve an MER with lenalidomide 
monotherapy and cross over to the combination therapy. Since it is assumed that 
the MER rate on the monotherapy arm is 30%, 74 patients from the monotherapy 
arm will fail to achieve MER.  If among them 60 patients cross over to the 
combination therapy arm, the 90% confidence interval of the MER rate of the 60 
patients will be no wider than 22.5%. A secondary analysis will be done on the 
rate of MER to salvage combination therapy by excluding those cross over 
patients whose epoetin alfa treatment was interrupted by the drug supply issue 
occurred in September 2010. 
The minor erythroid response rate will be compared between treatment arms by 
Fisher’s exact test.  In a prior study MDS-001 of patients with MDS, 2 minor 
erythroid responses were observed from 17 patients who were on the 
lenalidomide schedule of 10 mg/day for 21 days (10). If the minor erythroid 
response rate is 10% for the monotherapy arm and 30% for the combination 
therapy arm, there is 94% power to detect this difference at a two-sided 
significance level 0.05.   
Cytogenetic response rate will be calculated by treatment arm among patients 
with cytogenetic abnormalities, along with its 90% confidence interval. If 45% of 
patients are expected to have genetic abnormalities, the 90% confidence interval 
of the response rate is no wider than 25.6% for each arm.  
Bone marrow response (CR+PR) rate and its 90% Confidence Interval will be 
calculated by treatment arm. The 90% Confidence Interval of the bone marrow 
response rate is no wider than 16.8% for each arm. 
9.4 
Interim Analyses 
All interim analyses will be performed on patients randomized before May 19, 
2010 and after September 24. The 14 patients (7 on arm A; 7 on arm B) 
randomized between May 19, 2010 and September 24, 2010 will be excluded. 
The interim analyses will be conducted every six months, in conjunction with 
scheduled ECOG-ACRIN DMC meetings, starting at 25% information time, 
unless small increments of information (<10%) are gained during six months. 
Taking the delay of the initiation of accrual and the study suspension into 
account, the first and final analyses are anticipated to take place at 

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approximately 2.5 and 5.5 years after the study begins active accrual. The formal 
interim analyses will be conducted using the truncated O’Brien Fleming group 
sequential boundaries as described in Freidlin et.al. (1999). 
Table 1 summarizes the operating characteristics of this design.  For example, 
this trial can be stopped early at the fourth interim analysis (63% information 
time) in favor of an alternative hypothesis of adding lenalidomide to epoetin alfa 
improves the MER rate if the standardized test statistic comparing two MER rates 
is greater than 2.6523. 
Table 1: Operating Characteristics 
Analysis 
Information 
Time 
Eligible Cases 
for Two Arms 
Upper 
Boundary 
Nominal  
Significance level 
1 
0.25 
53 
3.2905 
0.0005 
2 
0.38 
80 
3.2905 
0.0005 
3 
0.51 
108 
3.0606 
0.0011 
4 
0.63 
133 
2.6523 
0.004 
5 
0.75 
159 
2.4101 
0.008 
6 
0.88 
186 
2.2094 
0.014 
7 
1.00 
212 
2.0703 
0.019 
Since lenalidomide in combination with epoetin alfa might not significantly 
improve the MER rate compared to lenalidomide alone, this study will be 
monitored for early stopping in favor of null hypothesis. Using repeated 
confidence interval methodology similar to that described by Jennison and 
Turnbull, at each interim analysis, a nominal 1- confidence interval on the 
difference in MER rates will be computed using the nominal one-sided 
significance level of the use function boundary at the information fraction at the 
particular analysis time.  The results will be provided to the DMC as a guideline 
to use when evaluating the study.  If the confidence interval does not contain the 
alternative of interest, 20%, consideration may be given to early termination of 
the study. 
9.4.1 
Early Stopping for Excessive Toxicity 
All toxicities will be monitored closely and reported using ECOG-
ACRIN’s standard AE mechanism. Since the proposed regimen of 
lenalidomide or lenalidomide + epoetin alfa has not been examined in 
a cooperative group setting, the tolerability of these regimens will be 
initially tested in the first 30 patients in Arm A and Arm B.  We will 
consider each regimen tolerable if the grade 3 or higher thrombo-
embolic events is 1% or less, and intolerable if the rate is 10% or 
higher.  In addition to thrombo-embolic events, we will consider each 
regimen tolerable if the grade 3 or higher regimen related other 
toxicity rate is 30% or less, and intolerable if the rate is 50% or greater 
with proper dose adjustment.  Hematologic toxicities are expected 
effects of the regimens and therefore will not be considered in the 
stopping rule.  If, in the first 30 patients treated in Arm A or Arm B, we 
observe 2 or more patients with grade 3 or higher thrombo-embolic 
events, or 13 or more patients with grade 3 or higher related other 
toxicity after proper dose adjustment, the study will be terminated to 
further accrual.  Assuming statistical independence of occurrence of 
thrombo-embolic events and other regimen related toxicities, with this 

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design, the probability of terminating the study early is 0.12 if the true 
but unknown rate of grade 3 or higher thrombo-embolic events is 1% 
and the true but unknown rate of grade 3 or higher other toxicity is 
30%; the probability of terminating the study early is at least 0.83 if the 
true but unknown rate of grade 3 or higher thrombo-embolic events is 
10% or the true but unknown rate of grade 3 or higher other toxicity is 
50%.  If the study does not meet those toxicity early stopping rules 
after the first 30 patients in arm B, additional 9 patients on arm B will 
be closely monitored for grade 3 or higher thrombo-embolic and other 
regimen related toxicities and the results will be reported to DMC. 
9.5 
Statistical Analysis for Correlative Studies 
We expect that at least 60-70% of samples collected for correlative studies will 
be adequate for analysis.  The statistical plan for the first and the third aim is 
based on the assumption of 132 patients (62% samples of 212 patients 
randomized before May 19, 2010 and after September 24) are available for 
analysis of correlative studies. The statistical plan for the second aim is based on 
the assumption of 16 del5q31.1 patients (62% samples of 26 del5q31.1 patients 
enrolled to the study) are available for analysis of correlative studies. 
9.5.1 
Evaluate the effect of CD45 isoform profile on lenalidomide 
enhancement of erythropoietin-induced STAT5 phosphorylation in 
CD71Hi erythroid precursors and the relationship to erythroid 
response. 
The association between the CD45 isoform profile and ex vivo 
augmentation of STAT5 phosphorylation by lenalidomide will be 
assessed by simple regressions.  The phosphorylation delta (PD) as 
quantified by the log10 ratio of p-STAT5 geometric mean fluorescence 
intensity (MFI) with lenalidomide (LEN)+ erythropoietin versus 
erythropoietin treatment alone (i.e., LEN+erythropoietin:EPO) will be 
regressed on RA:RO, RB:RO ratios separately.  With 132 non- 
del5q31.1 patients, there is 83% and 94% power to test this 
association at a two-sided significance level of 0.05, if the true but 
unknown correlation between PD and RA:RO (or RB:RO) ratio is 0.25 
and 0.3 respectively. The relationship between the CD45 isoform 
profile and MER response status will be assessed by treatment arm. 
RA:RO and RB:RO ratios will be compared between MER responders 
and non-responders within each treatment arm using the Wilcoxon 
rank sum test.  The same assessment will be performed on the 
relation between PD and MER response status, and on the relation 
between apoptosis reduction and MER response status. 
Prior studies show that response rate to erythropoietin varies for 
patients with different serum erythropoietin levels. To investigate if the 
addition of DA benefits the group of patients with sub-optimal 
erythropoietin production at baseline, MER response rates will be 
compared between treatment  arms in the subset of patients with low 
serum erythropoietin levels at baseline (defined as <500 mU/ml) using 
Fisher’s exact test. Furthermore, to investigate if primary resistance to 
lenalidomide monotherapy is due to low endogenous erythropoietin 
production, the change in serum erythropoietin levels at 16 weeks 

