Clinical trial NCT00352794
Conditions: Myelofibrosis
Keywords: Combination chemotherapy Myelofibrosis (MF)
Sponsor: M.D. Anderson Cancer Center
Start date: 2006-07-07; Completion date: 2018-03-08
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if lenalidomide in combination with prednisone can help to control myelofibrosis. The safety of lenalidomide and prednisone for the treatment of myelofibrosis will also be studied.

Detailed description:
Lenalidomide is designed to change the body's immune system. It may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, in theory, it may decrease or prevent the growth of cancer cells. Prednisone is designed to improve the results of lenalidomide and to help reduce the side effects.

If you are found to be eligible to take part in this study, you will take 1-2 capsules of lenalidomide by mouth daily. You will take lenalidomide daily for 21 days followed by 1 week rest. This 28-day period is called a study "cycle."

Swallow lenalidomide capsules whole with water at the same time each day. Do not break, chew or open the capsules.

If you miss a dose of lenalidomide, take it as soon as you remember on the same day. If you miss taking your dose for the entire day, take your regular dose the next scheduled day (do NOT take double your regular dose to make up for the missed dose).

You will take prednisone by mouth every day during Cycles 1-2, and every other day during Cycle 3. You may only take prednisone for Cycles 1-3.

You will be given a study drug diary. In this diary, you will record when you take the study drug(s).

During treatment, blood (about 1 tablespoon) will be drawn once every 1-2 weeks. Following the completion of 24 cycles, blood (about 1 tablespoon) will be drawn every 1- 3 months. The tests may be repeated more frequently to check for side effects.

Every month for the first 3 months, and then every 3 months, until you complete 24 cycles, you will have a study visit. You will have a bone marrow biopsy/aspirate every 3 months. Lenalidomide will be provided to you as a monthly (28-day) supply.

Following the completion of Cycle 24, you will have a study visit every 6 months. You will have a bone marrow biopsy/aspirate every 12 months. Lenalidomide will be provided to you as a monthly (28-day) supply.

Depending on side effects and the activity of the study drug against the disease, your dose of the study drug may be increased or decreased.

You may stay on study for as long as you are benefitting. You will be taken off study if you are not or are no longer benefitting or intolerable side effects occur.

This is an investigational study. Lenalidomide and prednisone are both FDA approved and commercially available. Lenalidomide is approved by the Food and Drug Administration (FDA) for the treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with the chromosome 5 abnormality with or without other chromosome abnormalities. Lenalidomide is also approved in combination with dexamethasone for the treatment of patients with multiple myeloma that have received at least one prior therapy. Myelodysplastic syndrome (MDS) and Multiple Myeloma (MM) are cancers of the blood. It is currently being tested in a variety of cancer conditions. In this case it is considered experimental. Prednisone is on the market for many different things but not specifically for Myelofibrosis. The use of these drugs in combination is considered investigational in this study. Up to 41 patients will take part in this study. All will be enrolled at M. D. Anderson.

Arms: arm 1: Lenalidomide oral 10 mg daily/days 1-21 of 28 day cycle. Prednisone starting dose oral 30 mg/day during cycle 1, 15 mg/day during cycle 2, and 15 mg every other day during cycle 3, and then it will be discontinued.
Interventions: intervention 1: Lenalidomide intervention 2: Prednisone
Intervention descriptions: intervention 1: Oral 10 mg daily/days 1-21 of 28 day cycle intervention 2: Starting dose oral 30 mg/day during cycle 1, 15 mg/day during cycle 2, and 15 mg every other day during cycle 3, and then it will be discontinued.

Protocol documents:
Prot_SAP_000.pdf: 
2005-0206
January 14, 2014
Page 1
Protocol Page
EVALUATION OF LENALIDOMIDE (CC-5013) AND PREDNISONE AS A 
THERAPY FOR PATIENTS WITH MYELOFIBROSIS (MF)
2005-0206
Core Protocol Information
Short Title 
LENALIDOMIDE FOR PATIENTS WITH MF
Study Chair: 
Srdan Verstovsek
Additional Contact:
Paula J. Cooley
Sandra L. Rood
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-7305
Unit:
428
Full Title: 
EVALUATION OF LENALIDOMIDE (CC-5013) AND PREDNISONE AS A THERAPY FOR 
PATIENTS WITH MYELOFIBROSIS (MF)
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 03/09/2018
Version:
30
Submitted by:
Sandra L. Rood--12/7/2017 10:41:13 AM
OPR Action:
Accepted by:  Yolanda Shorte -- 12/12/2017 11:06:49 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2005-0206
January 14, 2014
Page 2
Protocol Body
 
Scott Miller
Celgene Corporation
Medical Education Liaison 
2104 Vintage Court 
McKinney, TX  75070 
972-333-0548
1 800 832 4031


 
 
 
 
 
 
EVALUATION OF LENALIDOMIDE (REVLIMID®) AND PREDNISONE AS A 
THERAPY FOR PATIENTS WITH MYELOFIBROSIS (MF) 
 
 
 
 
 
 
 
 
 
 
 
University of Texas 
MD Anderson Cancer Center 
Leukemia Department, Unit 428 
Telephone: 713-792-7305 
 
Principal Investigator: Srdan Verstovsek, M.D., Ph.D. 
 
 
 
 
 
 
 


 
 
TABLE OF CONTENTS 
1.0 
HYPOTHESIS AND OBJECTIVES ..................................................................... 3 
1.1 
HYPOTHESIS ........................................................................................................... 3 
1.2 
OBJECTIVES ........................................................................................................... 3 
2.0 
BACKGROUND AND RATIONALE ................................................................... 3 
2.1 
MYELOFIBROSIS WITH MYELOID METAPLASIA ............................................................ 3 
2.2 
INTRODUCTION TO LENALIDOMIDE ............................................................................ 6 
2.3 
PREDNISONE ADDITION TO LENALIDOMIDE AS THERAPY FOR MF ............................... 12 
3.0 
BACKGROUND DRUG INFORMATION .......................................................... 12 
4.0 
PATIENT ELIGIBILITY CRITERIA ................................................................... 13 
4.10 INCLUSION CRITERIA .............................................................................................. 13 
4.2 
EXCLUSION CRITERIA ............................................................................................ 14 
5.0 
TREATMENT PLAN ......................................................................................... 15 
5.1 
DOSE REDUCTION OF LENALIDOMIDE ...................................................................... 15 
5.2  INSTRUCTIONS FOR LENALIDOMIDE DOSE MODIFICATIONS OR INTERRUPTION DURING A 
CYCLE .................................................................................................................. 16 
5.3 
PREDNISONE DOSE MODIFICATIONS ................................................................... 1718 
5.4 
INITIATION OF A NEW CYCLE OF THERAPY ............................................................... 18 
5.1 
CONCOMITANT THERAPY ....................................................................................... 18 
5.6 
TREATMENT COMPLIANCE ..................................................................................... 20 
5.7 
PRETREATMENT EVALUATION ................................................................................ 20 
5.8 
EVALUATION DURING STUDY ................................................................................. 22 
5.9 
BIRTH CONTROL REQUIREMENTS ....................................................................... 2322 
5.10 CRITERIA FOR REMOVAL FROM THE STUDY ......................................................... 2322 
6.0 
CRITERIA FOR RESPONSE AND TOXICITY .................................................. 23 
7.0 
ADVERSE EVENTS .......................................................................................... 28 
9.0 
STATISTICAL CONSIDERATIONS .................................................................. 34 
10.0 
CORRELATIVE STUDIES ................................................................................ 35 
11.0 
REFERENCES .................................................................................................. 37 
 


 
 
 
 
PROTOCOL BODY 
 
1.0 
HYPOTHESIS AND OBJECTIVES 
1.1 
Hypothesis 
Lenalidomide and prednisone in combination are effective and tolerable 
treatment for patients with myelofibrosis (MF). 
1.2 
Objectives 
Primary:  To determine the efficacy of lenalidomide and prednisone in 
combination in patients with MF, in achieving objective improvements in 
disease status: complete and partial response, hematological 
improvement. 
Secondary:  to determine the safety of lenalidomide and prednisone in 
combination, in patients with MF. 
Tertiary:  To examine pertinent morphological, biological, and molecular 
characteristics of MF in patient samples during therapy with lenalidomide 
and prednisone. 
2.0 
BACKGROUND AND RATIONALE 
2.1 
Myelofibrosis with Myeloid Metaplasia 
 
Myelofibrosis with myeloid metaplasia (MF) is a rare [0.73 per 100,000 
person years in males and 0.4 per 100,000 person years in females in the 
United Kingdom] clonal proliferative disorder of a pluripotent stem cell.  
This clone subsequently induces fibrogenic cytokines and/or growth 
factors in the marrow, which stimulate the deposition of extracellular 
matrix proteins by polyclonal fibroblasts.  Megakaryocytic hyperplasia-
dysplasia is frequently observed.  Invasion of the blood stream and 
colonization of extramedullary sites ensues, resulting in organomegaly and 
splenomegaly. Extensive marrow fibrosis and osteosclerosis may be 
observed in advanced MF, resulting in “dry taps”.  
 
The entity of MF can be either idiopathic (primary or agnogenic myeloid 
metaplasia), or representative of end-stage myeloproliferative diseases 
such as polycythemia vera (PV) or essential thrombocythemia (ET).  MF 
occurs in 25% to 50% of patients with PV and in 2% to 3% of patients with 
ET.  In the early cellular phase of MF with minimal marrow fibrosis, the 
differential diagnosis includes Philadelphia-positive CML, PV, and ET that 


 
 
must be distinguished, based on cytogenetics and clinicopathologic 
features.  Other entities that can induce myelophthisis include 
myelodysplastic syndrome (MDS), metastatic malignancies, lymphoma, 
Hodgkin’s disease, and plasma cell dyscrasias.  MF must be differentiated 
from acute megakaryocytic leukemia (AML, M7 of the French-American-
British classification) and CML with fibrosis. In acute megakaryocytic 
leukemia patients usually present with severe constitutional symptoms 
and pancytopenia but without organomegaly or peripheral blood 
myelophthisis. 
 
