Conditions: Alkylating Agent-Related Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
This phase II trial studies how well lenalidomide works in treating patients with acute myeloid leukemia that have had a decrease in or disappearance of signs and symptoms of cancer, although cancer still may be in the body and may be likely to come back or spread. Biological therapies, such as lenalidomide, use substances made from living organisms that may kill cancer cells by blocking blood flow to the cancer and by stimulating white blood cells to kill the cancer cells.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess relapse-free survival (RFS) of patients with acute myeloid leukemia (AML) treated with lenalidomide maintenance therapy after achieving remission.

SECONDARY OBJECTIVES:

I. To assess overall survival (OS) of patients with AML treated with lenalidomide maintenance.

II. To assess event-free survival (EFS) of patients with AML treated with lenalidomide maintenance.

III. To assess the duration of remission (CRd) of patients with AML treated with lenalidomide maintenance.

IV. To assess toxicity and safety of lenalidomide maintenance in patients with AML.

V. To assess the effects of lenalidomide maintenance on natural killer (NK) cell modulation and dynamics of minimal residual disease and their relationship to outcomes.

OUTLINE:

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-12 months.

Arms:
arm 1: Patients receive lenalidomide PO QD on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Lenalidomide
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO

Protocol document:
Prot_SAP_000.pdf: 
Protocol 2014-0116 
January 18, 2018 
1 
 
 
 
Phase II Study of Lenalidomide Maintenance in Patients with High Risk AML 
in Remission 
 
 
 
Principal Investigator 
Tapan Kadia, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Co-Investigator: 
Jorge Cortes, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Study Product: 
Lenalidomide 
Protocol Number: 
2014-0116 
Coordinating Center: 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2014-0116 
January 18, 2018 
2 
 
 
 
PHASE II Study of Lenalodimide Maintenance in Patients with High Risk AML in 
Remission 
 
1.0 
OBJECTIVES 
 
2.0 
BACKGROUND 
 
3.0 
PATIENT SELECTION 
 
4.0 
TREATMENT PLAN 
 
5.0 
PATIENT EVALUATION 
 
6.0 
DOSING DELAYS / DOSE MODIFICATIONS 
 
7.0 
AGENT FORMULATION AND PROCUREMENT 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
9.0 
MEASUREMENT OF EFFECT 
 
10.0 
REPORTING REQUIREMENTS 
 
11.0 
REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2014-0116 
January 18, 2018 
3 
 
 
 
 
1.0 OBJECTIVES 
 
1.1 Primary objective: 
To assess relapse-free survival (RFS) of patients with acute myeloid leukemia 
(AML) treated with lenalidomide maintenance therapy after achieving remission.  
 
1.2 Secondary objective 
 To assess overall survival (OS) of patients with AML treated with 
lenalidomide maintenance. 
 To assess event-free survival (EFS) of patients with AML treated with 
lenalidomide maintenance. 
 To assess the duration of remission (CRd) of patients with AML treated 
with lenalidomide maintenance. 
 To assess toxicity and safety of lenalidomide maintenance in patients with 
AML. 
 To assess the effects of lenalidomide maintenance on NK cell modulation 
and dynamics of minimal residual disease and their relationship to 
outcomes.  
 
2.0 BACKGROUND 
 
2.1 Acute Myeloid Leukemia (AML) 
 
AML is the cause of approximately 1.2% of all cancer deaths in the US with an annual incidence 
rate of 2.2 per 100,000 and approximately 10,000 new cases per year. Age-adjusted incidence 
ranges from 1 per 100,000 in people < 20 years to > 10 per 100,000 in the elderly. AML 
represents approximately 90% of all acute leukemias in adults, and accounts for about 25% of all 
cases of leukemia diagnosed in the Western hemisphere.1,2 AML is a clonal myelopoietic stem 
cell disorder characterized by the accumulation of neoplastic cells in the bone marrow and in the 
peripheral circulation. Current induction chemotherapy protocols combining cytarabine and an 
anthracycline administered as first-line treatment induce complete remissions in a majority (55% 
to 75%) of patients. Standard consolidation therapy with high doses of cytarabine leads to 
improved survival in younger patients.  Overall, up to 70% of patients can be expected to 
relapse, so that only about 20-30% attain long-term disease-free survival. 
 
Two major problems in the treatment of AML remain: primary resistant/refractory disease and 
high risk of relapse/recurrent disease.  While newer drug combinations and higher doses of 
therapy may begin to address upfront resistant disease, there are very few options, with the 
exception of allogeneic stem cell transplantation, for long term maintenance of remission after 
consolidation.  In acute lymphoblastic leukemia (ALL), maintenance therapy has become a 
standard part of treatment and has contributed to long term durable remissions and cures.  
Results of studies of maintenance therapy in AML have been mixed. In early studies by ECOG3,4 
and CALGB5, prolonged maintenance following a short consolidation failed to significantly 
prolong CR duration or overall survival.  On the other hand, studies from the German AML 
study group randomized patients after consolidation to prolonged maintenance vs. no further 


Protocol 2014-0116 
January 18, 2018 
4 
 
 
 
therapy.  Patients who received prolonged maintenance after consolidation had improved 
relapse-free survival, and this effect was more pronounced in higher risk patients.6-8.  
Lowenberg, et. al.9 randomized patients in CR after 1 cycle of consolidation to receive 8 monthly 
cycles of low dose araC maintenance vs. no further therapy.  Patients in the maintenance arm had 
improved recurrence free survival, but not OS.9  Finally, SWOG randomized patients in CR who 
were not eligible for an allogeneic stem cell transplant to receive one cycle of intensification 
followed by maintenance or intensification alone.  Patients receiving maintenance had improved 
disease free survival, but not OS.10  One of the shortcomings of these earlier approaches is that 
the therapeutic agents used in maintenance were often the same or similar agents that were used 
in induction and consolidation.  Residual leukemia cells which would have survived the 
induction therapy and are the source of relapses would be presumably resistant to ‘more of the 
same’.  Newer therapies, employing different mechanisms of action are less likely to be cross-
resistant to the initial cytotoxic induction regimens.  For example, Brune et. al.11 studied an 
immunotherapy approach investigating an IL2 + histamine maintenance therapy.  A cohort of 
320 patients in CR1 or greater were randomized to receive 10 cycles of IL2+histamine vs. no 
treatment.  At 3 years, the maintenance arm had a significant improvement in leukemia-free 
survival.11  Lenalidomide, a non-cytotoxic drug with activity in AML, has multiple unique 
mechanisms of action including immune modulation and alteration of intracellular signaling and 
may be an ideal candidate for long term maintenance in this disease. 
 
As a background, we know that AML patients (young and old) with: (1)primary refractory 
disease, (2)adverse cytogenetics, (3)FLT3 positive disease, (4)antecedent hematologic disorder, 
and (in relapsed patients) (5) short CR1 duration have a high risk of relapse, despite effective 
induction and consolidation therapy.  If these patients are not candidates for transplant, we are 
often beholden to “watch and wait” until their leukemia relapses.  In this setting, a long term, low 
intensity, easy to administer, and effective antileukemia treatment needs to be developed.  
Lenalidomide has been shown to have single-agent activity in AML as a higher dose induction 
followed by a longer term, lower dose maintenance strategy.12  Lenalidomide, in the treatment of 
myelodysplastic syndrome MDS and multiple myeloma (MM) has been shown to be safe during 
continuous, long term administration (MM, MDS) as well as in a maintenance strategy (MM).  
 
2.2 Lenalidomide in AML 
 
Lenalidomide, a derivative of thalidomide is currently approved for the treatment of multiple 
myeloma (MM) and MDS (myelodysplastic syndrome), but has been shown to have single-agent 
activity in AML as an induction – maintenance strategy.  In a phase II trial of older patients (age 
≥ 60 yrs) with untreated AML, lenalidomide was given at a high ‘induction’ dose, of 50 mg 
orally daily on a 28 day cycle (for up to 2 induction cycles), followed by a lower ‘maintenance’ 
dose of 10 mg orally daily for up to 12 months.  The CR/CRi rate was 30% overall and 53% in 
patients who completed all of the high-dose therapy.12  The median CR duration was 10 months 
(1 – 17+ months).  The treatment was well tolerated in this cohort of patients, with the most 
common grade 3-4 toxicities being myelosuppression and infection.  Based on this data of single 
agent activity in AML and its longer-term use in AML, MDS, and MM we propose to use this as 
a maintenance strategy for higher-risk patients who are in remission after induction/consolidation 
therapy.  The exact mechanism of action of lenalidomide is not known, but may involve 
immunomodulatory activity and reversal of an immunosuppressive environment present in 


Protocol 2014-0116 
January 18, 2018 
5 
 
 
 
malignancy.   
 
