Clinical trial NCT00946270
Conditions: Polycythemia Vera Thrombocythemia
Keywords: CC-4047 Pomalidomide polycythemia vera essential thrombocythemia myelofibrosis
Sponsor: M.D. Anderson Cancer Center
Start date: 2009-07-22; Completion date: 2018-05-22
Enrollment: 70 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if CC-4047 (now called pomalidomide) and prednisone can help to control MMM. The safety of this therapy will also be studied.

Detailed description:
The Study Drug:

CC-4047 is a drug that may also affect the growth of blood vessels that support tumor growth. If these blood vessels stop growing, it may stop cancer cell growth.

Prednisone is a corticosteroid that is similar to a natural hormone made by your body. Prednisone is often given in combination with other chemotherapy to treat cancer.

Study Drug Administration:

On Days 1- 28 of every 28-day study "cycle," you will take CC-4047 capsule(s) by mouth. You should take the capsule(s), about the same time every day. The capsule(s) should not be opened, broken, or chewed. CC-4047 should be taken without food, at least 2 hours before or 2 hours after a meal. If a dose of CC-4047 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, rather it should be taken at the next scheduled time point.

In order to take part in this study, you must register into and follow the requirements of the POMALYST REMS™ program of Celgene Corporation. This program provides education and counseling on the risks of exposing unborn children to the study drug, and the risks of blood clots and reduced blood counts. You will be required to receive counseling, follow the pregnancy testing and birth control requirements of the program that are appropriate for you, and take surveys regarding how well you are following with the POMALYST REMS™ program.

You will receive prednisone by mouth during the first 3 cycles of therapy. You will take it 1 time a day during Cycle 1. During Cycle 2, you will take a smaller dose 1 time a day. During Cycle 3, you will take the same dose as in Cycle 2, but only 1 time every other day.

On Days 1-28, you will also take low-dose aspirin. This should be taken at the same time as CC-4047. Aspirin is take to help prevent blood clots, which may occur from taking CC-4047. If you are unable to take aspirin, your study doctor will have you take another drug.

You will be given a study "diary". In this diary, you will record when you take each dose of the study drug. You will return any unused study drug and empty bottles at each visit.

Study Visits:

On Day 1 of Cycles 1 and 2, the following tests and procedures will be performed:

* You will have a physical exam, including measurements of your vital signs (blood pressure, temperature, and heart rate) and weight.
* You will be asked about any drugs you are taking and about recent blood transfusions you may have had.
* You will have a performance status evaluation.
* Blood (about 1 tablespoon) will be drawn for routine tests.

On Days 1, 8, 15, and 22 of Cycles 1 and 2, blood (about 4 teaspoons) will be drawn for routine tests.

On Day 28 of each cycle, the following tests and procedures will be performed:

* You will be asked about any drugs you are taking and about recent blood transfusions you may have had.
* You will be asked about any birth control methods you are using.
* Blood (about 4 tablespoons) will be drawn for routine tests.
* You will be asked about any new side effects or medical conditions you may have experienced.
* You will complete a questionnaire about your quality-of-life as well as an assessment of possible pain in your spleen. (Cycles 1 and 2 only)

On Day 28 of cycles 1,2,3 and every third cycle (Cycle 6, 9, and so on), the following tests and procedures will be performed:

* You will have a physical exam, including measurement of yur vital signs and weight.
* Measurements of your spleen and/or liver will be taken.
* You will have a performance status evaluation.

On Day 28 of every sixth cycle (Cycle 6, 12 and so on)the following tests and procedures will be performed:

* Blood (about 4 teaspoons) will be drawn to test your thyroid function.
* You will have an ECG.
* Response of disease to therapy will be assessed. Bone marrow biopsy and aspirate will be done to confirm a complete response if your doctor thinks it is needed.

Pregnancy Testing:

Women who are able to have children will have a pregnancy test every week during Cycle 1, and then every 28 days after that if your menstrual cycle is regular (If your menstrual cycle is not regular, you will have a blood pregnancy test every 2 weeks). These pregnancy tests will be part of a routine blood draw.

Length of Study:

You will remain on study treatment as long as the therapy is beneficial to you. You will be taken off study early if the disease gets worse or intolerable side effects occur.

End-of-Treatment Visit:

Once you are off study, you will have an end-of-study visit. At this visit, the following tests and procedures will be performed:

* You will have a physical exam, including measurements of your vital signs and measurements of your spleen and/or liver.
* You will have an ECG.
* You will be asked about any drugs you are taking and about any blood transfusions you may have had.
* Blood (about 4 tablespoons) and urine will be collected for routine tests and thyroid function tests. This routine blood draw will include a pregnancy test for women who are able to have children.
* You will be asked about any side effects you may have experienced.

Follow-Up Visit:

Women who are able to have children will have a blood (about 1 tablespoon) pregnancy test 28 days after the last dose of study drug. If your periods are irregular you will have 2 blood (about 1 tablespoon each time) pregnancy tests, one 14 days after the last dose of study drug and another 28 days after the last dose of study drug. Response of disease to therapy will be assessed at follow-up 28 days after last dose of study drug.

This is an investigational study. CC-4047 (pomalidomide) is FDA approved and commercially available for the treatment of certain types of MM. Its use in this study is investigational.

Prednisone is FDA approved and commercially available.

Up to 70 patients will take part in this study. All will be enrolled at M. D. Anderson.

Arms: arm 1: CC-4047 0.5 mg orally daily starting on day 1 through 28. Prednisone given during first 3 cycles of therapy. It will be dosed 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. arm 2: CC-4047 3.0 mg orally daily starting on day 1 through 21. arm 3: CC-4047 0.5 mg orally daily starting on day 1 through 28.
Interventions: intervention 1: CC-4047 intervention 2: Prednisone intervention 3: CC-4047
Intervention descriptions: intervention 1: 0.5 mg capsules daily by mouth day 1 through day 28. intervention 2: 30 mg by mouth daily during cycle 1, 15 mg/day during cycle 2, and 15 mg every other day during cycle 3, and then it will be discontinued. intervention 3: 3.0 mg capsules daily by mouth day 1 through 21.

Protocol documents:
Prot_SAP_000.pdf: 
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A PHASE 2, PROSPECTIVE, OPEN-LABEL STUDY (PO-
MMM-PI-0011) TO DETERMINE THE SAFETY AND 
EFFICACY OF CC-4047 IN SUBJECTS WITH PRIMARY, 
POST POLYCYTHEMIA VERA, OR POST ESSENTIAL 
THROMBOCYTHEMIA MYELOFIBROSIS (PMF; post-PV 
MF, or post-ET MF) 
 
 
 
 
Principal Investigator: 
 
 
 
 
Srdan Verstovsek, M.D., Ph.D. 
University of Texas M. D. Anderson Cancer Center 
Department of Leukemia, Unit 428 
PO Box  301402 
Houston, TX 77030 
Phone: 713-745-3429 
Fax: 713-745-0930 
E-mail: sverstov@mdanderson.org 
 
 
 
 