Thus, the clinical picture of MF involves constitutional symptoms (e.g., 
cachexia, night sweats, fatigue, fever), splenomegaly, anisopoikilocytosis 
with teardrop erythrocytes, progressive anemia, immature myeloid and 
erythroid precursors in the peripheral blood, elevated lactate 
dehydrogenase (LDH) levels, and fibrosis of the marrow (as evaluated by 
reticulin and trichome [collagen] stains).  The leukoerythroblastic picture is 
postulated to be related to both the intramedullary sinusoidal marrow and 
splenic hematopoiesis.  
 
The disease generally occurs in adults, with the median age ranging from 
54 to 62 years; 70% of the patients are over the age of 50 years.  In 40% 
of the patients, constitutional symptoms are present, including fever, 
weight loss, nocturnal sweating, pruritus, and bone pain.  Splenomegaly is 
present in 85% to 100% of the patients at diagnosis, and is massive in 
10%.  Hematologic disease features include anemia in 50% to 70% at 
diagnosis and 25% will have severe anemia with hemoglobin level < 8.0 
gm/dL.  Approximately half of the patients present with an elevated white 
cell count (WBC), 28% with thrombocytosis (platelet count > 500 x 109/L, 
and 37% with thrombocytopenia (platelet count < 150 x 109/L).  
Circulating blast cells are present in one-third of the patients. 
 
Complications of MF are varied.  Thrombotic obliteration of intrahepatic 
veins and splenomegaly may lead to portal hypertension; severe cases 
may be associated with ascites and/or variceal bleeding.  Left upper 
quadrant pain may herald splenic infarction; episodes are usually self-
limited and may persist for several days.  Supportive care measures such 
as analgesics and hydration are usually sufficient; refractory cases may 
require splenectomy or irradiation. Extramedullary hematopoiesis (EMH) 
may occur in locations other than the liver or spleen; involvement of such 
sites may be managed by low-dose irradiation.  Liver involvement is 
associated with increased levels of plasma alkaline phosphatase.  Clinical 
manifestations of EMH include cardiac tamponade, papular skin nodules, 
pleural effusions, and spinal cord compression. 


 
 
Autoimmune phenomena have been observed, including Coomb’s positive 
autoimmune hemolytic anemia, nephrotic syndrome, antinuclear 
antibodies, rheumatoid factor, and lupus-type anticoagulant.  Postulated 
etiologies include clonality of the lymphoid population or activation by 
abnormal monocyte-macrophage interaction with the immune system. 
Adverse prognostic factors for survival include older age and anemia 
(hemoglobin < 10 gm/dL).  The etiology for the latter finding is usually 
multifactorial and related both to marrow failure and hypersplenism.  Poor 
prognosis has also been correlated with leukocytosis, leukopenia, 
circulating blasts, increased numbers of granulocyte precursors, 
thrombocytopenia, abnormal karyotype, and hypercatabolic symptoms.  
The course of the disease is highly variable.  Median survival from time of 
diagnosis ranges from 3 to 6 years; survival rates at 2 and 5 years are 
68% and 40%, respectively.  Progressive marrow failure, transformation 
into acute myeloid leukemia, and portal hypertension lead to demise. 
Various prognostic models have been devised, with only hemoglobin at 
diagnosis a consistent prognostic factor among several studies.  Other 
parameters included constitutional symptoms, thrombocytopenia, and 
percentage of WBC precursors. 
Lille Scoring System [Hemoglobin < 10 gm/dL, WBC < 4 or > 30 x 109/L] 
 
No. of Adverse Prognostic 
Features 
Risk Group 
Median Survival 
(months) 
0 
Low 
93 
1 
Intermediate 
26 
2 
High 
13 
 
Age of the patient and abnormal karyotype are two additional prognostic 
features. The median survival of young, low-risk patients can range from 
13 to 15 years.  Overall median survival is estimated between 3 and 6 
years with infections, thrombosis and/or hemorrhage, and transformation 
to leukemic phase frequently leading to death.  Patients without any 
adverse features may survive as long as 10 years, whereas those with 
any two of these features have an expected survival less than 3 years. 
No standard therapy exists for MF.  Hydroxyurea is the most commonly 
used agent in the proliferative phases of the disease.  Interferon-alpha had 
yielded hematologic responses and reductions in splenomegaly 
(definitions varying among studies) in 30% to 50% of patients, especially 
those with proliferative phase, however, this agent tends to be poorly 


 
 
tolerated.  Agents used for the management of anemia include androgens 
and/or erythropoietin.  Splenectomy and/or splenic irradiation have been 
used to manage symptomatic splenomegaly.  Splenectomy has been 
associated with risk of leukemia transformation in some series, and 
splenic irradiation can result in severe myelosuppression. 
No medical therapy has been proven to prolong overall survival for these 
patients. Patients with an intact quality of life and no threatening 
hematologic abnormalities, such as erythrocytosis or thrombocytosis, have 
usually been considered to not require any therapy; however, new 
therapeutic modalities are currently being considered in determining 
treatment indications. 
In vitro data suggests that cytokines elaborated by megakaryocytes 
stimulate human bone marrow fibroblasts to divide and secrete collagens. 
In patients with MF, increased levels of transforming growth factor-beta 
(TGF-beta) have been observed in circulating peripheral blood 
mononuclear cells (PBMC) of megakaryocytic lineage.   
Increased levels of basic fibroblast growth factor (bFGF) have also been 
reported in patients with MF.  Both TGF-beta and bFGF are members of 
multifunctional polypeptide families that regulate cell growth and 
differentiation.  In addition to their potent fibrogenic activity, TGF-beta and 
bFGF regulate hematopoiesis by selective actions on primitive stem cells. 
Expression of TGF-beta in early CD34+ hematopoietic stem cells 
negatively regulated the cycle status; this effect could be abrogated by 
bFGF.  In addition, bFGF has been shown to augment the activity of stem 
cell factor (SCF), interleukin-3 (IL-3), granulocyte-macrophage colony 
stimulating factor (GM-CSF), or erythropoietin on committed progenitor 
cells.  Other cytokines/proteins that are disregulated in MF include; tumor 
necrosis factor-alpha (TNF-alpha) and angiogenic agents like vascular 
endothelial growth factor (VEGF).   
Serum interleukin-6 (IL-6) has multiple biological effects, including the 
regulation of hematopoiesis, immune responses, and acute phase 
reactions.  IL-6 appears to be a potent megakaryocytic maturation factor.  
Patients with ET appear to have IL-6 levels similar to controls, whereas 
patients with reactive thrombocytosis have higher IL-6 levels. 
2.2 
Introduction to Lenalidomide  
Lenalidomide is the lead compound in a proprietary class of Celgene 
compounds known as IMiDs® with immunomodulatory and anti-
angiogenic properties that could confer antitumor and antimetastatic 
effects. It is a derivative of thalidomide, combining higher efficacy and 
lower toxicity than its parent compound. Lenalidomide has been 
demonstrated to possess anti-angiogenic activity through inhibition of 


 
 
bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at 
least in part to inhibition of Akt phosphorylation response to bFGF.  In 
addition, lenalidomide has a variety of immunomodulatory effects.  
Lenalidomide stimulates T cell proliferation, and the production of IL-2, IL-
10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 
production.  
Clinical experience in solid tumors with lenalidomide 
Twenty patients with varying types of solid tumors (13 with malignant 
melanoma, 2 each with carcinoma of the pancreas and non-small-cell lung 
cancer [NSCLC], 1 each with renal carcinoma, breast carcinoma, and 
carcinoid-unknown primary) were enrolled in a Phase 1 study of 
lenalidomide conducted at the St. George Hospital, London, UK.  This was 
a non-randomized, open-label with-in patient dose-escalation design, 
where patients started on 5 mg/day for 7 days and then increased their 
dose every 7 days to 10 mg/day, 25 mg/day, and 50 mg/day for a total of 4 
weeks on therapy.  Investigators at the NCI have enrolled 20 patients, 
including 18 patients with recurrent high-grade gliomas and 2 with other 
refractory CNS malignancies (1 recurrent atypical meningioma and 1 
multiple recurrent spinal hemangioblastomas) into a phase I trial of 
lenalidomide given on Days 1 through 21 every 28 days.  Treatment has 
been well tolerated with 1 grade 2 myelosuppression as the only toxicity > 
grade 1.  
 
In an ongoing phase I trial in patients with refractory metastatic cancer 
conducted through the NCI, 12 patients with metastatic androgen 
independent prostate cancer have been enrolled.  Lenalidomide was 
administered in daily doses of 5mg (3 patients), 10mg (3 patients) and 
20mg (6 patients).  Dose limiting toxicity was seen at 20mg/day (1 grade 3 
thrombosis and 1 grade 3 hypotension).  Stable PSA values for at least 8 
weeks were observed in 6 patients. 
 
In a phase III, multi-center, randomized parallel group study comparing 
two dose regimens of lenalidomide, 293 patients with malignant melanoma 
were enrolled.  Subjects were randomized to receive treatment with 
lenalidomide at a dose of 5 mg per day orally for 28 days or to 25 mg per 
day orally for 21 days with a 7 day rest (28 day cycle).  Treatment 
continued until the patient developed disease progression or intolerable 
adverse events occurred.  Interim analysis failed to show an advantage of 
one regimen over the other with respect to survival.  Analysis of response 
rates is pending.  The toxicity profile was similar in both dose groups and 
the most frequent adverse events were fatigue, seen in 32% of patients, 
followed by nausea and diarrhea, seen in 24% and 20% of patients 
respectively.  Neutropenia and thrombocytopenia were seen in 2.4% and 
2.0% of patients respectively.  Grade 3 and 4 toxicities were seen 
infrequently (<15%). 
 


 
 
A second phase III randomized trial compared a lenalidomide dose of 25 
mg daily orally for 21 days with a 7 day rest (28 day cycle) to placebo in 
patients with metastatic melanoma.  Three hundred and five patients 
enrolled on this study and a preplanned interim analysis failed to 
demonstrate a survival advantage.  Response rates are being analyzed.  
The toxicity profile was favorable and similar to the previous phase III 
study. 
 
