Conditions: AL Amyloidosis
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
This study seeks to enroll patients with AL amyloidosis, for whom treatment with one of the standard melphalan chemotherapy-based regimens is either not recommended or is not their preference.

Pomalidomide (CC-4047) is a drug given by mouth, which can change or regulate the functioning of the immune system. So, in theory, it may reduce or prevent the production of the amyloid protein. Pomalidomide is not currently FDA-approved for AL Amyloidosis. Pomalidomide is chemically similar to thalidomide and lenalidomide, both of these drugs have been approved by the FDA for treatment of patients with multiple myeloma (MM), a disease similar to AL Amyloidosis.

Participants in this study will receive pomalidomide and dexamethasone. Phase I is a dose-escalation study and dose escalation will proceed through 3 dose-levels according to standard rules in which dose levels are started sequentially after complete evaluation of the occurrence of dose-limiting toxicities. In the Phase II portion, participants will receive pomalidomide and dexamethasone using the defined maximum tolerated dose.

Detailed description:
Primary objective:

Determine dose-limiting toxicity (DLT) and the maximal tolerated dose (MTD) of pomalidomide combined with dexamethasone in subjects with previously- treated light-chain (AL)-amyloidosis

Secondary objectives:

Determine the following at the MTD:

* Hematological complete (CR) very good partial (VGPR) and partial (PR) rates
* duration of response
* organ response
* Time-to-event
* Survival

Exploratory study objective:

To investigate the relationship of changes in the levels of the biomarkers B-type natriuretic peptide (BNP) and troponin I to frequency of specific adverse events and the occurrence of DLT

Arms:
arm 1: Pomalidomide 2 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle arm 2: Pomalidomide 3 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle arm 3: Pomalidomide 4 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle arm 4: Expansion Phase:

Pomalidomide 4 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle

Interventions: intervention 1: Pomalidomide intervention 2: Dexamethasone
Intervention descriptions: intervention 1: Cohort 1 = 2 mg/day, Cohort 2 = 3 mg/day, Cohort 3 = 4 mg/day: Days 1-21 of a 28 day cycle intervention 2: 10-20 mg on days 1, 8, 15, and 22

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Protocol version 5/11/15 
 
Protocol Title:  A Phase I/II Trial of Pomalidomide and 
Dexamethasone in Subjects with Previously-Treated AL 
Amyloidosis 
 
STUDY DRUG   
Pomalidomide (CC-4047) 
CELGENE REFERENCE 
NUMBER: 
 
PO-AMYL-PI-0024 
VERSION:  
5/11/15 
IND:  
112758 
NCT:  
NCT01570387 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to another party unless law or regulations 
require such disclosure.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
 
 
 
 
 
 


 
Confidential 
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Pomalidomide                                                                         Protocol: PO-AMYL-PI-0024 
 
Protocol version 5/11/15 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
Principal Investigator: 
 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
Printed Name of Investigator 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/EC procedures, instructions from Celgene representatives, 
the Declaration of Helsinki, ICH Good Clinical Practices guidelines, and 
the applicable parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical studies. 
 
 
 
 
 
 
 
 
 
 


 
Confidential 
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Pomalidomide                                                                         Protocol: PO-AMYL-PI-0024 
 
Protocol version 5/11/15 
STUDY PERSONNEL 
 
Supporter: 
 
Celgene Corporation 
86 Morris Ave, 
Summit,  NJ   07901 
1-800-742-3107 
 
 
 
Study Location: 
 
Boston Medical Center 
820 Harrison Avenue, FGH-1 
Boston, MA   02118 
Principal Investigator: 
 
 
Vaishali Sanchorawala, MD 
 
Co-Investigator:  
 
 
David C. Seldin, MD, PhD 
 
Biostatistician: 
 
 
Study Coordinator: 
 
 
 
Anthony Shelton, RN 
 
 
 


 
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Pomalidomide                                                                         Protocol: PO-AMYL-PI-0024 
 
Protocol version 5/11/15 
Table of Contents 
Protocol Synopsis…………………………………………………………….   
Section 1 
Schedule of Study Assessments……………………………………………….  
Section 2 
Background and Rationale……………………………………………………  
Section 3 
Study Objectives and End Points………………………………………………  
Section 4 
Investigational Plan…………………………………………………………….  
Section 5 
Serious Adverse Events………………………………………………………..  
Section 6 
Response Criteria………………………………………………………………  
Section 7 
Protocol Amendments and Deviations………………………………………….  Section 8 
Data Management……………………………………………………………… 
Section 9 
Biostatistical Analysis…………………………………………………………   
Section 10 
Regulatory Considerations…………………………………………………….    Section 11 
References………………………………………………………………………  Section 12 
Appendices……………………………………………………………………… Section 13 
1.   Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods  
Pomalidomide Education and Counselling Guidance Document  
Pomalidomide Information Sheet 
 