 
2.3 NK Cells as Immunosurveillance in Leukemia 
 
NK cells are an important component of the innate immune system and play a key role in the 
immune surveillance of cancer, including AML.13-16 NK cells can exert these effects through 
direct cytotoxicity, secretion of cytokines, and by coordinating other immune cells (T-cells, 
dendritic cells) to mount anti-tumor immunity.15,17,18 Although several studies in stem cell 
transplant and adoptive immunity have demonstrated the importance of NK cells in eliminating 
leukemia, immune evasion mechanisms or defects in autologous NK cells may thwart this anti-
leukemia effect.15,18  Among its mechanisms of action, lenalidomide has been shown to enhance 
NK cell mediated cytotoxicity by increasing NK cell numbers, increasing secretion of cytokines 
such as interferon gamma, and through enhancing ADCC by increasing IL2 secretion from T-
cells.19-23  Such reconstitution of AML immune-surveillance with lenalidomide in the 
maintenance setting could translate into long-term disease control and a higher cure rate.  This 
study provides us a unique opportunity to study the efficacy of this concept as well as determine 
the in vivo effects of lenalidomide on NK cells in AML patients. 
 
 
2.4 Rationale for studying lenalidomide as maintenance therapy in AML. 
 
Therapy for maintaining longer-term remissions after consolidation therapy in AML patients 
with high-risk disease is a critical need.  Unlike the treatment protocols for ALL, there is no 
current standard for maintenance therapy in AML.  Previous attempts at maintenance therapy in 
AML, utilizing redundant chemotherapy-based protocols have been met with minimal success.  
We therefore propose a clinical trial evaluating low intensity, continuous dosing of lenalidomide 
in patients with high risk AML who have responded to induction/consolidation chemotherapy 
and are not immediately candidates for BMT.  From our own data, the expected relapse free 
survival in this cohort of younger patients with higher risk disease who do not proceed for stem 
cell transplant is 8.5 months.  Approximately 25% of these patients may become eligible for and 
proceed to transplant, but the majority are left without meaningful therapy until relapse. 
 
Based on published data, NK cells are important mediators of immune surveillance, particularly 
in AML.  In addition to affecting direct cytotoxicity of AML blasts, NK cells may also alter the 
cytokine and immune cell (eg. T-lymphocytes) milieu to favor anti-leukemia immunity.  
Lenalidomide has been shown to enhance NK cell activity and numbers – making it an important 
agent to study in a setting of low disease burden (ie. minimal residual disease after 
chemotherapy).  As part of the clinical trial, we also aim to study the effects of lenalidomide on 
NK cell activity – both at baseline (prior to lenalidomide treatment) and at several time points 
during treatment.  This will help us derive more insight into the actions of lenalidomide on NK 
cell activity and how it relates to maintenance of remission in patients with AML. 
 
The rationale for the selected dosing of lenalidomide maintenance is drawn from previous 
experience in chronic dosing of lenalidomide for maintenance strategy.  In the AML experience 
described above, Fehniger, et. al. treated patients in the maintenance phase with 10 mg orally 


Protocol 2014-0116 
January 18, 2018 
6 
 
 
 
daily.  In multiple myeloma maintenance studies,24,25 lenalidomide was dosed at 10 – 15 mg 
orally daily, continuously.  These doses have therefore been shown to be safe and active in a 
long-term dosing strategy. 
 
  
2.5 Lenalidomide 
 
Background  
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.  IMiD® compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
antimetastatic effects.  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.26  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.27  Upregulation of T cell derived IL-2 production is achieved at least in part through 
increased AP-1 activity.28 
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.17  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.  Revlimid is also for the treatment of 
patients with mantle cell lymphoma (MCL)whose disease has relapsed or progressed after two 
prior therapies, one of which included bortezomib. 
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 


Protocol 2014-0116 
January 18, 2018 
7 
 
 
 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 
nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, 
chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
Lenalidomide Description 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure:  
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
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 


Protocol 2014-0116 
January 18, 2018 
8 
 
 
 
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 Error! Reference source not found..  Exposure (AUC) in multiple 
myeloma patients is 57% higher than in healthy male volunteers.  
 
Pharmacokinetic Parameters 
Distribution 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. 
The process exceeds the glomerular filtration rate and therefore is partially or entirely active.  
Half-life of elimination is approximately 3 hours.  
Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly 
known as RevAssist® Program).   
Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   


Protocol 2014-0116 
January 18, 2018 
9 
 
 
 
Packaging 
Lenalidomide will be shipped directly to patients or to the clinic site.   Bottles will contain a 
sufficient number of capsules for one cycle of dosing.    
Labeling 
Lenalidomide supplies are dispensed in individual bottles of capsules.  Each bottle will identify 
the contents as study medication.  In addition, the label will bear Celgene’s name, quantity 
contained and the standard caution statement as follows:  “Caution: New drug - Limited by 
Federal law to investigational use.” Lenalidomide should not be handled by FCBP unless 
wearing gloves.  
The study drug label must be clearly visible.  Additional labels must not cover the Celgene label. 
Receipt of study drug 
The Investigator or designee is responsible for taking an inventory of each shipment of study 
drug received, and comparing it with the accompanying study drug accountability form.  The 
Investigator will verify the accuracy of the information on the form, sign and date it, retain a 
copy in the study file, and return a copy to Celgene or its representative.   
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold.     
Unused study drug supplies 
Celgene will instruct the Investigator on the return or destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the source documents.  
Study drug supplies will be retained at the clinical site pending instructions for disposition by 
Celgene.  Patients will be instructed to return empty bottles or unused capsules to the clinic site.   
Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 


Protocol 2014-0116 
January 18, 2018 
1 
 
 
 
Phase II Study of Lenalidomide Maintenance in Patients with High Risk AML 
in Remission 
 
 
 
Principal Investigator 
Tapan Kadia, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Co-Investigator: 
Jorge Cortes, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Study Product: 
Lenalidomide 
Protocol Number: 
2014-0116 
Coordinating Center: 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2014-0116 
January 18, 2018 
1 
 
 
 
Phase II Study of Lenalidomide Maintenance in Patients with High Risk AML 
in Remission 
 
 
 
Principal Investigator 
Tapan Kadia, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Co-Investigator: 
Jorge Cortes, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Study Product: 
Lenalidomide 
Protocol Number: 
2014-0116 
Coordinating Center: 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2014-0116 
January 18, 2018 
2 
 
 
 
PHASE II Study of Lenalodimide Maintenance in Patients with High Risk AML in 
Remission 
 
1.0 
OBJECTIVES 
 
2.0 
BACKGROUND 
 
3.0 
PATIENT SELECTION 
 
4.0 
TREATMENT PLAN 
 
5.0 
PATIENT EVALUATION 
 
6.0 
DOSING DELAYS / DOSE MODIFICATIONS 
 
7.0 
AGENT FORMULATION AND PROCUREMENT 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
9.0 
MEASUREMENT OF EFFECT 
 
10.0 
REPORTING REQUIREMENTS 
 
11.0 
REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2014-0116 
January 18, 2018 
3 
 
 
 
 
1.0 OBJECTIVES 
 
1.1 Primary objective: 
To assess relapse-free survival (RFS) of patients with acute myeloid leukemia 
(AML) treated with lenalidomide maintenance therapy after achieving remission.  
 
1.2 Secondary objective 
 To assess overall survival (OS) of patients with AML treated with 
lenalidomide maintenance. 
 To assess event-free survival (EFS) of patients with AML treated with 
lenalidomide maintenance. 
 To assess the duration of remission (CRd) of patients with AML treated 
with lenalidomide maintenance. 
 To assess toxicity and safety of lenalidomide maintenance in patients with 
AML. 
 To assess the effects of lenalidomide maintenance on NK cell modulation 
and dynamics of minimal residual disease and their relationship to 
outcomes.  
 
2.0 BACKGROUND 
 
2.1 Acute Myeloid Leukemia (AML) 
 
AML is the cause of approximately 1.2% of all cancer deaths in the US with an annual incidence 
rate of 2.2 per 100,000 and approximately 10,000 new cases per year. Age-adjusted incidence 
ranges from 1 per 100,000 in people < 20 years to > 10 per 100,000 in the elderly. AML 
represents approximately 90% of all acute leukemias in adults, and accounts for about 25% of all 
cases of leukemia diagnosed in the Western hemisphere.1,2 AML is a clonal myelopoietic stem 
cell disorder characterized by the accumulation of neoplastic cells in the bone marrow and in the 
peripheral circulation. Current induction chemotherapy protocols combining cytarabine and an 
anthracycline administered as first-line treatment induce complete remissions in a majority (55% 
to 75%) of patients. Standard consolidation therapy with high doses of cytarabine leads to 
improved survival in younger patients.  Overall, up to 70% of patients can be expected to 
relapse, so that only about 20-30% attain long-term disease-free survival. 
 