Clinical experience in multiple myeloma with lenalidomide 
In 2 phase I studies in multiple myeloma, a total of 41 patients have been 
treated with lenalidomide.  In one study at the University of Arkansas, 15 
patients who relapsed or were refractory to high dose melphalan therapy 
with stem cell transplant were treated for 4 weeks in an open-label safety 
study and were permitted to continue therapy in an extension phase of the 
trial.  Patient cohorts were treated at the following daily doses: 5mg, 
10mg, 25mg, and 50mg.  In a similar study at the Dana Farber Cancer 
Institute, 27 patients with rapidly advancing refractory multiple myeloma 
were enrolled.  Anti-myeloma activity was observed in each of these 2 
phase I studies.  Decreases in neutrophil and platelet counts were the 
dose-limiting toxicities associated with lenalidomide.  The maximum 
tolerated dose (MTD) was not reached within 28 days.  Due to dose 
modifications associated with myelosuppression observed beyond Day 28 
at the 25mg and 50mg daily dose levels, the dose schedule most widely 
used in future studies has been lenalidomide on Days 1-21, repeated 
every 28 days.  
 
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).  
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. 
 No plasma accumulation was observed with multiple daily dosing.  Peak 
and overall plasma concentrations were dose proportional over the dosing 
range of 5mg to 50mg. 
 
A multicenter, randomized, phase II trial compared 2 syncopated dose 
schedules of lenalidomide used alone or in combination with 
dexamethasone in the treatment of relapsed or refractory multiple 
myeloma.  All patients were treated on Days 1-21 of a 28-day cycle.  
Patients treated with 15mg BID experienced more myelosuppression and 
dose reductions compared with patients treated with 30mg daily.  Anti-
myeloma activity was observed with each dose and schedule of single 
agent lenalidomide.  The addition of dexamethasone to lenalidomide 
yielded responses in some patients who had not responded to 
lenalidomide alone. 


 
 
 
A phase I/II trial of Liposomal doxorubicin (Doxil®), vincristine, 
dexamethasone (DVd) and lenalidomide in heavily pretreated 
relapsed/refractory multiple myeloma patients is ongoing.  The MTD of 
lenalidomide was 10mg on Days 1-21 in combination with Doxil® 
40mg/m2 IVPB on Day 1, vincristine 2mg IVP on Day 1 and 
dexamethasone 40mg PO on Days 1-4 cycled every 28 days.  All patients 
received amoxicillin, acyclovir and aspirin 81mg prophylactically.  The 
dose limiting toxicity with lenalidomide 15mg on Days 1-21 in combination 
with DVd was sepsis/septic shock.  Additional phase I trials of 
lenalidomide with chemotherapy in advanced malignancies are in 
progress. 
 
Celgene Corporation sponsored 2 multicenter, randomized, double-
blinded, placebo-controlled phase III trials [1 U.S. (MM-009) and 1 
international (MM-010)] in patients with relapsed or refractory multiple 
myeloma.  More than 350 patients were enrolled into each of these 
studies.  All patients had to be considered sensitive to dexamethasone 
and were treated with dexamethasone 40mg qd, Days 1-4, 9-12 and 17-
20.  In addition to receiving dexamethasone, patients were randomized to 
lenalidomide 25mg qd or placebo, Days 1-21.  Cycles were repeated 
every 28 days.   After 4 cycles, there was a predetermined reduction of the 
dexamethasone dose to 40mg daily, Days 1-4 repeated every 28 days. 
 
In both studies, a pre-specified interim analysis conducted by an 
Independent Data Monitoring Committee demonstrated that subjects 
receiving the combination of lenalidomide (Len) plus dexamethasone 
(Dex) had significantly longer times to progression and higher response 
rates than those treated with single-agent dexamethasone.  A New Drug 
Application (NDA) is currently being prepared for the use of lenalidomide 
in Multiple Myeloma.  Data continue to mature, but the preliminary interim 
analysis revealed the following results. 
 
 
MM-009  
Len/Dex 
MM-010 
Len/Dex 
MM-009 
Placebo/Dex 
MM-010 
Placebo/Dex 
 
CR+PR (%) 
61.2 
58.0 
22.8 
21.7 
P < 0.001 
CR (%) 
26.5 
13.6 
4.1 
4.0 
 
PR (%) 
34.7 
44.3 
18.7 
17.7 
 
SD (%) 
28.2 
33.5 
57.9 
64.6 
 
PD (%) 
2.9 
2.8 
12.3 
7.4 
 
Median TTP 15.0 
13.3 
5.1 
5.1 
P <0.000001 


 
 
(mos)  
 
Clinical experience in myelodysplastic syndromes (MDS) with 
lenalidomide 
An exploratory trial in 43 MDS patients with transfusion dependent or 
symptomatic anemia was conducted at the University of Arizona.  Patients 
received lenalidomide at doses of 25mg or 10mg per day, or of 10mg on 
Days 1-21, repeated every 28 days.  All patients had had no response to 
erythropoietin or had a high endogenous erythropoietin level.  Response 
rates were similar across the 3 dose schedules used.  Responses were 
observed in 24 patients overall (56%) including 21 patients with a major 
response and 20 patients with sustained transfusion independence.  
Patients with a major response reached a median hemoglobin level of 
13.2 grams per deciliter, with a corresponding 5.3 grams per deciliter 
median increase from baseline.  After a median follow-up of 81 weeks, the 
median duration of major response had not been reached and was more 
than 48 weeks.  Of 20 patients with karyotypic abnormalities, 10 (50%) 
patients had a complete cytogenetic remission.  The response rate was 
highest in patients with a clonal interstitial deletion involving chromosome 
5q31.1 (10 out of 12, 83%).  Neutropenia and thrombocytopenia were the 
most common adverse events, and resulted in dose delays or reductions 
in 25 patients (58%). 
 
Celgene Corporation sponsored a multicenter trial (MDS-003) of 148 MDS 
patients with a clonal interstitial deletion involving chromosome 5q31.1.  
Lenalidomide was given at a dose of 10mg on Days 1-21, repeated every 
28 days, to 44 patients, and at a dose of 10mg daily to the other 104 
patients.  Transfusion independence was achieved in 93 patients (64%), 
with a median hemoglobin increase of 3.9g/dl. Cytogenetic response was 
achieved in 76% of transfusion independent patients with 55% achieving a 
cytogenetic complete response. Pathologic complete response was 
documented in 32 out of 110 (29%) evaluable patients.  With a median 
follow-up of 9.3 months, the median response duration had not been 
reached.  Neutropenia (39%) and thrombocytopenia (35%) were the most 
common adverse events requiring dose delays or reductions. 
 
Another Celgene sponsored trial (MDS-002) in patients with low to 
intermediate-1 risk MDS enrolled 215 patients, of whom, 166 were 
documented to have low to intermediate-1 risk MDS.  Among the patients 
with documented low to intermediate-1 risk MDS, 84 patients (51%) 
responded to treatment.  Transfusion independence was achieved in 54 
patients (33%) and 30 patients (18%) achieved a minor response, defined 
as a 50% or greater decrease in blood transfusion requirement.  The 
median duration of transfusion-independence was 41 weeks.  The median 
baseline hemoglobin level was 8.0g/dl, which increased by 3.2g/dl in 


 
 
responding patients.  Among 20 patients evaluable for cytogenetic 
response, 9 patients (45%) experienced a cytogenetic remission.  
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® (lenalidomide) is approved by the FDA.  Revlimid® is 
indicated for the treatment of patients with transfusion-dependent anemia 
due to Low- or Intermediate-1-risk MDS associated with a deletion 5q 
cytogenetic abnormality, with or without additional cytogenetic 
abnormalities.  REVLIMID® in combination with dexamethasone is 
indicated for the treatment of multiple myeloma patients who have 
received at least one prior therapy. 
 
 
Clinical experience in myelofibrosis with myeloid metaplasia with 
lenalidomide 
A Phase II single agent study of lenalidomide in MF was recently 
performed at MDACC.  Forty one patients with platelet count of at least 30 
x 109/L were treated with 10mg/day oral lenalidomide. Thirty six patients 
(88%) had received prior treatments, including thalidomide. Twenty 
patients were evaluable for response and toxicity at the last review. 
Responses were observed in approximately 50% of the evaluable patients 
including CR in 2 patients (normalization of hemoglobin and WBC counts), 
PR in 2 patients (improvement in platelet and hemoglobin, and in 
splenomegaly), hematologic improvement in 6 patients (improvements in 
spleen size, platelets and WBC) and transfusion independence in 3 of 13 
patients. Common toxicities included rash (29%) and pruritus (20%). 
Grade > 3 toxicities included thrombocytopenia (2 patients), neutropenia 
(1 patient), rash (1 patient), and fatigue (1 patient).   
 
In another Phase II study of single agent lenalidomide in MF, Tefferi et al 
reported approximately 20% improvement in anemia. Some of these 
responses were dramatic and associated with specific cytogenetic 
abnormalities. In addition, they reported documentation of positive drug 
effect on constitutional symptoms, LDH, and splenomegaly in patients 
who did not show early response with anemia, suggesting the likelihood 
of higher responses with longer duration of therapy. 
 
Adverse Events with Lenalidomide  
Most frequently reported adverse events reported during clinical studies 
with lenalidomide in oncologic and non-oncologic indications, regardless of 
presumed relationship to study medication include: anemia, neutropenia, 
thrombocytopenia and pancytopenia, abdominal pain, nausea, vomiting 
and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, 
UTI, Upper respiratory infection, cellulitis, 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, tumor 
lysis syndrome, death not specified and fractures.  
 
Lenalidomide may cause breakdown products of the cancer cells to enter 
the blood stream, which may lead to heart rate abnormalities, kidney 
failure, muscle twitching, and/or muscle cramps. 
 
 
Please refer to lenalidomide package insert or Investigator Brochure for a 
complete list.  
 
2.3 
Prednisone addition to lenalidomide as therapy for MF 
 
Steroid preparations are commonly used as therapy for MF. Furthermore, 
when used in combination with other medications (e.g. thalidomide) they 
improve tolerance of those medications and improve results. While there 
is no experience with lenalidomide and steroids in combination in MF, 
extensive research has been done in multiple myeloma. The combination 
has been well tolerated and has demonstrated synergy in the relapsed 
and refractory multiple myeloma setting. Based on these results, the 
Eastern Oncology Cooperative Group has recently started a Phase II 
multicenter trial of the combination of lenalidomide and prednisone in MF, 
similar to this clinical study. It is expected that the combination will 
improve the tolerance of lenalidomide with subsequent improvement in the 
results of therapy. 
 