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from baseline of non- del5q31.1 patients on the monotherapy arm will 
be compared between MER responders and non-responders using 
Wilcoxon rank sum test.  It is hypothesized that the decline in serum 
erythropoietin levels correlates with non-response.  
The correlation between the magnitude of erythropoietin/STAT5-PD 
induced ex vivo by lenalidomide in pretreatment specimens and the 
magnitude of in vivo activation will be assessed using simple 
regressions by treatment arms.  With 66 non- del5q31.1 patients per 
arm, there is 84% and 93% power to test this association at a two-
sided significance level of 0.05, if the true but unknown correlation 
between PD and RA:RO (or RB:RO) ratio is 0.35 and 0.4 respectively. 
Characterize molecular targets relevant to lenalidomide cytotoxicity in 
del5q31.1 cells 
To determine whether lenalidomide modulates the phosphatase 
activity of Cdc25C and PP2A in bone marrow MNC from MDS 
patients with or without del5q31.1, a series of comparisons will be 
made.  The RNA and protein expression level of Cdc25C, PP2A and 
their phosphatase substrates, Cdc2phospho-Tyr15 and 
Cdc25Cphospho-Ser216 will be compared between 16 MDS patients 
with del5q31.1, 20 MDS patients with normal cytogenetics that are not 
receiving active therapy and 20 age-matched normal volunteers. Pair-
wise comparisons will be conducted by using t-test.  Under the 
assumption of equal variances of groups, with the above number of 
samples per group, the t-test has at least 82% power to detect an 
effect size of 1 standard deviation for each pair-wise comparison at a 
two-sided significance level of 0.05.  
In the factorial experiment for the investigation of whether reduction of 
either Cdc25C or PP2A alone or in combination leads to lenalidomide 
sensitization in patients with normal karyotype, each patient’s sample 
will be aliquotted to 4 equal portions which are randomly exposed to 4 
conditions, the cross of inhibition or not inhibition of gene expression 
of Cdc25C and PP2A by siRNAs.  This experiment will be performed 
in samples from twenty patients. Assume that 50% of MDS cases 
enrolled to the E2905 trial will have normal cytogenetics by 
conventional metaphase karyotyping and that 5% of MDS cases with 
normal cytogenetics may contain minor abnormalities in the 5q31.1 
CDR by SNA arrays, to arrive at 20 patients with normal karyotype, 45 
bone marrow samples (each from an individual MDS patient) eligible 
for analysis need to be obtained.  Apoptosis and cell cycle from this 
randomized blacks design will be analyzed by using Analysis of 
Variance (ANOVA) with the blocking variable patient as the random 
effect. 
9.5.2 
Evaluate the frequency of cryptic chromosome 5q31.1 deletions in 
patients with non- del5q31.1 MDS by array-based genomic scan, and 
to determine the relationship to hematologic response 
Signal intensity will be analyzed and SNP calls determined using 
Gene Chip Genotyping Analysis Software Version 4.0 (GTYPE). Copy 
number will be investigated using a Hidden Markov Model and Copy 

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Number Analyzer for Affymetrix GeneChip Mapping 1000K arrays 
(CNAG v.3.0)22. Segmental LOH will be identified by a statistical 
assessment of the likelihood that consecutive SNP loci would exhibit 
heterozygosity given the corresponding allelic frequency of particular 
SNP in the normal population (CNAG). Lesions identified by SNP 
arrays will be compared with the Cancer Genome Anatomy Project 
database (http://cgap.nci.nih.gov). The two-sided Fisher’s Exact test 
will be used to analyze the difference between the distributions of 
dichotomized variables among the groups.   Normal copy number 
polymorphisms will be identified according to 
http://projects.tcag.ca/variation/.  
LOH that correlates with response/refractoriness will be identified 
through the following approach. Frequencies of LOH within q-arm of 
chromosome 5 will be compared between hematologic responders 
and non-responders using Fisher's exact test. To control for false 
positives, nominal p-values from Fisher's exact tests will be adjusted 
such that the FDR (false positive rate) is controlled under 5%. 
Distribution of cryptic copy number changes of SNP on the q-arm of 
chromosome 5 will also be compared between hematologic 
responders and non-responders using the Chi-square test. False 
positives will also be controlled as in the LOH analysis. Analogous 
calculations are planned for the exploration of presence of "any 
lesion" throughout the genome, numbers of lesions and each specific 
lesion type (e.g. 7q, UPD7q etc) and its association with 
response/non-response. 
9.6 
Gender and Ethnicity 
Based on previous data from E1996 the anticipated accrual in subgroups defined 
by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
2 
2 
Not Hispanic or Latino 
93 
157 
250 
Ethnic Category: Total of all subjects 
93 
159 
252 
Racial Category 
American Indian or Alaskan Native 
0 
2 
2 
Asian 
0 
2 
2 
Black or African American 
2 
7 
9 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
White 
91 
148 
239 
Racial Category: Total of all subjects 
93 
159 
252 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup accrual 
targets. 

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9.7 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Monitoring Committee 
(DMC). The DMC meets twice each year. For each meeting, all monitored 
studies are reviewed for safety and progress toward completion. When 
appropriate, the DMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DMC. Any DMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DMC Policy can be 
obtained from the ECOG-ACRIN Operations Office - Boston.

