A Phase I/II Study of Lenalidomide Maintenance After Autologous Stem Cell Transplant for Elderly Patients With Acute Myeloid Leukemia (AML)
Phase: PHASE1
Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Adult Acute Myeloid Leukemia in Remission
Sponsor: Albert Einstein College of Medicine

Lenalidomide Maintenance protocol - version 5.7 – December 16, 2015 
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A Phase I/II study of lenalidomide maintenance after autologous stem 
cell transplant for elderly patients with Acute Myeloid Leukemia 
(AML). 
 
 
 
Principal Investigator: 
Ira Braunschweig, M.D. 
 
 
 
 
Montefiore-Einstein Cancer Center 
 
 
 
 
Montefiore Medical Center-Moses Division 
 
 
 
 
Department of Oncology, Hofheimer Pavilion, Room 100 
 
 
 
 
111 East 210th Street 
 
 
 
 
Bronx, New York 10467 
 
 
 
 
Phone 718-920-4826/Fax 718-798-7474 
 
 
 
 
Email : ibraunsc@montefiore.org 
 
 
Co- Investigator: 
 
Olga Derman, M.D. 
 
 
 
 
Montefiore-Einstein Cancer Center 
 
 
 
 
Montefiore Medical Center-Moses Division 
 
 
 
 
Department of Oncology, Hofheimer Pavilion, Room 100 
 
 
 
 
111 East 210th Street 
 
 
 
 
Bronx, New York 10467 
 
 
 
 
Phone 718-920-4826/Fax 718-798-7474 
 
 
 
 
Email : oderman@montefiore.org 
 
Co- Investigator: 
 
Ramakrishna Battini, MD 
 
 
 
 
Montefiore-Einstein Cancer Center 
 
 
 
 
Montefiore Medical Center-Moses Division 
 
 
 
 
Department of Oncology, Hofheimer Pavilion, Room 100 
 
 
 
 
111 East 210th Street 
 
 
 
 
Bronx, New York 10467 
 
 
 
 
Phone 718-920-4826/Fax 718-798-7474 
 
 
 
 
Email :RABATTIN@montefiore.org 
 
Co-Investigator: 
 
Amit K. Verma, M.B.B.S. 
 
 
 
 
Albert Einstein College of Medicine 
 
 
 
 
Jack and Pearl Resnick Campus,  
 
 
 
 
Chanin Building, Room 302B 
 
 
 
 
1300 Morris Park Avenue 
 
 
 
 
Bronx, New York 10461 
 
 
 
 
Phone 718-930-8761 
 
 
 
 
Email: amit.verma@einstein.yu.edu 
IRB NUMBER: 13-08-148
IRB APPROVAL DATE: 01/03/2016

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Co-Investigator: 
 
Noah Kornblum, M.D. 
 
 
 
 
Montefiore-Einstein Cancer Center 
 
 
 
 
Montefiore Medical Center-Moses Division 
 
 
 
 
Department of Oncology, Hofheimer Pavilion, Room 100 
 
 
 
 
111 East 210th Street 
 
 
 
 
Bronx, New York 10467 
 
 
 
 
Phone 718-920-4826/Fax 718-798-7474 
 
 
 
 
Email : nkornblu@montefiore.org 
 
Co-Investigator: 
 
Ulrich Steidl, MD PhD 
 
 
 
 
Albert Einstein College of Medicine 
 
 
 
 
Jack and Pearl Resnick Campus,  
 
 
 
 
Chanin Building, Room 306 
 
 
 
 
1300 Morris Park Avenue 
 
 
 
 
Bronx, New York 10461 
 
 
 
 
Phone 718-430-3437 
 
 
Email: ulrich.steidl@einstein.yu.edu 
 
Co-Investigator: 
Murali Janakiram, M.D. 
 
 
 
 
Montefiore-Einstein Cancer Center 
 
 
 
 
Montefiore Medical Center-Moses Division 
 
 
 
 
Department of Oncology, Hofheimer Pavilion, Room 100 
 
 
 
 
111 East 210th Street 
 
 
 
 
Bronx, New York 10467 
 
 
 
 
Phone 718-920-4826/Fax 718-798-7474 
 
 
 
 
 
Email : MJANAKIR@montefiore.org 
 
 
Co-Investigator: 
 
Ioannis Mantzaris, MD, MS 
 
 
 
 
Montefiore-Einstein Cancer Center 
 
 
 
 
Montefiore Medical Center-Moses Division 
 
 
 
 
Department of Oncology, Hofheimer Pavilion, Room 100 
 
 
 
 
111 East 210th Street 
 
 
 
 
Bronx, New York 10467 
 
 
 
 
Phone 718-920-4826/Fax 718-798-7474 
 
 
 
 
Email : imantzar@montefiore.org 
 
 
Research Nurse: 
 
Michelly Abreu, NP 
 
 
 
 
Montefiore-Einstein Cancer Center 
 
 
 
 
Montefiore Medical Center-Moses Division 
 
 
 
 
Department of Oncology, Hofheimer Pavilion, Room 100 
 
 
 
 
111 East 210th Street 
 
 
 
 
Bronx, New York 10467 
 
 
 
 
Phone 718-920-4826/Fax 718-798-7474 
IRB NUMBER: 13-08-148
IRB APPROVAL DATE: 01/03/2016

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Email : mabreu@montefiore.org 
 
Statistician: 
Study Coordinator/Data Management: 
Nan Xue, PhD 
 
Lawrence Almanzar 
 
Albert Einstein College of Medicine                      Montefiore Medical Center-Moses Division 
Jack and Pearl Resnick Campus 
 
Depart. of Oncology, Hofheimer Pavilion 100 
1300 Morris Park Avenue  
 
 
Bronx, NY 10467 
Belfer Building, Room 1303C  
 
Phone 718- 920-2006/718-405-8544 
Bronx, NY 10461    
 
 
 
Fax 718-798-7474/718-405-8544 
Phone: 718-430-2431  Pager: 917-218-6906 
Email: Xiaonan.xue@einstein.yu.edu  
      Email: lalmanzar@montefiore.org 
 
 
 
SYNOPSIS 
 
BACKGROUND: AML in patients 60 and over has a very poor prognosis. With standard induction 
chemotherapy and consolidation with autologous stem cell transplant a substantial proportion 
of patients will be able to achieve remission. Unfortunately, virtually all of those that achieve 
remission will relapse and die of their disease. Recently, lenalidomide has been shown to be an 
active agent for AML. In addition, lenalidomide has been shown to be a feasible and effective 
maintenance strategy for myeloma post autologous transplant. We therefore propose to study 
the feasibility and efficacy of lenalidomide maintenance after autologous transplant in AML.  
 
The primary objective is to determine the safety and efficacy of maintenance lenalidomide after 
autologous stem cell transplant in this setting. 
 Secondary Objectives are to determine the progression free survival and overall survival for 
patients treated with this approach. 
 
TREATMENTElderly patients with AML who have achieved morphologic remission will be 
treated with escalating doses of lenalidomide (starting at 10mg once daily 21 days each month) 
in groups of 3 until a maximum dose of 25mg once daily 21 days each month has been reached. 
 
Key Eligibility Criteria:Patients must have a diagnosis of Acute Myeloid Leukemia excluding 
Acute Promyelocytic Leukemia (M3). Age 60-80, No uncontrolled CHF. Adequate renal and liver 
function.  ECOG performance status  2, and a life expectancy of > 12 months. Patients will be 
excluded if they have an untransfused platelet count of < 75, are growth factor dependent, 
have uncontrolled infection, have HIV or HTLV-1 infection,  have active CNS disease, or prior 
malignancy other than adequately treated non-melanoma skin cancer. 
PARTICIPATING 
INSTITUTION 
PI’s NAME 
Telephone 
Email 
Comprehensive Cancer Center 
Wake Forest University 
David Hurd, MD 
(336)-713-5440 
dhurd@wakehealth.edu 
IRB NUMBER: 13-08-148
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Statistical Considerations:The aim of this proposal is to provide an accurate estimate of the 
two-year relapse free survival rate for elderly AML patients treated with lenalidomide 
maintenance after autologous stem cell transplantation. With approximately 30 patients, the 
study will be able to estimate the two year relapse free survival  rate with not more than 9% 
standard error(i.e., if the observed rate is 40%, the 95% CI will be (23%, 56%). In addition, our 
study will have over 80% power to conclude that the two year relapse rate is significantly 
reduced when patients are treated with lenalidomide, assuming 60% and 90% patients will 
relapse with and without lenalidomide, respectively. The observed relapse free survival rate will 
be calculated along with its 95% CI. A one sample test on proportion will be used to detect if 
the relapse free survival rate with lenalidomide is significantly higher than that without the 
treatment (relapse rate is expected to be >95%).Secondary analysis including Kaplan-Meier 
analysis on overall survival. 
 
 
 
 
 
TABLE OF CONTENTS 
 
Page 
 
SYNOPSIS ........................................................................................................................................ 3 
 
1. OBJECTIVES ............................................................................................................................... 7 
1.1 
Primary Objectives ........................................................................................................ 7 
1.2 
Secondary Objectives ................................................................................................... 7 
 
2. BACKGROUND and RATIONALE ............................................................................................... 7 
2.1 
Induction Therapy for Elderly AML Patients ................................................................. 7 
2.2 
Autologous Stem Cell Transplantation as Consolidation Therapy for AML .................. 8 
2.3 
Lenalidomide as Treatment of AML .............................................................................. 9 
2.4 
Lenalidomide as Maintenance Treatment post-Transplant ......................................... 9 
2.5 
Background Drug Information .................................................................................... 10 
2.6 
Correlative Studies ...................................................................................................... 15 
 
3. PATIENT SELECTION ............................................................................................................... 15 
3.1 
Inclusion Criteria  ........................................................................................................ 15 
3.2 
Exclusion Criteria ......................................................................................................... 16 
3.3 
Inclusion of Women and Minorities ........................................................................... 17 
 
4. REGISTRATION PROCEDURES ................................................................................................. 17 
4.1  
General Guidelines ...................................................................................................... 17 
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4.2  
Registration Process .................................................................................................... 18 
 
5. TREATMENT PLAN .................................................................................................................. 18 
5.1  
Dose Modification ....................................................................................................... 21 
 
5.2  
Concomitant Medications ........................................................................................... 23 
5.3 
Supportive Care ........................................................................................................... 23 
5.4 
Criteria for Removal from Study ................................................................................. 24 
 
6. SCHEDULE OF EVENTS ............................................................................................................ 25 
6.1  
Screening Period ......................................................................................................... 25 
6.2  Treatment Period .............................................................................................................. 26 
6.3 Supportive Care ................................................................................................................ 28 
6.4 
Follow up Period ......................................................................................................... 28 
 
7. CORRELATIVE / SPECIAL STUDIES .......................................................................................... 32 
 
8. MEASUREMENT OF EFFECT .................................................................................................... 33 
 
 
9. DATA REPORTING  .................................................................................................................. 34 
 
9.1      Definitions.................................................................................................................. 34 
9.2  
Determination of reporting requirements. ................................................................ 36 
9.3 
Reporting methods ..................................................................................................... 36 
9.4  
When to report an event in an expedited manner. ................................................... 36 
9.5 
Expedited Reporting ................................................................................................... 37 
 