3.0 
BACKGROUND DRUG INFORMATION 
3.1 
Lenalidomide 
Celgene Corporation will supply Revlimid® (lenalidomide) to study 
participants at no charge through the RevAssist® program.  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 Celgene’s RevAssist® program. 
 
Dosage form 
Lenalidomide will be supplied as 5 mg capsules for oral administration.  
 
Packaging 
Lenalidomide  will be shipped directly to the patient through the Celgene’s 
 RevAssist® program. 
 


 
 
 
 
Prescribing Information 
Lenalidomide (Revlimid®) will be provided to research subjects for the 
duration of their participation in this trial at no charge to them or their 
insurance providers.  Lenalidomide will be provided in accordance with the 
RevAssist® program.  Per standard RevAssist® requirements all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and all 
research subjects enrolled into this trial, must be registered in and must comply 
with all requirements of Celgene’s RevAssist® program.  Prescriptions must be 
filled within 7 days.  Only enough lenalidomide for one cycle of therapy will be 
supplied to the patient each cycle. 
 
3.2 
Prednisone  
 
Prednisone will be used from commercially available supplies. 
 
 
4.0 
PATIENT ELIGIBILITY CRITERIA 
4.1 
Inclusion criteria 
1. Diagnosis of myelofibrosis requiring therapy, including those 
previously treated and relapsed or refractory, or if newly diagnosed, 
with intermediate or high risk according to Lille scoring system (risk 
factors are: Hb < 10 g/dl, WBC < 4 or > 30 x 109/L; risk group: 0 
factor(s) = low, 1 factor(s) = intermediate, 2 factor(s) = high) or with 
symptomatic splenomegaly. 
2. Understanding and voluntary signing an IRB-approved informed 
consent form. 
3. Age ≥ 18 years at the time of signing the informed consent. 
4. Disease-free of prior malignancies for ≥ 2-years with exception of 
basal cell or squamous cell carcinoma of the skin, or carcinoma “in 
situ” of the cervix or breast. 
5. ECOG performance status 0 to 2. 
6. Patients must have adequate organ function as demonstrated by the 
following: 
 Total bilirubin < 2.0 mg/dL (unless higher due to MF).  
 Serum creatinine < 2.0 mg/dL (unless higher due to MF). 
 Absolute neutrophil count > 1 x 109/L  
 ALT  3 x upper limit of normal (unless higher due to MF) 


 
 
7. Females of childbearing potential (FCBP)† must have a negative 
serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 
within 10 – 14 days prior to and again within 24 hours of starting 
lenalidomide and must either commit to continued abstinence from 
heterosexual intercourse or begin TWO acceptable methods of birth 
control, one highly effective method and one additional effective 
method AT THE SAME TIME, at least 4 weeks before she starts 
taking lenalidomide.  FCBP must also agree to ongoing pregnancy 
testing.  Men must agree to use a condom during sexual contact with 
a female of child bearing potential even if they have had a successful 
vasectomy.  All patients must be counseled at a minimum of every 28 
days about pregnancy precautions and risks of fetal exposure.  See 
Appendix J: Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods. 
8. All study participants must be registered into the mandatory RevAssist® 
program, and be willing and able to comply with the requirements of 
RevAssist®. 
 
 
 
4.2 
Exclusion Criteria 
 
1. 
Use of any other standard (e.g. hydroxyurea, anagrelide, growth 
factors) or experimental drug or therapy within 28 days of starting 
lenalidomide and/or lack of recovery from all toxicity from previous 
therapy to grade 1 or better. 
2. 
Known prior clinically relevant hypersensitivity reaction to 
thalidomide, including the development of erythema nodosum if 
characterized by a desquamating rash. 
3. 
Prior therapy with lenalidomide. 
4. 
Any serious medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from signing the informed consent 
form. 
5. 
Suspected Pregnancy, Pregnant or lactating females. 
6. 
Any condition, including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in 
the study or confounds the ability to interpret data from the study. 
7. 
Known positive for HIV or infectious hepatitis, type A, B or C. 
8. 
Known prior clinically relevant hypersensitivity to prednisone. 
9. 
Participants with heard rate (HR) of less than or equal to 50, as a HR 
less than 50 indicates underlying cardiac abnormalities. 
                                            
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has 
had menses at any time in the preceding 24 consecutive months). 
 
 


 
 
10. Participants with prior history of thromboembolic disease (i.e. deep 
venous thrombosis (DVT) or pulmonary embolism (PE) within the last 
six months, as Lenalidomide has demonstrated a significantly increased 
risk of DVT or PE. 
11. Participant is unwilling or unable to comply with the RevAssist® 
Program. 
 
 
5.0 
TREATMENT PLAN 
 
The planned dose and schedule of investigation of lenalidomide is 10 mg/day 
orally (unless blood platelet count is below 100 x109/L, in which case the 
starting dose of lenalidomide is 5 mg/day).  Lenalidomide will be taken orally in 
the morning each day on days 1-21, followed by 7 days of no therapy of each 
28-day cycle.   
Lenalidomide capsules should be swallowed whole, and should not be broken, 
chewed or opened.  If a dose of lenalidomide is missed, it should be taken as 
soon as possible on the same day.  If it is missed for the entire day, it should 
not be made up. 
Patients who take more than the prescribed dose of lenalidomide should be 
instructed to seek emergency medical care if needed and contact study staff 
immediately.  Twenty eight days is considered one cycle of therapy.  Attempts 
will be made to provide an adequate treatment period of at least 6 months 
unless significant toxicity observed, to account for delayed time to response 
observed with biologic agents. Responders will continue therapy for 2 years 
unless progression of disease or toxicity warranting discontinuation of therapy 
is observed. 
 
Prednisone will be used orally at the dose of 30 mg/day during cycle 1, 15 
mg/day during cycle 2, and 15 mg every other day during cycle 3, and then it 
will be discontinued. 
 
All patients will be registered on the Patient Data Management System 
(PDMS) at MD Anderson Cancer Center after the informed consent is signed.  
Medication will be mailed to participants, per the RevAssist® Program.  
 
5.1 
Dose Modification Levels of Lenalidomide 
 
Dose 
Actions 
Dose Level +3 
25 mg on days 1-21 of every 28 day cycle 
Dose Level +2 
20 mg daily on days 1-21 of every 28 day cycle 


 
 
Dose 
Actions 
Dose Level +1 
15 mg daily on days 1-21 of every 28 day cycle 
Level 0 (starting dose if 
platelet counts is ≥ 
100x109/L) 
10 mg on days 1-21 of every 28 day cycle 
Dose Level –1 (starting 
dose if platelet counts is 
< 100x109/L) 
5 mg daily on days 1-21 of every 28 day cycle 
Dose Level –2 
5 mg every other day x 10 of every 28 day 
cycle 
 
5.2  
Instructions for Lenalidomide dose modifications or interruption during a 
cycle 
 
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
DOSAGE CHANGE 
Allergy/Immunology Allergic 
reaction/hypersensitivity 
(including drug fever) Grade 
3 
Omit lenalidomide for remainder 
of cycle.  Restart at planned start 
of next cycle at the next lower 
dose level if adverse event 
reduces to grade 1. 
 
Allergic 
reaction/hypersensitivity 
(including drug fever) Grade 
4 
Discontinue Lenalidomide 
Blood/Bone Marrow  Neutrophils/granulocytes 
(ANC/AGC) Grade 4 or 
grade 3 associated with 
fever (38.5 degree 
centigrade or higher) 
Omit Lenalidomide for remainder 
of cycle.  Restart at planned start 
of next cycle at the next lower 
dose level if ANC 1000/L. 
 
Platelets Grade 3 if ≥100 x 
109/L pretherapy or <50% of 
pretherapy value if <100 x 
109/L 
Omit Lenalidomide for remainder 
of cycle.  Restart at planned start 
of next cycle at the next lower 
dose level if platelet is ≥ 50 x 
109/L if ≥100 x 109/L before 
starting therapy, or at least 50% of 
the pre-therapy value if <100 x 
109/L before starting therapy.  
Cardiovascular 
Sinus bradycardia/other 
cardiac arrhythmia Grade 2 
Omit Lenalidomide for remainder 
of cycle.  Restart at planned start 


 
 
CTCAE 
CATEGORY 
 
ADVERSE EVENT 
 
DOSAGE CHANGE 
of next cycle at the next lower 
dose level if toxicity reduces to 
grade 1 or lower 
 
Sinus bradycardia/other 
cardiac arrhythmia Grade 3 
or 4 
Discontinue Lenalidomide 
 
Thrombosis/embolism Grade 
3 or 4 
Omit Lenalidomide for remainder 
of cycle and start systemic 
anticoagulation.  Restart at 
planned start of next cycle at the 
same dose level at investigator’s 
discretion and only if approved by 
the PI. (See section 5.5 for 
anticoagulation recommendations) 
Dermatology/Skin 
Rash/desquamation Grade 3 
Omit Lenalidomide for remainder 
of cycle.  Restart at planned start 
of next cycle at the next lower 
dose level if adverse event 
reduces to grade 1. 
 
Rash/desquamation Grade 4 
Discontinue Lenalidomide 
 
Rash: Erythema multiforme 
Discontinue Lenalidomide 
Endocrine 
Hyperthyroidism/ 
Hypothyroidism 
Omit Lenalidomide for remainder 
of cycle.  Evaluate etiology, initiate 
appropriate therapy.  Restart at 
planned start of next cycle at the 
next reduced dose level. 
Other non-
hematologic 
Grade 3 or 4 
Omit Lenalidomide for remainder 
of cycle.  Restart at planned start 
of next cycle at the next lower 
dose level if adverse event 
reduces to  grade 2. 
 
Dose escalation of lenalidomide may be indicated for patients with 
proliferative disease not controlled with combination of lenalidomide and 
prednisone after initial cycle of therapy.  Dose escalation will only be 
allowed for patients who have not had any grade 2 or greater clinically 
relevant drug related non-hematologic toxicity with the prior cycle of 
therapy.  Any other modifications in the dose of lenalidomide can be done 
if felt to be in the best interest of the patient, and approved by Principal 
Investigator. 
 