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10. 
Pathology Review 
NOTE:  
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (STS).  An 
STS shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.5.  
Pathology materials should be submitted for diagnostic review, classification and 
correlative studies. 
10.1 
Pathology Submission 
When a patient is registered to receive protocol therapy, the submitting 
pathologist and clinical research associate should refer to Appendix  (Pathology 
Submission Guidelines) which provides the following: 
10.1.1 
Instruction Sheet from ECOG-ACRIN Central Biorepository and 
Pathology Facility providing details for the Submission of Pathology 
Materials. 
10.1.2 
Memorandum to the submitting pathologist from Stanley Hamilton, 
M.D., chair, ECOG-ACRIN Laboratory Science and Pathology 
Committee, providing details for the Submission of Pathology 
Materials. 
10.1.3 
A list of required materials. 
10.2 
Materials required for this protocol: 
[Note deleted in Addendum #1] 
10.2.1 
Sample Tracking System Shipping Manifest Form 
In addition to the surgical pathology report, if immunologic studies (ex. 
flow cytometry) have been performed at the home institution, it is 
necessary that these be forwarded as well.  
10.2.2 
Biological Sample Submissions  
10.2.2.1 
Pathology Review (Mandatory): 
Baseline, Weeks 16 and 32, Year 1, and Progression/End 
of Treatment 
· 
Two (2) stained bone marrow smears to include 
one (1) Wright-Giemsa (W-G) stain and one (1) Iron 
Stain 
· 
One (1) H&E stained bone marrow biopsy slide 
· 
One (1) W-G stained peripheral blood smear 
[Note Deleted in Addendum #1] 
NOTE: 
Submission of pathologic materials for 
diagnostic review is mandatory in order for the 
patient to be considered evaluable. Failure to 
submit pathologic materials may render the 
case unevaluable. 
Rev. 10/09, 4/15 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09, 4/15 
Rev. 10/09 
Rev. 7/11 
Rev. 7/11  
Rev.4/15 
Rev. 7/11 
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10.2.2.2 
Correlative Studies (Optional Based on Patient Consent) 
Paraffin blocks from bone marrow trephine biopsies should 
be submitted at the following time points: 
· 
Baseline 
· 
Week 16 
· 
Week 32 
· 
Year 1 
· 
Relapse/End of Treatment 
NOTE: 
If blocks cannot be submitted, please submit 
five (5) unstained bone marrow biopsy level 
slides. If you have questions, please call Lynn 
Moscinski at (813) 979-3001. 
10.3 
Shipping Procedures 
Log the shipment into the ECOG-ACRIN Sample Tracking System (STS) the day 
of shipment. 
Ship using the CBPF’s FedEx account using the FedEx on-line ship manager 
10.3.1 
Submission Schedule  
10.3.1.1 
The required initial diagnostic materials must be submitted 
within one month of patient registration. Materials should 
be submitted within one month of collection for the 
additional time points. 
10.3.1.2 
For the blocks for correlative studies, materials should be 
submitted within one month of collection (Section 10.2.2.2). 
10.3.2 
Shipping Address: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
Toll Free Phone: (844) 744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
Access to the FedEx shipping account for shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained 
by logging onto fedex.com with an account issued by the ECOG-
ACRIN CBPF. For security reasons, the account number will no 
longer be given out in protocols, over the phone, or via email. If your 
site needs to have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org 
An STS shipping manifest form must be generated and shipped with 
all sample submissions. 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 7/11. 4/15 
Rev. 11/13 
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10.4 
ECOG-ACRIN Central Biorepository and Pathology Facility: Sample Processing 
and Routing 
Pathology review materials for confirmation of diagnosis, pathologic response 
and at progression will be forwarded to John Bennett, M.D. for review. Materials 
for the correlative studies will be forwarded to Dr. Lynn Moscinski at Moffitt 
Cancer Center. 
10.5 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all biological samples 
submitted on this trial be entered and tracked using the ECOG-ACRIN Sample 
Tracking System (STS). All sites, regardless of group affiliation, are required to 
use the ECOG-ACRIN STS. As of June 2007, the software will allow the use of 
either 1) an ECOG-ACRIN username or password previously assigned (for those 
already using STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important:  
Please note that the STS software creates pop-up windows, so 
you will need to enable pop-ups within your web browser while 
using the software. A user manual and interactive demo are 
available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to 
familiarize yourself with the software prior to using the system. 
A shipping manifest form must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to ecog-
acrin.tst@jimmy.harvard.edu. 
10.5.1 
Study Specific Notes 
Generic Specimen Submission Form (#2981) will be required only if 
STS is unavailable at time of sample submission.  Indicate the 
appropriate Lab on the submission form: 
· 
ECOG-ACRIN Central Biorepository and Pathology Facility 
· 
ECOG-ACRIN Cytogenetic Laboratory 
· 
Dr. Alan List Laboratory/H. Lee Moffitt Cancer Center 
NOTE: 
When collecting and shipping baseline research 
specimens (such as bone marrow and peripheral blood), 
there will be no screening # available. Please note patients 
must sign consent before the collection of the baseline 
bone marrow and peripheral blood. Therefore, Dr. List’s 
laboratory (813-745-8271) must be notified of specimen 
arrival, and then the specimens must be logged into the 
ECOG-ACRIN STS post-randomization, once the patient 
has an ECOG-ACRIN sequence number. Please call the 
receiving laboratories with the ECOG-ACRIN patient 
sequence number once the patient is randomized. 
Rev. 10/09 
Rev. 4/15 
Rev. 6/11 
Rev.4/15 
Rev. 11/13 
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Retroactively enter all specimen collection and shipping information 
when STS is available. 
10.6 
Banking  
Residual blocks and/or slides will be retained for banking at the ECOG-ACRIN 
Central Tissue Repository for possible use in future ECOG-ACRIN approved 
studies. If future use is denied or withdrawn by the patient, the samples will be 
removed from consideration for use in any future study. 

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11. 
Correlative Studies 
 
NOTE:  
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System.  An STS 
shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.5.  
NOTE: 
Institutions outside of the United States and Canada must confer with the 
receiving laboratory and the ECOG-ACRIN Operations Office - Boston 
regarding logistics for submission of fresh samples. 
11.1 
Cytogenetic Review (Mandatory) 
The cytogenetic review will be performed by the ECOG-ACRIN Cytogenetic 
Laboratory at Mayo Clinic. 
NOTE: All study participants/cooperative groups must submit karyotypes to the 
ECOG-ACRIN Cytogenetic Laboratory as outlined below. 
11.1.1 
Sample Submission Schedule  
Within 30 days of chromosome study for each applicable time point, 
investigators will send original karyotypes, cytogenetic laboratory 
report, and completed form #365R to the ECOG-ACRIN Cytogenetic 
Committee.   
Karyotypes must be submitted at: 
· 
Baseline 
· 
Week 16 (after study treatment) 
· 
Week 32  
· 
Year 1 
· 
Relapse/Progression/End of Treatment 
NOTE: 
Karyotypes are required at all time points. 
Direct questions to Gary Hicks at Tel: (507) 284-2950 or Fax: (507) 
284-0043. 
11.1.2 
Sample Preparation Guidelines 
The following materials are to be submitted within one month after 
each time point: 
· 
Two original karyotypes per clone 
· 
Institution’s cytogenetic laboratory report 
· 
The Leukemia Cytogenetics Form (#365R)  
11.1.3 
Shipping Procedures 
Log the shipment into the ECOG-ACRIN STS the day of shipment.  If 
the STS is unavailable, an Generic Specimen Submission Form 
(#2981) must be submitted with the samples.  Once STS is available, 
retroactively log the shipment into STS, using the actual collection and 
shipping dates. 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 6/11 
Rev. 4/15 
Rev. 7/11 
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The forms and original karyotypes are to be sent to: 
Gary Hicks 
Mayo Clinic Cytogenetics Laboratory 
970 Hilton 
200 First Street, S.W. 
Rochester, MN 55905 
Tel: (507) 284-2950 
Fax: (507) 284-0043 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.   
NOTE: 
If cytogenetic studies are not successful, submit the 
laboratory report and #365R form to Gary Hicks by mail or 
fax. 
Original karyoptypes will be returned upon written request when the 
review and analysis are complete. 
11.2 
Additional Laboratory Studies 
Biomarker studies described in the Statistical Section that are intended to 
investigate biological mechanisms of response and resistance to treatment will 
be performed under the direction of Dr. Alan List at the Moffitt Cancer Center. 
Peripheral blood and bone marrow aspirate samples are requested at the 
intervals indicated below.  
 