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Table of Contents 
1. Background and Rationale ....................................................................................................... 4 
1.1. 
Myelofibrosis with Myeloid Metaplasia .......................................................................... 4 
1.1.1. 
Differential Diagnosis .............................................................................................. 4 
1.1.2. 
Prognosis .................................................................................................................. 4 
1.1.3. 
Signs and Symptoms ................................................................................................ 5 
1.1.4. 
Treatment of MMM ................................................................................................. 6 
1.2. 
Rationale for 4047 in MMM ............................................................................................ 6 
2. Study Objectives and Endpoints ............................................................................................ 12 
2.1. 
Objectives ...................................................................................................................... 12 
2.1.1. 
Primary objectives ................................................................................................. 12 
2.1.2 
Secondary study objectives .................................................................................... 12 
2.2. 
Endpoints ....................................................................................................................... 12 
2.2.1. 
Primary Endpoint ................................................................................................... 12 
2.2.2. 
Secondary Endpoints ............................................................................................. 12 
3. Investigational Plan ................................................................................................................ 13 
3.1. 
Overall design ................................................................................................................ 13 
3.1.1. 
Investigational Drug ............................................................................................... 14 
3.2. 
Screening and Eligibility ................................................................................................ 15 
3.3. 
Inclusion and Exclusion Criteria .................................................................................... 15 
3.3.1. 
Key Inclusion criteria ............................................................................................. 16 
3.3.2. 
Key Exclusion Criteria ........................................................................................... 17 
3.4. 
Visit schedule and assessments ...................................................................................... 17 
3.5. 
Drug Administration ...................................................................................................... 18 
3.5.1. 
Treatment ............................................................................................................... 18 
3.5.2. 
Dosing regimen ...................................................................................................... 18 
3.5.3. 
Special Handling Instructions ................................................................................ 18 
3.5.4. 
Record of administration ........................................................................................ 19 
3.6. 
Dose Continuation, Modification and Interruption ........................................................ 19 
3.6.1. CC-4047 Dose Reduction Steps ................................................................................... 19 
3.6.2. 
Initiation of a New Cycle of Therapy .................................................................... 19 
3.6.3. Instructions for dose modifications or interruption during a cycle. ............................. 19 
3.6.4. Treatment compliance .................................................................................................. 21 
3.7. Concomitant therapy ........................................................................................................... 21 
3.7.1. Recommended concomitant therapy ............................................................................ 21 
3.7.2. Anticoagulation Consideration .................................................................................... 21 
3.7.3. Prohibited concomitant therapy ................................................................................... 21 
3.8. Discontinuation of Study Treatment ................................................................................... 22 
3.9. Follow-Up ........................................................................................................................... 22 
4. Serious Adverse Event rePORTING ...................................................................................... 23 
4.1 
Serious Adverse Event ................................................................................................... 23 
4.1.1.Expedited reporting by investigator to Celgene………………………………………26                            
4.1.2. 
Pregnancies ............................................................................................................ 25 
5. Biostatistical Analysis ............................................................................................................ 26 
5.1 
Overview ........................................................................................................................ 26 
5.2 
Datasets to be analyzed .................................................................................................. 26 
5.3 
Statistical Methodology ................................................................................................. 26 
5.3.1. 
Primary Endpoint ................................................................................................... 26 


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5.3.2. 
Study Design .......................................................................................................... 26 
5.3.3. 
Analysis Plan ......................................................................................................... 27 
5.4 
Safety evaluation ............................................................................................................ 28 
5.5 
Interim analyses ............................................................................................................. 28 
5.6. 
Sample size and power considerations ........................................................................... 28 
6 Regulatory Considerations ..................................................................................................... 30 
6.1 
Institutional Review Board/Ethics Committee approval ................................................ 30 
6.2 
Informed consent ........................................................................................................... 30 
6.3 
Subject confidentiality ................................................................................................... 30 
6.4 
Study records requirements ............................................................................................ 31 
6.5 
Premature discontinuation of study ................................................................................ 31 
6.5.1 
Single center ........................................................................................................... 31 
6.5.2 
Study as a whole .................................................................................................... 31 
7. References .............................................................................................................................. 32 
 


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1. 
BACKGROUND AND RATIONALE 
1.1. 
Myelofibrosis with Myeloid Metaplasia 
Myelofibrosis with myeloid metaplasia (MMM) is a rare (0.4-1.3 per 100,000 in Europe, 
Australia and USA), chronic, malignant disorder that was first described in 1879 by 
Henck who called it osteosclerosis.  MMM was classified as a myeloproliferative 
disorder (1951) and further characterized as a clonal proliferative disorder of a 
pluripotent stem cell (1978).   
There is some evidence of genetic transmission evidenced by a higher incidence rate in 
the Ashkenazi Jewish population in Northern Israel.  It is also theorized that exposure to 
Thorotrast, industrial solvents (benzene and toluene) and the atomic bomb predisposes 
people to development of the disorder. 
The primary pathogenetic mechanism of proliferation of a pluripotent stem cell clone 
leads to ineffective erythropoiesis, dysplastic-megakaryocyte hyperplasia, and an increase 
in the ratio of immature granulocytes to total granulocytes. This clonal myeloproliferation 
is characteristically accompanied by reactive myelofibrosis (bone marrow fibrosis) and 
by extramedullary hematopoiesis in the spleen or in multiple organs. The diagnosis is 
often suspected when teardrop-shaped red cells and myeloid precursors are detected in 
the peripheral blood. The typical clinical features include marked splenomegaly, 
progressive anemia, and constitutional symptoms. The terms “myeloid metaplasia” and 
“extramedullary hematopoiesis” are used interchangeably to describe a pathologic 
process of ectopic hematopoietic activity that may occur in any organ system but that 
affects primarily the liver and spleen. 
1.1.1. Differential Diagnosis 
The term “myelofibrosis with myeloid metaplasia” is usually reserved for subjects with 
agnogenic myeloid metaplasia (AMMM, also known as idiopathic myelofibrosis) and for 
those with a history of Polycythemia Vera (PV; 25-50% of subjects) or Essential 
Thrombocythemia (ET; 2-3% of subjects). Fibrosis can also be observed in Philadelphia-
positive chronic myelogenous leukemia (CML).  These three disease states are part of the 
differential diagnosis in the early cellular phase of MMM with minimal marrow fibrosis.  
These must be distinguished based on cytogenetics and clinicopathologic features.  Other 
entities that must be included in the differential diagnosis include acute megakaryocytic 
leukemia (AML), primary thrombocytopenia, lymphoma, Hodgkin’s disease, metastatic 
malignancies (e.g., breast and colon cancer), tuberculosis (TB), histoplasmosis, 
Myelodysplastic syndrome (MDS), Hairy Cell Leukemia and plasma cell dyscrasias.  
While the diagnosis is often one of exclusion, there are some discriminating findings.  
1.1.2. Prognosis 
At the molecular level, a JAK2 tyrosine kinase mutation (JAK2V617F) has recently been 
described in MMM with the reported mutational frequency ranging from 35% to 57% 
with 9-29% homozygosity. To date, however, the presence of JAK2V617F in MMM has 


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not been shown to have prognostic relevance. Presence of this mutation, change in its 
prevalence during the course of treatment, and associations with outcomes may provide 
further insight into its potential use as a biologic marker to track the effectiveness of 
therapies for MMM. 
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 are 68% at 2 and 40% at 5 years. The usual causes 
of death are progressive marrow failure, transformation into a nonlymphoblastic 
leukemia, and portal hypertension. 
1.1.3. Signs and Symptoms 
The clinical picture of MMM involves constitutional symptoms (e.g., cachexia, night 
sweats, bone pain, fatigue, fever—present in 40% of subjects), splenomegaly, 
anisopoikilocytosis with teardrop erythrocytes, progressive anemia, immature myeloid 
and erythroid precursors in the peripheral blood (in one-third of the subjects), elevated 
lactate dehydrogenase (LDH) levels, and fibrosis of the marrow (as evaluated by reticulin 
and trichrome [collagen] stains).  The leukoerythoblastic picture is postulated to be 
related to both the intramedullary sinusoidal marrow and splenic hematopoiesis.  
The disease generally occurs in adults, 70% of the subjects are over the age of 50 years 
and the median age ranges from 54 to 62 years. Anemia is apparent in 50% to 70% at 
diagnosis and 25% will have severe anemia with hemoglobin level < 8.0 gm/dL. 
Splenomegaly is present in 85% to 100% of the subjects at diagnosis, and is massive in 
10%.  Approximately half of the subjects 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).   
Growth factor and cytokine variations are multiple.  It is unclear whether the aberrations 
in cytokine production and in the vasculature are pathogenic or whether they represent a 
nonspecific reaction associated with the underlying clonal activity. Increased levels of 
basic fibroblast growth factor (bFGF) have been reported in subjects with MMM.  Both 
transforming growth factor–beta (TGF-beta) and bFGF 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.   Basic FGF 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.  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.  Other cytokines/proteins 
that are disregulated in MMM include; tumor necrosis factor-alpha (TNF-alpha) and 
angiogenic agents like vascular endothelial growth factor (VEGF).  