9.6 Reporting Second primary malignancies .................. ........................................................38 
9.7  
Reporting Pregnancies ................................................................................................ 38 
9.8 
Protocol-specific expedited adverse event reporting exclusions ............................... 39 
9.9  
Responsibilities of participating sites. ........................................................................ 39 
9.10 
Responsibilities of coordinating center and Celgene Corporation ............................. 40 
 
 
10. STATISTICAL CONSIDERATIONS ............................................................................................. 40 
10.1 
Study Design/Endpoints .............................................................................................. 40 
10.2 
Sample Size/Accrual .................................................................................................... 40 
 
 
11. DATA MANAGEMENT AND REGULATORY REQUIREMENTS  ................................................ 41 
 
11.1      Data Safety and Monitoring Plan ....... .........................................................................41 
11.2 
Recruitment and Consent. .......................................................................................... 42 
11.3 
Patient Protection ....................................................................................................... 42 
11.4 
Record Retention. ....................................................................................................... 42 
11.5 
Study Monitoring ........................................................................................................ 43 
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APPENDICES 
 
 
APPENDIX A 
Performance Status Criteria .............................................................................................. 44 
 
APPENDIX B 
 
Form 1 – Eligibility and Registration Form ........................................................................ 45 
 
 
APPENDIX C 
 
Handling and Shipping of Bone Marrow Specimens......................................................... 47 
 
APPENDIX D 
 
Required laboratory Parameters ...................................................................................... 49 
 
APPENDIX E 
 
Cockcroft-Gault Estimation of CrCl ................................................................................... 50 
 
APPENDIX F 
 
Risks of Fetal Exposure, Pregnancy Testing Guidelines, Acceptable Birth Control   
Methods and Precautions ................................................................................................. 51 
APPENDIX G 
 
Drug Insert and Full Prescribing Information .................................................................... 54 
 
APPENDIX H 
 
FDA MEDWATCH 3500A Form .......................................................................................... 55 
 
APPENDIX I 
 
NCI CTCAE version 4.0  ...................................................................................................... 56 
 
REFERENCES .................................................................................................................................. 57 
 
 
 
 
 
 
 
 
 
 
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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
To determine the safety and efficacy of maintenance lenalidomide post autologous 
peripheral blood stem cell transplantation (PBSCT)  for elderly patients with AML. 
 
1.2. 
Secondary Objectives 
 
1.2.1To define maximum tolerated dose (MTD) and establish therapeutic dose level (TDL) 
 
 
of lenalidomide given post autologous transplant for AML. 
 
1.2.2 To determine the progression free survival for patients treated with this approach. 
 
1.2.3To determine the overall survival for patients treated with this approach. 
 
1.2.4 To determine the role of residual AML stem cells on efficacy of lenalidomide  
 
 
 
maintenance after autologous PBSCT. 
 
 
2. BACKGROUND and RATIONALE 
 
 
2.1  
Induction Therapy for Elderly AML Patients 
AML is mainly a disease of the elderly with a median age of 69 years in the white US 
population, and prognosis worsens every decade beginning at age 30 to 40.1 A report by 
the German Acute Myeloid Leukemia Cooperative Group studied patients 16 to 85 years 
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of age enrolled in two consecutive trials who had AML. In a multivariate analysis of 
prognostic factors, age ≥ 60 years was a statistically significant poor prognostic factor 
for complete remission, overall survival, remission duration, and relapse free survival.2 
Population based studies have reported 3- and 5-year survival rates of only 9 to 10% and 
3 to 8%, respectively, in patients over age 60, compared with 5-year survival rates of up 
to 50% for younger patients.3Poorer outcome has traditionally been considered at least 
in part due to reluctance of physicians to treat this population aggressively. As such, 
lower levels of aggressive treatments may compound underlying prognostic differences 
associated with patient factors and disease biology.4 Recent studies have therefore 
focused on dose intensification of anthracyclines and/or postremission therapy. 
Lowenberg and colleagues compared induction therapy with daunorubicin (DNR) at a 
dose of 45 mg/m2or 90mg/m2 in 813 patients over age 60 with previously untreated 
AML. Although complete response (CR) rates were improved in the group that received 
the higher dose of DNR (64% vs 54%, P=.002) there was no significant difference in the 
two induction groups with respect to overall survival (OS) and event-free survival (EFS). 
Thirty-day mortality was 11% to 12% in both groups. Two year probabilities of relapse 
after CR for the standard versus intensified DNR groups were 61% versus 54%. Of note, 
dose reduced anthracycline led to inferior CR rates and survival was not as good in 
certain subgroups of patients.5 As such, although the superiority of higher dose 
anthracycline as induction is not established in AML patients over 60 there 1) seems to 
be no increased toxicities with these regimens and 2) there is certainly no reason to 
attenuate doses of anthracycline in AML patients over 60. Doses of DNR at 60mg/m2 or 
Idarubicin at 12mg/m2 for 3 days together with cytarabine would be appropriate to use.4 
 
2.2Autologous Stem Cell Transplantation as Consolidation Therapy for AML 
 
The antileukemic efficacy of autologous stem cell transplantation for AML has been well 
established for some time. Zittoun and colleagues randomized 623 AML patients in first 
remission to either further chemotherapy, allogeneic stem cell transplant or autologous 
stem cell transplant. Disease free survival at four years was 55% for allogeneic 
transplantation, 48% for autologous transplantation and 30% for intensive 
chemotherapy. The difference between autologous transplantation and chemotherapy 
was statistically significant.6More recently, Vellenga and colleagues randomized over 
500 patients with AML in first CR to either further intensive chemotherapy or 
autologous peripheral blood stem cell transplant. The transplant group showed a 
markedly reduced relapse rate (58% vs. 70%, P=.02) and better relapse free survival at 5 
years (38% vs 29%, P=.065) Overall survival was similar because of more opportunities 
for salvage with second-line chemotherapy and stem cell transplantation in patients 
relapsing on the chemotherapy arm.7 
 
Autologous stem cell transplantation has also been studied in the elderly patient with 
AML. Lashkari and colleagues studied 27 patients aged 60-71 years with newly 
diagnosed AML in first CR. They underwent high dose chemoradiotherapy followed by 
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peripheral blood stem cell transplant after a single cycle of cytarabine-based 
consolidation therapy. Leukemia free survival and overall survival at 3 years was 25% 
and 28% respectively. There was one death from transplant related mortality. The 
authors concluded that autologous transplantation of peripheral blood stem cells is well 
tolerated and feasible for patients ≥ 60 years of age with AML in first CR.8  Ferrara and 
colleagues studied sixty three patients with non-M3 AML. The median age was 69 with 
range between 61 and 81. Included were patients with AML secondary to 
myelodysplastic syndrome. The transplant related mortality was 0%. Those patients that 
received a transplant (n=17)had a significantly better overall survival and disease free 
survival when compared to those that did not undergo transplant(n=10).9 Oriol and 
colleagues evaluated the feasibility and  results of autologous stem cell transplant in 258 
AML patients in first CR who were over 60.  The probability of 2 year leukemia-free  
survival was 39% for those candidate patients who underwent transplant and 22% for 
those that did not (p=.07). The authors concluded that autologous transplantation has a 
tolerable toxicity and may have a positive impact on leukemia-free survival.10 
 
In summary then a few conclusions are reasonable to make for the  patient with AML: 1) 
Standard induction chemotherapy is feasible ,and certainly there is no role to reduce the 
dose of anthracycline for a fit elderly patient 2) Autologous stem cell transplant may 
have superior anti-leukemic efficacy in the young AML patient when compared with 
standard consolidation chemotherapy 3) There is some suggestion that the superior 
antileukemic efficacy  of autologous transplant may translate to benefit  the elderly 
patient with AML as well 4) Autologous stem cell transplant is feasible in the elderly 
patient with AML vis a vis toxicities 5) While remissions in the elderly patient with AML 
are attainable, relapse is still the major obstacle to reach the goal of long term 
leukemia-free survival. 
 
As such, new approaches are needed to enable those that achieve remission to remain 
in remission for the long term.  
 
2.3Lenalidomide as Treatment of AML 
 
Lenalidomide is a Food and Drug Administration (FDA) approved antineoplastic drug 
indicated for the treatment of myeloma in combination with dexamethasone, and for 
low or intermediate-1 risk myelodysplastic syndrome associated with a deletion 5q 
cytogenetic abnormality. A recent study has also shown that lenalidomide is an active 
agent for AML. Fehniger and colleagues evaluated the efficacy of lenalidomide as 
frontline therapy for older patients with AML. Patients 60 years of age or older with 
untreated AML received high-dose lenalidomide at 50mg daily for up to two twenty-
eight day cycles. If patients achieved a CR or a CR with incomplete blood count 
recovery(Cri) or did not progress after 2 cycles of high dose lenalidomide, they received 
low dose lenalidomide (10mg daily) until disease progression, an unacceptable adverse 
event, or completion of 12 cycles. Thirty-three patients were enrolled. Overall CR/Cri 
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rate was 30% and 53% in patients completing high dose lenalidomide. The median 
duration of CR/CRi was 10 months. The authors concluded that high dose lenalidomide 
has evidence of clinical activity as initial therapy for older AML patients.11 
 
2.4   Lenalidomide as Maintenance Treatment post-Transplant 
 
The CALGB randomized 460 myeloma patients who underwent autologous stem cell 
transplantation and had stable disease or better to either lenalidomide maintenance or 
placebo. Starting dose was 10 mg/day, and escalated to 15mg/day after 3 months and 
continued until disease progression. Drug was stopped and dose reduced according to 
the development of toxicity. Drug was held for ≥ grade 3 toxicity, restarted at resolution 
to ≤ grade 2, and de-escalated by 5 mg or maintained as tolerated at 15, 10, or 5 mg 
daily for 21 of 28 days per month. The number of events (progression or death) in 
patients randomized to lenalidomide was 44 compared to 91 among patients 
randomized to placebo. The median time to progression was 42 months in the 
lenalidomide group vs. 22 months in the placebo group. Patients receiving lenalidomide 
experienced a 61% reduction in the risk of disease progression or death when compared 
to patients receiving placebo. A minority of patients discontinued therapy due to 
adverse events (12%, 28 of 231 on lenalidomide vs. 2%, 5 of 229 on placebo). The 
authors concluded that long term administration of lenalidomide is feasible in this 
setting and that lenalidomide significantly delays time to progression when given post-
transplant.12 
 
French investigators randomized patients who underwent an autologous stem cell 
transplant for myeloma to receive lenalidomide consolidation (25mg/day, 21 
days/month, for 2 months) followed by maintenance with either placebo or 
lenalidomide (10 to 15 mg /day) until relapse. Lenalidomide maintenance improved the 
progression free survival(median 24 months from randomization in the placebo arm vs. 
42 months from randomization in the lenalidomide arm) and the treatment was well 
tolerated. The definitive interruption rate for serious adverse events during 
maintenance was similar in both arms.13 
 
We therefore propose to study the feasibility and efficacy of lenalidomide maintenance 
therapy for elderly patients with AML who have achieved a morphologic remission after 
induction and consolidation with autologous stem cell transplantation. The starting dose 
of 10mg/day is based on the tolerability of this dose in the post-transplant setting for 
myeloma. 
 