Sample Type 
Baseline 
Week 
16 
Week 
32 
Year 
1 
Relapse or  
End of Treatment 
Peripheral Blood  
(Two 10 mL Sodium 
Heparin tubes) 
X 
X 
X 
X 
X 
Bone Marrow Aspirate 
(5 mL EDTA tube) 
X 
X 
X 
X 
X 
If you have any questions, please contact Kathy McGraw or Ashley Basiorka at 
(813) 745-8271.   
NOTE: 
If patient has prior documentation of a chromosome 5q deletion, 
please make note in the comments section of the Sample 
Tracking System (STS). 
11.2.1 
Sample Preparation Guidelines   
All samples should be clearly labeled with detailed patient information, 
ECOG-ACRIN Protocol Number, ECOG-ACRIN Patient Sequence 
Number, Patient Initials, Date, and Type of Sample: Bone Marrow 
(BM)/Peripheral Blood (PBL). 
11.2.1.1 
Bone Marrow Aspirate 
BM aspirate samples should be collected after coating the 
syringe with a small amount of preservative-free sodium 
heparin then transfer it to sterile vacutainer tube(s) 
containing EDTA preservative (purple tops) for immediate 
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shipment.  The tube must be wrapped in absorbable 
material and then be placed in an airtight/leakproof 
container (such as a zip lock bag) and placed in a padded 
styrofoam container. Express mail envelopes alone are 
NOT adequate. 
11.2.1.2 
Plasma 
Peripheral blood should be drawn into two (2) standard 10 
mL sodium heparin tubes. 
11.2.2 
Shipping Procedures 
Log the shipment into the ECOG-ACRIN STS the day of shipment.  If 
the STS is unavailable, an Generic Specimen Submission Form 
(#2981) must be submitted with the samples.  Once STS is available, 
retroactively log the shipment into STS, using the actual collection and 
shipping dates. 
Heparinized bone marrow aspirates and plasma should be shipped 
overnight on cool packs (warm weather months), wrapping the vials to 
insure that the marrow does not freeze.  Specimens must be shipped 
via next day delivery on the day the specimen is obtained. 
DO NOT USE DRY ICE OR WET ICE. During hot summer days, 
place a cold pack in the container to keep the temperature in the 
container cool. 
Ship using the CBPF’s FedEx account using the FedEx on-line ship 
manager. 
Access to the FedEx shipping account can only be obtained by 
logging onto fedex.com with an account issued by the ECOG-ACRIN 
CBPF. For security reasons, the account number will no longer be 
given out in protocols, over the phone, or via email. If your site needs 
to have an account created, please contact the ECOG-ACRIN CBPF 
by email at eacbpf@mdanderson.org 
Call Kathy McGraw or Ashley Basiorka at (813) 745-8271 on the day 
of expected shipment to confirm delivery date. 
Shipping Address:  
For WEEKDAY Shipping (for ARRIVAL on Monday-Friday): 
H. Lee Moffitt Cancer Center 
Kathy McGraw, Dr. Alan List Laboratory 
SRB3/23234/K Rocha/x8271 
12902 Magnolia Drive 
Tampa, FL  33612 
Phone:  813-745-8271 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.   
Please only ship on Monday through Thursday. Please do not ship on 
Fridays or the day before a holiday. Specimens cannot be accepted 
on the weekends. 
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11.2.3 
Studies to be Performed: 
11.2.3.1 
To evaluate the effect of CD45 isoform profile on 
lenalidomide enhancement of erythropoietin-induced 
STAT5 PHN in CD71Hi erythroid precursors and the 
relation to erythroid response 
The goal of the proposed studies is to delineate the value 
of CD45 isoform profile and the capacity of LEN to 
augment erythropoietin/STAT5 PHN in CD71Hi erythroid 
precursors to predict response to study treatment, and to 
confirm the role of the CD45 PTP as a key negative 
regulator of the erythropoietin-R signal in non-del5q MDS.  
We hypothesize that LEN promotes erythropoiesis in non-
del5q MDS by relieving CD45 suppression of JAK2/Lyn 
kinase-mediated STAT5 activation after erythropoietin-
R/ligand engagement. Dual features of (a) large CD45 
isoform predominance, and (b) enhancement of 
erythropoietin/STAT5 activation by LEN in CD71Hi erythroid 
precursors, therefore, may identify non-del5q patients with 
rhu-erythropoietin resistance and potential responsiveness 
to LEN treatment. Moreover, these studies will further 
characterize the impact of CD45 isoform profile on 
erythropoietin-R signal capacity and erythroid progenitor 
survival. 
To validate this hypothesis, we will assess CD45-RA, -RB 
and -RO isoform distribution in pretreatment BM erythroid 
precursors (CD71Hi), and the magnitude of erythropoietin-
induced STAT5 PHN in the presence and absence of LEN 
using a sensitive flow cytometry assay.  Ex vivo 
augmentation of STAT5 PHN by LEN in CD71Hi cells (i.e., 
the PHN delta, PD) will be quantified by the log10 ratio of p-
STAT5 geometric mean fluorescence intensity (MFI) with 
LEN (LEN)+ erythropoietin versus erythropoietin treatment 
alone (i.e., LEN+erythropoietin: erythropoietin). CD45 
isoform profile in CD71Hi cells will be assessed by the 
RA:RO and RB:RO isoform geometric MFI ratios. 
Magnitude of LEN enhancement of erythropoietin/STAT5 
PHN (i.e., PD) according to CD45 isoform ratio and the 
linkage between isoform ratio and LEN associated 
reduction in erythroid apoptotic fraction will be evaluated 
as a continuum to determine the PD and isoform ratio 
associated with a threshold necessary for clinical response 
and augmentation of erythroid survival. Moreover, the 
capacity for LEN augmentation of STAT5 activation will be 
confirmed in vivo by comparing STAT5 PHN intensity in 
erythroid precursors by immunohisto-chemistry in fixed BM 
biopsy sections from pre-treatment and week16, post-
treatment BM specimens. Because our investigations 
indicate that the erythropoietic effects of LEN in non-del5q 
MDS are erythropoietin-dependent, clinical resistance to 

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LEN monotherapy (Arm A) may arise from endogenous 
erythropoietin under-production despite evidence for ex 
vivo erythropoietin/STAT5 activation. PB plasma 
erythropoietin concentration will be assessed prior to 
treatment and at week 16 of LEN monotherapy by enzyme-
linked immunosorbant assay (ELISA) and the findings 
correlated with treatment response and results of ex vivo 
p-STAT5 PD in the pre-treatment BM specimen.  The 
proposed studies will be the first to characterize the 
erythropoietin-R signal axis in MDS, its regulation by a key 
PTP, and the application of a pharmaco-dynamic model to 
identify patients responsive to a targeted therapeutic in a 
large, uniformly treated MDS population.  Moreover, 
primary and secondary treatment failure specimens 
provide a valuable resource to explore mechanism(s) of 
treatment resistance and the relationship to erythropoietin-
R signal suppression. 
11.2.3.2 
To characterize molecular targets relevant to lenalidomide 
cytotoxicity in del5q 
We have shown that LEN inhibits the PPT activity of both 
Cdc25C and PP2A in vitro.  We hypothesize that enforced 
reduction in Cdc25V expression, using siRNA, mimics the 
naturally occurring events of haplo-deficiency in del5q AML 
and MDS cells. The goal of this specific aim, using U937-
siCdc25c cells as a model, is to determine whether 
inhibition of Cdc25C mediates the cellular apoptotic events 
associated with LEN treatment. We will further define 
whether Cdc25C and PP2A coordinately regulate cell 
survival in U937 cells.  Finally, we will utilize a siRNA 
retroviral-based expression system targeting Cdc25C and 
PP2A to determine whether coordinated disruption of 
these two PPTs induce apoptosis in cells from non-del5q 
MDS patients in vitro.  Through experiments proposed in 
this specific aim, we will provide important biochemical and 
molecular information about LEN mechanisms of action. 
Understanding the signaling mechanisms of LEN will better 
enable the development of targeted drug therapy for MDS; 
selecting inhibitors for key signaling events that mediate 
survival and transformation of the leukemic clones. 
11.2.3.3 
To evaluate the frequency of cryptic chromosome 5q31 
deletions in patients with non-del5q MDS by array-based 
genomic scan, and to determine the relationship to 
hematologic response. 
The main goal of the proposed studies is to delineate sub-
microscopic chromosome 5q31 deletions that are not 
resolved by conventional metaphase cytogenetics. For that 
purpose, high-density array-based genome mapping will 
be performed to characterize molecular markers for 
response and identify cryptic chromosomal lesions that 