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1.1.4. Treatment of MMM 
No standard therapy exists for MMM.  Hydroxyurea is the most commonly used agent in 
the proliferative phases of the disease.  Interferon-alpha had yielded hematologic 
responses and reductions in splenomegaly in 30% to 50% of subjects, especially those in 
a proliferative phase; however, it tends to be poorly tolerated.  Therapies for anemia 
management include androgens and/or erythropoietin.  Splenectomy and/or splenic 
irradiation have been used to manage symptomatic splenomegaly.  Splenectomy has been 
associated with risk of leukemic transformation in some series, and splenic irradiation 
can result in severe myelosuppression. 
No medical therapy has been proven to prolong overall survival for these subjects. 
Subjects with an intact quality of life and no threatening hematologic abnormalities, such 
as erythrocytosis or thrombocytosis, have usually been observed without any therapy; 
however, new therapeutic modalities are currently being considered in determining 
treatment indications. 
Advances in the pathogenesis of MMM are expected to facilitate the development of 
molecularly targeted therapy. In the meantime, current management strategies include 
observation for low risk cases, participation in experimental drug therapy at the 
intermediate risk level and allogeneic stem cell transplantation for high-risk disease. 
From a therapeutic standpoint, benefit to a subset of subjects has been demonstrated for 
both allogeneic stem cell transplantation and novel drugs, including the thalidomide-
derived immunomodulatory analogs known as immunomodulatory drugs. 
1.2. 
Rationale for CC-4047 in MMM 
The efficacy of thalidomide has been significantly limited by adverse effects, which 
include sedation, neuropathy, constipation, and deep vein thrombosis. This toxicity 
profile seems dose-related and duration-related, spurring the development of IMiDs, 
which have the potential of improved potency and reduced toxicity.  By modifying 
thalidomide structure through the addition of an amino group at the 4 position of the 
phthaloyl ring (to generate CC-4047) and with the further removal of a carbonyl on the 
ring to form another analog (CC-5013), such analogs are up to 50,000 times more potent 
at inhibiting TNF-alpha than the thalidomide parent compound in vitro and are markedly 
more stable. Indeed, when CC-5013 was tested at a dose range of 5 to 50 mg/d, 25 mg/d 
was determined to be the maximum tolerated dose without a significant level of the side 
effects of constipation and neuropathy as had been typical of thalidomide. Along with the 
improved tolerability, impressive response rates were realized in the treatment of multiple 
myeloma (MM) and MDS.   
In multiple myeloma IMiDs not only act to inhibit angiogenesis through inhibition of 
bFGF, VEGF and TNF-alpha induced endothelial cell migration, but also block the 
increased secretion of myeloma cell growth, survival, and migratory factors such as 
interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and vascular endothelial 
growth factor (VEGF). In addition, they expand natural killer (NK) cell and T-cell 
numbers and are potent co-stimulators of T-cells when activated through the T-cell 
receptor.  CC-4047, an IMiD, enhances production of gamma interferon (INFγ) and 
interleukin (IL)-2, and augments IL-10 production. Many of the cytokines active in MM 


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are similar to those noted in MMM:  increased levels of bFGF, TNF-alpha, VEGF and 
IL–6. Therefore, there is reason to expect that CC-4047 may have a beneficial effect in 
the treatment of MMM.  
In vitro models of anti-TNF activity have shown that CC-4047 has an IC50 of 24 nM 
(6.55 ng/mL) and 25 nM (6.83 ng/mL) against TNF produced by Lipo-polysaccharide 
(LPS)-stimulated human peripheral blood mononuclear cells and LPS-stimulated human 
whole blood respectively. Thalidomide, by comparison, has a TNF IC50 in human 
peripheral blood mononuclear cells of approximately 194 µM (50.1 µg/mL). 
There is previous human experience with the treatment of MMM by the original IMiD, 
thalidomide.  Single-agent thalidomide at “conventional” doses (> 100 mg/d) has been 
evaluated in MMM based on its antiangiogenic properties and the prominent 
neoangiogenesis that occurs in MMM. Thalidomide monotherapy at such doses produces 
approximately a 20% response rate in anemia but is poorly tolerated (an adverse dropout 
rate of >50% in 3 months). To improve efficacy and tolerability, 21 symptomatic subjects 
(hemoglobin level < 10 g/dL or symptomatic splenomegaly) with MMM were treated 
with low-dose thalidomide (50 mg/d) along with a 3-month oral prednisone taper 
(beginning at 0.5 mg/kg/d). The combination therapy was well tolerated in all enrolled 
subjects, with 20 subjects (95%) able to complete 3 months of treatment. An objective 
clinical response was demonstrated in 13 (62%) subjects, all improvements in anemia. 
Among 10 subjects who were transfusion dependent, 7 (70%) improved and 4 (40%) 
became transfusion independent. Improvements in anemia correlated with lower 
pretherapy CD34+cell counts in the peripheral blood (median, 81.2 CD34+ cells/μL 
versus 554 CD34+ cells/μL [nonresponders]; P = 0.03) as well as lower numbers of 
circulating blasts (median, 0.8% versus 4.7% in nonresponders; P = 0.03).  Among 8 
subjects with thrombocytopenia (platelet count <100 x 109/L), 6 (75%) experienced a 
50% or higher increase in their platelet count. In 4 of 21 subjects (19%), spleen size 
decreased by more than 50%. Responses observed were mostly durable after 
discontinuation of the prednisone. The dose of thalidomide in this study (50 mg/d) was 
better tolerated than the higher doses used in previous studies. Adverse events associated 
with corticosteroid therapy were mild and transient. Clinical responses did not correlate 
with improvements in either intramedullary fibrosis or angiogenesis. The thalidomide-
prednisone combination was well tolerated and appeared to be a promising drug regimen 
for treating cytopenias in subjects with MMM.  
Ten of the MMM subjects completed an additional 3 month thalidomide-only treatment 
phase of the study.  After discontinuation of the prednisone, clinical responses were 
maintained in 62% in terms of anemia, 66% in terms of thrombocytopenia, and 50% of 
the splenomegaly responses. (Mesa, 2003) 
In 2006, results of 2 similarly designed but separate phase 2 studies involving single-
agent lenalidomide (CC-5013, Revlimid) have been published, involving in a total of 68 
patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol 
treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 
100 x 10(9)/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 
additional months, in case of response. Overall response rates were 22% for anemia, 33% 
for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed 


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impressive in 8 patients whose hemoglobin level normalized from a baseline of either 
transfusion dependency or hemoglobin level lower than 100 g/L. Additional treatment 
effects in these patients included resolution of leukoerythroblastosis (4 patients), a 
decrease in medullary fibrosis and angiogenesis (2 patients). Grade 3 or 4 adverse events 
included neutropenia (31%) and thrombocytopenia (19%). The authors (Tefferi, 2006) 
concluded that lenalidomide engendered an intriguing treatment activity in a subset of 
patients with MMM that includeed an unprecedented effect on peripheral blood and bone 
marrow abnormalities. Interestingly, some patients previously treated with thalidomide 
responded to lenalidomide. 
 
Prompted by the activity of single-agent oral lenalidomide (LEN) in primary or secondary 
(post-essential thrombocythemia or post-polycythemia vera) myelofibrosis (MF), 
Quintas-Cardama and colleagues (2008) sought to evaluate the safety and efficacy of the 
combination of LEN and prednisone (LEN+PRD) in a phase II study for patients with 
MF. The rationale was that the potent antiangiogenic and cytokine-modulating activity of 
LEN may be enhanced by PRD to reduce marrow fibrosis and improve hematopoiesis in 
MF. Therapy consisted of LEN 10mg/d PO (dose level [DL] 0) on days 1–21 of a 28-day 
cycle in combination with PRD 30mg/d PO during cycle 1, 15mg/d during cycle 2, and 15 
mg/d every other day during cycle 3. LEN was to be given for a minimum of 6 cycles and 
continued indefinitely in responders. LEN dose could be reduced to 5 mg/d (DL –1) or to 
5 mg/d every other day (DL –2), or increased to 15 mg/d (DL +1) or 20 mg/d (DL +2) 
according to toxicity or lack of response. Forty patients (23 male) have been treated. 
Median age was 62 years (range, 41–86), time from MF diagnosis to LEN+PRD therapy 
10 months (range, 0–122), WBC count 87x109/L (range, 1.1–89), hemoglobin 9.8 g/dL 
(range, 7.8–17.3), and palpable splenomegaly 10cm (range, 0–25). Patients had received a 
median of 1 prior therapy (range 0–4), including hydroxyurea (n=14), azacitidine (n=6), 
thalidomide (n=4), and IFN-  (n=3). Ten (25%) patients were treatment-naïve. The 
JAK2V617F mutation was detected in 18 (50%) of 36 tested patients and 20 (50%) of 40 
had abnormal cytogenetics. 341 cycles have been administered. Patients have received 
therapy for a median of 18 months (range, 6–24.5). According to the International 
Working Group for Myelofibrosis Research and Therapy (IWG-MRT) criteria, 12 (30%) 
patients responded, including 8 JAK2V617F-positive, 3 previously untreated, and 2 who 
had failed prior thalidomide-based therapy. Three (7.5%) partial response (PR), and 9 
(22.5%) clinical improvement (CI) were seen. Anemia improved in 7 (30%; 3 PR and 4 
CI) of 23 patients with pretreatment Hb <10g/dL or transfusion dependency. 
Splenomegaly significantly decreased in 10 (42%; 2 PR and 8 CI) of 24 patients. Again, 
few patients previously exposed to thalidomide responded to lenalidomide therapy. 
Responses occurred after a median of 12 weeks (range, 2–32), have been sustained for a 
median of 15 months (range, 4.1–20), and are ongoing in 10 of 12 responders still 
receiving LEN. After 12 months of therapy, a significant decrease was observed in the 
JAK2V617F allele burden among the 8 JAK2V617F positive responders (p=0.03). Four of the 
8 JAK2V617F-positive responders had >50% reduction of the mutant allele burden, 
becoming undetectable in 1. Serial histopathology analyses revealed significant 
reductions in bone marrow cellularity (p=0.01) and reticulin fibrosis (p=0.02) after 12 
months of therapy in 8 assessable responders. The most frequent grade 3–4 toxicities were 
neutropenia (65%), anemia (50%), fatigue (30%), and thrombocytopenia (20%). Twenty-