5.3 
Prednisone Dose Modifications 
 


 
 
Dose modifications/discontinuation for prednisone therapy will be at the 
discretion of the clinician but must be documented clearly when it 
happens. Prednisone dose modification/discontinuation will not require 
withdrawal from the study; the patient may continue taking lenalidomide 
alone. Treatment of hyperglycemia with either oral hypoglycemic agents or 
insulin does not necessarily require discontinuation of prednisone if the 
hyperglycemia is controlled with these medications. 
 
 
5.4 
Initiation of a New Cycle of Therapy 
A new course of treatment may begin on the scheduled Day 1 of a new cycle 
if: 
 The ANC is ≥ 1,000/μL; 
 The platelet count is ≥ 50x109/L if ≥100x109/L before starting therapy, or 
at least 50% of the pre-therapy value if <100x109/L before starting 
therapy; 
 Any lenalidomide-related allergic reaction/hypersensitivity or sinus 
bradycardia/ other cardiac arrhythmia adverse event that may have 
occurred has resolved to ≤ grade 1 severity; 
 Any other lenalidomide-related adverse event that may have occurred 
has resolved to ≤ grade 2 severity. 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated weekly and a new cycle of lenalidomide (with/without prednisone 
after cycle 3) will not be initiated until the toxicity has resolved as described 
above.   
 
If lenalidomide dosing was omitted for the remainder of the previous cycle or 
if the new cycle is delayed due to toxicity newly encountered on the 
scheduled Day 1, then the new cycle will be started with a one-level dose 
reduction.  If the toxicity has not resolved as described above within 4 weeks, 
the patient will discontinue treatment.  In unusual circumstance this rule may 
be modified by Principal Investigator if felt to be in the best interest of the 
patient (for example, responding patient with neutropenia or low platelets, 
that resolve past 4 weeks may be restarted on therapy); this case must be 
fully documented. 
 
5.5 
Concomitant Therapy 
All medications (prescription and non-prescription), treatments and therapies 
taken from the first day of study through the end of study, must be recorded 
on the source documents.   
The use of filgrastim (G-CSF) for subjects in this study is permitted when 
used to treat neutropenia secondary to therapy. Erythropoietin therapy is not 
allowed. Subjects should receive full supportive care, including transfusions of 


 
 
blood products, antibiotics and antiemetics and prophylactic treatment for 
potential hypersensitivity reactions and tumor lysis syndrome when 
appropriate. 
 
Prophylactic Anticoagulation: 
Lenalidomide increases the risk of thrombotic events in patients who are at 
high risk or with a history of thrombosis, in particular when combined with 
other drugs known to cause thrombosis. When lenalidomide is combined with 
other agents such as steroids (e.g. dexamethasone, prednisone), 
anthracyclines (Doxil, adriamycin) and erythropoietin the risk of thrombosis is 
increased.  Consideration should be given to the use of aspirin (81 or 325 mg) 
or some other form of prophylaxis as deemed appropriate. Low molecular 
weight heparin may be utilized in patients that are intolerant to aspirin. 
Coumadin should be used with caution and close monitoring of INR is 
required. 


 
 
 
 
5.6 
Treatment Compliance 
 
To monitor treatment compliance, reconciliation of lenalidomide capsules will 
be done at each visit. Subject diaries will be provided to assist in the 
collection of dosing information to monitor compliance. 
 
5.7 
Pretreatment Evaluation 
 
The mandatory pre-treatment evaluation (within 2 weeks, unless otherwise 
specified) will be aimed at confirming/establishing the diagnosis.  The 
evaluation will consist of a thorough assessment of the following:  
 
 A complete primary evaluation with physical examination and description 
of constitutional symptoms 
 CBC, differential  
 Serum BUN, alkaline phosphatase, creatinine, bilirubin, ALT, sodium, 
potassium, chloride, carbon dioxide, glucose, lactate dehydrogenase 
 Bone marrow aspiration and biopsy (within 3 months if no therapy was 
given, alternative within one month) to include staining for fibrosis and 
molecular test for JAK 2 mutation (blood test is acceptable alternative), 
cytogenetic studies, (within one year). 
 CD34+ cell count in blood 
 Serum or urine pregnancy test (sensitivity of at least 50 mIU/mL), 10 – 14 
days pre therapy and again within 24 hours of initiation of therapy for all 
females of child bearing potential (FCBP).  Counseling for all men about 
the requirement for latex condom use during sexual contact with females 
of childbearing potential and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days. During counseling, subjects 
must be reminded to not share study drug and to not donate blood, sperm, 
or semen. Please refer to Appendix J. 
 TSH 
 EKG 
 Correlative studies (see section 10.0) every 3 months – optional. 
 Refer to Appendix K for pre-treatment evaluation schedule. 
 
In addition, the analysis of total and phosphorylated c-Jun protein in peripheral blood will 
be done. Sample processing will be performed in the laboratory of Dr. Carlos Bueso-
Ramos at MD Anderson, while sample analysis will take place at the Celgene 
Corporation. Samples will be obtained pre-therapy, after 6 and 18 months of therapy. 
Not all samples might be obtained at all time points. Peripheral blood will be collected 
into 2 specialized CPT 8 mL vacutainer tubes. Peripheral blood mononuclear cells 
(PBMC) will be separated, pelleted, lysed, and stored frozen at -70 C until shipping. 
Samples will be coded so that patient confidentiality will be preserved. They will be 


 
 
shipped on dry ice to the Celgene Corporation, San Diego. Contact person is: Brydon 
Bennett, Celgene, 4550 Towne Centre Court, San Diego, CA 92121, Phone: 858 558 
7500, Email: bbennett@celgene.com (see appendix G) 


 
 
 
5.8 
Evaluation During Study 
 
Time parameters for mandatory evaluations during the study are:  +/-5 
days for blood tests, +/- two weeks for bone marrow exams, and +/-2 
weeks for MD Anderson visits.  Exception for these rules can be made in 
unusual circumstances (e.g. long holiday) if approved by Prinicipal 
Investigator and documented. 
 
 Follow up visits at MD Anderson are required initially monthly (+/- 1 week), 
with review of constitutional symptoms and physical exam.  Following the 
completion of cycle 3, patients that are on a stable dose of lenalidomide 
and have no serious drug related side effects, and the physician feels it is 
in the patients best interest, may return to MDA every three months.  
Following the completion of cycle 24, patients that are on a stable dose of 
lenalidomide, have no serious drug related side effects, and the physician 
feels it is in the patients best interest, may return to MDA every 6 months 
(+/-2 weeks). Only one, 28 day supply of Lenalidomide may be provided to 
a patient per monthly cycle.  In this case, a monthly phone assessment of 
toxicity, review of required blood tests (pregnancy test if applicable) and 
confirmation of the requirements for the initiation of a new cycle must be 
done.   
 CBC with differential every other week x 8, then every 1 month or more 
frequently as clinically indicated.  Following the completion of cycle 24, 
CBC every 1-3 months while participating on the study.  
 Bone marrow aspiration and biopsy every 3 months (to include staining for 
fibrosis); cytogenetics every 3 months if abnormal prior to therapy; JAK2 
mutation analysis every 3 months if mutation present prior to therapy. 
Following the completion of Cycle 24, bone marrow aspiration and biopsy 
every year, cytogenetics every year if abnormal prior to therapy; JAK2 
every year if mutation present prior to therapy. 
 Serum BUN, alkaline phosphatase, creatinine, bilirubin, ALT, sodium, 
potassium, chloride, carbon dioxide, glucose, lactate dehydrogenase 
every other week x 6, then every 1 month. Following the completion of 
cycle 24, complete every 3-6 months while participating on the study 
 TSH every 3 months. Following the completion of Cycle 24, TSH every 6 
months. 
 CD34+ cell counts in blood every 3 months. Following the completion of 
Cycle 24 CD34+ every year. 
 Serum or urine pregnancy test (sensitivity of at least 50 mIU/mL) every 
week x 4, then monthly for all FCBP with regular menstrual cycles, or 
every 2 weeks if irregular cycles. 
 Correlative studies (see section 10.0) every 3 months – optional. 
Following the completion of Cycle 24, correlative studies every 6 months-
optional. 
 Refer to Appendix K for Schedule of Events During Study 


 
 
 
5.9 
Birth Control Requirements 
See Appendix J for detailed procedures. 
 
5.10 Criteria for Removal from the Study 
Subjects have the right to withdraw from the study at any time for any 
reason.  An excessive rate of withdrawals can render the study not 
interpretable; therefore, unnecessary withdrawal of subjects should be 
avoided.  Should a subject decide to withdraw, or is being removed from 
the study, all efforts will be made by clinical study personnel to complete 
and report (as a progress note) the observations as thoroughly as 
possible. The date of discontinuation and reason(s) for patient 
discontinuation for the study will be recorded in the chart and PDMS. An 
attempt to complete all evaluations which are required at the final study 
visit must be conducted for each patient who discontinues treatment, 
regardless of the reason. 
Criteria for discontinuation of therapy include:  
 
Clearly documented progressive disease, or loss of a response; 
 
No response within 6 months from the start of therapy; 
 
Severe toxicities not responding to dose adjustments; 
 
Major protocol violation (i.e. noncompliance to protocol 
requirements); 
 
Development of other conditions for which, in the Investigator’s 
opinion, it is in the subject’s best interest to be withdrawn from the 
study; 
 
Confirmed or suspected pregnancy; 
 
Death; 
 
Lost to follow up; 
 
Withdrawal of consent. 
 
Non-compliance with the RevAssist® Program. 
 
6.0 
CRITERIA FOR RESPONSE AND TOXICITY 
 
Standard response criteria will be applied in this study.  These criterias have 
been used in all our studies in the last 10years including the lenalidomide single 
agent study. 
 
CR = Absence of signs or symptoms of the disease. 
 WBC between 1 to 10 x 109/L with no peripheral blasts, 
promyelocytes, or myelocytes, and with normalization of bone 
marrow (< 5% blasts in normocellular or hypercellular marrow, 
irrespective of marrow fibrosis). 


 
 
 
 Resolution of pretreatment cytopenias:  
o 
ANC > 1.5 x 109/L without G-CSF or GM-CSF. 
o 
Hb >12.0 gm/dl (11.0 gm/dl for females) without 
erythropoietin or transfusion support. 
o 
PLT > 100 x 109/L without growth factor or transfusion 
support. 
 