 
 
 
2.5   Background Drug Information 
 
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.  IMiD® 
compounds have both immunomodulatory and anti-angiogenic properties which could 
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confer antitumor and antimetastatic effects.  Lenalidomide has been demonstrated to 
possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced 
endothelial cell migration, due at least in part to inhibition of Akt phosphorylation 
response to bFGF. In addition, lenalidomide has a variety of immunomodulatory effects.  
Lenalidomide stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-
gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 production. Upregulation of T 
cell derived IL-2 production is achieved at least in part through increased AP-1 activity.  
 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a 
number of mechanisms are postulated to be responsible for lenalidomide’s activity 
against multiple myeloma.  Lenalidomide has been shown to increase T cell 
proliferation, which leads to an increase in IL-2 and IFN-gamma secretion.  The increased 
level of these circulating cytokines augment natural killer cell number and function, and 
enhance natural killer cell activity to yield an increase in multiple myeloma cell lysis. In 
addition, lenalidomide has direct activity against multiple myeloma and induces 
apoptosis or G1growth arrest in multiple myeloma cell lines and in multiple myeloma 
cells of patients resistant to melphalan, doxorubicin and dexamethasone.  
 
Indications and Usage:  
 
Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion-
dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes 
associated with a deletion 5q cytogenetic abnormality with or without additional 
cytogenetic abnormalities. Revlimid® is also approved in combination with 
dexamethasone for the treatment of patients with multiple myeloma that have received 
at least one prior therapy.  
 
Lenalidomide Description 
 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with 
anti-angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-
isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:  
 
Chemical Structure of Lenalidomide 
 
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione. The empirical 
formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.  
 
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic 
solvent/watermixtures, and buffered aqueous solvents. Lenalidomide is more soluble in 
organic solvents and low pH solutions. Solubility was significantly lower in less acidic 
buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon 
atom and can exist as the optically active forms S(-) and R(+), and is produced as a 
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racemic mixture with a net optical rotation of zero. 
 
CLINICAL PHARMACOLOGY 
 
Mechanism of Action:  
 
The mechanism of action of lenalidomide remains to be fully characterized. 
Lenalidomide 
possesses 
immunomodulatory 
and 
antiangiogenic 
properties.  
Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the 
secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells.  
Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) in some but 
not all cell lines.  Of cell lines tested, lenalidomide was effective in inhibiting growth of 
Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) 
but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell 
line, also with a deletion of one chromosome 5) and other cell lines without 
chromosome 5 deletions.  Lenalidomide inhibited the expression of cyclooxygenase-2 
(COX-2) but not COX-1 in vitro.   
 
Pharmacokinetics and Drug Metabolism: 
 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration 
with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-
dose. Co administration with food does not alter the extent of absorption (AUC) but 
does reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic 
disposition of lenalidomide is linear. Cmax and AUC increase proportionately with 
increases in dose. Multiple dosing at the recommended dose-regimen does not result in 
drug accumulation. 
 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in 
the phase I studies.  Absorption was found to be rapid on both Day 1 and Day 28 with 
time to maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 
10mg, 25mg, and 50mg).  No plasma accumulation was observed with multiple daily 
dosing.  Plasma lenalidomide declined in a monophasic manner with elimination half-life 
ranging from 2.8 to 6.1 hours on both Day 1 and 28 at all 4 doses.  Peak and overall 
plasma concentrations were dose proportional over the dosing range of 5mg to 50mg. 
Exposure (AUC) in multiple myeloma patients is 57% higher than in healthy male 
volunteers.  
 
Distribution: 
In vitro (14◦C)-lenalidomide binding to plasma proteins is approximately 30%. 
 
Metabolism and Excretion: 
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The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through 
urinary excretion. The process exceeds the glomerular filtration rate and therefore is 
partially or entirely active.  Half-life of elimination is approximately 3 hours.  
 
Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no 
charge through the RevAssist® program.   
 
Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   
 
Packaging 
Lenalidomide will be shipped directly to patients.   Bottles will contain a sufficient 
number of capsules for one cycle of dosing.    
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold.     
 
Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless 
they are wearing gloves. 
 
Prescribing Information  
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  
Lenalidomide will be provided in accordance with the RevAssist® program of Celgene 
Corporation.  Per standard RevAssist® requirements all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial, and all research subjects 
enrolled into this trial, must be registered in and must comply with all requirements of 
the RevAssist® program.  Prescriptions must be filled within 7 days.  Only enough 
lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
 
Pregnancy Testing    
Pregnancy testing is required, and must be performed within 24 hours prior to 
prescribing lenalidomide. Risks of Fetal Exposure, Pregnancy Testing Guidelines, 
Acceptable Birth Control Methods and other Precautions are presented in Appendix F. 
 
Adverse Events 
Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication include: anemia, neutropenia, thrombocytopenia and 
pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, 
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itching, infections, sepsis, pneumonia, Urinary Tract Infections (UTI) , Upper respiratory 
infection, atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, 
weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, 
pleural effusion, pulmonary embolism, deep vein thrombosis, Cerebrovascular attacks 
(CVA), convulsions, dizziness, spinal cord compression, syncope, disease progression, 
death not specified and fractures. 
 
Lenalidomide has been studied in healthy volunteers and in patients with cancer of the 
blood and other organs of the body as well as in patients with other diseases.  As with 
any other experimental treatment there may be side effects or risks associated with 
lenalidomide, some of which are not yet known.   
 
The following is a list of the most medically significant or most common side effects 
reported in completed and ongoing studies considered to be related to lenalidomide. In 
some cases, side effects can be serious, long-lasting, may never go away, or can cause 
death.   
 
Common (between a 1-10% chance that this will happen): 
Anemia; Decrease in cells that help your blood clot; Low white blood cells with or 
without fever; Pneumonia or other infections; Fever; Abnormal heart beats; Shortness 
of breath; Blood clots in lower extremities, lungs, heart, brain or other organs; Abnormal 
kidney function; Diarrhea with or without bleeding; Loss of fluid; Other cancers; Pain 
including muscles, joints and non-heart pain; Altered sense of taste. 
 
Uncommon (between a 0.1-1% chance that this will happen): 
 
Heart attack; Heart and lungs stop working; Bleeding including bleeding in individual 
organs; Stroke; Seizure; Dizziness; Fainting; Diabetes; Depression; Confusion; Worsening 
of general condition/ disease; Feeling tired, weak and unwell; Chills; Constipation; 
Blockage of intestine; Nausea; Vomiting; Decreased appetite; Weight loss; Swelling 
including swelling of individual organs; Gall bladder problem; Chemical imbalance; 
Abnormal liver lab tests; Allergic reactions including serious allergic skin reactions 
including involvement of the lining of the nose, mouth, stomach and intestines or rash 
leading to the separation of the top layer of skin; Skin irritation; Fracture; Problems 
urinating; Cough; Breathing disorder; Abnormal blood pressure; Low oxygen to tissues 
of the body including heart; Absence of blood cells due to defective development; Rapid 
death of cancer cells where the accumulating contents of dying cancer cells cause an 
imbalance in the chemistry of the body which can lead to kidney damage; Sudden 
increase in tumor size. 
 
Rare (less than a 0.1% chance that this will happen): 
Abnormal lymph gland; Heart pain; Shock; Weak heart muscle; Deafness; Blindness; 
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Abnormal eye pressure; Vision changes; Tear in intestine; Decreased action of intestine; 
Food poisoning; Indigestion; Stomach ulcer with or without bleeding; Problem with 
thyroid; Problem with adrenal gland; Liver failure; Abnormal liver function; Destruction 
of red blood cells; Abnormal bone marrow test result; Blood vessel narrowing; Lack of 
blood supply leading to tissue damage; Arthritis with infection; Worsening of chronic 
lung disease with infection; Too much fluid in body; Trouble speaking; Trouble walking; 
Muscular inflammation; Coma; Abnormal sense of touch; Lowered level of 
consciousness, with drowsiness, listlessness and apathy; Headache; Neurologic problem; 
Pain and decreased sensation in nerves; Parkinson's disease; Repetitive speech; 
Sleepiness; Shaking; Irritable; Excited; Hallucination; Not able to sleep; Moody; Fluid in 
lungs; Runny nose; Sore throat; Blister; Change in skin color; Skin ulcer; Blood not 
getting to extremities; Itching; Destruction of muscle that can lead to kidney damage. 
 
 
 
2.6 Correlative Studies 
 
To determine the role of residual AML stem cells on efficacy of lenalidomide 
maintenance after autotransplant. 
 
Myeloid malignancies can arise from a small population of quiescent cancer-initiating 
cells that are not eliminated by conventional cytotoxic therapies. Eliminating leukemia 
stem cells can reduce the rates of relapse and increase leukemia free survival. Thus it is 
important to evaluate the role of persistent leukemia stem cells in the efficacy of 
lenalidomide maintenance regimens. 
 
Flow cytometry will be done on bone marrow aspirates to estimate the persistence of 
leukemic stem cells. We have established protocols to isolate rigorously defined long-
term hematopoietic stem cells (LT-HSC, Lin-, CD34+, CD38-, CD90+), short-term 
hematopoietic stem cells (ST-HSC, Lin-, CD34+, CD38-, CD90-), common myeloid 
progenitors (CMP, Lin-, CD34+, CD38+, CD123+, CD45RA-), granulocyte- monocyte 
progenitors (GMP, Lin-, CD34+, CD38+, CD123+, CD45RA+), and megakaryocyte-
erythrocyte progenitors (MEP, Lin-, CD34+, CD38+, CD123-, CD45RA-) from primary 
bone marrow aspirates.14  Sorted cells will have FISH studies done on them to estimate 
the number of stem cells with clonal cytogenetic alterations (Leukemic stem cells). 
Functional assays will also be done on these sorted cells to demonstrate clonogenic 
potential in vitro, and leukemia-initiating potential in vivo. A recently discovered marker 
of AML stem cells, IL1RAP15, will also be evaluated on AML stem cells and correlated 
with clinical response.  
 
Whole transcriptome sequencing, exome sequencing, and global methylome analysis on 
sorted cells will also be done and correlated with response. This will allow us to 
correlate molecular markers with relapse or remission. 
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Detailed procedures for correlative studies are discussed in Section 7.  
 
 
3. PATIENT SELECTION 
 
3.1  
Inclusion Criteria 
 
 
3.1.1. Patients must have a Confirmed diagnosis of non-M3 AML. Antecedent MDS is  
 
 
 
acceptable. 
 
3.1.2. Post autologous Stem Cell Transplant Bone marrow biopsy core that is consistent  
 
 
 
 
with morphologic remission. 
 
3.1.3. Age between 60 and 80years old. 
 
3.1.4. Must have received induction and consolidation chemotherapy, and autologous  
 
 
 
 
stem cell transplant for AML. 
 
3.1.5. Life expectancy of greater than 12 months. 
 
3.1.6. Karnofsky Performance Status 70 or greater (see Appendix A) 
 
 
3.1.7. Patients must have normal organ and marrow function as defined below: 
- 
Leukocytes ≥2,000/mcL  
- 
Absolute neutrophil count ≥ 1,000/mcL  
- 
Platelets ≥ 75,000/mcL  
- 
Total bilirubin ≤4 X institutional upper limit of normal unless 2nd to Gilbert’s 
 
disease 
- 
AST(SGOT) and ALT(SGPT) ≤ 4 X institutional upper limit of normal 
 
- 
Creatinine <1.5 X institutional upper limit of normal OR creatinine clearance ≥ 30 
 
 
 
mL/min/1.73 m2 for patients with creatinine levels above institutional normal. 
 
 
3.1.8 Able to take aspirin, or warfarin, or low molecular weight heparin as prophylactic  
 
 
 
 
anticoagulation. 
 