October 21, 2013 
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four (60%) patients required one dose level reduction (5 required further reduction to dose 
level -2), 1 (2.5%) had the dose escalated, and 15 (25%) remained at the initial dose level. 
Thirty (75%) patients discontinued therapy due to lack of response (n=15), pt’s decision 
(n=3), grade 3–4 toxicity (n=9), allogeneic stem cell transplant (n=1), loss of response 
(n=1), and poor compliance (n=1). No transformation to acute myeloid leukemia has been 
observed. In summary, prolonged administration of LEN is generally well-tolerated, and 
yields long-lasting clinical, histopathological, and molecular responses in patients with 
MF when administered in a continuous manner. 
 
Very recently, a dose-escalation trial to determine whether CC-4047 can be given safely 
to MMM patients has been concluded (Mesa 2009). A classic phase-I 3 x 3 trial was done 
in persons with symptomatic MMM (anemia and/or symptomatic splenomegaly). The 
starting dose was 2.5 mg/d d 1-21 every 28 d. Dose-escalation at increments of 0.5 mg/d 
was done if no subject had a DLT (≥grade-4 hematologic toxicity, ≥grade-3 febrile 
neutropenia or ≥grade-3 non-hematologic toxicity) in cycle-1. Subsequent cohorts were 
treated until the maximum tolerated dose (MTD) was reached (dose level before that 
resulting in DLT in >1 of 6 subjects). 12 subjects with MMM were enrolled 06/08-12/08.  
8 had primary MMM, 3, post-polycythemia vera MMM and 1, post-essential 
thrombocythemia MMM.  Median age was 67 years (range, 51-83), 7 were female. 9 had 
a JAK2-V617F mutation.  11 were RBC-transfusion–dependent and 1 had a hemoglobin 
<10 g/dL.  Median WBC was 4.5 x 10e9/L (range, 2–64 x 10e9/L).  Median platelets 
were 111 x 10e9/L (range, 52-538 x 10e9/L). 10 subjects had splenomegaly, median size 
of 12 cm below the LCM (range, 4-26 cm). 3 subjects were enrolled in each of the 2.5, 
3.0, and 3.5 mg dose cohorts.  DLTs were observed at the 3.5 mg level: 2 of 3 subjects 
had grade-4 neutropenia and 1, grade-3 thrombocytopenia.  3 more subjects were enrolled 
at the 3.0 mg level cohort confirmed this dose as the MTD.  4 of 9 subjects receiving ≥3.0 
mg/d had grade-3 neutropenia and 1 had grade-3 thrombocytopenia.  Other toxicities 
were <grade-3 including fatigue, dyspnea, rash, lymphadenopathy and headaches. 
Subjects received a median of 3 cycles (range, 2-6 cycles).  8 subjects remain on-study; 
reasons for discontinuation were progression (N=2) and no response (N=2).  Therefore, 
data indicate the dose of CC-4047 can be increased to 3.0 mg/d for 21 d of a 28 d cycle.  
The DLT at higher doses is neutropenia.   
ADDENDUM 11/10/09: 
An update of the Phase 1 trial done at the Mayo clinic (Dr. Ruben Mesa, personal 
communication) was provided. Nineteen MMM patients were enrolled between June, 
2008 and March, 2009. Most of the subjects were intermediate-2 or high risk by the 
International Prognostic Scoring System for MF. Median duration of disease at 
enrollment was 24 months (range, 1-173 months). Most were RBC-transfusiondependent 
and had symptomatic splenomegaly. Three subjects enrolled into the 2.5 mg/d, 3.0 g/d, 
and 3.5 mg/d cohorts (given for 3 weeks, with one week break). The dose limiting 
toxicity (DLT) was bone marrow suppression which occurred in 2 of 3 subjects in the 3.5 
mg/d cohort. 3 additional subjects received 3.0 mg/d confirming this as the MTD. 7 
additional subjects were enrolled at the MTD of 3.0 mg/d. Because no efficacy was seen 
at 3.0 mg/d (21 of 28 days) the dose was decreased to 0.5mg/d (given continuously daily 
for 4 weeks; no break in therapy) after three cycles in 8 subjects. 7 subjects responded 
using the International Working Group for Myelofibrosis Research and Treatment criteria 


October 21, 2013 
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10
for Clinical Improvement (IWGMRT CI). All responders had an IWG-MRT CI for 
anemia (6 previously RBC transfusion-dependent). 2 of these anemia responders also had 
a decrease in splenomegaly. The eligibility criteria excluded the possibility of an IWG-
MRT CI for thrombocytopenia. However all 5 subjects with pre-study platelets of 50-
100x109/L had an increase in their platelet number, with 3 of these achieving normal 
platelet levels. Responses occurred after a median of 4 months (range, 2-9 months) and 
only after reduction to 0.5mg/d in 5 responders including the 2 subjects with decreased 
spleen size. These responses occurred after 1 and 2 cycles after dose reduction, 
respectively (1-3 months). Responses were durable; 5 responders continue on-study. 
 
In addition, results of randomized Phase II study have been published (Tefferi, 2009). In 
a phase II randomized, multicenter, double-blind, adaptive design study, four treatment 
arms were evaluated: pomalidomide (2 mg/day) + placebo, pomalidomide (2 mg/day) + 
prednisone, pomalidomide (0.5 mg/day) + prednisone, and prednisone + placebo. 
Pomalidomide was administered for up to twelve 28-day treatment cycles. Prednisone (30 
mg/day) was given in a tapering dose schedule during the first three cycles. Response 
was assessed by International Working Group criteria. Eighty four patients with MMM-
associated anemia were randomly assigned to the above-listed treatment arms: 22, 19, 22 
and 21, respectively. All active patients have completed six cycles of treatment. Response 
in anemia was documented in 20 patients, including 15 who became transfusion-
independent. Response rates in the four treatment arms were 23%, 16%, 36% and 19%. 
The corresponding figures for patients receiving  3 cycles of treatment (n=62) were 
38%, 23%, 40% and 25%. Response to pomalidomide  prednisone was durable (range 
3.2-16.9+ months) and significantly better in the absence of leukocytosis (37% vs. 8%; 
p=0.01); JAK2V617F or cytogenetic status did not affect response. Grade 3 toxicities 
were infrequent and included (in each treatment arm) neutropenia (9%-16%-5%-5%), 
thrombocytopenia (14%-16%-9%-5%) and thrombosis (9%-5%-0%-0%). Pomalidomide 
therapy at 0.5  an abbreviated course of prednisone is well tolerated in patients with 
myelofibrosis and active in the treatment of anemia.  
 