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86 
may explain clinical heterogeneity of patients with and 
without 5q31 deletions with regard to the speed of disease 
progression, response failure or emergence of treatment 
resistance. Our strategy is to perform, in addition to routine 
metaphase cytogenetic analysis, a high density genomic 
scan of hematopoietic cells to detect clonal somatic 
chromosomal defects. We hypothesize that micro-
deletions, smaller previously cryptic defects and/or UPD of 
5q regions may be associated with responsiveness to LEN 
in patients with non 5q31 metaphase cytogenetics. 
Furthermore, we suggest that resistance, whether primary 
or developed in the course of therapy, may be associated 
with additional previously cryptic lesions affecting other 
chromosomal regions.  First, we will correlate the presence 
of specific defects with the therapy response or 
refractoriness and subsequently we will monitor 
detection/appearance of new aberrations that may convey 
resistance. Finally, we plan to study the commonly affected 
regions of characteristic shared lesions for the presence of 
genes that can play a role in the pathogenetic 
mechanisms. 
11.3 
Banking  
The residuals and/or derivatives of bone marrow and blood samples collected for 
the correlative studies will be retained at the ECOG-ACRIN Leukemia 
Translational Studies Laboratory for possible use in ECOG-ACRIN approved 
future studies. If future use is denied or withdrawn by the patient, the samples will 
be removed from consideration for use in any future study. 
11.4 
Sample Inventory Submission Guidelines  
Inventories of all samples collected and aliquoted, and used on the above 
mentioned laboratory correlative studies will be submitted to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis. Inventories will be submitted 
electronically or by diskette by any laboratory holding and/or using any 
specimens associated with this study. Electronic submissions should be 
submitted to ecog.labdata@jimmy.harvard.edu. All other correspondence should 
be addressed to the attention of the Translational Science Team. 
11.5 
Lab Data Transfer Guidelines  
The data collected on the above mentioned correlative studies will be submitted 
to the ECOG-ACRIN Operations Office - Boston by the central laboratories on a 
quarterly basis. The quarterly cut-off dates are March 31, June 30, September 
30, and December 31. Data is due at the ECOG-ACRIN Operations Office - 
Boston 1 week after these cut-off dates. Electronic submissions should be 
submitted to ecog.labdata@jimmy.harvard.edu. All other correspondence should 
be addressed to the attention of the Translational Science Team. 

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12. 
Records to Be Kept 
Please refer to the E2905 Forms Packet for the forms submission schedule and copies 
of all forms. The E2905 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
12.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
· 
two years  from the date of  the FDA review 
· 
two years from the notification of the withdrawal of the IND 
Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying 
any source documents. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. 
List AF, Sandberg AA, Doll DC. Myelodysplastic syndromes. In: Wintrobe’s 
Clinical Hematology. Lippincott Williams & Wilkins Publishers 2004, 11th Edition: 
2207-2234. 
2. 
Hellström-Lindberg E. Efficacy of erythropoietin in the myelodysplastic 
syndromes: A meta-analysis of 205 patients in 17 studies. Br J Haematol 1995; 
89: 67-71. 
3. 
Hellström-Lindberg E, Ahlgren T, Beguin Y, et al. Treatment of anemia in 
myelodysplastic syndromes with granulocyte colony-stimulating factor plus 
erythropoietin: Results from a randomized phase II study and long-term follow-up 
of 71 patients. Blood 1998; 92: 68-75. 
4. 
Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision 
model for treating the anaemia of myelodysplastic syndromes with erythropoietin 
+ granulocyte colony-stimulating factor: Significant effects on quality of life. Br J 
Haematol 2003; 120: 1037-1046.   
5. 
Bartlett J, Dredge K, Dalgleish A.  The evolution of thalidomide and its IMiD 
derivatives as anticancer agents.  Nat Rev Cancer. 4:314-322, 2004.List AF, 

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Kurtin, Roe DJ, et al. Efficacy of CC-5013 in myelodysplastic syndromes. NEJM 
2005; 352: 11-1: 549-557. 
6. 
List A., Kurtin S, Roe D, Buresh A, Mahadevan D, Fuchs D, et al.  Efficacy of 
lenalidomide in myelodypslastic syndromes.  N Engl J Med. 352:549-557, 2005. 
7. 
A. List, G. Dewald, J. Bennett, A. Giagounidis, A. Raza, E. Feldman, B. Powell, 
P. Greenberg, D. Thomas, R. Stone, C. Reeder, K. Wride, J. Patin, M. Schmidt, 
J. Zeldis, R. Knight, Lenalidomide in the myelodysplastic syndrome with 
chromosome 5q deletion, The New England journal of medicine 355 (2006) 
1456-1465. 
8. 
Raza A, Reeves J, Feldman E, Deeg HJ, Dreisbach L, Schiffer C, et al.  Phase II 
study of lenalidomide in transfusion-dependent, low- and intermediate-1-risk 
myelodysplastic syndromes with karyotypes other than deletion 5q.  Blood 2008; 
11: 86-93. 
9. 
List A, Estes M, Williams A, Sekharam M, et al. Lenalidomide promotes 
erythropoiesis in myelodysplastic syndromes (MDS) by CD45 Protein Tyrosine 
Phosphatase (PTP) inhibition. BLOOD 2006; 108 (11): 397a 
10. 
Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working 
group to standardize response criteria for myelodysplastic syndromes. Blood 
2000; 96(12):3671-3674. 
11. 
Greenberg P, Cox C, LeBeau MM, et al. International scoring system for 
evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89(6):2079-
2088. 
12. 
List AF, Lancet J, Melchert M, Saba H, et al. Two-Stage Pharmacokinetic & 
Efficacy Study of Lenalidomide Alone or Combined with Recombinant 
Erythropoietin (EPO) in Lower Risk MDS EPO-Failures [PK-002]. Blood 
2007;110 (11): 230B. 
13. 
Weber D.  Thalidomide and its derivatives:  new promise for multiple myeloma.  
Cancer Control Sept/Oct 2003 10(5):  375-383. 
14. 
Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple 
myeloma. N Engl J Med. 2006 May 11;354(19):2079-80.  
15. 
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, 
Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj 
M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. 
Lenalidomide plus dexamethasone for relapsed multiple myeloma in North 
America. NEJM 2007; 357: 2133-2144. 
16. 
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, 
San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, 
Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. 
Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. 
NEJM 2007; 357: 2183-2186. 
17. 
Glaspy JA, Jadela JS, Justice G, et al. Darbepoetin alfa given every 1 or 2 weeks 
alleviates anaemia associated with cancer chemotherapy. Brit J Cancer 2002; 
87: 268-276. 
18. 
Hedenus M, Hansen S, Taylor K, et al. Randomized, dose-finding study of 
darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. Brit J 
Haematol 2002; 119: 79-86. 

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19. 
Kotasek D, Steger G, Faught W, et al. Darbepoetin alfa administered every 3 
weeks alleviates anaemia in patients with solid tumors receiving chemotherapy; 
results of a double-blind, placebo-controlled, randomized study. Eur J Cancer 
2003; 39: 20226-2034. 
20. 
Vansteenkiste J, Pirker R, Massuti B, et al. A dose-finding and placebo-
controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients 
receiving chemotherapy. J Natl Cancer Inst 2002; 94: 1211-1220. 