 Resolution of pretreatment leukocytosis and/or thrombocytosis: 
(without the use of hydroxyurea and/or anagrelide). 
 
o 
WBC < 10 x 109/L without peripheral blasts, 
promyelocytes, or myelocytes 
o 
PLT > 100 x 109/L but less than 450 x 109/L 
 
 Resolution of organomegaly (splenomegaly or hepatomegaly) on 
physical exam 
 
PR = Improvement in at least 2 of the parameters (if abnormal) listed 
below: 
 
 Increase of ANC by > 50% and to > 1.0 x 109/L without G-CSF or 
GM-CSF 
 Increase of Hb by > 2 g/dL, if below 10 g/dL before therapy, without 
erythropoietin or transfusion support. 
 Increase of PLT by > 50% and to > 30 x 109/L without growth factor 
or transfusion support. 
 Resolution of pretreatment leukocytosis to WBC < 10 x 109/L, without 
hydroxyurea 
 Resolution of pretreatment thrombocytosis to PLT > 100 x 109/L but 
less than 450 x 109/L, without hydroxyurea and anagrelide 
 Decrease in transfusion requirements by at least 50% without 
erythropoietin support. 
 Reduction of splenomegaly by > 50% by palpation, without 
hydroxyurea  
 Reduction of marrow blasts by > 50%, without hydroxyurea 
 Reduction of marrow or blood macrocytes by > 50%, without 
hydroxyurea 
 
HI = Improvement in at least 1 of the parameters (if abnormal) listed 
above under PR 
 
In addition, we will attempt to validate in this study, recently published response 
criteria developed by the international working group for myelofibrosis.  These 
criteria have not yet been used in any clinical study. 
 


 
 
 
Complete remission (CR): Requires all of the following in the absence of 
both transfusion and growth factor support;  
 Complete resolution of disease-related symptoms and signs including 
palpable hepatosplenomegaly. 
 Peripheral blood count remission defined as hemoglobin > 11 g/dL, 
platelet count ≥ 100 x 109/L, and absolute neutrophil count ≥ 1.0 x 109/L. 
 Normal leukocyte differential including disappearance of nucleated red 
blood cells and immature myeloid cells in the peripheral smear, in the 
absence of splenectomy.* 
 Bone marrow histological remission defined as the presence of age-
adjusted normocellularity, < 5% myeloblasts, and an osteomyelofibrosis 
grade of ≤ 1.**  
 
 
Partial remission (PR): Requires all of the above criteria for CR except the 
requirement for bone marrow histological remission. However, a repeat bone 
marrow biopsy is required in the assessment of PR and may or may not 
show favorable changes that do not however fulfill criteria for CR. 
 
Clinical improvement (CI): Requires one of the following in the absence of 
both disease progression (as outlined below) and CR/PR assignment (CI 
response is validated only if it lasts for ≥ 8 weeks). 
 A ≥ 2 g/dL increase in hemoglobin level or becoming transfusion 
independent (applicable only for patients with baseline hemoglobin level 
of < 10 g/dL).§ 
 Either a ≥ 50% reduction in palpable splenomegaly of a spleen  that is ≥ 
10 cm at baseline or a spleen that is palpable at > 5 cm at baseline 
becomes not palpable.§§ 
 A ≥ 100% increase in platelet count and an absolute platelet count of ≥ 
50,000 x 109/L. (applicable only for patients with baseline platelet count of 
< 50 x 109/L). 
 A ≥ 100% increase in ANC and an ANC of ≥ 0.5 x 109/L (applicable only 
for patients with baseline absolute neutrophil count of < 1 x 109/L). 
 
Progressive disease: Requires one of the following;¶ 
 Progressive splenomegaly that is defined by the appearance of a 
previously absent splenomegaly that is palpable at > 5 cm below the 
left costal margin or a ≥ 100% increase in palpable distance for 
baseline splenomegaly of 5-10 cm or a ≥ 50% increase in palpable 
distance for baseline splenomegaly of > 10 cm. 
 Leukemic transformation confirmed by a bone marrow blast count of ≥ 
20%.  
 An increase in peripheral blood blast percentage of ≥ 20% that lasts for 
≥ 8 weeks. 
 
Stable disease: None of the above. 


 
 
 
Relapse: Loss CR, PR, and CI. In other words, a patient with CR or PR is 
considered to have undergone relapse when he or she no longer fulfils the 
criteria for CI. 
 
*Because of subjectivity in peripheral blood smear interpretation, CR does not 
require absence of morphological abnormalities of red cells, platelets, and 
neutrophils.  
 
** In patients with CR, a complete cytogenetic response is defined as failure to 
detect a cytogenetic abnormality in cases with a pre-existing abnormality. A partial 
cytogenetic response is defined as 50% or greater reduction in abnormal 
metaphases. In both cases, at least 20 bone marrow- or peripheral blood-derived 
metaphases should be analyzed. A major molecular response is defined as the 
absence of a specific disease-associated mutation in peripheral blood granulocytes 
of previously positive cases. In the absence of a cytogenetic/molecular marker, 
monitoring for treatment-induced inhibition of endogenous myeloid colony formation 
is encouraged. Finally, baseline and post-treatment bone marrow slides are to be 
stained at the same time and interpreted at one sitting by a central review process. 
 
§Transfusion dependency is defined by a history of at least 2 units of red blood cell 
transfusions in the last month for a hemoglobin of < 8.5 g/dL that was not associated 
with clinically overt bleeding. Similarly, during protocol therapy, transfusions for a 
hemoglobin of ≥ 8.5 g/dL is discouraged unless it is clinically indicated. 
 
§§In splenectomized patients, palpable hepatomegaly is substituted with the same 
measurements. 
 
¶It is acknowledged that worsening cytopenia might represent progressive disease 
but its inclusion as a formal criterion was avoided because of the difficulty 
distinguishing disease-associated from drug-induced myelosuppression. However, a 
decrease in hemoglobin of ≥ 2 g/dL, a 100% increase in transfusion requirement, 
and new development of transfusion dependency, each lasting for more than 3 
months after the discontinuation of protocol therapy can be considered disease 
progression.  
  
7.0 
ADVERSE EVENTS 
As per MDACC and Leukemia phase I-II studies (Appendix C and Appendix F). 
Toxicity will be scored using CTCAE Version 3.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 3.0 can be downloaded from the CTEP 
homepage (http://ctep.info.nih.gov).  All appropriate treatment areas should have 
access to a copy of the CTCAE Version 3.0.  All adverse clinical experiences, 
whether observed by the investigator or reported by the patient, must be 
recorded, with details about the duration and intensity of each episode, the action 
taken with respect to the test drug, and the patient’s outcome.  The investigator 
Commented [SM1]: Add appropriate appendix number 
Commented [SM2]: Add appropriate appendix number here 
as well 


 
 
m u st e v al u at e e a c h a d v er s e e x p er i e n c e f or it s r el ati o n s hi p t o t h e t e st dr u g a n d 
f or it s s eri o u s n e s s. 
M y el o s u p pr e s si o n a n d a s s o ci at e d c o m pli c ati o n s ar e e x p e ct e d e v e nt s d uri n g 
l e u k e mi a t h er a p y a n d ar e p art of t h e tr e at m e nt s u c c e s s ( m arr o w e m pt yi n g of 
l e u k e mi c c ell s). T h er ef or e, m yel o s u p pr e s si o n a n d a s s o ci at e d c o m pli c ati o n s s u c h 
a s f e v er, i nf e cti o n s, bl e e di n g a n d  r el at e d h o s pit ali z ati o n s will n ot b e r e p ort e d a s 
i n di vi d u al A D R s, b ut will b e s um m ari z e d i n t h e u p d at e d a n d fi n a l r e p ort s.  O nl y 
pr ol o n g e d m y el o s u p pr e s si o n, a s d ef i n e d b y t h e n e w N CI crit eri a s p e cifi c f or 
l e u k e mi a, i. e., m arr o w c ell ul arit y < 5 % o n d a y 4 2 or l at er ( 6 we e k s) fr o m st art of 
t h er a p y wit h o ut e vi d e n c e of l e u ke mi a, will b e r e p or t e d a s a n A DR a n d c o n si d er e d 
i n d efi ni n g t h e m a xi m u m t ol er at e d d o s e ( M T D) a n d d o s e-li miti n g t o xi cit y ( D L T) of 
p arti c ul ar a g e nt s or r e gi m e n s.   
 
M D A n d er s o n ( S p o n s or) R e p orti n g R e q uir e m e nt s f or S eri o u s A d v er s e E v e nt s a n d 
D o s e Li miti n g T o xi citi e s :  
 
Seri o us A d verse E ve nt ( S A E) Defi niti o n  
A s eri o u s a d v er s e e v e nt i s o n e t h at at a n y d o s e (i n cl u di n g o v er d o s e): 
  
R e s ult s i n d e at h 
  
I s lif e-t hr e at e ni n g1  
  
R e q uir e s i n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n 
  
R e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y or i n c a p a cit y2  
  
I s a c o n g e nit al a n o m al y or birt h d ef e ct 
  
I s a n i m p ort a nt m e di c al e v e nt3  
  
S u s p e ct e d p o siti v e Pr e g n a n c y 
 
 1“ Lif e-t hr e at e ni n g” m e a n s t h at t h e s u bj e ct w a s at i m m e di at e ri s k  of d e at h at t h e 
ti m e of t h e s eri o u s a d v er s e e v e nt; it d o e s n ot r ef er t o a s eri ou s a d v er s e e v e nt 
t h at h y p ot h eti c all y mi g ht h a v e c a u s e d d e at h if it w er e m or e s e v er e. 
2 “ P er si st e nt or si g nifi c a nt di sa bilit y or i n c a p a c it y” m e a n s t h at t h er e i s a 
s u b st a nti al di sr u pti o n of a p er s o n’ s a bilit y t o c arr y o ut n or m a l lif e f u n cti o n s. 
3 M e di c al a n d s ci e ntifi c j u d g m e nt s h o ul d b e e x er ci s e d i n d e ci di n g  w h et h er 
e x p e dit e d r e p orti n g i s  a p pr o pri at e i n situ ati o n s w h er e n o n e of t h e o ut c o m e s li st e d 
a b o v e o c c urr e d.  I m p ort a nt m e di c al e v e nt s t h at m a y n ot b e i m m e d i at el y lif e-
t hr e at e ni n g or r e s ult i n d e at h or h o s pit ali z ati o n b ut m a y j e o p ar di z e t h e p ati e nt or 
m a y r e q uir e i nt er v e nti o n t o pr e v e nt o n e of t h e ot h er o ut c o m e s l i st e d i n t h e 
d efi niti o n a b o v e s h o ul d al s o u s u all y b e c o n si d er e d s eri o u s.  E x a m pl e s of s u c h 
e v e nt s i n cl u d e all er gi c br o n c h o s p a s m r e q uiri n g i nt e n si v e tr e at m e nt i n a n 
e m er g e n c y r o o m or at h o m e, bl o o d d y s cr a si a s  or c o n v ul sio n s t h at  d o n ot r e s ult 
i n i n p ati e nt h o s pit ali z ati o n, or t h e d e v el o p m e nt of dr u g d e p e n de n c y or dr u g 


 
 
abuse.  A new diagnosis of cancer during the course of a treatment should be 
considered as medically important.  
 