3.1.9. Ability to understand and the willingness to sign a written informed consent   
 
 
 
 
document. 
3.1.10 Must be registered into the mandatory RevAssist® program and be willing and  
 
able to comply with the requirement of RevAssist®. 
 
 
 
3.2  
Exclusion Criteria 
 
 
 
3.2.1. Patient received chemotherapy or radiotherapy within 2 weeks prior to entering  
 
 
 
 
the study or has not recovered from adverse events due to agents administered  
 
 
 
 
more than 4 weeks earlier. 
 
 
3.2.2 Patient received another investigational agent after post autologous stem cell  
 
 
 
 
transplant. 
 
 
3.2.3 Patient who will be receiving another investigational product during the study. 
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3.2.4 Patient who is growth factor or transfusion dependent. 
3.2.5 Patient has CNS leukemia. 
3.2.6 History of allergic reactions attributed to thalidomide or lenalidomide. 
3.2.7 History of erythema nodosum, characterized by a desquamating rash  
 
 
while taking thalidomide or similar drugs. 
3.2.8 Prior history of metastatic malignancy. 
3.2.9 Uncontrolled illness including, but not limited to ongoing or active infection,  
 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social  
 
 
situations that would limit compliance with study requirements. Patients must  
 
not have suffered recent (< 6 months) myocardial infarction, unstable angina,  
 
uncontrolled hypertension, or difficult to control cardiac arrhythmias. 
3.2.10 Evidence of uncontrolled Congestive Heart Failure (CHF). 
3.2.11 Active Hepatitis B as defined by Hepatitis B surface antigen positivity, unless able  
 
 
to start dual anti-HepB therapy, or already on dual anti-HepB therapy 
3.2.12 Patients who are positive for Hepatitis B core antibody, but negative for the  
 
 
hepatitis B surface antigen, should be on lamivudine 100 mg daily until at least 3  
 
 
months post-transplant 
3.2.13 Patient is positive for HIV or HTLV-1. 
3.2.14 Women of childbearing potential (defined as a sexually mature woman who has  
 
 
not undergone a hysterectomy or who has had menses at any time in the  
 
 
preceding 24 consecutive months). 
3.2.15 Men who did not agree not to father a child and who refused to use a latex  
 
 
condom during any sexual contact with women of childbearing potential while  
 
 
taking lenalidomide and for 4 weeks after therapy is stopped, even if they have  
 
 
undergone a successful vasectomy. 
 
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for 
this trial.  
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
The coordinating center is: Montefiore-Einstein Cancer Center 
 
 
 
 
 
Montefiore Medical Center-Moses Division 
 
 
 
 
Department of Oncology, Hofheimer100 
 
 
 
 
111 East 210th Street 
 
 
 
 
Bronx, New York 10467 
 
 
 
 
Phone 718-920-2006 or 718-405-8544 
 
 
 
 
Fax 718-798-7474 or 718-405-4712 
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Coordinator: Lawrence Almanzar 
Email:  lalmanzar@montefiore.org 
 
Eligible patients will be entered on study centrally at the Montefiore-Einstein Cancer 
Center Coordinating Center by the Study Coordinator.  All sites should call the Study 
Coordinator Lawrence Almanzar; phone 718- 920-2006 to verify eligibility.  The required 
forms (eligibility and registration form; form 1) can be found in the Appendix (Appendix 
B). 
 
Following registration, patients should begin protocol treatment within 96 hours.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator 
(PI).  If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible. 
4.2 
Registration Process 
 
To register a patient, the following documents should be completed by the research 
nurse or data manager and faxed or e-mailed to the Study Coordinator at the 
Montefiore-Einstein Cancer Center Coordinating Center Lawrence Almanzar; phone 718- 
920-6642, fax 718-798-7474 or email: lalmanzar@montefiore.org 
 
 Form 1 (Appendix B) 
 Copy of required laboratory tests and procedures 
 Signed patient consent form 
 HIPAA authorization form 
 
The research nurse or data manager at the participating site will then call the Study 
Coordinator at the Montefiore-Einstein Cancer Center Coordinating Center Lawrence 
Almanzar, phone 718- 920-2006, fax 718-798-7474 or email: lalmanzar@montefiore.org 
 
to verify eligibility.  To complete the registration process, the Coordinator will - after 
 
discussion with the PI,Dr. Ira Braunschweig:  
 
 Assign a patient study number 
 Register the patient on the study 
 Fax or e-mail the patient study number to the participating site 
 Call the research nurse or data manager at the participating site and verbally 
confirm registration. 
 
Once patients are found eligible for the study, they will be registered with the 
Montefiore-Einstein Cancer Center Coordinating Center.  A patient number will be 
assigned, and a copy of appendix B including the patient number will be faxed back to 
the participating center/investigator.  
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5. TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis. Lenalidomide 2.5 mg, 5 mg, 10 mg, 15 
mg and 25 mg capsules are to be taken orally (PO).  In Phase I, the starting dose of 
Lenalidomide  is 10 mg taken PO daily for 3 three consecutive weeks (Days 1-21) following one 
week off therapy (Days 22-28). One cycle is 4 weeks (Figure 1).  
 
 
In phase 1, it is anticipated that 6 - 18 evaluable patients will be treated. Three to six patients 
will be treated at each dose level of three dose levels of Lenalidomide  (10 mg, 15 mg, 25 mg) 
daily doses (Table 1). The initial dose is 10 mg. Patients will receive repeated cycles of 
Lenalidomide  until disease progression or unacceptable toxicity. If no Lenalidomide related 
Dose Limited Toxicity (DLT) is seen in three patients at a dose level during first cycle (by day 
28), the escalation to the next dose level is allowed. Each cohort will be monitored for a DLT 
during the first cycle before deciding to escalate the dose for the next cohort.  
 
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Dose escalation determination is summarized in Table 2. If one DLT occurs at a dose level, up to 
3 additional patients will be added to that cohort and if one or more of this group suffers DLT, 
then dose escalation is stopped, and this dose is declared the Maximally Tolerated Dose (MTD). 
Three additional patients will be entered at the next lower dose level if only three patients 
were treated previously at that dose.  
 
 
 
If no DLT is observed at the final 25 mg dose level in the first three patients, three additional 
patients at the 25 mg dose level will be recruited. In Phase 1, in order to declare Therapeutic 
Dose Level (TDL), a minimum of six patients must be recruited at that dose level. Therapeutic 
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Dose Level (TDL) is defined as the dose level where DLT occurred in less or equal to one out of 
six patients below the MaximallyTolerated Dose level.TDL will be the recommended dose for 
Phase 2.  
 
If a DLT is observed in two or more patients at the first dose level (10 mg), then dose level -1 (5 
mg) will be tested with three patients first. Three additional patients will be enrolled at the 5 
mg dose, if one or less DLT is observed. If one or more of this group suffers DLT, then the study 
is stopped and lenalidomide maintenance for elderly AML patients post autologous transplant 
is not deemed feasible (same as if ≥2 had a DLT to initial cohort of 5 mg). 
 
Decisions about DLTs, expansion of a cohort to six subjects, escalation to the next dose level, or 
reduction to the next lower level will be made by Principle Investigator.  
 
In Phase 1, subjects will continue study drug, lenalidomide until disease progression or 
unacceptable toxicity. Reported adverse events and potential risks for lenalidomide are 
described in Section 2.5.  Dose modifications are described in Sections 5.1 and in Table 3.  
Subjects whoare withdrawn without a DLT before completing Cycle 1 will not be used to 
evaluate theMTD or TDL, but will be included in the overall safety analysis. 
 
In Phase 2, patientswill receive the lenalidomide dose recommended in the Phase 1 portion. 30 
patients will be enrolled in Phase 2. Study procedures are the same as the Phase 1 portion. 
Subjects will be able to continue the study treatment until disease progression or unacceptable 
toxicity. Detailed discontinuation information is provided in Section 5.4.   
 
A new course of treatment may begin on the scheduled day 1 of a new cycle if;  
 
 Absolute neutrophil count  ≥ 1,000 / mcL 
 Platelets count ≥ 50,000 
 Resolution of adverse events to ≤ grade 1 (Details in Section 5.1). 
 
 
5.1   Dose modifications 
 
At Phase 1, subjects who develop any DLT during cycle 1 will be taken off the study. 
During cycle 2 and onward, dose reductions are allowed. Dose reduction rules are the 
same for subjects enrolled in Phase 2 (Table 3). Reduced doses will not be re-escalated 
for any subject during the study. Subjects may not continue Lenalidomide after the third 
dose reduction or beyond dose of 2.5 mg. 
 
 
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* Subjects may not continue Lenalidomide after third dose reduction or beyond dose of 2.5 mg. 
 
 
A non-hematologic DLT is defined as a National Cancer Institute (NCI)-Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4 (Oct/09) Grade 3 or 4 
adverse events (AE) considered related to the study drug. Grade 3 anorexia and Grade 3 
fatigue are excluded since it is very common to develop anorexia and fatigue during any 
chemotherapy.  
 
A hematologic DLT is defined as a grade 4 hematologic toxicity complicated by infection, 
severe hemorrhage, or marrow aplasia persisting greater than 2 weeks considered 
related to the study drug.  
5.1.1 Dose Modification for hematologic toxicities after cycle 1 (for Phase 1)  
and during allcycles (for Phase 2): 
 
If the ANC is less than 500/µL or the platelet count is less than 30,000/µL, then the study 
drug may be held for up to 8 weeks. Study drug may be re-instituted at the next lower 
level (i.e. from 15mg to 10 mg) if ANC is ≥ 500/ µL or the platelet count is ≥ 30,000/µL. If 
however, after an 8 week treatment delay, the ANC remains <500/µL or the platelet 
count <30,000/ µL, the patient will be removed from protocol therapy.  
 
 
5.1.2 Dose Modification for Non-Hematologic Toxicities after cycle 1 (for Phase 1)  
and during all cycles (for Phase 2): 
 
Neurologic Toxicity 
If a patient experiences ≥ 3 neurologic toxicity, then the study drug may be held for as 
many as 8 weeks. If toxicity resolves to ≤ 1, then the study drug may be reinstituted at 
the next lower dose. If, however, after an 8 week treatment delay, the toxicity does not 
resolve to ≤ 1 the patient will be removed from protocol therapy. 
 
Cardiac Toxicity 
If a patient experiences ≥ 2 cardiac toxicity, then the study drug may be held for as many 
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as 8 weeks. If toxicity resolves to ≤ 1, then the study drug may be reinstituted at the 
next lower dose. If, however, after an 8 week treatment delay, the toxicity does not 
resolve to ≤ 1 the patient will be removed from protocol therapy. 
 
Venous Thrombosis  
Patients who develop signs or symptoms suggestive of thrombosis should be evaluated 
and treated as clinically indicated. Lenalidomide should be held for patients with venous 
thrombosis. Lenalidomide may resume when patient are adequately anti-coagulated. 
Patients with recurrent thrombosis despite adequate anticoagulation should be 
removed from protocol therapy.  
 
Renal Toxicity  
For creatinine clearance (CrCI) < 30 mL/min skip lenalidomide and reassess in four 
weeks. If CrCI remains < 30 mL/min after four weeks, then protocol therapy should be 
terminated.  
 
For CrCI < 60 mL/min but 2: 30 mL/min:  
Decrease lenalidomide to next lower dose level. Reassess after four weeks and attempt 
to re-escalate lenalidomide.  
 