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Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Version Date: 9/22/2011 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials 
(English Language) [DELETED IN ADDENDUM #7] 
 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
 

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Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. 
Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. 
Instructional memo to submitting pathologists 
3. 
List of Required Materials for E2905 
4. 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
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Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials 
to the ECOG-ACRIN Central Biorepository and Pathology Facility: 
· 
Institutional Surgical Pathology Report 
· 
Pathology materials (see attached List of Required Material) 
Instructions: 
1. 
Complete blank areas of the pathologist's instructional memo and forward it, 
along with the List of Required Material to the appropriate pathologist. 
2. 
The pathologist should return the required pathology samples and surgical 
pathology reports. If any other reports are required, they should be obtained from 
the appropriate department at this time. 
3. 
Double-check that ALL required forms, reports and pathology samples are 
included in the package to the Central Biorepository and Pathology Facility. (See 
appropriate List of Required Material.)  
Pathology specimens submitted WILL NOT be processed by the Central 
Biorepository and Pathology Facility until all necessary items are received. 
4. 
Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
Toll Free Phone: (844) 744-2420 (713-745-4440 Local or International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility by telephone (844) 744-2420 or by email eacbpf@mdanderson.org. 
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List of Required Material 
E2905: 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid 
Response (MER) to Treatment with Lenalidomide (Revlimid®) Alone and in 
Combination with Epoetin Alfa (Procrit®) in Subjects with Low- or Intermediate-1 
Risk MDS and Symptomatic Anemia 
All samples submitted must be entered and tracked via the online ECOG-ACRIN Sample 
Tracking System (STS) and an STS shipping manifest form included with every 
shipment.  See Section 10.5. 
Baseline, Weeks 16 and 32, Year 1 and Progression/End of Treatment 
1. Generic Specimen Submission Form (#2981) 
2. Institutional pathology report (must be included with EVERY pathology submission). 
3. Materials submitted for: 
a. Pathology Review: 
· 
Two (2) stained bone marrow smears to include one (1) Wright-Giemsa (W-G) 
stain and one (1) Iron Stain  
· 
One (1) H&E stained bone marrow biopsy slide 
· 
One (1) W-G stained peripheral blood smear 
NOTE: Submission of pathology materials for diagnostic review is mandatory in order 
for the patient to be considered evaluable. Failure to submit pathologic 
materials may render the case unevaluable. 
b. Correlative Studies: 
Paraffin blocks from bone marrow trephine biopsies should be submitted at the following 
time points: 
· 
Baseline 
· 
Week 16 
· 
Week 32 
· 
Year 1 
· 
Relapse/End of Treatment 
NOTE: 
If blocks cannot be submitted, please submit five (5) unstained bone marrow 
biopsy level slides. 
 
 
Rev. 10/09, 
          7/11 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 10/09 
Rev. 7/11 
Rev. 4/15 

 
94 
MEMORANDUM 
TO:  
 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
 
SUBJECT: 
Submission of Pathology Materials for E2905, Randomized Phase III 
Trial Comparing the Frequency of Major Erythroid Response (MER) to 
Treatment with Lenalidomide (Revlimid®) Alone and in Combination 
with Epoetin Alfa (Procrit®) in Subjects with Low- or Intermediate-1 
Risk MDS and Symptomatic Anemia 
 
A patient has been entered onto an ECOG-ACRIN protocol by 
______________________________ (ECOG-ACRIN Investigator).  This protocol 
requires the submission of pathology materials for pathology review and correlative 
studies. 
Please return, the surgical pathology report(s), the slides and/or blocks, and any other 
required material (see attached List of Required Material) to the Clinical Research 
Associate (CRA).  The CRA will forward all required pathology material to the ECOG-
ACRIN Central Biorepository and Pathology Facility. 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN 
Central Repository for use in future ECOG-ACRIN approved studies. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, therefore the block may not be returned. 
If you have any questions regarding this request, please feel free to contact the Central 
Biorepository and Pathology Facility at Tel: (844) 744-2420 or email: 
eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 
Rev. 7/11 
Rev. 4/15 
Rev. 11/13 
Rev. 4/15 

ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
95 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
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Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
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Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG web site at http://www.ecog.org. As this is a personal 
letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
97 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix IV 
 
World Health Organization (WHO) Diagnostic criteria for MDS 
 
Once a diagnosis of MDS is established, eight subtypes of MDS are recognized in the 
WHO classification that are distinguished by the percentage of myeloblasts, the 
presence of ringed sideroblasts, number of dysplastic lineages, and karyotype as 
summarized in the following table: 
World Health Organization Classification and Criteria 
for the Myelodysplastic Syndromes (MDS) 
MDS Subtype 
Blood Findings 
Bone Marrow Findings 
Refractory anemia (RA)  
  
Anemia  
No or rare blasts 
Erythroid dysplasia only 
< 5% blasts 
< 15% ringed sideroblasts  
Refractory anemia with ringed 
sideroblasts (RARS) 
Anemia  
No blasts 
Erythroid dysplasia only 
> 15% ringed sideroblasts 
< 5% blasts  
Refractory cytopenia with 
multilineage dysplasia (RCMD)  
Cytopenias (bi- or pancytopenia)  
No or rare blasts  
No Auer rods 
<1 x 109/L monocytes  
Dysplasia in ≥10% of cells in 2 or 
more myeloid cell lines 
< 5% blasts in marrow 
No Auer rods 
< 15% ringed sideroblasts  
Refractory cytopenia with 
multilineage dysplasia and 
ringed sideroblasts (RCMD-RS)  
Cytopenias (bi- or pancytopenia)  
No or rare blasts  
No Auer rods 
<1 x 109/L monocytes  
Dysplasia in ≥10% of cells in 2 or 
more myeloid cell lines 
> 15% ringed sideroblasts 
<5% blasts 
No Auer rods 
Refractory anemia with excess 
blasts-1 (RAEB-1) 
Cytopenias 
<5% blasts 
No Auer rods  
<1 x 109/L monocytes  
Unilineage or multilineage dysplasia 
5% to 9% blasts 
No Auer rods 
Refractory anemia with excess 
blasts-2 (RAEB-2) 
Cytopenias 
<5% to 19% blasts 
Auer rods ± 
<1 x 109/L monocytes  
Unilineage or multilineage dysplasia 
10%-19% blasts 
Auer rods ±  
Myelodysplastic syndrome, 
unclassified (MDS-U) 
Cytopenias 
No or rare blasts 
No Auer rods 
Unilineage dysplasia in granulocytes 
or megakaryocytes 
<5% blasts 
No Auer rods 
MDS associated with isolated 
del(5q) 
Anemia 
<5% blasts 
Platelets normal or increased 
Normal to increased megakarocytes 
with hypolobated nuclei 
< 5% blasts 
No Auer rods 
Isolated del(5q) 
Adapted from reference 14. (see Section 14 of protocol) 
 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
98 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix V 
 
ECOG Performance Status Score 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
99 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix VI 
 
[DELETED IN ADDENDUM #4] 
 
Rev. 6/11 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
100 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix VII 
 
Cooperative Research and Development Agreement (CRADA) 
NCI/ DCTD Standard Protocol Language 
NCI/ DCTD Standard Protocol Language to Be Incorporated into All Protocols Involving 
Agent(s) Covered by a Clinical Trials Agreement (CTA) or a Cooperative Research and 
Development Agreement (CRADA), hereinafter referred to as Collaborative Agreement: 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the design 
of the proposed combination protocol, and the existence of any obligations that 
would tend to restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Rev. 4/15 

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Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected , used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication. Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s 
confidential and proprietary data, in addition to Collaborator(s)’s intellectual property rights, 
are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also 
be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
Rev. 4/15 
Rev. 4/15 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
102 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix VIII 
 
Medication Diary 
Please complete this diary on a daily basis. Write in the amount of the dose of lenalidomide that 
you took in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
If you experience any health/medical complaints or take any medication other than lenalidomide 
or epoetin alfa, please record this information. 
For patients on Arm B, epoetin alfa will be administered by a health care professional. As a 
result, patients do not have to record their epoetin alfa injections in this diary. 
Cycle # (Month): 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
lenalidomide 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
lenalidomide 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
lenalidomide 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
lenalidomide 
 