Adverse Drug Reaction Reporting 
Toxicity will be scored using CTCAE Version 3.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 3.0 can be downloaded from the CTEP 
homepage (http://ctep.info.nih.gov).  All appropriate treatment areas should have 
access to a copy of the CTCAE Version 3.0.  All adverse clinical experiences, whether 
observed by the investigator or reported by the patient, must be recorded, with details 
about the duration and intensity of each episode, the action taken with respect to the 
test drug, and the patient’s outcome.  The investigator must evaluate each adverse 
experience for its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and 
about the patient’s outcome. 
 
Serious Adverse Events Reporting:  The principle investigator has the obligation to 
report all serious adverse events to the University of Texas M. D. Anderson Cancer 
Center (MDACC) IRB via the Office of Protocol Research and to Celgene within 24 
hours.  
 
In IND studies, all serious adverse events must be reported to the FDA by the 
investigator through the Office of Research Education & Regulatory Management 
(ORERM) as required by 21 CFR 312.32.  These reports are to be filed utilizing the 
University of Texas M. D. Anderson Cancer Center Adverse Event Reporting Form.  
This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences.  
All other serious adverse events not requiring expedited reporting should be reported to 
MDACC IRB and ORERM within 5 business days.    
 
All deaths during treatment or within 30 days following completion of active protocol 
therapy must be reported within 24 hours of knowledge regardless of the attribution. 
SAEs beyond 4 weeks after the end of study drug administration will be reported if 
thought to be drug related. 
 
NOTE:  Instructions concerning procedures and reporting for pregnancies below. 
 
Pregnancies 
Pregnancies occurring while the subject is on lenalidomide or within 4 weeks after the 
subject’s last dose of lenalidomide are considered expedited reportable events.  If the 
subject is on lenalidomide, it is to be discontinued immediately and the subject is to be 
instructed to return any unused portion of lenalidomide to the Investigator.  The 
pregnancy must be reported by the investigator to MDACC IRB and ORERM AND to 


 
 
Celgene Corporation Worldwide Drug Safety Surveillance (WWDSS) within 24 hours of 
the Investigator’s knowledge of the pregnancy by phone and facsimile using the SAE 
Form. 
 
The Investigator will follow the subject until completion of the pregnancy, and must notify 
Celgene Corporation Worldwide Drug Safety Surveillance (WWDSS) of the outcome as 
specified below.  The Investigator will provide this information as a follow-up to the initial 
SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE 
(i.e., spontaneous abortion [any congenital anomaly detected in an aborted fetus is to 
be documented], stillbirth, neonatal death, or congenital anomaly), the Investigator 
should follow the procedures for reporting SAEs (i.e., report the event to Celgene 
Corporation Worldwide Drug Safety Surveillance (WWDSS)  by facsimile within 24 
hours of the Investigator’s knowledge of the event) and report the event to MDACC IRB 
and ORERM. 
 
Any suspected fetal exposure to lenalidomide must be reported to Celgene, MDACC 
IRB AND ORERM within 24 hours of being made aware of the event.  The patient 
should be referred to an obstetrician/gynecologist experienced in reproductive toxicity 
for further evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to lenalidomide should also be reported. 
In the case of a live “normal” birth, Celgene Corporation Worldwide Drug Safety 
Surveillance (WWDSS), MDACC IRB AND ORERM should be advised as soon as the 
information is available. 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Worldwide Drug Safety Surveillance (WWDSS) 
86 Morris Avenue 
Summit, N.J. 07901 
 
Toll Free:   (800)-640-7854 
Phone:  
(908) 673-9667 
Fax:  
(908) 673-9115 
e-mail:  
clinicaldrugsafety@celgene.com 
 
 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
Serious Adverse Events Reporting:  The principle investigator has the obligation to 
report all serious adverse events to the University of Texas M. D. Anderson Cancer 


 
 
Center (MDACC) IRB via the Office of Protocol Research and also to Celgene within 24 
hours.  
 
IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 
CRF 312.33 provides the data elements that are to be submitted in the report.  The 
Annual Report should be filed with MD Anderson’s ORERM, who will then forward to 
FDA.  An additional copy should be placed in the study's Regulatory Binder and a copy 
must be sent to Celgene Corporation as a supporter of this study as follows. 
 
 
Celgene Corporation 
 
Attn: Medical Development 
 
86 Morris Avenue 
 
Summit, NJ  07901 
 
Tel: (908) 673-9000 
 
All adverse experience reports must include the patient number, age, sex, weight, 
severity of reaction (mild, moderate, severe), relationship to study drug (probably 
related, unknown relationship, definitely not related), date and time of administration of 
test medications and all concomitant medications, and medical treatment provided.   
The investigator is responsible for evaluating all adverse events to determine whether 
criteria for “serious” and as defined above are present.  The investigator is responsible 
for reporting adverse events to Celgene as described below. 
 
Expedited reporting by Principal Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator should inform 
Celgene of any SAE within 24 hours of being aware of the event.  The date of 
awareness should be noted on the report.  This must be documented on an MD 
Anderson SAE form.  This form must be completed and supplied to MDACC IRB, 
ORERM and Celgene within 24 hours/1 business day at the latest on the following 
working day.  The initial report must be as complete as possible, including details of the 
current illness and (serious) adverse event, and an assessment of the causal 
relationship between the event and the investigational product(s).  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 MD 
Anderson SAE form.  A final report to document resolution of the SAE is required.  The 
Celgene protocol number (RV-MF-PI-0102) should be included on SAE reports 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. 
 


 
 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of 
a serious adverse event according to institutional policy. 
   
Sponsor Reporting to the FDA 
Adverse drug reactions that are Serious, Unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) in writing by each investigator/physician engaged 
in clinical research.  A clear description of the suspected reaction should be provided 
along with an assessment as to whether the event is drug or disease related.   
 
The sponsor shall notify the FDA by telephone or by fax of any unexpected fatal or life 
threatening experience associated with the use of the drug. As soon as possible, but no 
later than 7 calendar days after the sponsors initial receipt of the information.    Each 
phone call or fax shall be transmitted to the FDA new drug review division in the Center 
for Drug Evaluation and Research or the product review division in the Center for 
Biologics Evaluation and Research that has responsibility for review of the IND if 
applicable. 
Adverse event updates/IND safety reports 
Celgene shall notify the Investigator via an IND Safety Report of the following 
information: 
 
 Any AE associated with the use of study drug in this study or in other studies that 
is both serious and unexpected. 
 Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file. 
 
Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed by Celgene.  Amendments should only be submitted to IRB/EC after 
consideration of Celgene review.  Written verification of IRB/EC approval will be 
obtained before any amendment is implemented.   
Protocol deviations 


 
 
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject.  A decision will be made as soon as 
possible to determine whether or not the subject (for whom the deviation from protocol 
was effected) is to continue in the study.  The subject’s medical records will completely 
describe the deviation from the protocol and state the reasons for such deviation.  In 
addition, the Investigator will notify the IRB/EC in writing of such deviation from protocol. 
 
8.0 
Study Monitoring and Auditing 
Investigator responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in 
the US Code of Federal Regulations. 
Investigators must enter study data into MDACC’s PDMS.  The Investigator will permit study-
related monitoring visits and audits by MDACC’s ORERM, Celgene, or its representatives, IRB/EC 
review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the 
facilities where the study took place, to source documents, to CRFs, and to all other study 
documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some time 
during monitoring visits to review data and resolve any queries and to allow direct access to the 
subject’s records (e.g., medical records, office charts, hospital charts, and study related charts) for 
source data verification.  The data collection must be completed prior to each visit and be made 
available to MDACC ORERM and the Celgene representative so that the accuracy and completeness 
may be checked. 
 
Regulatory Considerations / Institutional Review Board/Ethics Committee 
approval 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed consent, 
must also be in accordance with principles enunciated in the declaration, as well as ICH Guidelines, 
Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human Subjects and Part 
56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the relevant IRB/EC 
and obtaining written approval for this study.  The approval will be obtained prior to the initiation of 
the study. 
The approval for both the protocol and informed consent must specify the date of approval, protocol 
number and version, or amendment number. 


 
 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the 
Investigator to the IRB/EC for approval.  The Investigator is also responsible for notifying the 
IRB/EC of any serious deviations from the protocol, or anything else that may involve added risk to 
subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use. 
 
Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to any study 
related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process should be recorded in the subject’s source documents.  The original 
consent form signed and dated by the subject and by the person consenting the subject prior to the 
subject’s entry into the study, must be maintained in the Investigator’s study files. 
 
Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the study drug, that is copies of CRFs and source documents (original 
documents, data, and records [e.g., hospital records; clinical and office charts; laboratory notes; 
memoranda; subject’s diaries or evaluation checklists; pharmacy dispensing records; recorded data 
from automated instruments; copies or transcriptions certified after verification as being accurate 
copies; microfiches; photographic negatives, microfilm, or magnetic media; x-rays; subject files; and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical study; documents regarding subject treatment and study drug accountability; original 
signed informed consents, etc.]) be retained by the Investigator for as long as needed to comply with 
national and international regulations (generally 2 years after discontinuing clinical development or 
after the last marketing approval).  The Investigator agrees to adhere to the document/records 
retention procedures by signing the protocol. 
Premature discontinuation of study 
 
Single center 
The responsible local clinical Investigator as well as Celgene have the right to discontinue this study 
at any time for reasonable medical or administrative reasons in any single center.  Possible reasons 
for termination of the study could be but are not limited to: 
 Unsatisfactory enrollment with respect to quantity or quality. 


 
 
 Inaccurate or incomplete data collection. 
 Falsification of records. 
 Failure to adhere to the study protocol. 
 
Study as a whole 
Celgene reserves the right to terminate this clinical study at any time for reasonable medical or 
administrative reasons. 
Any possible premature discontinuation would be documented adequately with reasons being stated, 
and information would have to be issued according to local requirements (e.g., IRB/EC, regulatory 
authorities, etc. 
 
 
Patients will be given instructions and the M.D. Anderson contact name (principal 
investigator/MD Anderson Leukemia staff treating physician), phone, and fax 
numbers.  The referring oncologist will be identified, contacted, and the protocol 
details discussed. 
All therapy will be given under the care of MD Anderson Leukemia staff treating 
physician.  The referring oncologist should contact the MD Anderson Leukemia 
staff treating physician with any questions or problems and the modifications 
should be initiated only by the MD Anderson Leukemia staff treating physician or 
principal investigator, and complications will be recorded in a progress note at 
each follow-up visit. 
From past experience, it is recognized collaboration with oncologist outside MD 
Anderson may occasionally result in some difficulties such as 1) not performing 
tests as required, 2) not sending results of tests or updates of patient condition, 
3) and not informing on toxicities and hospitalizations.  Therefore: 1) we will 
discuss with the referring oncologist about the protocol and doses, 2) we will 
make significant efforts (contact at least twice and document) to retrieve the 
information (tests, toxicities, hospitalizations), and 3) we will record in a progress 
note all the information on follow-up visits. Since information may still be missing 
in one or more components in some patients (e.g. missing once CBC), these 
types of difficulties will be collected and documented as protocol deviations.   
 
9.0 
STATISTICAL CONSIDERATIONS 
 
The primary objective of phase II of this study is to assess efficacy in terms of 
the objective response rate (complete and partial response, and clinical 
improvement) with lenalidomide and prednisone in patients with MF.  The 
MinMax two-stage design proposed by Simon will be implemented.  Sample size 
and decision criteria are chosen to reduce the expected accrual if the treatment 


 
 
is ineffective in regard to response relative to having no interim stopping rule.  
The target response rate is 35%.  A response rate of 20% or less will be 
considered unacceptable and treatment with the therapy will be discontinued. 
Given the response rates stated above, if the probability of inappropriately 
accepting a poor therapy is 10%, a total sample size of 41 patients will result in 
80% power.  
 
In the first stage of the design, a total of 22 patients will be enrolled and the 
study will be put on hold to assess response.  If four or fewer patients respond 
to the combination therapy, after being treated for 6 months, then the study will 
be terminated and the therapy will be declared ineffective.  However, as soon 
as 5 or more patients respond to the lenalidomide, an additional 19 patients will 
be enrolled to complete the study. 
 
After a total of 41 patients have been enrolled into the study, if eleven or fewer 
patients respond to the therapy, the therapy will be declared ineffective.  
However, if greater than 11 patients respond to the therapy, the therapy will be 
considered efficacious.  The probability of early termination due to unacceptable 
response rate is 54%. 
 
Descriptive statistics will be utilized to assess response, time to response, and 
response duration.  Responses will be categorized as the best response 
achieved during the course of the study.  Time to response is defined as the 
time from start of therapy until the response criteria are fulfilled.  Response 
duration will be defined as the time from response until relapse (progressive 
disease) or death. 
 
The safety analysis will include subjects who are enrolled to treatment and take 
at least one dose of study medication.  Toxicity will be graded according to the 
NCI criteria.  Descriptive statistics will be used to describe adverse events 
related to the study drug. Adverse events will be listed and tabulated. 
 
10.0 CORRELATIVE STUDIES 
 
Correlative studies will be done pre-therapy and then every 3 months until patient 
completes 24 cycles, then every 6 months while on therapy.  In the peripheral 
blood and bone marrow aspirate we will measure the levels of TGF-beta, bFGF, 
and PDGF.  Attempt will be made to collect all samples, but it is possible that 
some samples might be missed. These tests will be done at M.D. Anderson, in 
the laboratory of Dr. Bueso-Ramos.  For the testing in blood samples, 10cc 
purple top tube will be obtained and for the testing in bone marrow aspirate 
samples, 3cc purple top tube will be obtained. 
 
In addition, the analysis of total and phosphorylated c-Jun protein in peripheral 
blood will be done. Sample processing will be performed in the laboratory of Dr. 
Carlos Bueso-Ramos at MD Anderson, while sample analysis will take place at 


 
 
the Celgene Corporation. Samples will be obtained pre-therapy, after 6 and 18 
months of therapy. Not all samples might be obtained at all time points. 
Peripheral blood will be collected into 2 specialized CPT 8 mL vacutainer tubes. 
Peripheral blood mononuclear cells (PBMC) will be separated, pelleted, lysed, 
and stored frozen at –70 C until shipping. Samples will be coded so that patient 
confidentiality will be preserved. They will be shipped on dry ice to the Celgene 
Corporation, San Diego. Contact person is: Brydon Bennett, Celgene, 4550 
Towne Centre Court, San Diego, CA 92121, Phone: 858 558 7500, Email: 
bbennett@celgene.com (see Appendix I) 


 
 
 
11.0 REFERENCES  
 
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Dredge K, Horsfall R, Robinson S, Zhang L-H, Lu L, et al.  Orally 
administered lenalidomide (lenalidomide) is anti-angiogenic in vivo and 
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(2) 
Corral LF, Haslett PAJ, Muller FW, Chen R, Wong LM, Ocampo CJ, 
Patterson RT, Stirling DI, Kaplan G.  Differential cytokine modulation and T 
cell activation by two distinct classes of thalidomide analogues that are potent 
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(3) 
Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man H-W, et al.  
Enhancement of cytokine production and AP-1 transcriptional activity in T 
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(4) 
Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar 
K, Gupta D, Chauhan D, Treon SP, Richarson PG, Schlossman RL, Morgan 
GJ, Muller GW, Stirling DI, Anderson KC.  Thalidomide and 
immunomodulatory derivatives augment natural killer cell cytotoxicity in 
multiple myeloma.  Blood. 2001;98:210-216. 
(5) 
Hideshima T, Chauhan D, Shima Y, Raje N, Davies F, Tai YT, Treon SP, Lin 
B, Schlossman RL, Richarson P, Muller G, Stirling DI, Anderson KC.  
Thalidomide and its analogs overcome drug resistance of human multiple 
myeloma cells to conventional therapy.  Blood. 2000;96:2943-2950. 
(6) 
Bartlett JB, Michael A, Clarke IA, Dredge K, Nicholson S, et al.  Phase I study 
to determine the safety, tolerability and immunostimulatory activity of 
thalidomide analog lenalidomide in patients with metastatic malignant 
melanoma and other advanced cancers.  British J of Cancer (2004) 90, 955-
961 
(7) 
Fine HA, Kim L, Royce C, Duic JP, Cohen LJ, Mitchell S.  A phase I trial of 
lenalidomide, a potent thalidomide analog, in patients with recurrent high-
grade gliomas and other refractory CNS malignancies.  Proc ASCO 2003, 
Abstract #418. 
(8) 
Liu Y, Tohnya TM, Figg WD, Gulley JL, Arlen PM, et al.  Phase I study of 
lenalidomide (Revlimid), a thalidomide derivative, in patients with refractory 
metastatic cancer.  Proc ASCO 2003, Abstract #927. 
(9) 
Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B.  Results 
of phase I study of lenalidomide for the treatment of multiple myeloma (MM) 
patients who relapse after high dose chemotherapy (HDCT). Blood 2001; 
98:775a (Abstract #3226). 
(10) 
Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, et al.  
Immunomodulatory drug (lenalidomide) overcomes drug resistance and is 


 
 
well tolerated in patients with relapsed multiple myeloma.  Blood 2002; 
100:3063-3067. 
(11) 
Wu A, Scheffler MR.  Multiple-dose pharmacokinetics and safety of 
lenalidomide in 15 multiple myeloma patients.  Proc ASCO 2004, Abstract 
#2056. 
(12) 
Richardson PG, Jagannath S, Schlossman R, Zeldenrust S, Rajkumar SV, et 
al.  A multi-center, randomized, phase 2 study to evaluate the efficacy and 
safety of two CDC-5013 dose regimens when used alone or in combination 
with dexamethasone (Dex) for the treatment of relapsed or refractory multiple 
myeloma (MM). Blood 2003, Abstract #825. 
(13) 
Hussein MA, Karam MA, Brand C, Pearce G, Reed J, et al.  Doxil (D), 
vincristine (V), reduced frequency dexamethasone (d) and Revlimid (R) 
(DVd-R) a phase I/II trial in advanced relapsed/refractory multiple myeloma 
(Rmm) patients.  Blood 2004, Abstract #208. 
(14) 
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List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, et al.  Efficacy of 
lenalidomide in myelodysplastic syndromes.  N Engl J Med 2005; 352:549-
57. 
(16) 
List AF, Dewald G, Bennett J, Giagounadis A, Raza A, et al.  Hematologic 
and cytogenetic (CTG) response to lenalidomide (lenalidomide) in patients 
with transfusion-independent (TD) myelodysplastic syndrome (MDS) and 
chromosome 5q31.1 deletion: Results of the multicenter MDS-003 study.  
Proc ASCO 2005, abstract #5. 
(17) 
Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med 
2000;342:1255-65. 
(18) 
Reilly J. Pathogenesis and management of idiopathic myelofibrosis. Baillieres 
Clin Haematol 1998;11:751-67 
(19) 
Barosi G. Myelofibrosis with myeloid metaplasia: diagnostic definition and 
prognostic classification for clinical studies and treatment guidelines. J Clin 
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