Finally, 20 patients have been accrued into current study so far, with starting dose of 
3mg/day. After median follow up of 2 months, most patients had to interrupt the therapy 
due to side effects: 13 patients experienced myelosuppression, 3 had rash/swelling. The 
study accrual has been put on hold, pending modification of the dose to 0.5mg/day (given 
continuously). 
 
ADDENDUM 3/30/11: 
Since the last amendment final results (previous amendment provided preliminary 
results) of the Phase I study of pomalidomide has been published (Phase1/-2 study of 
Pomalidomide in myelofibrosis. Mesa RA, Pardanani AD, Hussein K, Wu W, Schwager 
S, Litzow MR, Hogan WJ, Tefferi A. Am J Hematol. 2010 Feb;85(2):129-30.): “We 
conducted a dose-escalation study to see if higher doses of pomalidomide (previously 
shown to be safe and effective for myelofibrosis associated anemia at 0.5 mg/day [with 
prednisone] or 2.0 mg/day) increased anemia responses. 3.0 mg/d given for 21 of 28 
consecutive days was the maximum-tolerated dose (MTD), with myelosuppression being 


October 21, 2013 
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11
dose limiting. Nonresponders at the MTD had their dose decreased and the therapy 
interval increased to daily. Seven of 19 subjects had an anemia-response and two had a 
spleen response. Most responses occurred after dose-reduction to 0.5 mg/d, suggesting 
higher doses are associated with increasing myelosuppression without increasing (or 
possibly decreasing) efficacy. 
 
Very recently, a Phase II study results were published, examining low dose 
pomalidomide 0.5mg/day as a single agent, without prednisone (A phase-2 trial of low-
dose pomalidomide in myelofibrosis. Begna KH, Mesa RA, Pardanani A, Hogan WJ, 
Litzow MR, McClure RF, Tefferi A. Leukemia. 2011 Feb;25(2):301-4.): “In a previous 
study, we reported on the safety and efficacy of low-dose (0.5 mg) pomalidomide and 
prednisone and pomalidomide alone (2 mg/day), for the treatment of anemia associated 
with myelofibrosis (MF). The current study examined the value of low-dose 
pomalidomide alone. The main eligibility criterion was transfusion-dependency or 
hemoglobin of 10gm per 100 ml. Anemia response was assessed by International 
Working Group criteria. Pomalidomide (0.5 mg/day) was given to 58 patients (median 
age 68 years); 46 (79%) were transfusion-dependent. Anemia response was seen in 17% 
of patients. Grade 3 or 4 thrombocytopenia/neutropenia occurred in 2%/ 0% of patients”. 
This experience was not as good as previously published result when pomalidomide 
0.5mg/day was combined with prednisone (36% response in anemia), as explained above 
in the “ADDENDUM 11/10/09” (Tefferi, 2009). 
 
Finally, preliminary interim results of this study are available, as described in section 5.5: 
20 evaluable patients have been observed for at least 6 cycles on therapy with single 
agent CC-4047 at 0.5mg/day. We have observed 3 patients that has become transfusion 
independent (response rate of 15%). In terms of toxicity, the therapy with such a low 
dose of pomalidomide was very safe: one occurrence of neutropenic fever and one 
occurrence of leg DVT (both in the same patient). Therefore, we propose to study low 
dose pomalidomide 0.5mg/day in combination with prednisone, to extend previously 
noted activity of the combination (22 patients treated with 36% response rate) as reported 
by Tefferi (2009). 
 
 


October 21, 2013 
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12
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. Primary objectives 
 To determine the effect of CC-4047 and prednisone in the treatment of Primary, 
Post Polycythemia Vera, or Post Essential Thrombocythemia Myelofibrosis 
(PMF, post-PV MF, or post-ET MF).   
 To determine the safety of CC-4047 and prednisone in the treatment of Primary, 
Post Polycythemia Vera, or Post Essential Thrombocythemia Myelofibrosis 
(PMF, post-PV MF, or post- ET MF).  
2.1.2    Secondary study objectives 
 To further explore the nature and quality of responses to CC-4047 and prednisone 
2.2. 
Endpoints 
2.2.1. Primary Endpoint 
 Best overall response as determined by International Working Group Criteria over 
the first 6 cycles (168 days) of study treatment 
 Safety (type, frequency, severity [National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0] of adverse events 
(AEs), and relationship of AEs to CC-4047) 
2.2.2. Secondary Endpoints 
 Duration of response 
 Time to response 
 Best overall response as determined by International Working Group Criteria over 
the first 12 cycles (336 days) of study treatment 
 Cytogenetic response in subjects with a baseline abnormality 
 Molecular response (JAK2V617F mutation burden) in peripheral blood in mutation 
positive subjects  
 Bone marrow fibrosis improvement 
 Quality of Life (QoL) assessments [the four components (Physical, Social/Family, 
Emotional and Functional Well-Being) and total of the 27-item FACT-G, together 
with the 13-item fatigue subscale, the total of the Additional Concerns, and a 
Likert Pain Scale for splenic pain. 


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13
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall design 
CC-4047 is a phase 2, prospective, open-label study to determine the efficacy and safety 
of CC-4047 at a 0.5 mg dose, in combination with prednisone, to study further in subjects 
with primary, post polycythemia vera, or post essential thrombocythemia myelofibrosis  
Screening: 
Potential subjects will enter screening and be evaluated for the inclusion and exclusion 
criteria for the Treatment Period of this study. The screening period will not last more 
than 28 days.  The assessments and procedures that will be performed during screening 
are outlined in Appendix M:  Schedule of Events.  Screening assessments will include an 
informed consent, medical history, review of prior medications, complete physical exam, 
ECOG performance status assessment, complete blood count (CBC) with differential, 
serum chemistries, urinalysis, thyroid function tests, 12-lead ECG, bone marrow biopsy 
and aspirate to confirm diagnosis and for standard cytogenetics, JAK2 mutation (by 
quantitative polymerase chain reaction [PCR], and PCR or fluorescent in situ 
hybridization (FISH) for bcr/abl, spleen and/or liver (if spleen is absent) measurements, 
and QoL Assessments.   
Females of reproductive potential1 must adhere to the scheduled pregnancy testing 
as required in the POMALYST REMS™ program. All study participants must be 
registered into the mandatory POMALYST REMS™ program, and be willing and 
able to comply with the requirements of the POMALYST REMS™ program. 
Before starting study drug:  
Subjects must follow pregnancy testing requirements as outlined in the 
POMALYST REMS™ program.  
  
Treatment Period: 
Subjects meeting all inclusion and exclusion criteria will receive 0.5mg CC-4047. 
Prednisone will be given during first 3 cycles of therapy.  It will be dosed 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. Prednisone will be used from 
commercially available supplies. 
Subjects will remain on study treatment in the Treatment Period in the absence of disease 
progression or toxicity warranting discontinuation of therapy.  Twenty-eight days is 
considered one cycle of therapy.  Subjects may be taken off study at 6 months if there is 
no response, however, they should continue to be followed until disease progression or 
initiation of an alternate therapy. 
                                                
1 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). 


October 21, 2013 
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14
Study assessments and serial measurements of safety and efficacy will be performed as 
outlined in Appendix M:  Schedule of Assessments.  All scheduled visits will have a ±3-
day window unless otherwise stated. Beginning with Cycle 6 scheduled visits will have a 
+/-7 day window. 
CBCs will be monitored weekly for the first 56 days of study treatment and then, at 
minimum, every 28 days. Study visits will occur at least every 28 days.  Study visits 
should occur whether or not study drug has been interrupted for an adverse event. Repeat 
bone marrow aspirate, biopsy and cytogenetic studies will be performed to confirm a 
complete response and when clinically indicated.  Cytogenetic analysis may be 
performed on the peripheral blood if necessary. Patients who have been on the study for 
at least 3 cycles and had no grade 3 or 4 toxicity, will be allowed to return to MD 
Anderson at the end of Cycle 6, then subsequently every 6 cycles. In this case mandatory 
monthly visits will be done at the local referring doctor’s office, and will also include 
phone contact by the study staff. 
Pregnancy Testing    
Patients must follow pregnancy testing requirements as outlined in the POMALYST 
REMS™ program.  
3.1.1. Investigational Drug  
3.1.1.1. 
Supplier(s) 
Celgene Corporation will supply POMALYST® (CC-4047) to study participants at 
no charge through Celgene’s Pomalidomide Risk Evaluation and Mitigation 
Strategy (POMALYST REMS™).  
3.1.1.2. 
Dosage form 
CC-4047 will be supplied as 0.5mg capsules for oral administration.   
3.1.1.3. 
Packaging 
 
CC-4407 will be shipped directly to the pharmacy at the study site. Bottles will 
contain a sufficient number of capsules for one cycle of dosing.    
3.1.1.4. 
Labeling 
CC-4047 investigational 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.  The study drug label 
must be clearly visible. Additional labels must not cover the Celgene label. 
CC-4047 should not be handled by FCBP unless wearing gloves.   