 
 
 
 
 
 
Week of: _________________________ 

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Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
103 
HEALTH/MEDICAL COMPLAINTS 
Please record all health/medical complaints you may have experienced below. 
Please describe what you experienced 
Date started 
Date stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER MEDICATION 
Record only medication (prescription and/or over-the-counter, including herbal medications and 
vitamins) taken other than lenalidomide or prednisone. 
Name of Medication 
Why did you take the 
medication? 
Date medication 
started? 
Date medication 
stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________________________ 
Patient Signature 
_____________________________ 
Date

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
104 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix IX 
 
Specimen Submission Instructions for Southwest Oncology Group Patients  
[DELETED IN ADDENDUM #1] 

ECOG-ACRIN 
E2905 
Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
105 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix X 
 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods 
Risks Associated with Pregnancy 
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. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as any woman, regardless of sexual 
orientation, or whether they have undergone tubal ligation, who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following 
are met (i.e., all females of childbearing potential must be counseled concerning the following 
risks and requirements prior to the start of lenalidomide):  
· 
She understands the potential teratogenic risk to the unborn child 
· 
She understands the need for effective contraception, without interruption, 4 weeks 
before starting study treatment, throughout the entire duration of study treatment, dose 
interruption and 28 days after the end of study treatment 
· 
She should be capable of complying with effective contraceptive measures 
· 
She is informed and understands the potential consequences of pregnancy and the 
need to notify her study doctor immediately if there is a risk of pregnancy 
· 
She understands the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test 
· 
She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol 
She acknowledges that she understands the hazards and necessary precautions associated 
with the use of lenalidomide 
The investigator must ensure that for females of childbearing potential: 
· 
Complies with the conditions for pregnancy risk minimization, including confirmation that 
she has an adequate level of understanding 
Rev. 7/11 

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· 
Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (i.e., all females NOT of childbearing potential must be counseled concerning 
the following risks and requirements prior to the start of lenalidomide):  
· 
She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
Traces of lenalidomide have been found in semen.  Male patients taking lenalidomide must 
meet the following conditions (i.e., all males must be counseled concerning the following risks 
and requirements prior to the start of lenalidomide): 
· 
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a female of childbearing potential 
· 
Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or 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 
contact during the following time periods related to this study: 1) for at least 28 days before 
starting study drug; 2) while participating in the study; 3) during dose interruptions; and 4) for at 
least 28 days after study treatment discontinuation.  
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:   
· 
Highly effective methods: 
− Intrauterine device (IUD) 
− Hormonal (birth control pills, injections, implants) 
− Tubal ligation 
− Partner’s vasectomy 
· 
Additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
− 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. 

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Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 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 study drug 
Female Patients: 
FCBP must have two negative pregnancy tests (minimum sensitivity of 25 mIU/mL) prior to 
starting study drug.  The first pregnancy test must be performed within 10 to 14 days prior to the 
start of study drug and the second pregnancy test must be performed within 24 hours prior to 
the start of study drug.  The patient may not receive study drug until the study doctor has 
verified that the results of these pregnancy tests are negative. 
Male Patients: 
Must practice complete abstinence or  agree to use a condom during sexual contact with a 
pregnant female or a female of childbearing potential while participating in the study, during 
dose interruptions and for at least 28 days following study drug discontinuation, even if he has 
undergone a successful vasectomy.   
During study participation and for 28 days following study drug discontinuation  
Female Patients: 
· 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly 
for the first 28 days of study participation and then every 28 days while on study, at 
study discontinuation, and at day 28 following study drug discontinuation. If menstrual 
cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and 
then every 14 days while on study, at study discontinuation, and at days 14 and 28 
following study drug discontinuation.   
· 
At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control. 
· 
Counseling about pregnancy precautions and the potential risks of fetal exposure must 
be conducted at a minimum of every 28 days. 
· 
If pregnancy or a positive pregnancy test does occur in a study patient, study drug 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.  Study treatment must be 
discontinued during this evaluation. 
· 
Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after study drug discontinuation. 
Male Patients: 
· 
Counseling about the requirement for complete abstinence or condom use during sexual 
contact with a pregnant female or a female of childbearing potential and the potential 
risks of fetal exposure to lenalidomide must be conducted at a minimum of every 28 
days.   
· 
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. 

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Additional precautions 
· 
Patients should be instructed never to give this medicinal product to another person and 
to return any unused capsules to the study doctor at the end of treatment. 
· 
Female patients should not donate blood during treatment and for at least 28 days 
following discontinuation of lenalidomide. 
· 
Male patients should not donate blood, semen or sperm during treatment or for at least 
28 days following discontinuation of lenalidomide. 
· 
Only enough study drug for 28 days or one cycle of therapy (whichever is shorter) may 
be dispensed with each cycle of therapy. 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
109 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix XI 
 
Lenalidomide Education and Counseling Guidance Document 
To be completed prior to each dispensing of study drug. 
Protocol Number: ____________________________________________ 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
Female:  □ 
If female, check one: 
□ FCBP (Female of childbearing potential): sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (i.e., has had menses at 
any time during the preceding 24 consecutive months) 
□ NOT FCBP 
Male: 
□ 
Do Not Dispense study drug if: 
· 
The patient is pregnant. 
· 
No pregnancy tests were conducted for a FCBP. 
· 
The patient states she did not use TWO reliable methods of birth control 
(unless practicing complete abstinence of heterosexual contact) [at least 28 
days prior to treatment, during treatment and during dose interruption]. 
FCBP: 
1. I verified that the required pregnancy tests performed are negative. 
2. I counseled FCBP regarding the following: 
· 
Potential risk of fetal exposure to lenalidomide:  If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby.  Females are 
advised to avoid pregnancy while taking lenalidomide. The teratogenic potential of 
lenalidomide in humans cannot be ruled out.  FCBP must agree not to become 
pregnant while taking lenalidomide.  
· 
Using TWO reliable methods of birth control at the same time or complete 
abstinence from heterosexual contact [at least 28 days prior to treatment, during 
treatment, during dose interruption and 28 days after discontinuation of 
lenalidomide]. 
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· 
That even if she has amenorrhea she must comply with advice on contraception   
· 
Use of one highly effective method and one additional method of birth control AT 
THE SAME TIME. The following are examples of highly effective and additional 
effective methods of contraception:   
− Highly effective methods: 
− Intrauterine device (IUD) 
− Hormonal (birth control pills, injections, implants) 
− Tubal ligation 
− Partner’s vasectomy 
− Additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
· 
Pregnancy tests before, during, and after treatment, even if the patient agrees not to 
have reproductive heterosexual contact.  Two pregnancy tests will be performed 
prior to receiving study drug, one within 10 to 14 days and the second within 24 
hours of the start of study drug. 
· 
Frequency of pregnancy tests to be done: 
− Every week during the first 28 days of this study and a pregnancy test every 28 
days during the patient’s participation in this study if menstrual cycles are regular 
or every 14 days if cycles are irregular.   
− If the patient missed a period or has unusual menstrual bleeding.   
− When the patient is discontinued from the study and at day 28 after study drug 
discontinuation if menstrual cycles are regular.  If menstrual cycles are irregular, 
pregnancy tests will be done at discontinuation from the study and at days 14 
and 28 after study drug discontinuation. 
− Stop taking study drug immediately in the event of becoming pregnant and to call 
their study doctor as soon as possible.  
− NEVER share study drug with anyone else. 
− Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
− Do not breastfeed a baby while participating in this study and for at least 28 days 
after study drug discontinuation. 
− Do not break, chew, or open study drug capsules. 
− Return unused study drug to the study doctor. 
3. Provide Lenalidomide Information Sheet to the patient. 
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT LEAST 
24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL OOPHORECTOMY): 