Two major problems in the treatment of AML remain: primary resistant/refractory disease and 
high risk of relapse/recurrent disease.  While newer drug combinations and higher doses of 
therapy may begin to address upfront resistant disease, there are very few options, with the 
exception of allogeneic stem cell transplantation, for long term maintenance of remission after 
consolidation.  In acute lymphoblastic leukemia (ALL), maintenance therapy has become a 
standard part of treatment and has contributed to long term durable remissions and cures.  
Results of studies of maintenance therapy in AML have been mixed. In early studies by ECOG3,4 
and CALGB5, prolonged maintenance following a short consolidation failed to significantly 
prolong CR duration or overall survival.  On the other hand, studies from the German AML 
study group randomized patients after consolidation to prolonged maintenance vs. no further 


Protocol 2014-0116 
January 18, 2018 
4 
 
 
 
therapy.  Patients who received prolonged maintenance after consolidation had improved 
relapse-free survival, and this effect was more pronounced in higher risk patients.6-8.  
Lowenberg, et. al.9 randomized patients in CR after 1 cycle of consolidation to receive 8 monthly 
cycles of low dose araC maintenance vs. no further therapy.  Patients in the maintenance arm had 
improved recurrence free survival, but not OS.9  Finally, SWOG randomized patients in CR who 
were not eligible for an allogeneic stem cell transplant to receive one cycle of intensification 
followed by maintenance or intensification alone.  Patients receiving maintenance had improved 
disease free survival, but not OS.10  One of the shortcomings of these earlier approaches is that 
the therapeutic agents used in maintenance were often the same or similar agents that were used 
in induction and consolidation.  Residual leukemia cells which would have survived the 
induction therapy and are the source of relapses would be presumably resistant to ‘more of the 
same’.  Newer therapies, employing different mechanisms of action are less likely to be cross-
resistant to the initial cytotoxic induction regimens.  For example, Brune et. al.11 studied an 
immunotherapy approach investigating an IL2 + histamine maintenance therapy.  A cohort of 
320 patients in CR1 or greater were randomized to receive 10 cycles of IL2+histamine vs. no 
treatment.  At 3 years, the maintenance arm had a significant improvement in leukemia-free 
survival.11  Lenalidomide, a non-cytotoxic drug with activity in AML, has multiple unique 
mechanisms of action including immune modulation and alteration of intracellular signaling and 
may be an ideal candidate for long term maintenance in this disease. 
 
As a background, we know that AML patients (young and old) with: (1)primary refractory 
disease, (2)adverse cytogenetics, (3)FLT3 positive disease, (4)antecedent hematologic disorder, 
and (in relapsed patients) (5) short CR1 duration have a high risk of relapse, despite effective 
induction and consolidation therapy.  If these patients are not candidates for transplant, we are 
often beholden to “watch and wait” until their leukemia relapses.  In this setting, a long term, low 
intensity, easy to administer, and effective antileukemia treatment needs to be developed.  
Lenalidomide has been shown to have single-agent activity in AML as a higher dose induction 
followed by a longer term, lower dose maintenance strategy.12  Lenalidomide, in the treatment of 
myelodysplastic syndrome MDS and multiple myeloma (MM) has been shown to be safe during 
continuous, long term administration (MM, MDS) as well as in a maintenance strategy (MM).  
 
2.2 Lenalidomide in AML 
 
Lenalidomide, a derivative of thalidomide is currently approved for the treatment of multiple 
myeloma (MM) and MDS (myelodysplastic syndrome), but has been shown to have single-agent 
activity in AML as an induction – maintenance strategy.  In a phase II trial of older patients (age 
≥ 60 yrs) with untreated AML, lenalidomide was given at a high ‘induction’ dose, of 50 mg 
orally daily on a 28 day cycle (for up to 2 induction cycles), followed by a lower ‘maintenance’ 
dose of 10 mg orally daily for up to 12 months.  The CR/CRi rate was 30% overall and 53% in 
patients who completed all of the high-dose therapy.12  The median CR duration was 10 months 
(1 – 17+ months).  The treatment was well tolerated in this cohort of patients, with the most 
common grade 3-4 toxicities being myelosuppression and infection.  Based on this data of single 
agent activity in AML and its longer-term use in AML, MDS, and MM we propose to use this as 
a maintenance strategy for higher-risk patients who are in remission after induction/consolidation 
therapy.  The exact mechanism of action of lenalidomide is not known, but may involve 
immunomodulatory activity and reversal of an immunosuppressive environment present in 


Protocol 2014-0116 
January 18, 2018 
5 
 
 
 
malignancy.   
 
 
2.3 NK Cells as Immunosurveillance in Leukemia 
 
NK cells are an important component of the innate immune system and play a key role in the 
immune surveillance of cancer, including AML.13-16 NK cells can exert these effects through 
direct cytotoxicity, secretion of cytokines, and by coordinating other immune cells (T-cells, 
dendritic cells) to mount anti-tumor immunity.15,17,18 Although several studies in stem cell 
transplant and adoptive immunity have demonstrated the importance of NK cells in eliminating 
leukemia, immune evasion mechanisms or defects in autologous NK cells may thwart this anti-
leukemia effect.15,18  Among its mechanisms of action, lenalidomide has been shown to enhance 
NK cell mediated cytotoxicity by increasing NK cell numbers, increasing secretion of cytokines 
such as interferon gamma, and through enhancing ADCC by increasing IL2 secretion from T-
cells.19-23  Such reconstitution of AML immune-surveillance with lenalidomide in the 
maintenance setting could translate into long-term disease control and a higher cure rate.  This 
study provides us a unique opportunity to study the efficacy of this concept as well as determine 
the in vivo effects of lenalidomide on NK cells in AML patients. 
 
 
2.4 Rationale for studying lenalidomide as maintenance therapy in AML. 
 
Therapy for maintaining longer-term remissions after consolidation therapy in AML patients 
with high-risk disease is a critical need.  Unlike the treatment protocols for ALL, there is no 
current standard for maintenance therapy in AML.  Previous attempts at maintenance therapy in 
AML, utilizing redundant chemotherapy-based protocols have been met with minimal success.  
We therefore propose a clinical trial evaluating low intensity, continuous dosing of lenalidomide 
in patients with high risk AML who have responded to induction/consolidation chemotherapy 
and are not immediately candidates for BMT.  From our own data, the expected relapse free 
survival in this cohort of younger patients with higher risk disease who do not proceed for stem 
cell transplant is 8.5 months.  Approximately 25% of these patients may become eligible for and 
proceed to transplant, but the majority are left without meaningful therapy until relapse. 
 
Based on published data, NK cells are important mediators of immune surveillance, particularly 
in AML.  In addition to affecting direct cytotoxicity of AML blasts, NK cells may also alter the 
cytokine and immune cell (eg. T-lymphocytes) milieu to favor anti-leukemia immunity.  
Lenalidomide has been shown to enhance NK cell activity and numbers – making it an important 
agent to study in a setting of low disease burden (ie. minimal residual disease after 
chemotherapy).  As part of the clinical trial, we also aim to study the effects of lenalidomide on 
NK cell activity – both at baseline (prior to lenalidomide treatment) and at several time points 
during treatment.  This will help us derive more insight into the actions of lenalidomide on NK 
cell activity and how it relates to maintenance of remission in patients with AML. 
 
The rationale for the selected dosing of lenalidomide maintenance is drawn from previous 
experience in chronic dosing of lenalidomide for maintenance strategy.  In the AML experience 
described above, Fehniger, et. al. treated patients in the maintenance phase with 10 mg orally 


Protocol 2014-0116 
January 18, 2018 
6 
 
 
 
daily.  In multiple myeloma maintenance studies,24,25 lenalidomide was dosed at 10 – 15 mg 
orally daily, continuously.  These doses have therefore been shown to be safe and active in a 
long-term dosing strategy. 
 
  
2.5 Lenalidomide 
 
Background  
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.  IMiD® compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
antimetastatic effects.  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.26  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.27  Upregulation of T cell derived IL-2 production is achieved at least in part through 
increased AP-1 activity.28 
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.17  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.  Revlimid is also for the treatment of 
patients with mantle cell lymphoma (MCL)whose disease has relapsed or progressed after two 
prior therapies, one of which included bortezomib. 
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 


Protocol 2014-0116 
January 18, 2018 
7 
 
 
 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 
nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, 
chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
Lenalidomide Description 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure:  
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
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 


Protocol 2014-0116 
January 18, 2018 
8 
 
 
 
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 Error! Reference source not found..  Exposure (AUC) in multiple 
myeloma patients is 57% higher than in healthy male volunteers.  
 