October 21, 2013 
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15
3.1.1.5. 
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.   
3.1.1.6. 
Storage 
At the study site, all investigational study drugs will be stored in a locked, safe area to 
prevent unauthorized access. 
The study drug should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold. 
3.1.1.7. 
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.  Subjects will be instructed to return empty bottles or unused 
capsules.   
3.1.1.8  
Drug dispensing requirements 
Pomalidomide (POMALYST®) will be provided to research subjects for the duration of 
their participation in this trial at no charge to them or their insurance providers. 
Pomalidomide will be provided in accordance with the Celgene Corporation’s 
POMALYST REMS™ program. Per the standard POMALYST REMS™ program 
requirements, all physicians who prescribe pomalidomide 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 POMALYST REMS™ program.   
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for 
IND studies. Only enough pomalidomide for one cycle of therapy will be supplied to the 
patient each cycle.  This is in accordance with the POMALYST REMS™ program. 
 
3.2. 
Screening and Eligibility 
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study.  All subjects will be screened for eligibility.  
Screening procedures are outlined in Section 2, Schedule of Study Assessments and 
unless otherwise specified, must take place within 28 days prior to initiation of therapy.  
3.3. 
Inclusion and Exclusion Criteria 
Subjects are to be assessed for suitability for entry into the study based on the following 
inclusion and exclusion criteria. 


October 21, 2013 
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3.3.1. Key Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study: 
1. Must be > 18 years of age at the time of voluntarily signing an Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) – approved informed consent 
form. 
2. Must be diagnosed with myelofibrosis requiring therapy including myelofibrosis 
with myeloid metaplasia (MMM), de novo presentation (i.e. agnogenic myeloid 
metaplasia [AMMM], and developing after an antecedent history of Polycythemia 
vera (i.e., post-polycythemic myeloid metaplasia [PPMM]), or essential 
Polycythemia (i.e., post thrombocythemic myeloid metaplasia [PTMM]). 
3. Screening total hemoglobin level < 10 g/dL or transfusion-dependent anemia 
defined as per IWG criteria (transfusion dependency defined by a history of a least 
2 units of red blood cell transfusions in the last 28 days for hemoglobin < 8.5 g/dL 
that was not associated with overt bleeding). 
4. Must have adequate organ function as demonstrated by the following < 14 days 
prior to starting study drug: 
 ALT (SGOT) and AST(SGPT)  3 x upper limit of normal (ULN), [unless 
upon judgment of the treating physician, it is believed to be due to 
extramedullary hematopoiesis (EMH)] 
 Total bilirubin < 3 x ULN or Direct Bilirubin < 2 x ULN 
 Serum creatinine  2.5 mg/dL 
 Absolute neutrophil count ≥ 1,000/µL (≥1.0 x 109/L) 
 Platelet count  50,000/µL (≥50 x 109/L) 
5. Subjects must be willing to receive transfusion of blood products. 
6. ECOG performance status (PS) of 0, 1, or 2 at screening. 
7. Must be willing to adhere to the study visit schedule and other protocol 
requirements. 
8. No active malignancies with the exception of basal cell or squamous cell 
carcinoma of the skin, or carcinoma “in situ” of the cervix or breast. 
9. All study participants must be registered into the mandatory POMALYST 
REMS™ program, and be willing and able to comply with the requirements of the 
POMALYST REMS™ program. 
10. Females of reproductive potential (FCBP†) must adhere to the scheduled 
pregnancy testing as required in the POMALYST REMS™ program. Able to take 
                                                
† 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). 


October 21, 2013 
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17
aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to 
ASA may use warfarin or low molecular weight heparin). 
3.3.2. Key Exclusion Criteria 
1. Known positive status for HIV, hepatitis B carrier, or active hepatitis C infection. 
2. The use of any growth factors, cytotoxic chemotherapeutic agents (e.g. 
hydroxyurea), corticosteroids, or experimental drug or therapy within 14 days of 
starting CC-4047 and/or lack of recovery from all toxicity from previous therapy 
to grade 1 or better. 
3. Any serious medical condition or psychiatric illness that would prevent, (as 
judged by the treating physician) the subject from signing the informed consent 
form or 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. 
4. Pregnant or lactating females.  
5. Prior use of CC-4047. 
6. Currently enrolled on another clinical trial or receiving investigational agent 
3.4. 
Visit schedule and assessments 
Screening Assessments and all on-study scheduled visits and assessments are outlined in 
Appendix M: Schedule of Assessments.  
For females of child bearing potential, counseling about pregnancy precautions 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. 
Pregnancy testing and counseling must be performed if a subject misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment must be 
discontinued during this evaluation. 
In addition to the required pregnancy testing, the Investigator must confirm with FCBP 
that she is continuing to use two reliable methods of birth control at each visit.   
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. 
An unscheduled visit can occur at any time during the study.  Source documentation must 
be maintained for these unscheduled visits. The date for the visit and any data generated 
                                                                                                                                              
 
 


October 21, 2013 
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18
must be recorded on the appropriate source.  Source documents for these unscheduled 
visits must also be maintained. 
At treatment discontinuation, subjects will undergo off study evaluations as outlined in 
Appendix M:  Schedule of Assessments.  In addition, a safety assessment will be done 
approximately 28 days post the last dose of study drug.   
3.5. 
Drug Administration 
3.5.1. Treatment 
Subjects who meet entry criteria will be eligible to receive 0.5mg CC-4047 and 
prednisone. 
3.5.2. Dosing regimen 
Initial dosing of CC-4047 for eligible subjects will be 0.5mg daily. Subjects will receive 
oral CC-4047 from day 1 through day 28, continuously, in the absence of disease 
progression or toxicity warranting discontinuation of therapy.  Twenty-eight days is 
considered one cycle of therapy.  Dosing will be at approximately the same time each 
day. CC-4047 capsules should be swallowed whole, and should not be broken, chewed or 
opened.  CC-4047 should be taken without food, at least 2 hours before or 2 hours after a 
meal. If a dose of CC-4047 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, rather it should be taken 
at the next scheduled time point. Patients who take more than the prescribed dose of CC-
4047 should be instructed to seek emergency medical care if needed and contact study 
staff immediately.   
Only one cycle of study drug will be supplied to the subject each cycle. Prednisone will 
be given during first 3 cycles of therapy.  It will be dosed 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.  
Subjects must also receive oral low-dose aspirin (81 mg) as prophylactic anti-thrombotic 
treatment unless it is contraindicated or the subject has a platelet count less than 
75,000/µL.  If low-dose aspirin is contraindicated, the investigator should prescribe 
another appropriate prophylactic anti-thrombotic therapy. 
Single oral CC-4047 doses of 1 and 50 mg in healthy adult males were safe and resulted 
in Cmax values of 11.2 and 288 ng/mL respectively. Given the short half-life in healthy 
adult male humans (approximately 8 to 11 hours) and once daily dosing, minimal 
accumulation is expected. A daily dosing schedule will be utilized for this study. 
Subjects experiencing adverse events may need study treatment modifications (Table 1). 
3.5.3. Special Handling Instructions 
Females of childbearing potential should not handle or administer the clinical dosage 
forms unless they are wearing gloves. 


October 21, 2013 
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19
3.5.4. Record of administration 
Accurate recording of all study drug administration (including dispensing and dosing) 
will be made in the appropriate section of the source documents.   
3.6. 
Dose Continuation, Modification and Interruption 
All adverse events/toxicities are to be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE Version 3.0). Subjects who cannot tolerate dose of 
0.5mg are to discontinue treatment.  The dose of CC-4047 is not to be escalated.   
3.6.1. CC-4047 Dose Reduction Steps 
No reduction of the dose below 0.5mg a day is planned (Table 1). 
3.6.2. 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 (≥ 1 X 109/L); 
 The platelet count is ≥ 50,000/μL (≥ 50 X 109/L); 
 Any CC-4047-related allergic reaction/hypersensitivity or sinus bradycardia/ other 
cardiac arrhythmia adverse event that may have occurred has resolved to ≤ grade 1 
severity; 
 Any other CC-4047-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 CC-4047 will not be initiated until the toxicity has resolved as 
described above. 
3.6.3. Instructions for dose modifications or interruption during a cycle. 
 