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4. I counseled the female NOT of child bearing potential regarding the following: 
− Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP) 
− NEVER share study drug with anyone else. 
− Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
− Do not break, chew, or open study drug capsules 
− Return unused study drug capsules to the study doctor. 
5. Provide Lenalidomide Information Sheet to the patient. 
MALE: 
6. I counseled the Male patient regarding the following: 
− Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP). 
− To engage in complete abstinence or use a condom when engaging in sexual 
contact (including those who have had a vasectomy) with a pregnant female or a 
female of childbearing potential,  while taking study drug, during dose 
interruptions and for 28 days after stopping study drug. 
− Males should notify their study doctor when their female partner becomes 
pregnant and female partners of males taking study drug should be advised to 
call their healthcare provider immediately if they get pregnant. 
− NEVER share study drug with anyone else. 
− Do not donate blood, semen or sperm while taking study drug and for 28 days 
after stopping study drug. 
− Do not break, chew, or open study drug capsules. 
− Return unused study drug capsules to the study doctor. 
7. Provide Lenalidomide Information Sheet to the patient. 
Counselor Name (Print): ____________________  
Counselor Signature: _______________________  Date: _____/_____/_____ 
 
**Maintain a copy of the Lenalidomide Education and Counseling Guidance Document in the 
patient records** 

ECOG-ACRIN 
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Version Date: November 7, 2019 
 
NCI Update Date: August 18, 2010 
112 
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix XII 
 
Lenalidomide Information Sheet 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES  
Please read this Lenalidomide Information Sheet before you start taking study drug and each 
time you get a new supply. This Lenalidomide Information Sheet does not take the place of an 
informed consent to participate in clinical research or talking to your study doctor or healthcare 
provider about your medical condition or your treatment.   
What is the most important information I should know about 
lenalidomide? 
8. Lenalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide 
causes life-threatening birth defects. Lenalidomide has not been tested in pregnant 
women but may also cause birth defects. Findings from a monkey study indicate that 
lenalidomide caused birth defects in the babies of female monkeys who received the 
drug during pregnancy. 
If you are a woman who is able to become pregnant: 
· 
Do not take study drug if you are pregnant or plan to become pregnant 
· 
Either do not have sexual intercourse at all or use two reliable, separate forms 
of effective birth control at the same time:  
− for 28 days before starting lenalidomide 
− while taking lenalidomide 
− during dose interruptions of lenalidomide 
− for 28 days after stopping lenalidomide 
· 
You must have pregnancy testing done at the following times: 
− within 10 to 14 days and again 24 hours prior to the first dose of lenalidomide 
− weekly for the first 28 days 
− every 28 days after the first month or every 14 days if you have irregular 
menstrual periods 
− if you miss your period or have unusual menstrual bleeding 
− 28 days after the last dose of lenalidomide (14 and 28 days after the last dose if 
menstrual periods are irregular) 
· 
Stop taking study drug if you become pregnant during treatment 
− If you suspect you are pregnant at any time during the study, you must stop 
lenalidomide immediately and immediately inform your study doctor. Your study 
doctor will report all cases of pregnancy to the National Cancer Institute and the 
pharmaceutical collaborator, Celgene Corporation. 
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· 
Do not breastfeed while taking study drug 
· 
The study doctor will be able to advise you where to get additional advice on 
contraception. 
If you are a female not of childbearing potential: 
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor 
will confirm that you are not able to become pregnant. 
If you are a man: 
Lenalidomide is detected in trace quantities in human semen. The risk to the fetus in 
females of child bearing potential whose male partner is receiving lenalidomide is 
unknown at this time.   
· 
Men (including those who have had a vasectomy) must either abstain from sexual 
intercourse or use a condom during sexual contact with a pregnant female or a 
female that can become pregnant: 
− While you are taking lenalidomide 
− During dose interruptions of lenalidomide 
− For 28 days after you stop taking lenalidomide 
· 
Men should not donate sperm or semen while taking study drug and for 28 days 
after stopping lenalidomide.  
· 
If you suspect that your partner is pregnant any time during the study, you 
must immediately inform your study doctor. The study doctor will report all 
cases of pregnancy to the National Cancer Institute and the pharmaceutical 
collaborator, Celgene Corporation. Your partner should call their healthcare 
provider immediately if she gets pregnant. 
9. Restrictions in sharing lenalidomide and donating blood: 
· 
Do not share lenalidomide with other people. It must be kept out of the reach 
of children and should never be given to any other person. 
· 
Do not donate blood while you take lenalidomide and for 28 days after stopping 
study drug.  
· 
Do not break, chew, or open study drug capsules. 
· 
You will get no more than a 28-day supply of lenalidomide at one time. 
· 
Return unused study drug capsules to your study doctor. 
Additional information is provided in the informed consent form and you can ask your 
study doctor for more information. 

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Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix XIII 
 
CPPCP Site Counselor Form 
 
• 
Please provide at least two (2) counselors and fax back to 888.314.2392  
• 
Use one form per counselor.  
• 
Identified counselors must be a licensed healthcare professional (e.g. RN, PA, RPh, 
PhD, LPN, CNP or MD).  
• 
If you have any questions, please contact coop_ma@celgene.com  
 
General Information  
 
Principal Investigator: ___________________Institution Name: 
______________________ 
CTEP site ID: _________________ 
Counselor Information  
First Name: __________________________  Middle Initial:______   Last Name: 
______________________________  
License Type: (circle one) MD PhD PA  CNP  RN LPN  RPh  Other:_____________________  
Email Address: 
__________________________________________________________________________  
Phone: _________________________________________ Fax: _______________________ 
Institution Street Address: _____________________________________________________ 
City: __________________________________State/Region: _________________________ 
Zip/Post Code: _________________________Country: ____________________________ 
Previously approved as a ___________ Counselor? □ No □ Yes 
If Yes, which Protocol: ________________  
 
 
 
 
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Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) 
to Treatment with Lenalidomide (Revlimid®) Alone and in Combination with Epoetin Alfa 
(Procrit®) in Subjects with Low- or Intermediate-1 Risk MDS and Symptomatic Anemia 
Appendix XIV 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on Lenalidomide, or within 
28 days of the patient’s last dose of Lenalidomide must be reported in an expeditious manner.  
The outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be reported 
via NCI’s Adverse Event Expedited Reporting System (CTEP-AERS) 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/CTEP-AERS.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported?  
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
· 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
· 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
· 
The start date of the pregnancy should be reported as the calculated date of conception.   
· 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
What else do I need to know when a pregnancy occurs to a patient? 
· 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
· 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office - Boston.  Please contact the ECOG-ACRIN Operations Office - Boston to 
ask for a conference call to be set up with the appropriate individuals.   
· 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if 
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the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the NCI Medical 
Help Desk at 301-897-7497 or CTEP-AERSmd@tech-res.com, for it will need to be discussed 
on a case by case basis. 
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy loss” under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A death occurring during the first 28 days after birth” 
that is felt by the investigator to be at least possibly due to the investigational agent/intervention. 
However, for this protocol, any neonatal death that occurs within 28 days of birth, without regard 
to causality, must be reported via CTEP-AERS AND any infant death after 28 days that is 
suspected of being related to the in utero exposure to Lenalidomide must also be reported via 
CTEP-AERS. 
It must be reported via CTEP-AERS as Grade 4 “Death Neonatal” under the System Organ 
Class (SOC) “General disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-897-7404). This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportFor
m.pdf) 
 
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