Other Non-Hematologic Toxicity  
For other grade 3 non-hematologic toxicity,lenalidomideshould be held until toxicity 
resolves to ≤ grade 2, then the study drug should be resumed at the next lower dose 
level. Subjects are not allowed to continue study treatment if toxicity persists more than 
8 weeks.  
 
For patients who develop grade ≤ 2 non-hematologic toxicity, an attempt will be made 
to maintain the patient at that dose level. If the patient cannot tolerate this dose level, 
the treating physician should decrease the dose to the next lower dose level.  
 
For other grade 4 non-hematologic toxicity, discontinue study drug and contact the 
Study Chair or Co-Chair.  
 
In the event of any grade 1 or 2 toxicity that the patient finds intolerable, the study drug 
may be held until the toxicity resolves and the study drug resumed at the next lower 
dose level. Alternatively, the study drug may be continued at the next lower dose level 
without cessation of study drug. However, study drug should be held for the occurrence 
of a rash consistent with evolving Stevens-Johnson syndrome or toxic epidermal 
necrolysis (bullous, blistering that is purpuric in nature) until appropriate evaluation is 
made. Study drug may be held for up to 8 weeks. Contact the Study Chair or Co-Chair for 
consultation.  
 
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5.2 Concomitant Medications 
 
No investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the patient's malignancy. 
 
Participants who receive radiation therapy or chemotherapy after transplantation 
areconsidered to have treatment failure, unless the radiation was pre-planned 
consolidation and that decision was made before transplantation. 
 
Any other treatments (including drugs, biological products, and blood products) the patient 
isreceiving at the time of screening or has received within one tofour weeks prior to 
registration andduring therapy should be recorded on the concomitant medications page of 
the case reportforms (CRFs). Use of colony stimulating factors (G-CSF or GM-CSF) and 
Erythropoietin are prohibited during the study. Subjects who need colony stimulating 
factors or erythropoietin should be taken off from the study.  
 
All concomitant medications and supportive therapy received during studytreatment must 
be recorded. 
 
5.3  Supportive Care 
 
Prophylactic aspirin or low molecular weight heparin are to be given to all patients receiving 
lenalidomide (as DVT prophylaxis) unless contraindicated. Prophylactic blood product 
support is discouraged however blood product transfusions are allowed for symptomatic 
patients who have clinically significant anemia or thrombocytopenia.  
 
 
5.4  Removal from the study 
 
Subjects may take the study drug indefinitely unless removed or withdrawn from the 
study.The following are criteria for removal from the study: 
 
 
Disease progression. Disease progression is defined as a bone marrow biopsy 
showing >5% myeloblasts. 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Occurrence of any adverse event (AE), intercurrent illness or abnormality in 
laboratory assessmentresults which, in the opinion of the investigator, warrants the 
subject’s permanentwithdrawal from the trial 
 
 
Treatment with a prohibited concomitant medication other than the use of 
appropriatemedications for the treatment of adverse events under direction of the 
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investigator (Protocol section 5.2) 
 
 
Participant becomes pregnant 
 
 
Participant is lost to follow-up 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
If a participant discontinues the trial prematurely, the reason given must be fully 
evaluated and recorded appropriately in source documents and the CRF. If the subject is 
being withdrawn because of an adverse event (AE), that AE should be indicated as the 
reason for withdrawal. 
 
All participants have the right to withdraw at any time during treatment without 
prejudice.The investigator can discontinue a subject’s participation in the trial at any 
time ifmedically necessary. The Principal Investigator should be notified promptly when 
a subject is withdrawn. 
 
 
 
 
 
6 
SCHEDULE OF EVENTS 
 
Study procedures are same for subjects enrolled in Phase 1 and Phase 2(Table 4). 
 
6.1. Screening Period (Post-transplant Day15 to Day100) 
 
Subjects will be screened post autologous transplant after engraftment and up to day 
100 of transplant which will qualify patients for study. Patients without adequate 
platelet count and/or WBC (see inclusion/exclusion criteria Sections 3.1 and 3.2) by day 
100 will not be eligible for study.  
 
A post-transplant bone marrow aspirate and biopsy will be required to document 
remission (defined here as <5% myeloblasts and CBC parameters as per Sections 3.1 and 
3.2) before registration.  Study procedures and information regarding the nature of the 
study will be reviewed with potential subjects and written informed consent will be 
obtained prior to any study related procedures. If deemed eligible, the followingdata 
will be obtained: 
 
 Informed consent. 
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 Demographic information. 
 Medical 
history, 
including 
previous 
treatment 
history 
(disease 
characteristics). 
 A physical examination, including weight and height. 
 Vital signs (blood pressure, heart rate and temperature) will be assessed 
after the subject has been supine for at least 3 minutes. 
 Complete Blood counts with differential and serum chemistries (see 
Appendix D for details). 
 Karnofsky performance status will be assessed. Data from Karnofsky 
status at initial diagnosis will also be obtained if available. 
 Concomitant medications within four weeks prior to registrationwill be 
recorded. 
 Adverse events will be assessed. 
 Subjects will be instructed to avoid any restricted medications. 
 10ml of Bone marrow Aspirate will be sent to Amit Verma’s laboratory 
(for shipping and handling instruction see Appendix C). 
 Buccal Swab. 
 Serum β-hCG for all female subjects.Serum β-hCG must be performed 
within 24 hours prior to prescribing lenalidomide.  Subjects may not 
receive lenalidomide until the Investigator has verified that the results of 
these pregnancy tests are negative. 
 
 
6.2. TreatmentPeriod 
 
Cycle 1 - Day 1 (Week 1) visit:  
 
All assessments must be completed prior to dosing with Lenalidomide. If Cycle 1 Day 1 
date is no more than three days from screening laboratory assessments, then labs 
performed during screening may be used.  
 
Assessments required for Cycle 1 Day 1: 
 Physical Examination 
 Karnofsky performance status 
 Vital signs (blood pressure, heart rate and temperature) 
 Complete Blood counts with differential and serum chemistries (see 
Appendix D for details). 
 Concomitant medications assessment 
 Adverse events assessment 
 Start of Lenalidomide treatment 
 
Cycle 1 - Week 2 &Week 3 visits: 
 
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All assessments must be completed on planned day of the week (± 1 day). Assessments 
required for Cycle 1 - Weeks 2 and 3:  
 
 Physical Examination 
 Karnofsky performance status 
 Vital signs (blood pressure, heart rate and temperature) 
 Complete Blood counts with differential and serum chemistries (see 
Appendix D for details). 
 Concomitant medications assessment 
 Adverse events assessment 
 Lenalidomide treatment 
 Review of Pill diary 
 
Cycle 1 – Week 4 visit: 
 
 Physical Examination 
 Karnofsky performance status 
 Vital signs (blood pressure, heart rate and temperature) 
 Complete Blood counts with differential and serum chemistries (see 
Appendix D for details). 
 Concomitant medications assessment 
 Adverse events assessment 
 Review of Pill diary 
 
Cycle 2 - Week 1 Visit: 
 
All assessments must be completed on planned day of the week (± 1 day). Assessments 
required for Cycle 2 - Weeks 1 visit: 
 Physical Examination 
 Karnofsky performance status 
 Vital signs (blood pressure, heart rate and temperature) 
 Complete Blood counts with differential and serum chemistries (see 
Appendix D for details). 
 Concomitant medications assessment 
 Adverse events assessment 
 Lenalidomide treatment 
 Review of pill diary 
 
Cycle 2 - Week 3 Visit: 
 
All assessments must be completed on planned day of the week (± 1 day). Assessments 
required for Cycle 2 - Weeks 3 visit: 
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 Physical Examination 
 Karnofsky performance status 
 Vital signs (blood pressure, heart rate and temperature) 
 Complete Blood counts with differential and serum chemistries (see 
Appendix D for details). 
 Concomitant medications assessment 
 Adverse events assessment 
 Lenalidomide treatment 
 Review of pill diary 
 
 
Cycle 3and onward - Week 1 Visits: 
 
Beginning with cycle 3, study visits will be performed once every cycle, during the first 
week. Subjects will continue study treatment with Lenalidomide on three-weeks-on, 
one-week-off schedule. All assessments must be completed on planned day of the week 
(± 2 days). Assessments required for Cycle 3 - Weeks 1 visit: 
 
 Physical Examination 
 Karnofsky performance status 
 Vital signs (blood pressure, heart rate and temperature) 
 Complete Blood counts with differential and serum chemistries (see 
Appendix D for details). 
 Concomitant medications assessment 
 Adverse events assessment 
 Lenalidomide treatment 
 Review of pill diary 
 
Bone marrow biopsies 
 
Bone Marrow biopsy should be performed prior to or during Cycle 4 Week 1 visit, and 
should be repeated every four cycles during the first year, and every 6-8 cycles 
thereafterat the discretion of investigator, until disease progression.  
 
6.3 End of Study Visit:  
 
An End of study visit should be performed within two weeks after last dose or subject’s 
removal decision. Criteria for removal from the study are outlined on Section 5.4. 
 
 Physical Examination 
 Karnofsky performance status 
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 Vital signs (blood pressure, heart rate and temperature) 
 Complete Blood counts with differential and serum chemistries (see Appendix D 
for details). 
 Concomitant medications assessment 
 Adverse events assessment 
 Serum β-hCG for all female subjects. 
 
 
6.4 
Follow-up period 
 
 
Follow-up Visits:  
 
Any adverse eventthat occurred during the study treatment should be monitored by 
follow-up visits until it resolves to grade 1 or less, or until a new therapy is started. In 
case of an unresolved adverse event, a first follow-up visit must be scheduled no later 
than 30 days after end of study visit. Depending on the nature of the adverse events, 
follow-up visits should be scheduled regularly per investigator’s discretion. If a subject is 
taken off the study before disease progression, bone marrow aspiration biopsies should 
be performed as described in Appendix C.Assessments required but not limited, during 
follow-up visits are;  
 
 Physical Examination 
 Karnofsky performance status 
 Vital signs (blood pressure, heart rate and temperature) 
 Complete Blood counts with differential and serum chemistries (see Appendix D 
for details). 
 Concomitant medications assessment 
 Adverse events assessment 
 
Phone follow-ups: 
 
After follow-up visits, subjects should be contacted to gather survival data every six 
months. Secondary malignancy information should also be obtained during phone 
follow-ups. Any secondary malignancy should be recorded and reported to coordinating 
center.   
 
 
 
 
 
 
 
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Table 4: Study Calendar 
 
 
Screening 
Cycle 1 
(Weeks) 
Cycle 2 
(Weeks) 
Cycle 3 
Cycle 
4& 
onward 
End of 
Study 5 
Follow 
up        
Visits 7 
Phone 
Follow-up 8 
W1 
W2 
W3 
W4 
W1 
W2 
W3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Performance Status (KPS) 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
CBC with differential 1 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Serum chemistry 1 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Concomitant Medications 2 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Adverse Event Assessment 2 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Buccal Swab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration Biopsy 3 
X 
 
 
 
 
 
 
 
 
X3 
 
 
 
Lenalidomide Treatment 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Review of pill diary 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Urine β-hCG 6 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Instructions for restricted drugs 2 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Secondary malignancy reporting 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Information 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
See next page for footnotes.  
 