Table 1:  CC-4047 Dose Modification Guidelines 
CTCAE 
CATEGORY 
ADVERSE EVENTS 
DOSING CHANGE 
Allergy/Immunology 
Allergic reaction/ 
hypersensitivity (including drug 
fever) Grade 2 
Discontinue CC-4047. 
Allergic reaction/ 
hypersensitivity (including drug 
fever) Grade 3 
Discontinue CC-4047. 
Blood/ Bone Marrow 
Neutropenia 
ANC < 500/μL 
(Grade 4) for >7 Days 
Discontinue CC-4047. 


October 21, 2013 
2007-0199 
 
20
CTCAE 
CATEGORY 
ADVERSE EVENTS 
DOSING CHANGE 
Blood/Bone Marrow 
Thrombocytopenia 
Platelet count < 25,000/μL 
(Grade 4) for >7 Days 
Discontinue CC-4047. 
Cardiovascular 
Thrombosis/Embolism  
Grade 3 or 4 
Hold CC-4047 and start systemic 
anticoagulation.  Restart at the 
same dose level at investigator’s 
discretion and only if approved by 
the Principal Investigator based 
on established significant benefit 
to the patient. The patient must 
sign consent form again to restart 
the therapy. 
Dermatology/Skin 
Grade 3 Rash 
Discontinue CC-4047. 
Desquamating/Blistering Rash 
Discontinue CC-4047. 
Rash:  Erythema multiforme 
Discontinue CC-4047. 
Endocrine 
Elevated or Reduced Thyroid 
Function Test results without 
symptoms of hyper- or hypo-
thyroidism 
 
Elevated or Reduced Thyroid 
Function Test results with 
symptoms of hyper- or hypo-
thyroidism 
Confirm test results. If significant, 
refer for appropriate therapy.  
Maintain dose of CC-4047 if 
appropriate. 
 
Hold study drug.  Evaluate 
etiology and refer for appropriate 
therapy.  Restart at the prior dose. 
Neurology 
Neuropathy – 
Cranial/motor/sensory  
Grade 2 
Hold CC-4047.  Restart once 
adverse event is completely 
resolved. 
Neuropathy – 
Cranial/motor/sensory  
Grade 3 
Discontinue CC-4047. 
Neuropathy – 
Cranial/motor/sensory  
Grade 4 
Discontinue CC-4047. 
Other non-
hematological, 
clinically significant 
toxicity 
Grade 3 
Discontinue CC-4047. 
Grade 4 
Discontinue CC-4047. 
 


October 21, 2013 
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21
3.6.4. Treatment compliance 
At all times, when dispensing study drug, research center personnel will review the 
instructions, printed on the packaging, with subjects. Subjects will be asked to maintain a 
diary to record the drug administration. Subjects will be asked to bring any unused study 
drug to the research center at their next visit.  Research personnel will count and record 
the number of used and unused study drug capsules at each visit and reconcile with the 
subject diary.   
3.7. Concomitant therapy   
3.7.1. Recommended concomitant therapy   
All supportive measures consistent with optimal subject care will be given throughout the 
study.  Packed red blood cell transfusions are allowed when necessary.  Growth factor 
use (including erythropoietin) is not allowed with the exception of the use of filgrastim 
(G-CSF) or pegfilgrastim, which is permitted when used to treat febrile neutropenia or 
those who have ≥ grade 3 neutropenia and at the investigators discretion for prolonged 
neutropenia.  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. Splenic infarcts 
occasionally occur and should be managed with analgesics at the discretion of the 
clinician and do not necessarily require withdrawal from the study.  
3.7.2. Anticoagulation Consideration   
CC-4047 may increase the risk of thrombotic events in subjects who are at high risk or 
with a history a thrombosis, in particular when combined with other drugs known to 
cause thrombosis. When CC-4047 is combined with other agents such as steroids (e.g. 
dexamethasone, prednisone), anthracyclines (Doxil, adriamycin) and erythropoietin the 
risk of thrombosis may be increased.  
Subjects must receive oral low-dose aspirin (81 mg) as prophylactic anti-thrombotic 
treatment unless it is contraindicated or the subject has a platelet count less than 
75,000/µL.  If low-dose aspirin is contraindicated, the investigator should prescribe 
another appropriate prophylactic anti-thrombotic therapy. 
3.7.3. Prohibited concomitant therapy 
Concomitant use of growth factors (including erythropoietin and excluding G-CSF and 
pegfilgrastim), cytotoxic chemotherapeutic agents (e.g. hydroxyurea), or other 
experimental drug or therapy for myelofibrosis while the subject is on study is prohibited. 
Filgrastim (G-CSF) is permitted for use during the study when used to treat febrile 
neutropenia or those who have ≥ grade 3 neutropenia and at the investigators discretion 
for prolonged neutropenia. Chronic use (>2 weeks) of greater than physiologic doses of a 
corticosteroid agent (dose equivalent to >10 mg/day of prednisone) is not permitted 
during the study. Anagrelide is allowed to be used during the study to control elevated 
platelet count. 


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3.8. Discontinuation of Study Treatment  
Subjects will receive oral CC-4047 daily from day 1 through day 28 every 28 days in the 
absence of disease progression or toxicity warranting discontinuation of therapy. Therapy 
will continue as long as there is a benefit, as judged by treating physician. 
Treatment with study drug is to be discontinued when any of the following occurs: 
 Lack of therapeutic effect 
 Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of study drug. 
 Withdrawal of consent 
 Lost to follow up 
 Death 
 Suspected pregnancy 
3.9. Follow-Up   
Subjects who discontinue treatment for any reason, will be followed every three months 
until disease progression or initiation of alternate therapy.  At treatment discontinuation, 
subjects will undergo a safety assessment approximately 28 days post the last dose of 
study drug.  In addition, off study evaluations per the Schedule of Assessments, 
Appendix M will be done. 


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4. 
SERIOUS ADVERSE EVENT REPORTING 
4.1 
Serious Adverse Event  
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or the sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening adverse drug experience – any adverse 
experience that places the patient, in the view of the initial 
reporter, at immediate risk of death from the adverse experience as 
it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions. 
 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). 
 Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
IND Office. 
 All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for Investigators 
on Reporting Unanticipated Adverse Events for Drugs and Devices”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the Safety Project Manager in the 
IND Office.   
 Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  


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 Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of drug, 
unless the participant withdraws consent. 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. 
 Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the 
IND Office. This may include the development of a secondary 
malignancy. 
 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team 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. 
 
4.1.1. Expedited reporting by investigator to Celgene 
 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 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 the investigational product(s), if 
available.  Information not available at the time of the initial report (e.g., an end 
date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  A final report to document resolution of the 
SAE is required.  The Celgene tracking number (PO-MMM-PI-0011) 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. 
 
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 


October 21, 2013 
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4.1.2. 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 IP, or within (insert time-frame which must be at least 28 days of the 
subject’s last dose of IP), are considered immediately reportable events. IP is to be 
discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form. 
The female subject should be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the pregnancy, 
and must notify Celgene Drug Safety immediately about the outcome of the 
pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form, or approved equivalent form.  
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the 
abnormal outcome meets any of the serious criteria, it must be reported as an SAE 
to 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, or approved equivalent 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, or approved equivalent form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking IP should notify the Investigator immediately, 
and the pregnant female partner should be advised to call their healthcare provider 
immediately. 
 