Pharmacokinetic Parameters 
Distribution 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. 
The process exceeds the glomerular filtration rate and therefore is partially or entirely active.  
Half-life of elimination is approximately 3 hours.  
Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly 
known as RevAssist® Program).   
Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   


Protocol 2014-0116 
January 18, 2018 
9 
 
 
 
Packaging 
Lenalidomide will be shipped directly to patients or to the clinic site.   Bottles will contain a 
sufficient number of capsules for one cycle of dosing.    
Labeling 
Lenalidomide supplies are dispensed in individual bottles of capsules.  Each bottle will identify 
the contents as study medication.  In addition, the label will bear Celgene’s name, quantity 
contained and the standard caution statement as follows:  “Caution: New drug - Limited by 
Federal law to investigational use.” Lenalidomide should not be handled by FCBP unless 
wearing gloves.  
The study drug label must be clearly visible.  Additional labels must not cover the Celgene label. 
Receipt of study drug 
The Investigator or designee is responsible for taking an inventory of each shipment of study 
drug received, and comparing it with the accompanying study drug accountability form.  The 
Investigator will verify the accuracy of the information on the form, sign and date it, retain a 
copy in the study file, and return a copy to Celgene or its representative.   
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold.     
Unused study drug supplies 
Celgene will instruct the Investigator on the return or destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the source documents.  
Study drug supplies will be retained at the clinical site pending instructions for disposition by 
Celgene.  Patients will be instructed to return empty bottles or unused capsules to the clinic site.   
Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 


Protocol 2014-0116 
January 18, 2018 
1 
 
 
 
Phase II Study of Lenalidomide Maintenance in Patients with High Risk AML 
in Remission 
 
 
 
Principal Investigator 
Tapan Kadia, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Co-Investigator: 
Jorge Cortes, MD 
Department of Leukemia 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 428 
Houston, TX 77030 
(713)792-7305 
Study Product: 
Lenalidomide 
Protocol Number: 
2014-0116 
Coordinating Center: 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2014-0116 
January 18, 2018 
2 
 
 
 
PHASE II Study of Lenalodimide Maintenance in Patients with High Risk AML in 
Remission 
 
1.0 
OBJECTIVES 
 
2.0 
BACKGROUND 
 
3.0 
PATIENT SELECTION 
 
4.0 
TREATMENT PLAN 
 
5.0 
PATIENT EVALUATION 
 
6.0 
DOSING DELAYS / DOSE MODIFICATIONS 
 
7.0 
AGENT FORMULATION AND PROCUREMENT 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
9.0 
MEASUREMENT OF EFFECT 
 
10.0 
REPORTING REQUIREMENTS 
 
11.0 
REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2014-0116 
January 18, 2018 
2 
 
 
 
PHASE II Study of Lenalodimide Maintenance in Patients with High Risk AML in 
Remission 
 
1.0 
OBJECTIVES 
 
2.0 
BACKGROUND 
 
3.0 
PATIENT SELECTION 
 
4.0 
TREATMENT PLAN 
 
5.0 
PATIENT EVALUATION 
 
6.0 
DOSING DELAYS / DOSE MODIFICATIONS 
 
7.0 
AGENT FORMULATION AND PROCUREMENT 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
9.0 
MEASUREMENT OF EFFECT 
 
10.0 
REPORTING REQUIREMENTS 
 
11.0 
REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2014-0116 
January 18, 2018 
3 
 
 
 
 
1.0 OBJECTIVES 
 
1.1 Primary objective: 
To assess relapse-free survival (RFS) of patients with acute myeloid leukemia 
(AML) treated with lenalidomide maintenance therapy after achieving remission.  
 
1.2 Secondary objective 
 To assess overall survival (OS) of patients with AML treated with 
lenalidomide maintenance. 
 To assess event-free survival (EFS) of patients with AML treated with 
lenalidomide maintenance. 
 To assess the duration of remission (CRd) of patients with AML treated 
with lenalidomide maintenance. 
 To assess toxicity and safety of lenalidomide maintenance in patients with 
AML. 
 To assess the effects of lenalidomide maintenance on NK cell modulation 
and dynamics of minimal residual disease and their relationship to 
outcomes.  
 
2.0 BACKGROUND 
 
2.1 Acute Myeloid Leukemia (AML) 
 
AML is the cause of approximately 1.2% of all cancer deaths in the US with an annual incidence 
rate of 2.2 per 100,000 and approximately 10,000 new cases per year. Age-adjusted incidence 
ranges from 1 per 100,000 in people < 20 years to > 10 per 100,000 in the elderly. AML 
represents approximately 90% of all acute leukemias in adults, and accounts for about 25% of all 
cases of leukemia diagnosed in the Western hemisphere.1,2 AML is a clonal myelopoietic stem 
cell disorder characterized by the accumulation of neoplastic cells in the bone marrow and in the 
peripheral circulation. Current induction chemotherapy protocols combining cytarabine and an 
anthracycline administered as first-line treatment induce complete remissions in a majority (55% 
to 75%) of patients. Standard consolidation therapy with high doses of cytarabine leads to 
improved survival in younger patients.  Overall, up to 70% of patients can be expected to 
relapse, so that only about 20-30% attain long-term disease-free survival. 
 
Two major problems in the treatment of AML remain: primary resistant/refractory disease and 
high risk of relapse/recurrent disease.  While newer drug combinations and higher doses of 
therapy may begin to address upfront resistant disease, there are very few options, with the 
exception of allogeneic stem cell transplantation, for long term maintenance of remission after 
consolidation.  In acute lymphoblastic leukemia (ALL), maintenance therapy has become a 
standard part of treatment and has contributed to long term durable remissions and cures.  
Results of studies of maintenance therapy in AML have been mixed. In early studies by ECOG3,4 
and CALGB5, prolonged maintenance following a short consolidation failed to significantly 
prolong CR duration or overall survival.  On the other hand, studies from the German AML 
study group randomized patients after consolidation to prolonged maintenance vs. no further 


Protocol 2014-0116 
January 18, 2018 
4 
 
 
 
therapy.  Patients who received prolonged maintenance after consolidation had improved 
relapse-free survival, and this effect was more pronounced in higher risk patients.6-8.  
Lowenberg, et. al.9 randomized patients in CR after 1 cycle of consolidation to receive 8 monthly 
cycles of low dose araC maintenance vs. no further therapy.  Patients in the maintenance arm had 
improved recurrence free survival, but not OS.9  Finally, SWOG randomized patients in CR who 
were not eligible for an allogeneic stem cell transplant to receive one cycle of intensification 
followed by maintenance or intensification alone.  Patients receiving maintenance had improved 
disease free survival, but not OS.10  One of the shortcomings of these earlier approaches is that 
the therapeutic agents used in maintenance were often the same or similar agents that were used 
in induction and consolidation.  Residual leukemia cells which would have survived the 
induction therapy and are the source of relapses would be presumably resistant to ‘more of the 
same’.  Newer therapies, employing different mechanisms of action are less likely to be cross-
resistant to the initial cytotoxic induction regimens.  For example, Brune et. al.11 studied an 
immunotherapy approach investigating an IL2 + histamine maintenance therapy.  A cohort of 
320 patients in CR1 or greater were randomized to receive 10 cycles of IL2+histamine vs. no 
treatment.  At 3 years, the maintenance arm had a significant improvement in leukemia-free 
survival.11  Lenalidomide, a non-cytotoxic drug with activity in AML, has multiple unique 
mechanisms of action including immune modulation and alteration of intracellular signaling and 
may be an ideal candidate for long term maintenance in this disease. 
 
As a background, we know that AML patients (young and old) with: (1)primary refractory 
disease, (2)adverse cytogenetics, (3)FLT3 positive disease, (4)antecedent hematologic disorder, 
and (in relapsed patients) (5) short CR1 duration have a high risk of relapse, despite effective 
induction and consolidation therapy.  If these patients are not candidates for transplant, we are 
often beholden to “watch and wait” until their leukemia relapses.  In this setting, a long term, low 
intensity, easy to administer, and effective antileukemia treatment needs to be developed.  
Lenalidomide has been shown to have single-agent activity in AML as a higher dose induction 
followed by a longer term, lower dose maintenance strategy.12  Lenalidomide, in the treatment of 
myelodysplastic syndrome MDS and multiple myeloma (MM) has been shown to be safe during 
continuous, long term administration (MM, MDS) as well as in a maintenance strategy (MM).  
 
2.2 Lenalidomide in AML 
 
Lenalidomide, a derivative of thalidomide is currently approved for the treatment of multiple 
myeloma (MM) and MDS (myelodysplastic syndrome), but has been shown to have single-agent 
activity in AML as an induction – maintenance strategy.  In a phase II trial of older patients (age 
≥ 60 yrs) with untreated AML, lenalidomide was given at a high ‘induction’ dose, of 50 mg 
orally daily on a 28 day cycle (for up to 2 induction cycles), followed by a lower ‘maintenance’ 
dose of 10 mg orally daily for up to 12 months.  The CR/CRi rate was 30% overall and 53% in 
patients who completed all of the high-dose therapy.12  The median CR duration was 10 months 
(1 – 17+ months).  The treatment was well tolerated in this cohort of patients, with the most 
common grade 3-4 toxicities being myelosuppression and infection.  Based on this data of single 
agent activity in AML and its longer-term use in AML, MDS, and MM we propose to use this as 
a maintenance strategy for higher-risk patients who are in remission after induction/consolidation 
therapy.  The exact mechanism of action of lenalidomide is not known, but may involve 
immunomodulatory activity and reversal of an immunosuppressive environment present in 


Protocol 2014-0116 
January 18, 2018 
5 
 
 
 
malignancy.   
 