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Footnotes: 
 
1. Lab requirements are outlined in Appendix D. 
2. Continuous collection of data during the study. 
3. Must be performed at baseline, prior to or during Cycle 4 Week 1 visit, and be repeated every four cycles during the first 
year, and every 6-8 cycles thereafter in the discretion of investigator until disease progression. 
4. If Cycle 1 Day 1 date is no more than three days from screening laboratory assessments, then labs performed during 
screening may be used.  
5. Must be performed within two weeks after last dose or subject’s removal decision. 
6. Required for all female subjects.  Must be performed within 24 hours prior to prescribing lenalidomide.   
7. Any adverse event occurred during the study treatment should be monitored by follow-up visits until resolves to grade 1 or 
less, or until a new therapy is started. In case of an unresolved adverse event, first follow-up visit must be scheduled no later 
than 30 days after end of study visit. Depending on the nature of the adverse events, follow-up visits should be scheduled 
regularly per investigator’s discretion. . If a subject is taken off the study before disease progression, bone marrow aspiration 
biopsies should be performed as described in Appendix C of protocol. 
8. Subject must be contacted every six months.
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7 CORRELATIVE/SPECIAL STUDIES 
 
Correlative studies will be performed on all subjects. Specifically, our aims will include: 
 
Aim 1: To determine role of residual AML stem cells on efficacy of Lenalidomide maintenance 
after autotransplant. 
 
Aim 2: To determine molecular markers of clinical response after Lenalidomide maintenance in 
AML 
 
Myeloid malignancies can arise from a small population of quiescent cancer-initiating cells that are 
not eliminated by conventional cytotoxic therapies. Eliminating leukemia stem cells can reduce the 
rates of relapse and increase leukemia free survival. Thus it is important to evaluate the role of 
persistent leukemia stem cells in the efficacy of Lenalidomide maintenance regimens. 
 
 
Aim 1: Analysis of AML stem cells pre and post treatment with lenalidomide and their correlation 
with response (Study co-investigator Dr. Ulrich Steidl is an expert in flow sorting of leukemia stem 
cells and their functional characterization, both in vitro and in vivo). Using high-speed multi-
parameter fluorescence-activated cell sorting we will separate bone marrow progenitors into long-
term and short-term hematopoietic stem cells as well as more committed myeloid, erythroid and 
megakaryocytic progenitors, as performed previously16,17. Sorted cells will have FISH studies done on 
them to estimate the number of stem cells with clonal cytogenetic alterations (Leukemic stem cells). 
Functional assays will also be done on these sorted cells to demonstrate clonogenic potential in 
vitro. A recently discovered marker of AML stem cells and putative predictor of overall survival, 
IL1RAP15, will also be evaluated on AML stem cells and correlated with clinical response.  
 
 
Our preliminary studies indicate that primitive stem cells (LT-HSCs and ST-HSCs) and certain 
progenitors (GMP) are expanded in AML and harbor initiating karyotypic abnormalities and striking 
alterations in DNA methylation with an accumulation of aberrantly hypermethylated loci. 14 
Furthermore, we and others observe that karyotypically abnormal stem cells persist in the bone 
marrow even after morphological complete remission and thus may potentially lead to relapse of 
AML18. These preliminary data lead us to hypothesize that a pool of disease-initiating stem or early 
progenitor cells exists in AML that contains and progressively acquires genetic and epigenetic 
alterations and may persist after conventional treatments.  The study of these AML cells-of-origin 
and disease-initiating cell populations will reveal fundamentally new information about the 
persistence and elimination with lenalidomide maintenance treatment, 
Quantitative and cytogenetic assessment of AML stem and progenitor cells from marrow samples at 
the pretreatment and relapse stages will be performed. Karyotypic, transcriptomal, as well as 
methylomic analysis of these cells will be conducted to assess clonality and epigenetic profile . 
Comparison of pretreatment and post treatment samples will demonstrate whether a decrease in 
clonal AML stem cells correlates with clinical response. We will also determine whether persistence 
of clonal stem cells in responders correlates with a risk of future relapse. 
 
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Also, a recently discovered marker of AML stem cells, IL1RAP2, will be evaluated on bone marrow 
aspirate cells, in combination with other known stem cell markers. IL1RAP expression on phenotypic 
stem cells and the frequency/kinetics of such cells upon treatment will be correlated with clinical 
outcomes. 
 
Aim 2: Molecular markers of relapse and remission: 
 
a. Whole transcriptome and exome sequencing of AML bone marrow stem and progenitors 
and correlation with response. Bone marrow aspirates will be used for these studies. Bone 
marrow stem cells will be sorted and RNA and DNA will be isolated. Sequencing libraries will 
be generated and subjected to massive parallel sequencing using an Illumina HiSeq2000 
instrument.. The transcriptome patterns will be correlated with response. In addition to 
gene expression patterns, this study will also correlate mutations and single nucleotide 
polymorphisms (from exome sequencing) with response to lenalidomide. Somatic mutations 
will be identified by comparison of marrow and germline (toenail clippings or cheek swabs) 
samples. 
 
b. Methylome profiling and clinical response: DNA methylation has been shown to have 
clinical relevance and can be used to define AML patients into prognostic subgroups.19,20 
DNA isolated from AML stem and progenitor cells will be used for global methylome analysis 
as done previously.21,22 Methylation patterns will be correlated with response and overall 
survival. 
 
 
A bone marrow (BM) aspirate will be performed within the framework of the routine 
staging as outlined in Section 6.2. An extra tube of 10cc will be sent within 24 hours to the 
Albert-Einstein College of Medicine Department of Molecular Biology Laboratory where 
they will be processed and centrally analyzed. A detailed description of specimen collection, 
handling and shipping can be found in Appendix C. 
 
In addition to bone marrow aspiration buccal swabs with brushes will be done at baseline 
and stored in RNA later solution. RNA/DNA will be isolated from these samples and 
compared to bone marrow samples to determine somatic mutations in AML stem cells. 
 
 
8 
MEASUREMENT OF EFFECT 
 
8.1 Response Assessment 
 
For the purposes of this study, subjects’ bone marrow aspirate and biopsies will be used 
at regular intervals to assess progression. Please see Section 6.2 for the schedule. 
 
       8.2       Survival End Points 
 
Progression-Free Survival 
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Progression free survival (PFS) is defined as the duration of time from starting 
lenalidomide to time of progression. 
 
 
Progressive diseasea is defined by the following: 
 5% myeloblasts on bone marrow aspirate and biopsy. 
 
Abbreviations: CR, complete response; DFS, disease-free survival. 
aAll relapse categories require two consecutive assessments made at anytime before 
classification as relapse or disease progression and/or theinstitution of any new therapy. 
 
Event-free survival (EFS): The definition of an event is 1) disease progression or 2) death 
from any cause. EFS is the time from stem cell transplant until an event as defined 
above has occurred. 
 
TTP (Time to Progression): This is the time from start of treatment to 
diseaseprogression with deaths owing to causes other than progressionnot counted, but 
censored. This is a helpful method toassess the durability of treatment benefit. 
 
Overall survival (OS) is defined as the time from transplant until death of any cause. 
 
 
 
9. DATA REPORTING  
 
9.1 Definitions 
 
Adverse Event:An Adverse Event (AE) is defined as any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product and that 
does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of lenalidomide whether 
or not considered related to lenalidomide. 
During clinical trials, adverse events can be spontaneously reported or elicited during open-
ended questioning, examination, or evaluation of a subject. (In order to prevent reporting 
bias, subjects should not be questioned regarding the specific occurrence of one or more 
adverse events.) 
AEs will be recorded in the case report form for the duration of the trial, regardless of 
whether or not the event(s) are considered related to trial medication. All AEs considered 
related to trial medication will be followed until resolution even if this occurs post-trial. 
 
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Serious adverse event (SAE) 
An adverse event occurring at any dose that results in any of the following outcomes 
(CFR 312.32): 
 death 
 a life-threatening adverse drug experience 
 inpatient hospitalization or prolongation of existing hospitalization excluding  those 
for study drug administration, transfusional support, disease staging/re-staging 
procedures, bone marrow biopsy or placement of an indwelling catheter, unless 
associated with other serious events. 
 persistent or significant disability or incapacity, 
 congenital anomaly / birth defect.  
 
The definition of serious adverse event (experience) also includes important medical event. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening orresult indeath or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These should also usually be considered serious.  Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. A new diagnosis of cancer during the course of treatment 
should be considered an important medical event. 
 
The definition of “related” being that there is a reasonable possibility that the drug caused 
the adverse experience. 
 
Unexpected Adverse Event 
An adverse event that is not mentioned in the Investigator's Brochure or package insert or 
the specificity or severity of which is not consistent with the investigator's brochure or 
package insert. 
 
Life-threatening 
Any adverse drug experience that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred.  It does not include 
a reaction that, had it occurred in a more severe form, might have caused death. 
 
Adverse events (AEs) will use the descriptions and grading scales found in the revised 
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Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
 
 
9.2 Determination of reporting requirements 
 
Steps to determine if an adverse event is to be reported in an expedited manner: 
 
Step 1:Identify the type of event using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0. The CTCAE provides descriptive terminology and a grading 
scale for each adverse event listed. A copy of the CTCAE can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE that provides help for classifying and locating terms. All 
appropriate treatment locations should have access to a copy of the CTCAE. 
 
Step 2:Grade the event using the NCI CTCAE. 
 
Step 3: Determine whether the adverse event is related to the protocol 
therapy(lenalidomide). 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 consideredunexpected, for expedited reporting purposes only, when 
either the type of event is NOTlisted in section 2.5or in drug-insert.  
 
Step 5:Review the ”Additional instructions, requirements, and exceptions for this 
protocolspecific requirements for expedited reporting of specific adverse events that 
require specialmonitoring. 
 
Step 6: Determine if the protocol treatment given prior to the adverse event included 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents. 
 
 
9.3 Reporting methods 
 
Adverse event log form (using Montefiore-Einstein AE form) should be faxed or emailed to 
the Montefiore Medical Coordinating Center.  
 
9.4 When to report an event in an expedited manner 
 
This trial will be monitored by the Albert Einstein Cancer Center Data Safety Monitoring 
Committee (AECC DSMC). Data monitoring plan is provided in Section 11.1. 
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Follow guidelines in section 9.5 regarding criteria that required reporting of adverse events 
that required require 24-hour notification. 
 
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 must be reported on an 
expedited adverse event report form. 
 
9.5 Expedited reporting  
 
This section outlines adverse events that require expedited reporting.  
 
 
The following be reported as a SAE: 
 
 Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are Unexpected 
and Possibly, Probably or Definitely Related/Associated with  lenalidomide. 
 
 ALL Grade 4 (life threatening or disabling) Events – Unless expected AND 
specifically listed in protocol as not requiring reporting (see section 9.8). 
 
 ALL Grade 5 (fatal) Events – When participant is enrolled and actively participating 
in the trial OR when event occurs within 30 days of the last study intervention. 
 
MEDWATCH 3500A form will be used to report SAEs to Montefiore Medical Coordinating 
Center and to Celgene Corporation for this study.  
 
 
Expedited AE reporting timelines: 
 
24 Hours; 5 calendar days – The investigator must initially report the AE within 24 hours of 
learning of the event followed by a completed  AE report within 5 calendar days of the 
initial 24-hour report. 
 
10 calendar days – A complete AE report on the AE must be submitted within ten 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 (Section 9.8) 
 
Hospitalizations are defined as lasting 24 hours or longer and these events must be 
reported via an expedited manner. 
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Any event that results in persistent or significant disability/incapacity, congenitalanomaly, 
or birth defect must be reported via an expedited AE mechanism. 
 