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5. 
BIOSTATISTICAL ANALYSIS 
5.1 
Overview 
This is two stage, phase II trial designed to assess the effect of CC-4047 and prednisone 
in subjects with Primary, Post Polycythemia Vera, or Post Essential Thrombocythemia 
Myelofibrosis (PMF, post-PV MF, or post-ET MF). Secondary objective is to determine 
the safety of CC-4047 and prednisone in this population.  
5.2 
Datasets to be analyzed 
All subjects meeting the eligibility criteria that have signed a consent form and have 
begun treatment will be evaluable for response. 
5.3 
Statistical Methodology 
5.3.1. Primary Endpoint 
The primary endpoint of this trial is best overall response. An evaluable subject will be 
classified as a treatment success for the primary endpoint if the subject’s best overall 
response is CR, PR or CI (Clinical Improvement) as determined by International 
Working Group Criteria over the first 6 cycles of study treatment at 0.5mg/day dose. The 
largest success proportion where the proposed treatment regimen would be considered 
unpromising in this population is 5%, representing the probability of a response by 
chance. The smallest success proportion that would warrant further subsequent studies 
with the proposed treatment regimen in this subject population is 20%. 
5.3.2. Study Design 
Subjects receiving CC-4047 alone, and the new study cohort of patients receiving CC-
4047 and prednisone in combination will be evaluated using the same statistical design: a 
two stage design with one interim analysis will be used to permit early reporting of 
efficacy results if there is strong evidence that the study regimen is inactive. 37 evaluable 
subjects will be accrued onto this study unless undue toxicity is encountered. We 
anticipate accruing an additional 10-20% of subjects to account for ineligibility or 
cancellation; i.e. we may accrue as many as 70 subjects to this study. Subjects who have 
been taken off study due to toxicity related to high dose pomalidomide (i.e. those who 
started therapy with 3mg/day) will be replaced with new patients that will start therapy 
with 0.5mg/day), so that the goals of the study can be accomplished.   
 
 Decision Rule: If 3 or fewer treatment successes are observed after all 37 evaluable 
subjects have been followed for at least 6 cycles, we will conclude that the treatment 
is insufficiently active in this subject population. If 4 or more treatment successes are 
observed, then this will be considered adequate evidence of promising activity, and 
the treatment may be recommended for further testing in subsequent studies.  


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 Over accrual: if more than the target number of subjects are accrued, the additional 
subjects will not be used to evaluate the stopping rule or used in any decision making 
process. However, they will be included in final point estimates and confidence 
intervals. 
 Study duration: The anticipated accrual rate for this group of subjects is 
approximately 3 subjects per month. It will take approximately 14 months to accrue 
37 evaluable subjects. The analysis can begin as soon as the 37th evaluable subject has 
been observed for 6 cycles (168 days), i.e., approximately 20 months after the trial 
opens.  
5.3.3. Analysis Plan 
Primary Endpoint 
The observed response rate over the first 6 cycles of therapy at 0.5mg/day will be 
estimated by the number of responses (confirmed CR, PR or CI) over the first 6 cycles 
divided by the total number of evaluable subjects. Confidence intervals for the true 
response rates will be calculated according to the approach of Duffy and Santner. 
Secondary Endpoints 
Duration of response: duration of response is defined as the date at which the subject’s 
objective status is first noted to be a CR, PR or CI to the date progression is documented 
(if one has occurred) or to the date of last follow-up (for those subjects who have not 
progressed). 
Time to response: The time to response is defined as the time from study registration to 
the first date at which the subject’s objective status was classified as a response (CR, PR 
or CI). In subjects who do not achieve a response, time to response will be censored at 
the subject’s last evaluation date. The distribution for each of these event-time variables 
(duration of response and time to response) will be estimated by Kaplan-Meier curves.  
Best overall response as determined by the International Working Group Criteria over the 
first 12 cycles of study treatment: will be estimated by the number of responses 
(confirmed CR, PR or CI) over the first 12 cycles divided by the total number of 
evaluable subjects. Confidence intervals for the true response rates will be calculated 
according to the approach of Duffy and Santner. 
Cytogenetic responses and molecular response: cytogenetic responses and molecular 
responses will be summarized as well as evaluated graphically. Correlations among 
clinical responses and laboratory variables will be explored using a Wilcoxon/Kruskal-
Wallis test for ordered contingency tables. Mutation status will be explored in relation to 
clinical outcome (response) using Fisher’s exact test.  
Quality of Life (QOL) assessments: For each of the QOL assessment components, 
changes from baseline to each of the follow-up time points will be reported. The change 
will be compared between two subgroups: subjects who response to the treatment and 
subjects who do not response. Normality testing via the Shapiro-Wilk procedure will 
determine whether or not parametric or nonparametric procedures will from the basis for 
analysis (two-sample t-test, Wilcoxon rank sum test).  


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Toxicity: As per NCI CTCAE Version 3.0, the term toxicity is defined as adverse events 
that are classified as either possibly, probably, or definitely related to study treatment. 
Such adverse events will be captured by Principal Investigator and his staff in a database. 
The maximum grade for each type of toxicity will be recorded for each subject, including 
start/stop dates, and frequency tables for each group will be reviewed to determine 
toxicity patterns. In addition, we will review all adverse event data that is graded as 3, 4, 
or 5 and classified as either “unrelated or unlikely to be related” to study treatment in the 
event of an actual relationship developing. 
5.4 
Safety evaluation 
Data from all subjects who receive any study drug will be included in the safety analyses. 
Subjects who entered the study and did not take any of the study drug and had this 
confirmed, will not be evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v3.0 whenever 
possible.  
Toxicity Stopping Rule:  
This phase II clinical trial will have a stopping rule based on toxicity defined as an 
adverse event considered to be at least possibly related to treatment. In particular accrual 
to the study will be temporarily suspended if: a) 2 or more among the first 10 subjects 
treated on this trial experiences a Grade 4 cardiac, lung, liver or neurological toxicity that 
is felt to be drug related. b) 20% or more of subjects (when more than 10 subjects have 
been accrued) experience a Grade 4 cardiac, lung, liver or neurological toxicity that is felt 
to be drug related. After consideration by the study team (study chair[s], statistician, etc.) 
a decision will be made as to whether accrual can resumed. 
5.5 
Interim analyses  
An interim analysis will be performed after the first 20 evaluable subjects have been 
observed for at least 6 cycles. If 1 or fewer treatment successes are observed in these 20 
subjects, this treatment regimen will be considered inactive in this population and accrual 
will be terminated. If 2 or more treatment successes are observed in these 20 subjects, 
decisions about activity must await the final analysis. Enrollment into the study will 
continue while waiting for the 20th eligible subject to complete at least 6 cycles of 
treatment. These additional subjects will not be used to evaluate the interim stopping rule. 
5.6. 
Sample size and power considerations 
Assuming that the number of successes is binomially distributed, this decision rule has a 
significance level of 0.09; i.e., there is a 9% chance of finding the drug to be effective 
when it truly is not. The probability of declaring that this regimen warrants further studies 
(i.e. statistical power) under various success proportions and the probability of stopping 
after the first stage can be tabulated as a function of the true success proportion as shown 
in the following table: 
If the true success proportion is . . . . . 
0.05 
0.10 
0.15 
0.20 
0.25 
then the probability of declaring that the 0.09 
0.44 
0.75 
0.91 
0.97 


October 21, 2013 
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29
regimen warrants further studies is . . . . 
And the probability of stopping at stage I 
is: 
0.74 
0.39 
0.18 
0.07 
0.02 
In particular, this decision rule has 91% power to detect an effective treatment given that 
the true response rate is at least 20% using this treatment.  If the true success rate is 5%, 
the chance of stopping early at the first stage is 0.74 and the chance of concluding that the 
treatment is active is 0.09. If the true success rate is 20%, the chance of stopping early at 
the first stage is 0.07 and the chance of concluding that the treatment is active is 0.91 
(power). 
 


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6 
REGULATORY CONSIDERATIONS 
6.1 
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. 
6.2 
Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents.  
The original consent form, signed and dated by the subject and by the person consenting 
the subject prior to the subject’s entry into the study, must be maintained in the medical 
records, and copy filed in the regulatory binder. 
6.3 
Subject confidentiality 
Celgene affirms the subject’s right to protection against invasion of privacy.  In 
compliance with United States federal regulations, Celgene requires the Investigator to 
permit Celgene’s representatives and, when necessary, representatives of the FDA or 
other regulatory authorities to review and/or copy any medical records relevant to the 
study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual. 


October 21, 2013 
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6.4 
Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the study drug, that is copies of eCRF 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. 
6.5 
Premature discontinuation of study 
6.5.1 Single center 
The responsible local clinical Investigator, MDACC 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. 
6.5.2 Study as a whole 
Celgene and MDACC reserve 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.). 


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7. 
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