 
2.3 NK Cells as Immunosurveillance in Leukemia 
 
NK cells are an important component of the innate immune system and play a key role in the 
immune surveillance of cancer, including AML.13-16 NK cells can exert these effects through 
direct cytotoxicity, secretion of cytokines, and by coordinating other immune cells (T-cells, 
dendritic cells) to mount anti-tumor immunity.15,17,18 Although several studies in stem cell 
transplant and adoptive immunity have demonstrated the importance of NK cells in eliminating 
leukemia, immune evasion mechanisms or defects in autologous NK cells may thwart this anti-
leukemia effect.15,18  Among its mechanisms of action, lenalidomide has been shown to enhance 
NK cell mediated cytotoxicity by increasing NK cell numbers, increasing secretion of cytokines 
such as interferon gamma, and through enhancing ADCC by increasing IL2 secretion from T-
cells.19-23  Such reconstitution of AML immune-surveillance with lenalidomide in the 
maintenance setting could translate into long-term disease control and a higher cure rate.  This 
study provides us a unique opportunity to study the efficacy of this concept as well as determine 
the in vivo effects of lenalidomide on NK cells in AML patients. 
 
 
2.4 Rationale for studying lenalidomide as maintenance therapy in AML. 
 
Therapy for maintaining longer-term remissions after consolidation therapy in AML patients 
with high-risk disease is a critical need.  Unlike the treatment protocols for ALL, there is no 
current standard for maintenance therapy in AML.  Previous attempts at maintenance therapy in 
AML, utilizing redundant chemotherapy-based protocols have been met with minimal success.  
We therefore propose a clinical trial evaluating low intensity, continuous dosing of lenalidomide 
in patients with high risk AML who have responded to induction/consolidation chemotherapy 
and are not immediately candidates for BMT.  From our own data, the expected relapse free 
survival in this cohort of younger patients with higher risk disease who do not proceed for stem 
cell transplant is 8.5 months.  Approximately 25% of these patients may become eligible for and 
proceed to transplant, but the majority are left without meaningful therapy until relapse. 
 
Based on published data, NK cells are important mediators of immune surveillance, particularly 
in AML.  In addition to affecting direct cytotoxicity of AML blasts, NK cells may also alter the 
cytokine and immune cell (eg. T-lymphocytes) milieu to favor anti-leukemia immunity.  
Lenalidomide has been shown to enhance NK cell activity and numbers – making it an important 
agent to study in a setting of low disease burden (ie. minimal residual disease after 
chemotherapy).  As part of the clinical trial, we also aim to study the effects of lenalidomide on 
NK cell activity – both at baseline (prior to lenalidomide treatment) and at several time points 
during treatment.  This will help us derive more insight into the actions of lenalidomide on NK 
cell activity and how it relates to maintenance of remission in patients with AML. 
 
The rationale for the selected dosing of lenalidomide maintenance is drawn from previous 
experience in chronic dosing of lenalidomide for maintenance strategy.  In the AML experience 
described above, Fehniger, et. al. treated patients in the maintenance phase with 10 mg orally 


Protocol 2014-0116 
January 18, 2018 
6 
 
 
 
daily.  In multiple myeloma maintenance studies,24,25 lenalidomide was dosed at 10 – 15 mg 
orally daily, continuously.  These doses have therefore been shown to be safe and active in a 
long-term dosing strategy. 
 
  
2.5 Lenalidomide 
 
Background  
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.  IMiD® compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
antimetastatic effects.  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.26  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.27  Upregulation of T cell derived IL-2 production is achieved at least in part through 
increased AP-1 activity.28 
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.17  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.  Revlimid is also for the treatment of 
patients with mantle cell lymphoma (MCL)whose disease has relapsed or progressed after two 
prior therapies, one of which included bortezomib. 
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 


Protocol 2014-0116 
January 18, 2018 
7 
 
 
 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 
nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, 
chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
Lenalidomide Description 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) 
piperidine-2,6-dione and it has the following chemical structure:  
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
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 


Protocol 2014-0116 
January 18, 2018 
8 
 
 
 
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 Error! Reference source not found..  Exposure (AUC) in multiple 
myeloma patients is 57% higher than in healthy male volunteers.  
 
Pharmacokinetic Parameters 
Distribution 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. 
The process exceeds the glomerular filtration rate and therefore is partially or entirely active.  
Half-life of elimination is approximately 3 hours.  
Supplier(s) 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly 
known as RevAssist® Program).   
Dosage form 
Lenalidomide will be supplied as capsules for oral administration.   


Protocol 2014-0116 
January 18, 2018 
9 
 
 
 
Packaging 
Lenalidomide will be shipped directly to patients or to the clinic site.   Bottles will contain a 
sufficient number of capsules for one cycle of dosing.    
Labeling 
Lenalidomide supplies are dispensed in individual bottles of capsules.  Each bottle will identify 
the contents as study medication.  In addition, the label will bear Celgene’s name, quantity 
contained and the standard caution statement as follows:  “Caution: New drug - Limited by 
Federal law to investigational use.” Lenalidomide should not be handled by FCBP unless 
wearing gloves.  
The study drug label must be clearly visible.  Additional labels must not cover the Celgene label. 
Receipt of study drug 
The Investigator or designee is responsible for taking an inventory of each shipment of study 
drug received, and comparing it with the accompanying study drug accountability form.  The 
Investigator will verify the accuracy of the information on the form, sign and date it, retain a 
copy in the study file, and return a copy to Celgene or its representative.   
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold.     
Unused study drug supplies 
Celgene will instruct the Investigator on the return or destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the source documents.  
Study drug supplies will be retained at the clinical site pending instructions for disposition by 
Celgene.  Patients will be instructed to return empty bottles or unused capsules to the clinic site.   
Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 


Protocol 2014-0116 
January 18, 2018 
10 
 
 
 
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  Celgene Corporation’s Revlimid REMS® program.  Per 
standard Revlimid REMS® program requirements,  all physicians who prescribe lenalidomide 
for research subjects enrolled into this trial, and all research subjects enrolled into this trial, must 
be registered in, and must comply with, all requirements of the Revlimid REMS® program.   
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each 
cycle. 
Pregnancy Testing    
Must follow pregnancy testing requirements as outlined in the Revlimid REMS® program 
material. 
 
 
3.0 PATIENT SELECTION 
 
3.1 Inclusion Criteria:  
 
1. Patients aged 18 to 55 years with high risk (as defined in #2) AML who have achieved 
their FIRST CR or CRi within 12 months of enrollment and are not immediately 
candidates for allogeneic stem cell transplant.  Patients above age 55 who are not eligible 
for other protocols may be considered for enrollment on a case by case basis after 
discussion with the PI. 
2. Patients in their FIRST CR or CRi may be eligible for enrollment only if they have a 
high risk feature, including, but not limited to: adverse karyotype, FLT3 mutation, history 
of antecedent hematologic disorder (AHD), presence of dysplasia in the bone marrow, 
therapy-related AML, history of requiring more than 1 cycle of intensive induction 
chemotherapy to achieve first remission, or presence of persistent minimal residual 
disease (detected by cytogenetics, molecular markers, or flow cytometry) at any point 
after initial induction cycle. Patients aged > or = 18 years with AML who have achieved 
a SECOND CR or CRi within 12 months of enrollment and are not immediately 
candidates for allogeneic stem cell transplant are also eligible. 
3. Patients should have received induction chemotherapy for AML and at least 1 
consolidation.  
4. Patients with history of extramedullary AML, except for CNS involvement that is 
currently controlled, will not be eligible for enrollment. 
5. ECOG performance status of < or = 3 
6. Adequate organ function as follows: 
a. Serum total bilirubin < or = to 1.5 X the Upper Limit of Normal (ULN) 
b. Serum creatinine < or = to 2.5 x ULN 
7. Adequate BM reserve: 
a. Absolute neutrophil count (ANC) > 0.5 x 109/L 
b. Platelet count > or = 30 x 109/L 


Protocol 2014-0116 
January 18, 2018 
10 
 
 
 
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  Celgene Corporation’s Revlimid REMS® program.  Per 
standard Revlimid REMS® program requirements,  all physicians who prescribe lenalidomide 
for research subjects enrolled into this trial, and all research subjects enrolled into this trial, must 
be registered in, and must comply with, all requirements of the Revlimid REMS® program.   
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each 
cycle. 
Pregnancy Testing    
Must follow pregnancy testing requirements as outlined in the Revlimid REMS® program 
material. 
 