 
Additional instructions, requirements and exceptions for this protocol: 
 
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”. 
 
9.6 Reporting Second Primary Malignancies (SPMs) 
 
SPMs are considered events of interest and should be included as part of the assessment of 
adverse events throughout the course of the study. Investigators are to report any second 
primary malignancies as serious adverse events regardless of causal relationship to 
lenalidomide, occurring at any time for the duration of the study. For all subjects who 
develop second primary malignancies, sites will be required to submit all diagnostic reports 
(e.g. pathology, cytogenetics, flow cytometry results) from the indication diagnostic 
confirmation samples submitted at screening and all reports for the tumor samples from 
the SPM diagnosis. For SPMs diagnosed at another institution (outside the investigational 
site) sites are to make every effort to obtain these reports for the SPM confirmation. 
 
9. 7 Reporting Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on lenalidomide, or 
within 30 days of the subject’s last dose of lenalidomide, are considered immediately 
reportable events. Lenalidomide is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Montefiore Medical 
Center Coordinating Center AND Celgene Drug Safety immediately by facsimile, or other 
appropriate method, using the Pregnancy Initial Report Form, or approved equivalent form. 
Local IRB should be notified per institutional guidelines. The female subject should be 
referred to an obstetrician-gynecologist, preferably one experienced in reproductive toxicity 
for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Montefiore Medical Center Coordinating Center  AND Celgene Drug Safety 
immediately about the outcome of the pregnancy (either normal or abnormal outcome) 
using the Pregnancy Follow-up Report Form, or approved equivalent form. If the outcome 
of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets 
any of the serious criteria, it must be reported as an SAE to Montefiore Medical Center 
Coordinating Center AND Celgene Drug Safety immediately by facsimile, or other 
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appropriate method, within 24 hours of the Investigator’s knowledge of the event using 
MEDWATCH 3500A form.  
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 30 days that the Investigator suspects 
is related to the in utero exposure to lenalidomide should also be reported to Montefiore 
Medical Center Coordinating Center AND Celgene Drug Safety immediately by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event 
using MEDWATCH 3500A form. 
 
 
9.8 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, certain AEs/grades are exceptions to the Expedited Reporting 
Guidelines and do not require reporting in an expedited manner. The following AEs (Table 
5) must be reported through the routine reporting mechanism (Section 9.1): 
 
Table 5:Expedited Adverse Event Reporting Exclusions 
 
 
CTCAE Category 
 
Adverse Event 
 
Grade 
Hospitalization
/ Prolongation 
of 
Hospitalization 
 
Attribution 
 
Comments 
Blood and 
lymphatic 
system 
Anemia 
3-4 
n/a 
Lenalidomide lenalidomide produces expected 
myelosuppression. 
Blood and 
lymphatic 
system 
Neutropenia 
3-4 
n/a 
Lenalidomide As above; report only if longer 
than 15 days unless related to 
relapsed AML 
Blood and 
lymphatic 
system 
Thrombocytop
enia 
3-4 
n/a 
Lenalidomide As above; report only if longer 
than 15 days unless related to 
relapsed AML 
 
 
9.9 Responsibilities of Participating Sites 
 
Adverse events will be reported to each participating institution according to 
protocolguidelines and local policies and procedures governing the local Institutional 
Review 
Board. 
 
A principal Investigator in a participating institution is required to notify Institutional Review 
Board (IRB) of a serious adverse event according to institutional policy. 
 
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A copy of all SAE’s as defined in section 9.1 should be faxed to the Coordinating Center, 
Montefiore Medical Center within two working days by the participating site. All Events 
described in protocol sections 9.6 and 9.7 must be reported via an expedited AE 
mechanism.  
 
Participating study sites should NOT report SAEs to the FDA.  Rather, participating sites 
should report SAEs to the primary study site, Montefiore Medical Center and to Celgene. 
The primary site will be responsible for reporting to FDA. 
 
 
9.10 Responsibilities of the Coordinating Center (Montefiore Medical Center) and 
CelgeneCorporation.  
 
The Coordinating Center (Montefiore Medical Center) will maintain records andprovide 
reports to Celgene Corporation for the following Adverse Experiences:  
 
1. All serious, unexpected, adverse events,  
2. Any significant increase in the frequency of serious expected adverse events, and  
3. An annual progress report including number of patients accrued, date on study, date 
off study, vital status (alive/dead and date alive/dead). 
 
Celgene Corporation willsupply study drug, lenalidomide free of charge.  
 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 Study Design/Endpoints 
 
The aim of this proposal is to provide an accurate estimate of the two-year relapse free 
survival rate for elderly AML patients treated with lenalidomide maintenance after 
autologous stem cell transplantation. With about 30 patients, the study will be able to 
estimate the two year relapse free survival  rate with not more than 9% standard error(i.e., 
if the observed rate is 40%, the 95% CI will be (23%, 56%). In addition, our study will have 
over 80% power to conclude that the two year relapse  rate is significantly reduced when 
patients are treated with lenalidomide, assuming 60% and 90% patients will relapse with 
and without lenalidomide, respectively. The observed relapse free survival rate will be 
calculated along with its 95% CI. A one sample test on proportion will be used to detect if 
the relapse free survival rate with lenalidomide is significantly higher than that without the 
treatment (relapse rate is expected to be >95%).Secondary analysis including Kaplan-Meier 
analysis  on  overall survival. 
 
10.2 
Sample Size/Accrual Rate 
 
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The primary and coordinating site will be the Montefiore-Einstein Cancer Center (MECC). 
The Bone Marrow Transplantation team at MECC sees on average 15 patients per year that 
would meet the eligibility criteria for the study.  
 
We anticipate an annual accrual of 8 patients. The projected time for completion of the 
study is 45 months. Should the accrual be less than 8 patients per twelve month period from 
the start of activation of the protocol, we will be actively approaching other sites to 
participate in the study. Montefiore is a founding member of the Tri-State Transplant 
Consortium as well as a member of the Blood and Marrow Transplant Clinical Trials 
Network.  Both of these cooperative groups  may be utilized as sources of collaboration to 
boost accrual. 
 
 
11 Data Management and Regulatory Requirements: 
 
Data on toxicities and patient outcomes will be collected at the individual participating 
institution treating the patient on protocol. Every 4 weeks the collected data will be submitted 
to the Montefiore-Einstein Cancer Center Research Study Coordinator Lawrence Almanzar. 
Data submitted as Case Report Forms (CRF)will be submitted by participating institutions for 
central data management to the Montefiore-Einstein Cancer Center Research Study 
Coordination Center on a monthly basis, where they will be merged with the other data 
available for each study participant into one master data set. 
 
11.1 Data Safety and Monitoring Plan 
 
During the recruitment and follow up phases of the trial, the Albert Einstein Cancer 
Center Data and Safety Monitoring Committee (DSMC) will monitor data and oversee 
patient safety. The principal investigator will participate in the meetings as a non-voting 
member. The DSMC meets every monthand will review adverse events. DSMC will also 
reviewadherence to protocol and study progresson a quarterly basis. All adverse events 
will be reported, as per policy, to the CCI/IRB. The DSMC will make recommendations 
regarding study performance and continuation. Ira Braunschweig will provide requested 
data to the DSMC to assess progress toward resolving research questions. 
 
In addition, Dr. Ira Braunschweig (PI) will review case report forms (CRFs) and any other 
toxicity data from all patients enrolled in this trial at regular frequent intervals. Biweekly 
conference calls will be conducted between the participating institutions to discuss trial 
patient enrolment, adverse events and protocol adherence.  
 
Each participating investigator will have primary responsibility for the safety of 
individual participants under his/her care and will review the data and safety on an 
ongoing basis. In addition, the independent DSMC will have primary responsibility for 
monitoring the accumulating study data for sign of adverse trends in morbidity / 
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mortality and drug toxicity. 
 
 
11.2 Recruitment and Consent 
 
Patients who are identified by clinicians at the participating sites as being eligible for the 
study will be approached by the local PI or co-PI about their potential participation. An 
informed consent document in English and Spanish will be provided to the patient. The 
investigational nature of the study, its objectives, the procedures and the potential risks 
and benefits involved will be explained to the patient in simple and direct lay language 
avoiding medical terms. The patient and the person taking the consent will sign the 
consent form and a copy of it will be given to the patient. A copy of the consent and the 
protocol will be left in the patient’s chart. 
 
11.3 Patient Protection 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice and 
the applicable regulatory requirements. All research personnel will receive the required 
education and training needed for conducting clinical research related to the protection 
of human subjects and personal health information according to the Institutional 
Review board and the Health Insurance Portability and Accountability Act of 1996 Public 
Law 104-191. As mentioned above, each patient will be assigned a study identification 
number at the time of recruitment. Records will be kept confidential. As this research 
involves a drug, the U.S. Food and Drug Administration (FDA) may inspect the research 
records and medical records as may the Office for Human Research Protections (OHRP) 
and employees fromCelgene Pharmaceutical Co, Ltd. The research study doctors and 
research staff will review medical records and will keep the information private. No 
patient will be identified in any written or verbal report with the following exception: 
the local human research committees of the participating institutions may inspect the 
patient records. All hard copies of information will be stored in locked cabinets, to which 
only senior research personnel has access. The study data files will be stored on 
password protected computers.  
 
 
11.4 Record Retention: 
 
U.S. FDA regulations (21CFR312.62[c] require all records and documents pertaining to 
the conduct of this study and the distribution of investigational drug, including CRFs, 
consents forms, laboratory test results and medication inventory records, must be 
retained by the Principal Investigator for 2 years after marketing application approval. If 
no application is filed, these records must be kept 2 years after the investigation is 
discontinued and the FDA and the applicable local health authorities are notified. 
 
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11.5 Study Monitoring: 
 
Site visits can be conducted by an authorized representative of the PI, Dr. Ira 
Braunschweig to inspect study data, subjects’ medical records, and CRFs in accordance 
with ICH and GCP guidelines.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX A 
 
Performance Status Criteria 
 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
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APPENDIX B – FORM 1 (REGISTRATION AND ELIGIBILITY) 
 
SUBJECT Initials: _____   
MR# ________________  
DOB: _________  
 
CENTER:______________ 
Date: ______________ 
 
Treating Physician: ______________________________ 
 
“A Phase I/II study of lenalidomide maintenance after autologous stem cell transplant for 
elderly patients with Acute Myeloid Leukemia (AML).” 
 
 
Inclusion Criteria:  
The answers to the following questions must be YES in order for the patient to be eligible.  
YES 
NO 
3.1.1. Patient has a confirmed diagnosis of non-M3 AML. Antecedent MDS is acceptable. 
 
 
3.1.2. Post autologous Stem Cell Transplant Bone marrow biopsy core that is consistent with 
morphologic remission. 
 
 
3.1.3. Agebetween 60and 80years old. 
 
 
3.1.4. Patient received induction and consolidation chemotherapy, and autologous stem cell transplant 
for AML. 
 
 
3.1.5.Life expectancy of greater than 12 months. 
 