2.  SWOG Performance Status 
 
3.   NCI CTCAE Version 4.0 
 


 
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Pomalidomide                                                                         Protocol: PO-AMYL-PI-0024 
 
Protocol version 5/11/15 
 
1  Protocol Synopsis 
PROTOCOL TITLE: A Phase I/II Trial of Pomalidomide and Dexamethasone for the 
treatment of subjects with previously treated AL Amyloidosis 
PROTOCOL NUMBER: 
PO-AMYL-PI-0024 
DATE PROTOCOL FINAL: 
 
STUDY DRUG: 
Pomalidomide (CC-4047) 
INDICATION: 
AL Amyloidosis 
STUDY PHASE: 
I/II 
BACKGROUND AND RATIONALE:   
AL amyloidosis is a variant plasma cell disorder in which clonal bone marrow plasma 
cells produce immunoglobulin light chains that misfold into fibrils that are deposited in 
visceral organs, leading to organ dysfunction and failure.  Untreated, the disease has a 
median survival of only about one year. Oral treatment with melphalan and 
dexamethasone produces improvement in survival, with hematologic remissions and 
improvement in organ function. Aggressive treatment with high dose intravenous 
melphalan with autologous stem cell transplantation (HDM/SCT) produces complete 
hematologic responses (CR) in about 40% of subjects and partial responses in a similar 
proportion; these are frequently accompanied by stabilization or improvement in organ 
function. Unfortunately only about half of referred subjects are eligible for HDM/SCT. 
Furthermore, it has been observed by us as well as other groups that achievement of a 
hematologic complete response after treatment with oral melphalan and dexamethasone 
as well as HDM/SCT is associated with improved survival, QOL, and clinical/organ 
response. Thus, we continue to seek more effective regimens for subjects ineligible for 
aggressive treatment with HDM/SCT or not achieving a complete hematologic response 
to HDM/SCT or other modalities.  
 
The advent of novel agents in the treatment of multiple myeloma has changed the 
therapeutic landscape of plasma cell dyscrasias. Thalidomide has been studied as a single 
agent and in combination with dexamethasone for the treatment of AL amyloidosis. 
Unfortunately, thalidomide is poorly tolerated with 50-65% of subjects experiencing 
grade 3 and 4 toxicities, leading to drug withdrawal in approximately half of the subjects. 
 
We are concluding a phase II study of lenalidomide alone and in combination with 
dexamethasone for subjects with AL amyloidosis. This study included untreated as well 
as relapsed subjects after HDM/SCT. Interim analysis of the first 34 subjects suggests 
achievement of a complete hematologic response CR in ~30% subjects and of partial 


 
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Pomalidomide                                                                         Protocol: PO-AMYL-PI-0024 
 
Protocol version 5/11/15 
hematologic response in ~40% subjects, with most responses occurring with the 
lenalidomide/dexamethasone combination. A variety of toxicities have been observed, 
including leukopenia, rash, venous thrombosis, and intolerance to the dexamethasone. 
This report indicated better tolerability than thalidomide, however, 20% of subjects still 
stopped treatment with lenalidomide due to toxicities. We have extended our study to 
subjects on dialysis, using attenuated doses, with good preliminary results. A study using 
lenalidomide in combination with melphalan and dexamethasone is ongoing; this study is 
not suitable for subjects with significant prior exposure to alkylator agent.  
 
Pomalidomide (CC4047), a 2nd generation immune-modulatory drug, has shown 
promising activity in phase-2 trial in combination with low-dose dexamethasone for 
relapsed or refractory multiple myeloma and AL amyloidosis. Responses were seen in 
50% of subjects previously-failing thalidomide and/or lenalidomide in AL amyloidosis.  
 
Given these promising results of pomalidomide in plasma cell dyscrasias, we propose a 
study of pomalidomide and low dose dexamethasone in persons with previously-treated 
AL amyloidosis.  
 