 
3.0 PATIENT SELECTION 
 
3.1 Inclusion Criteria:  
 
1. Patients aged 18 to 55 years with high risk (as defined in #2) AML who have achieved 
their FIRST CR or CRi within 12 months of enrollment and are not immediately 
candidates for allogeneic stem cell transplant.  Patients above age 55 who are not eligible 
for other protocols may be considered for enrollment on a case by case basis after 
discussion with the PI. 
2. Patients in their FIRST CR or CRi may be eligible for enrollment only if they have a 
high risk feature, including, but not limited to: adverse karyotype, FLT3 mutation, history 
of antecedent hematologic disorder (AHD), presence of dysplasia in the bone marrow, 
therapy-related AML, history of requiring more than 1 cycle of intensive induction 
chemotherapy to achieve first remission, or presence of persistent minimal residual 
disease (detected by cytogenetics, molecular markers, or flow cytometry) at any point 
after initial induction cycle. Patients aged > or = 18 years with AML who have achieved 
a SECOND CR or CRi within 12 months of enrollment and are not immediately 
candidates for allogeneic stem cell transplant are also eligible. 
3. Patients should have received induction chemotherapy for AML and at least 1 
consolidation.  
4. Patients with history of extramedullary AML, except for CNS involvement that is 
currently controlled, will not be eligible for enrollment. 
5. ECOG performance status of < or = 3 
6. Adequate organ function as follows: 
a. Serum total bilirubin < or = to 1.5 X the Upper Limit of Normal (ULN) 
b. Serum creatinine < or = to 2.5 x ULN 
7. Adequate BM reserve: 
a. Absolute neutrophil count (ANC) > 0.5 x 109/L 
b. Platelet count > or = 30 x 109/L 


Protocol 2014-0116 
January 18, 2018 
11 
 
 
 
8. For females of childbearing age, they may participate it they: 
a. Have a negative serum or urine pregnancy test within 10 to 14 days of enrolling 
(A second pregnancy test will be performed within 24hrs of starting therapy and 
both negative pregnancy tests will be required for starting therapy.) 
b. Agree to either abstinence or 2 effective contraceptive methods throughout the 
treatment period and up to 28 days after discontinuing treatment. 
9. For male patients with a female partner of childbearing age, they may participate if they 
agree to either abstinence or 2 effective contraceptive methods throughout the treatment 
period and up to 28 days after discontinuing treatment. 
10. All study participants must be willing and able to comply with the requirements of the 
REMS® program. 
11. Females of reproductive potential must be willing to adhere to the scheduled pregnancy 
testing as required in the Revlimid REMS® program. 
12. Ability to understand and sign informed consent. 
 
3.2 Exclusion Criteria 
1. Diagnosis of acute promyelocytic leukemia (APL), AML - M3 by FAB classification 
based on morphology, immunophenotype, molecular, or cytogenetic s studies. 
2. Diagnosis of AML associated with the following karyotypes: inv(16), t(16;16), t(8;21), or 
t(15;17). Patients with t(9;22) are also ineligible unless they are unable or unwilling to 
receive therapy with a tyrosine kinase inhibitor. 
3. Uncontrolled intercurrent illness including, but not limited to ongoing or active 
uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
4. Patients with active CNS disease. 
5. Previous treatment with lenalidomide for AML. 
6. Patients with documented hypersensitivity to any components of the study program. 
7. Females who are pregnant. 
 
 
4.0 TREATMENT PLAN 
 
This is a single arm, open label phase II clinical trial evaluating low intensity, continuous dosing 
of lenalidomide in patients with high risk AML who have responded to induction/consolidation 
therapy and are NOT immediately candidates for stem cell transplant. 
 
Treatment will be continued during the duration of the study, up to 24 months unless patient 
exhibits evidence of clinically significant treatment failure, clinically significant disease 
progression, unacceptable toxicity, treatment with stem cell transplantation, or if the investigator 
determines that discontinuation is in the best interest of the patient.  Relapsing patients (that is 
not clinically significant) may remain on the study if participation in the study is still providing 
clinical benefit and is considered in the best interest of the patient after discussion with the 
principal investigator.   
 


Protocol 2014-0116 
January 18, 2018 
12 
 
 
 
Patients will be treated with the study drug per protocol, based on fixed dosing as outlined 
below.   
 
The objective is to determine the effect of lenalidomide maintenance on relapse free survival 
(RFS), overall survival (OS), and CR duration in patients with high risk AML in remission.  We 
will also determine toxicity and tolerability of this regimen, as well as the effect of lenalidomide 
maintenance on NK cell biology and the dynamics of minimal residual disease.  
 
All patients will be registered for the protocol via the Clinical Oncology Research (CORe) 
system at MDACC (single institution study).   
 
4.1 Treatment Schema 
 
4.1.1 Maintenance Lenalidomide Dosing: 
 
Lenalidomide continuous dosing on days 1- 28 of a 28 day cycle. 
 
Dose of lenalidomide is as follows: 
 
- Starting dose (DOSE LEVEL 0): 10mg orally daily during cycle 1 
 
- If after one cycle, the patient has persistent evidence of (1) minimal residual disease or (2) 
morphologically active disease AND is tolerating their starting dose of lenalidomide, their dose 
may be increased to the next higher dose level for the remainder of the study.  A maximum of 2 
dose escalations per patient are allowed if well tolerated. 
 
Table 1. Dose escalation and de-escalation table. 
Dose Level 
Lenalidomide Dosing 
-2 
5 mg PO Every other Day 
-1 
5 mg PO Daily 
0 (Starting dose level) 
10 mg PO Daily 
1 
15 mg PO Daily 
2 
20 mg PO Daily 
 
One cycle of therapy is considered 28 days.  Therapy will be continuous; interruptions and dose-
adjustments for toxicity will be implemented as needed.  
 
4.2 Supportive Care Measures during treatment 
 
Necessary supportive measures for optimal medical care can be given throughout the study as 
indicated by the treating physician's assessment of the patient's medical need and by the 
institutional guidelines. Administration of antiemetics during drug administration and throughout 
treatment course is permitted as clinically indicated and according to departmental guidelines.  
Blood products should be transfused as indicated and in accordance with institutional guidelines. 
The use of other anti-leukemia therapy is not allowed during the course of therapy. Concomitant 


Protocol 2014-0116 
January 18, 2018 
13 
 
 
 
intrathecal chemotherapy and/or radiation therapy is permitted where indicated in patients with 
extramedullary disease. 
  
4.2.1 Hematopoietic growth factors 
 
Hematopoietic growth factors such as filgrastim (GCSF) or pegfligrastim is permitted as 
clinically indicated at the discretion of the treating physician. 
 
4.2.2 Infection prophylaxis 
 
Antibacterial, antifungal, and antiviral agents may be used in patients being treated on this study 
in accordance with the standard of care. 
 
4.3 Duration of Therapy 
 
In the absence of treatment delays due to adverse events, the treatment will be administered 
continuously for a total of 24 months. The patient will continue on the study unless one of the 
following criteria applies: 
 
 Clinically significant progressive disease as defined by Modified International 
Working Group Criteria (see section 9). 
 Undergoing allogeneic bone marrow transplant. 
 Intercurrent illness that prevents further administration of treatment. 
 Patient request. 
 Unacceptable toxicity. 
 Need for alternative treatment. 
 General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator or treating 
physician. 
 
 
5.0 PATIENT EVALUATION 
 
5.1 Pretreatment Evaluation. (To be completed within 14 days of study entry unless otherwise 
indicated) 
 
a. History and physical examination, including vital signs, height, weight and 
performance status. 
b. Bone marrow aspirate and/or biopsy within 28 days of treatment start. 
Cytogenetics, flow cytometry and molecular studies may be performed as 
clinically indicated. 
c. CBC with differential (within 7 days). 
d. Serum chemistry: BUN, creatinine, bilirubin, AST and/or ALT, magnesium, 
glucose, uric acid (within 7 days). 
e. Have a negative serum or urine pregnancy test within 10 to 14 days of enrolling 


Protocol 2014-0116 
January 18, 2018 
14 
 
 
 
(A second pregnancy test will be performed within 24hrs of starting therapy and 
both negative pregnancy tests will be required for starting therapy.) 
f. Peripheral blood for baseline correlative immune studies (if patient agrees to 
correlatives). 
g. Signed informed consent. 
 
5.2 During treatment Evaluation. 
 
a. Physical examination (including vital signs, weight, performance status) every 28 
days (±7 days) for the first 3 months, then every 3 months until 12 months from 
the start of therapy; then every 6 months (±2 months). 
b. CBC with differential (differential not required if WBC ≤0.5 x109/L), at least 
once weekly for the 1st cycle, then every 2 to 4 weeks during cycles 2-6, and then 
every 4 weeks (±14 days) thereafter as long as they are on study. 
c. Serum chemistry profile at least once weekly for the 1st cycle, then every 2 to 4 
weeks during cycles 2-6, and then at least every 4 weeks (±14 days) during active 
treatment. 
d. Bone marrow aspiration and/or biopsy after cycle 1, after 3 months of therapy (±2 
weeks), then every 3 months (±1 month) until month 12, then every 6 months (±2 
months).  No repeat bone marrow is necessary if non-response or progressive 
disease can be unequivocally diagnosed from peripheral blood tests or, in patients 
with a WBC <0.4 x109/L, if the bone marrow is considered non-contributory by 
the investigator at any point. 
e. Flow cytometry for MRD after cycle 1, after 3 months of therapy (±2 weeks), 
then every 3 months (±1 month) until month 12, then every 6 months (±2 
months).     
f. Peripheral blood for correlative immune studies once weekly for the 1st cycle, and 
once at the end of cycle 3, 6, and 12. (if patient agrees to correlatives) 
g. Patients will be followed for survival every 6 to 12 months after completion of 
active treatment and while still on study or be enrolled on the leukemia 
department long-term follow-up umbrella protocol. 
h. Women of child bearing potential must have a negative pregnancy test prior to 
each cycle of therapy. 
 