 
3.1.6. Karnofsky Performance Status 70 or greater (see Appendix A) 
 
 
3.1.7. Patients have normal organ and marrow function as defined below: 
- 
Leukocytes ≥2,000/mcL  
- 
Absolute neutrophil count≥ 1,000/mcL  
- 
Platelets≥ 75,000/mcL  
- 
Total bilirubin≤4 X institutional upper limit of normal unless 2nd to Gilbert’s disease 
- 
AST(SGOT) and ALT(SGPT)≤ 4 X institutional upper limit of normal 
- 
Creatinine<1.5 X institutional upper limit of normal ORcreatinine clearance≥ 30 mL/min/1.73 m2
 
for patients with creatinine levels above institutional normal. 
 
 
3.1.8 Able to take aspirin, or warfarin, or low molecular weight heparin as prophylactic anticoagulation. 
 
 
3.1.9.Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.1.10 Patient will be registered into the mandatory RevAssist® program and be willing and able to 
comply with the requirement of RevAssist®. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Exclusion Criteria:  
The answers to the following questions must be NO in order for the patient to be eligible.  
 
YES 
 
NO 
3.2.1. Patient received chemotherapy or radiotherapy within 2 weeks prior to entering the study or has 
not recovered from adverse events due to agents administered more than 4 weeks earlier. 
 
 
3.2.2 Patient received another investigational agent after post autologous stem cell transplant. 
 
 
3.2.3 Patient will be receiving another investigational product during the study. 
 
 
3.2.4 Patient who is growth factor or transfusion dependent. 
 
 
3.2.5Patient has CNS leukemia. 
 
 
3.2.6Patient has a history of allergic reactions attributed to thalidomide orlenalidomide. 
 
 
3.2.7 Patient has a history of erythema nodosum, characterized by a desquamating rash while taking 
thalidomide or similar drugs. 
 
 
3.2.8History of metastatic malignancy. 
 
 
3.2.9Presence of uncontrolled illness including, but not limited to ongoing or active infection, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. Patients must not have suffered recent (< 6 months) myocardial infarction, 
unstable angina, uncontrolled hypertension, or difficult to control cardiac arrhythmias. 
 
 
3.2.10 Evidence of uncontrolled Congestive Heart Failure (CHF). 
 
 
3.2.11Active Hepatitis B as defined by Hepatitis B surface antigen positivity, unless able to start dual 
anti-HepB therapy, or already on dual anti-HepB therapy 
 
 
3.2.12Patientis positive for Hepatitis B core antibody, but negative for the hepatitis B surface antigen, 
and is on lamivudine 100 mg daily until at least 3 months post-transplant 
 
 
3.2.13Patient is positive for HIV or HTLV-1. 
 
 
3.2.14 Patient is woman of childbearing potential (defined as a sexually mature woman who has not 
undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive 
months).  
 
 
3.2.15 Patient is a man who agreed not to father a child and agreed to use a latex condom during any 
sexual contact with women of childbearing potential while taking lenalidomide and for 4 weeks after 
therapy is stopped, even if they have undergone a successful vasectomy. 
 
 
 
Fax Registration Form to: Montefiore-Einstein Coordinating Center (see cover page) 
To be completed by Coordinating Center and faxed back to Site: 
 
Patient Eligible:  
 
Yes  
No  
 
 
 
 
Patient ID :  
 
 
 
 
 (this should be used as patient identifier) 
 
 
___ ___________________________ 
 
 
____________  
 
 
 
 
 
 
 
 
Coordinating Center Staff Signature 
 
 
Date 
 
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APPENDIX C 
 
HANDLING AND SHIPPING OF BONE MARROW SPECIMENS: 
 
HANDLING AND SHIPPING OF BONE MARROW AND OTHER SPECIMENS FOR CORRELATIVE 
STUDIES: 
 
 
All specimens for correlative studies must be labeled with the patient’s code number, which will 
be assigned by the Data Management Office, and should not bare the patient’s identity.  The 
specimens must be kept at room temperature and sent by fedex to: 
 
Amit Verma, MD 
Albert Einstein College of Medicine, 
1300 Morris Park Ave, Chanin 302B 
Bronx, NY 10461 
Tel : 718 430 8761 
Fax: 718 430 8702  
amit.verma@einstein.yu.edu 
 
 
Bone Marrow Aspirate: 10cc of heparinized marrow aspirate will be required.  We will perform 
flow cytometry and genome wide sequencing from these samples. RNA and DNA from patient 
bone marrow specimens at baseline will be sequenced to correlate expression patterns and 
mutational patterns with response. Three unstained slides containing bone marrow aspirate 
will be required for further studies 
 
1. Prepare a conical tube for the bone marrow specimen by adding 0.5 ml of preservative-free 
sodium heparin (400 U/ml stock solution) to a 50 ml polypropylene conical tube. 
2. Collect 10 cc, if possible of bone marrow using a needle/syringe with preferably citrate or if 
citrate is not available, then with heparin, and transfer it to the tube containing heparin. 
3. Add RPMI-1640, at 1:1 ratio (i.e.; 20 ml bone marrow plus 20 ml RPMI-1640).   
4. Invert the tube to mix thoroughly and minimize clotting potential 
5. Screw the cap on the tube, and tightly wrap the lower edge of the cap with parafilm. 
 
 
Peripheral Blood: If the bone marrow aspirate cannot be obtained then we will require 3 green 
top tubes, with 8 cc of blood each. Mononuclear cells from patient’s peripheral blood will be 
purified by Ficoll-Hypaque sedimentation and these cells used for flow cytometry and sorting. 
These samples will also be used for interphase FISH studies (if abnormal cytogenetics found at 
diagnosis). Cells will be frozen for future RNA extraction to perform gene expression studies. 
 
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Buccal swabs: Buccal swabs with brushes will be done at baseline and stored in RNA later 
solution. RNA/DNA will be isolated from these samples and compared to bone marrow samples 
to determine somatic mutations in AML stem cells. 
 
 
Banking of Samples: Peripheral blood, bone marrow, cell lysates, and cell products obtained 
from the previously mentioned samples will be stored for subsequent research related to this 
project. 
 
6. * Please page or call Dr. Amit Verma (phone: 646-468-1055) to notify him that a shipment 
has been sent and for any questions. Sodium heparin (400 U/ml stock solution) to a 50 ml 
polypropylene conical tube. 
7. Collect 10 cc, if possible of bone marrow using a needle/syringe with preferably citrate or if 
citrate is not available, then with heparin, and transfer it to the tube containing heparin. 
8. Add RPMI-1640, at 1:1 ratio (i.e.; 20 ml bone marrow plus 20 ml RPMI-1640).   
9. Invert the tube to mix thoroughly and minimize clotting potential 
10. Screw the cap on the tube, and tightly wrap the lower edge of the cap with parafilm. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix D –Required Laboratory Parameters 
 
 
Complete Blood Count (CBC) with differential:  
 
White Blood Cells (WBC) count 
Red Blood Cells (RBC) count 
Hemoglobin 
Platelet count  
Neutrophil (%) 
Lymphocyte (%) 
Monocyte (%) 
Eosinophil (%) 
Basophil (%) 
Absolute Neutrophil count 
Absolute Lymphocyte count 
 
 
Biochemistries: 
 
Sodium 
Potassium 
Chloride 
C02 
Glucose 
Urea Nitrogen 
Calcium 
Creatinine 
Albumin 
Bilirubin (total) 
Bilirubin (direct) 
Alkaline Phosphatase 
SGOT 
SGPT 
Total Protein 
 
Clinical significant lab results must be graded and recorded in Adverse Event Page.  
 
 
 
 
 
 
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Appendix E – Cockcroft-Gault estimation of CrCl:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix F: Risks of Fetal Exposure, Pregnancy Testing Guidelines, Acceptable Birth 
Control Methods and Precautions. 
 
Risks Associated with Pregnancy 
 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor 
has the effect of the lenalidomide on human eggs and sperm.  Lenalidomide is structurally 
related to thalidomide.  Thalidomide is a known human teratogenic active substance that 
causes severe life-threatening birth defects.  An embryo-fetal development study in animals 
indicates that lenalidomide produced malformations in the offspring of female monkeys 
who received the drug during pregnancy.  The teratogenic effect of lenalidomide in humans 
cannot be ruled out.  Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
 
All study participants must be registered into the mandatory RevAssist® program, and be 
willing and able to comply with the requirements of RevAssist®.Criteria for females of 
childbearing potential (FCBP)This protocol defines a female of childbearing potential as a 
sexually mature female who:  
 
1) has not undergone a hysterectomy or bilateral oophorectomy or  
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 consecutive months). 
 
 
Contraception 
 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual intercourse during the following time periods related to this study:  
 
1) for at least 28 days before starting lenalidomide;  
2) throughout the entire duration of lenalidomide treatment;  
3) during dose interruptions; and  
4) for at least 28 days after lenalidomide discontinuation.  
 
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) 
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- 
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.  
 
 
Pregnancy testing 
 
Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential 
who commit to complete abstinence, as outlined below. 
 
 
Before starting lenalidomide 
 
Female Patients: 
 
FCBP must have negative pregnancy test 24 hours prior to prescribing lenalidomide.  The 
patient may not receive lenalidomide until the Investigator has verified that the results of 
these pregnancy tests are negative. 
 
Male Patients: 
 
Must agree to practice complete abstinence or agree to use a condom during sexual contact 
with pregnant females or females of childbearing potential throughout the entire duration 
of lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.   
 
 
The investigator must ensure that: 
 
• Females of childbearing potential comply with the conditions for pregnancy risk 
minimization, including confirmation that she has an adequate level of understanding. 
• Females NOT of childbearing potential acknowledge that she understands the hazards 
and necessary precautions associated with the use of lenalidomide. 
• Male patients taking lenalidomide acknowledge that he understands that traces of 
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lenalidomide have been found in semen, that he understands the potential teratogenic risk 
if engaged in sexual activity with a female of childbearing potential or pregnant female, and 
that he understands the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a female of childbearing potential or pregnant female.   
 Subject is continuing to use two reliable methods of birth control at each visit during the 
time that birth control is required.   
• If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide 
must be immediately discontinued. 
• Pregnancy testing and counseling must be performed if a patient misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide treatment must be 
temporarily discontinued during this evaluation. 
• Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after lenalidomide discontinuation. 
• male subjects must practice complete abstinence or use a condom during sexual contact 
with pregnant females or females of childbearing potential throughout the entire duration 
of lenalidomide treatment, during dose interruptions and for at least 28 days following 
lenalidomide discontinuation, even if he has undergone a successful vasectomy.   
• If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
• Male patients are instructed not to donate semen or sperm during therapy or for at 
least 28 days following discontinuation of lenalidomide. 
 
 
Additional precautions 
 
• Subjects should be instructed never to give lenalidomide to another person. 
• Subjects should not donate blood during therapy and for at least 28 days following 
discontinuation of lenalidomide. 
• Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of 
therapy.  
• Any unused lenalidomide must be returned as instructed through RevAssist program. 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix G – Drug insert and Full Prescribing Information  
 
Most recent drug insert; highlights and full prescribing information for lenalidomide are 
available online at: 
 
http://www.revlimid.com/docs/Revlimid-Full-PI.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix H: FDA MEDWATCH 3500A Form: 
 
 
FDA MedWatch 3500A Form is available online at: 
 
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm103114.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix I : NCI CTCAE Version 4.0 
 
 
 
Toxicity will be scored using NCI  CTC Version 4.0 for toxicity and adverse event reporting.  A 
copy of the NCI CTC Version 4.0 can be downloaded from the CTEP homepage: 
(http://ctep.info.nih.gov).   
 
All appropriate treatment areas have access to a copy of the CTC Version 4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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