STUDY OBJECTIVES: 
Primary:   
 Determine dose-limiting toxicity (DLT) and the maximum tolerated dose 
(MTD) of pomalidomide combined with dexamethasone in persons with 
previously-treated light-chain (AL)-amyloidosis. 
Secondary:   
 Determine the following at the MTD: 
 Hematological complete (CR) very good partial (VGPR) and partial 
(PR) rates 
 Response-duration 
 Organ response 
 Time–to-event 
 Survival 
 
Exploratory:   
 To investigate the relationship of changes in the levels of the biomarkers 
BNP and troponin I to frequency of specific adverse events and the 
occurrence of DLT.   
STUDY DESIGN: 
 Phase-I/II dose-escalation study of pomalidomide and dexamethasone in persons with 
previously-treated AL-amyloidosis.  During the Phase I portion the MTD will be 
determined based on DLTs in the first cycle.  At the MTD an expanded cohort of 12 
subjects will be evaluated to estimate efficacy. 


 
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Pomalidomide                                                                         Protocol: PO-AMYL-PI-0024 
 
Protocol version 5/11/15 
The study includes a screening period, a treatment (dose escalation) period, and a 
follow-up period for survival.  After giving written informed consent, subjects will be 
evaluated for eligibility for enrollment in the study and baseline evaluations will be 
performed.  Subjects who satisfy all inclusion and exclusion criteria will begin study drug 
treatment with dose escalation.  Standard dose escalation rules will be used. 
Subjects will be monitored every cycle for safety, hematological status, and organ 
function during therapy or until the occurrence of progressive disease (PD).   
Treatment Group Assignments and Subject Replacement 
This is a dose-escalation study and dose escalation will proceed through 3 dose-levels 
according to standard rules in which dose levels are started sequentially after complete 
evaluation of the occurrence of DLT.  Based on the dose escalation scheme, as many as 
30 subjects could be enrolled in the study.  Subjects who discontinue pomalidomide for 
reasons other than DLT before completing at least 2 treatment cycles are to be replaced. 
Subpopulations 
An additional 12 subjects will be enrolled in an expanded cohort for analysis of efficacy 
at each schedule studied. 
Subjects in this cohort will be treated at the dose defined as the MTD for that schedule. 
 
Schema: 
Phase-I: 
Pomalidomide 2 mg/day D1-21 – dose escalation to 4 mg/day by 1 mg units* 
Dexamethasone 10-20 mg D1, 8, 15, 22 
 
* Pomalidomide dosing for Phase I cohorts 1 and 2 given on days 1-28 of a 28-day cycle and changed to 
Days 1-21 of a 28 day cycle with Cohort 3. 
 
This cycle will be repeated every 28 days. 
 
Subjects will take aspirin 325 mg/day to prevent venous thrombosis whilst on-study. 
 
A proton pump inhibitor will be used for GI prophylaxis. 
 
Phase-II: 
 
Pomalidomide [MTD] mg/day D1-21  
Dexamethasone 10-20 mg D1, 8, 15, 22 
 
This cycle will be repeated every 28 days. 
 
Subjects will take aspirin 325 mg/day for prophylaxis against venous thrombosis while 
on study. 
 
A proton pump inhibitor will be used for GI prophylaxis. 


 
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Pomalidomide                                                                         Protocol: PO-AMYL-PI-0024 
 
Protocol version 5/11/15 
STUDY ENDPOINTS 
Primary:   
 Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of 
pomalidomide in combination with dexamethasone  
Secondary:   
To be determined for MTD: 
 Hematological complete (CR) very good partial (VGPR) and partial (PR) rates 
 Response-duration 
 Organ response 
 Time–to-event 
 Survival 
 
Exploratory:  
 relationship of changes in the levels of the biomarkers BNP and troponin I 
compared to frequency of specific adverse events and the occurrence of DLT 
STUDY DURATION: Treatment may continue until 
subject experiences unacceptable toxicities or disease 
progression.  Follow-up will take place every 3 months 
until disease progression, then annually for survival. 
Accrual ~24 months 
TOTAL SAMPLE SIZE: 30 
subjects 
DOSING REGIMEN(S): 
Phase I portion: 
  
Pomalidomide 2 mg/day D1-21 –  
dose escalation to 4 mg/day in 1 mg increments in  
phase I*   
Dexamethasone 10-20 mg D1, 8, 15, 22 
 
The above cycle will be repeated every 28 days. 
 