6.0 DOSING DELAYS / DOSE MODIFICATIONS FOR SUBSEQUENT CYCLES 
 
6.1 Dose levels for dose adjustments Table 1 
 
Dose Level 
Lenalidomide Dosing 
-2 
5 mg PO Every other Day 
-1 
5 mg PO Daily 
0 (Starting dose level) 
10 mg PO Daily 
1 
15 mg PO Daily 
2 
20 mg PO Daily 
 


Protocol 2014-0116 
January 18, 2018 
15 
 
 
 
6.1.1. Dose levels different than dose described may be allowed after discussion with 
the PI.  
 
Table 2.  Non-Hematologic Toxicity 
Drug-related Grade 2 Toxicity 
Initiation/continuation of treatment will be delayed if a > Grade 1 drug-related clinically significant non-
hematologic toxicity2 has occurred or worsened and not yet returned to < Grade 2 prior to the start of the 
next dose. 
Infection 
If a patient develops a clinically significant infection1 of any grade, treatment may be delayed or withheld 
until the infection is clinically controlled (e.g., the patient is afebrile and with 
improving signs/symptoms). Treatment may then resume at the same dose.    
Description of Event: Non-Hematologic 
Dose Modifications 
Drug-related clinically significant non-hematologic 
Grade 3-4 adverse event.3 
 
 
 
 
 
 
 
 
 
Hold therapy until recovery to Grade  1, then re-
start and reduce dose by one dose level. If toxicity 
recurs, hold therapy until recovery to grade 1, then 
re-start and reduce one dose level.  Dose reductions 
below dose level -2 will be not be considered.  If 
dose level -2 is considered intolerable, the patient 
will should be taken off study.  
Persistent grade 2 toxicity considered clinically 
significant or unacceptable.2 
Consider holding therapy until recovery to Grade  
1, then re-start and reduce one dose level. If toxicity 
recurs, hold therapy until recovery to grade 1, then 
re-start and reduce one dose level.  Dose reductions 
below dose level -2 will be not be considered.  If 
dose level -2 is considered intolerable, the patient 
will should be taken off study. 
Any occurrence of >/= drug related Grade 2 
neurologic events 
The patient's study drug doses are to be 
re-evaluated in consultation with the Principal 
Investigator, and may be reduced according to the 
above parameters, or discontinued based on the 
event, and the time to resolution to </= Grade 1.   
1 Includes, but is not limited to, bacteremia, systemic fungal infections, cytomegalovirus (CMV) infection, 
Pneumocystis carinii pneumonia (PCP), disseminated Varicella, etc. 
2 Excludes NCI CTC >/= grade 2 drug-related neurologic toxicities, grade 2 alopecia, and grade 3 
anorexia, transient elevations in hepatic transaminases or alkaline phosphatase based on institutional 
normals without clinical significance, and nausea/vomiting, diarrhea or mucositis that resolves (with or 
without supportive care) to < grade 2 within 48 hours of onset to grade 3. 
3 Excludes NCI CTC grade 4 transient elevations in hepatic transaminases or alkaline phosphatase 
based on institutional normals without clinical significance. 
 
Therapy will be continuous; interruptions and dose-adjustments for toxicity will be 
implemented as needed, based on above table. 
 
6.2 Myelosuppression: Patients with leukemias and MDS usually present with abnormal 
peripheral blood counts at the time therapy is started and some myelosuppression is 
an expected event during the course of therapy for acute leukemias and 
myelodysplastic syndromes. Thus, dose-adjustments or treatment interruptions for 
myelosuppression will be planned only for confirmed, severe neutropenia or 


Protocol 2014-0116 
January 18, 2018 
16 
 
 
 
thrombocytopenia that is confirmed for at least 1 week according to the following 
guidelines: 
 
6.2.1.1 Patients in remission who have sustained low counts (for at least 7 
days) of neutrophils <0.5 x109/L or a platelet count <20 x x109/L 
should have therapy held until resolution.  The patient may then 
receive subsequent treatment at 1 dose level reduction.  A 
reduction of 2 dose levels may be considered if the 
myelosuppression was deemed severe and/or life threatening by 
the treating physician, and if it is in the patient's best interest. 
 
 
 
7.0 AGENT FORMULATION AND PROCUREMENT 
 
Lenalidomide will be supplied by Celgene as part of this investigational study.  Commercial drug 
supply will be used. 
 
7.5 CORRELATIVE STUDIES 
 
Collection of Immune Modulation Studies will be requested from all patients on study.   
Heparanized blood specimens will be collected for assays to assess correlates of immune system 
activity prior to beginning treatment, at day 7, 14, 21, and 28 of Cycle 1 (+/- 3 days), and at the 
end of Cycle 3, 6 and 12 (+/- 14 days).  The assays include:  
1. Enumeration of immune cells (by multi-parameter flow cytometry) 
2. Quantification of cytokines/chemokines (by Luminex® Multiplex assay) 
3. NK cell functional assay (by Calcein-release direct cytotoxicity) 
4. KIR genotyping (by SSP- or SSO-PCR analysis) 
5. NK cell gene expression profile (using custom NK cell codeset on the nanoString 
platform) 
 
These assays will be used to identify biological correlates of lenalidomide immune-modulatory 
activity, and to correlate immune function, genotype, and immunomodulation with disease 
response or relapse. 
 
Sample requirements: 
10 mL of blood drawn into a sodium heparin (green top) tube. 
 
Sample preparation/handling: 
Keep samples at room temperature.  Notify the Lee Lab by email for same-day sample pickup.  
Use pager or phone as backup contact: 
 
Dean Lee 
e-mail: dalee@mdanderson.org 
Phone: (713) 563-5404 
Pager: (713) 404-3014 


Protocol 2014-0116 
January 18, 2018 
17 
 
 
 
 
Cecele Denman 
e-mail: cjdenman@mdanderson.org 
Phone: (713) 792-9938 
 
 
8.0 STATISTICAL CONSIDERATIONS 
 
STATISTICAL CONSIDERATIONS 
 
This is a phase II study of lenalidomide as a maintenance therapy in patients with high risk AML 
and in first or second remission.  The primary objective is to assess whether the maintenance 
therapy can improve relapse-free survival (RFS), which is defined as the time interval from date 
of treatment start until the date of death or disease relapse. Patients who are alive and relapse-
free at the last follow-up date will be censored at that time.  
 
The study will be continuously monitored for the primary endpoint, RFS, using the method of 
Thall, Wooten, and Tannir (2005).  Our goal is to improve the median RFS from 8 months 
(based on historical treatment) to 10.5 months using lenalidomide maintenance therapy. It is 
assumed that the RFS time is exponentially distributed with a median of E among patients who 
receive lenalidomide as a maintenance therapy, and a median of H is assumed for the historical 
treatment.   Further, we assume that H follows an inverse gamma distribution, i.e., H ~ IG(3.6, 
20.8), which has a mean of  8 months and variance of 40. To reflect the little prior knowledge of 
E we assume an inverse gamma prior distribution with the same mean of 8 months and a much 
larger variance of 500, i.e., E ~ IG(2.128,9.024).  The trial will be stopped early if Pr(E  > H 
+δ|data) < pL, where δ = 2.5 months and pL=0.05 and this futility monitoring rule will be first 
applied when 10 patients have been enrolled. A maximum of 50patients will be enrolled into this 
study at an expected accrual rate of 1 patient per month.  From historical experience, 25% of 
patients in this cohort may become eligible for stem cell transplant and may come off study.  For 
purposes of this analysis, these patients will be censored at the time of receiving transplant  .  
Patients will be followed up for an additional 12 months after all patients have been enrolled. 
The trial will be conducted using the Clinical Trial Conduct (CTC) website maintained by the 
Department of Biostatistics at MDACC.  
 
The operating characteristics of the design, based on an overall assumed accrual rate of 2 patients 
per month with 5000 simulated trials per scenario, are given in the following table. One-Arm  
Time-to-Event Simulator (version3.0.1) was used for the design and simulation. 
 
Scenario 
True Median   
(months) 
Pr(Stopped 
Early) 
Mean  
No. patients  
Average Trial 
Duration  
(months) 
1 
4 
0.968 
18.9 
21.5 
2 
6 
0.410 
37.7 
30.6 
3  
8 
0.102 
46.4 
34.8 
4 
10.5 
0.030 
48.9 
36.0 


Protocol 2014-0116 
January 18, 2018 
18 
 
 
 
5 
12 
0.017 
49.3 
36.2 
 
For the primary analysis of the efficacy endpoint, we will compute the Bayesian posterior 
probability of Pr(E  > H +δ|data). As a secondary analysis, we will perform a competing risk 
analysis treating stem cell transplant as a competing event for RFS.  
 
In addition, we will continuously monitor treatment-related toxicities using the Bayesian 
approach of Thall, Simon, Estey (1995).  Specifically, the trial will be stopped if Prob(πT>0.30 | 
data)>0.92, where πT is the toxicity rate and we assume a beta (0.6, 1.4) prior for πT That is, if at 
any given time, there is more than 92% probability that the toxicity rate of the maintenance 
therapy with lenalidomide is greater than 30%, the trial will be stopped. For the purpose of 
toxicity monitoring, toxicities are defined as any treatment –related clinically significant grade 3 
or 4 non-hematologic AEs occurred any time during the trial, which are also outlined in Table 2.  
We will apply this stopping rule starting from the 10th patient and in cohort size of 10. The 
stopping boundaries corresponding to this toxicity monitoring rule are described in the following 
table: 
 
Stopping boundaries for treatment-related grade 3, 4 non-hematologic toxicities 
 
The number of patients evaluated 
for toxicities 
10 20 30 40 
50 
Stop the trial if greater than or 
equal to this many of patients 
with toxicities 
6 
10 13 17 
20 
 
The operating characteristics for toxicity monitoring are described in the following table. 
MultcLean Desktop 2.1.0 was used for the design and simulations for toxicity monitoring.  
 
Operating characteristics for Toxicity Monitoring 
 
True Toxicity 
Rate 
Early Stopping 
Probability 
Sample Size 
25th percentile 
Median 
75th percentile 
0.10 
0.0002 
50 
50 
50 
0.20 
0.010 
50 
50 
50 
0.30 
0.135 
50 
50 
50 
0.40 
0.542 
20 
40 
50 
0.50 
0.904 
10 
20 
30 
 
 
The correlative biology studies are considered exploratory; trends and associations will be used 
to gain insight into the potential activity of this regimen and to help select potential biomarkers 
for further investigation in follow-up studies. 
 
Correlative data will be reported by dose level with simple summary statistics: means (possibly 
after transformation) or medians, ranges, and standard deviations (if numbers and distribution 


Protocol 2014-0116 
January 18, 2018 
19 
 
 
 
permit). Scatterplots will be used to explore possible associations between the dose and the 
immunomodulatory parameters, and between the immunomodulatory parameters and toxicity 
experienced (as reflected in the maximum grade of toxicity experienced or in clinical 
measurements). Scatterplots will also be used to explore possible associations between the 
immunomodulatory parameters, MRD, and relapse. 
 
 
9.0 MEASUREMENT OF EFFECT 
 
 
9.1 Criteria for Response 
 
 
9.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment on study. 
 
Evaluable for response.  Patients who have received at least one cycle of therapy, 
and have had their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
9.1.2 Response Criteria 
 
  
Response Criteria are based on the Revised Recommendations of the International 
Working Group Response Criteria in Acute Myeloid Leukemia.  They are 
summarized below. 
 
 
 
9.1.3 Complete remission (CR) 
 
 
 
 
 
Disappearance of all clinical and/or radiologic evidence of disease, including 
extramedullary leukemia. Neutrophil count ≥ 1.0 x 109/L and platelet count ≥ 100 
x 109/L, and bone marrow differential showing ≤ 5% blasts. 
 
 
 
9.1.4  Complete remission without platelet recovery (CRi) 
 
 
 
 
 
 
 
 
Have met all criteria for CR, except for either residual neutropenia (ANC < 1.0 x 
109/L) or thrombocytopenia (platelet count < 100 x 109/L). 
 
 
 
9.1.5 Partial remission (PR) 
 
 
 
 
 
Blood count recovery as for CR, but with a decrease in marrow blasts of at least 
50% and not more than 6 to 25% abnormal cells in the bone marrow. 
 


Protocol 2014-0116 
January 18, 2018 
20 
 
 
 
 
 
9.1.6 Confirmed Relapse  
 
 
 
 
 
 
Recurrence of disease as noted by: > 30% peripheral blasts, or > 20% bone 
marrow blasts.  If the bone marrow blasts are between 6% and 20%, 2 serial bone 
marrow examinations at least 2 weeks apart demonstrating successive increase in 
blasts by at least 2% will also be a confirmed relapse. 
 
 
 
 
9.1.7 Relapse-free survival (RFS) 
 
 
 
 
 
Time from CR or CRi until confirmed relapse or death. 
. 
 
 
9.1.8 Event-free survival (EFS) 
 
 
 
 
 
 
 
 
 
Time from treatment start until date of first documented event.  Event will be 
defined as: confirmed relapse, withdrawal from study due to adverse event, or 
death due to any cause. 
 
 
 
9.1.9 CR duration (CRd) 
 
 
 
 
 
Time from CR or Cri until date of first objective documentation of confirmed 
relapse. 
 
 
 
9.1.10 Overall survival (OS) 
 
 
 
 
 
 
 
 
 
Time from date of treatment start until date of death due to any cause. 
 
 
 
 
10. REGULATORY AND REPORTING REQUIREMENTS 
 
10.1 Regulatory and Reporting Requirements 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
will be utilized for AE reporting.  The CTEP Active Version of the CTCAE is identified and 
located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All appropriate 
treatment areas should have access to a copy of the CTEP Active Version of CTCAE. 
 
Refer to Section 10.2 for Leukemia-Specific Adverse Event Recording Guidelines.  The 
Principal Investigator will sign the PDMS Case Report Form toxicity pages per each patient at 
the completion of each course.  Following signature, the Case Report Form will be used as 
source documentation for the adverse events. 
 


Protocol 2014-0116 
January 18, 2018 
21 
 
 
 
10.2 
Leukemia-specific Adverse Event Recording and Reporting Guidelines 
 
These guidelines serve to bring the Department of Leukemia in compliance with the institutional 
policy on Reporting of Serious Adverse Events-definition of expected AE-“ All clinical 
protocols should include a list of the expected and anticipated events or hospitalizations relating 
to the study treatment” and Guideline for Good Clinical Practice 4.11.1 “All serious adverse 
events (SAEs) should be reported immediately to the sponsor except for those SAEs that the 
protocol or other document  (e.g., Investigator’s Brochure) identifies as not needing immediate 
reporting”. 
 
Adverse event is any untoward medical occurrence that may present during treatment with a 
pharmaceutical product but which does not necessarily have a causal relationship with this 
treatment. 
 
Adverse drug reaction is a response to a drug which is noxious and unintended and which occurs 
at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the 
modification of physiologic function. 
 
Assessing causal connections between agents and disease is fundamental to the understanding of 
adverse drug reactions. In general, a drug may be considered a contributory cause of an adverse 
event if, had the drug not been administered, 1) the event would not have happened at all, 2) the 
event would have occurred later than it actually did, or 3) the event would have been less severe. 
 
Adverse Events (AEs) will be evaluated according to current CTC version in each protocol. Only 
unexpected AEs will be recorded in the Case Report Form (CRF).  Expected events during 
leukemia therapy are: 
1. Myelosuppression related events (due to disease or leukemia therapy) 
a. febrile or infection episodes not requiring management in the intensive care unit 
b. epistaxis or bleeding except for catastrophic CNS or pulmonary hemorrhage 
c. anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia, leukocytosis 
2. Disease related events 
a. symptoms associated with anemia 
i. fatigue 
ii. weakness 
iii. shortness of breath 
b. electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, magnesium) 
c. chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, albumin, uric 
acid, alkaline phosphatase, glucose) 
d. coagulation abnormalities 
e. disease specific therapy (induction, maintenance, salvage, or stem cell therapy) 
f. alopecia 
g. bone,  joint, or muscle pain 
h. liver function test abnormalities associated with infection or disease progression 
i. disease progression 
3.  General therapy related events 
a. catheter related events 


Protocol 2014-0116 
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b. renal failure related to tumor lysis syndrome or antibiotic/antifungal therapy 
c. rash related to antibiotic use 
4. Hospitalization for the management of any of the above expected events 
 
Abnormal hematologic values will not be recorded on the CRF. For abnormal chemical values 
grade 3 or 4, the apogee will be reported per course in the CRF. 
 
 
Serious Adverse Event Reporting (SAE) 
 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose  
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity  
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
 
 Serious adverse events will be captured from the time the patient signs consent until 30 
days after the last dose of drug. Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the event. 
 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on lenalidomide, or within  28 
days of the subject’s last dose of lenalidomide, are considered immediately reportable events. 
Lenalidomide  is to be discontinued immediately. The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Celgene Drug Safety immediately by facsimile or 
email using the Pregnancy Initial Report Form. The female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 


Protocol 2014-0116 
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23 
 
 
 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form.  If the outcome of the 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form.  
 
Male Subjects 
 
If a female partner of a male subject taking lenalidomide becomes pregnant, the male subject 
taking lenalidomide should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax:  
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 
 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene in 
writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of 
being aware of the event.  The written report must be completed and supplied to Celgene by 
facsimile within 24 hours/1 business day.  The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and lenalidomide.  
Information not available at the time of the initial report (e.g., an end date for the adverse event 
or laboratory values received after the report) must be documented on a follow-up report.  A 
final report to document resolution of the SAE is required.  The Celgene tracking number (RV-
XX-PI-###) and the institutional protocol number should be included on SAE reports (or on the 
fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report 
to Celgene should be attached to the SAE and retained with the patient records. 
 
Reporting to FDA 
 


Protocol 2014-0116 
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24 
 
 
 
It is the responsibility of the PI and the research teams to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
Reporting of external SAEs 
 The MDACC institutional policy for reporting of external SAEs will be followed. 
 
 


Protocol 2014-0116 
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25 
 
 
 
11.0 REFERENCES 
 
 
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