* Pomalidomide dosing for Phase I cohorts 1 and 2 given on days 1-
28 of a 28-day cycle and changed to Days 1-21 of a 28 day cycle 
with Cohort 3. 
 
Phase II portion:  
 
Pomalidomide [MTD] mg/day D1-28  
Dexamethasone 10-20 mg D1, 8, 15, 22 
 
This cycle will be repeated every 28 days. 
STUDY DRUG SUPPLIES: 
Celgene 
Corporation 
will 
supply pomalidomide as  1.0 
mg and 2.0 mg 


Celgene Corporation 
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  Protocol  
 
Protocol version 5/11/15 
2 Schedule of Study Assessments *  
Procedure 
Pre-Study 
1 
Cycle One* 
Cycles 
2,  3 
Cycles*  
5, 6, 8,  
9, 11, 12 
Cycles* 
4, 7 and 
10 ∞ 
*30 days of 
discontinuation 
From Study Drug 
Follow-Up8 
Phase 
Day 
1 
Day  
8 § 
Day  
15 
 Day  
22  § 
Day  
1 
Day  
1 
Day  
1 
 
Every 3 
months 
Physical examination, vital 
signs, weight 
X 
X 
 
 
X 
X 
 
X 
X 
X 
SWOG performance status 
X 
X 
 
 
X 
X 
 
X 
X 
X 
CBC with differential  
X 
X 
X6 
X6 
X6 
X6 
X6 
X 
 
X 
Pregnancy test 2 
X2, 3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
Education and counseling 
guidance 7 
 
X 7 
 
 
 
X7 
X7 
X7 
 
 
Sodium, chloride, CO2, 
Glucose 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
BUN, creatinine, 
potassium, Magnesium, 
phosphorous 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ALT, AST, albumin, alk 
phos, bilirubin 
X 
X 
 
 
 
X 
X 
 
 
X 
calcium 
X 
X 
 
 
 
X 
X 
X 
 
X 
Cholesterol, triglyceride, 
TSH 
X 
 
 
 
 
 
 
X 
 
X 
Total Protein, LDH, INR, 
PTT 
X 
X 
 
 
 
 
 
X 
 
X 
BNP, uric acid 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
C-reactive protein, Beta 2-
microglobulin 
X 
 
 
 
 
 
 
X 
 
X 
IgG, IgA, IgM 
X 
 
 
 
 
 
 
X 
 
X 
Serum immunofixation 
electrophoresis 
X 
 
 
 
 
 
 
X 
 
X 
Urine immunofixation 
electrophoresis 
X 
 
 
 
 
 
 
X 
 
X 
24 hour urine protein 
X 
 
 
 
 
 
 
X 
 
X 
Free light chain assay  
X 
 
 
 
 
X 
X 
X 
 
X 
Bone marrow biopsy and 
aspirate  
X 
 
 
 
 
 
 
X5 
 
X5 
EKG 
X 
 
 
 
 
 
 
X 
 
X 
ECHO 
X 
 
 
 
 
 
 
X5 
 
X5 
CXR 
X 
 
 
 
 
 
 
X5 
 
X5 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
X 


Celgene Corporation 
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  Protocol  
 
Protocol version 5/11/15 
Dispensement of  Cycle 1 
study drug 
 
X 
 
 
 
 
 
 
 
 
Record adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Record concomitant 
therapies/procedures 
 
X 
 
 
 
X 
X 
X 
X 
 
Dispense study drug for 
next cycle 
 
X 
 
 
 
X 
X 
X 
 
 
Perform drug 
accountability 
 
X 
 
 
 
X 
X 
X 
X 
 
* Pre-cycle evaluations may be done up to 7 days 
prior to Day 1 to allow time for results and drug 
distribution. All other exams may be done +\- 4 
days. 
§  Phase I participants only 
1 All pre-study evaluations to be completed within 
28 days of initiation of therapy except for bone 
marrow, which must have been repeated following 
any previous therapy > 1 cycle.  ECHO must be 
done within 60 days of first dose of pomalidomide. 
2  A female of childbearing potential (FCBP) is a 
sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has 
not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 
3   Pregnancy tests must occur 7 days and again 
within 24 hours prior to initiation of pomalidomide.  
FCBP with regular or no menstruation must have a 
pregnancy test weekly for the first 4 weeks and 
then every 28 days while on therapy (including 
breaks in therapy); at discontinuation of 
pomalidomide and at Day 28 post the last dose of 
pomalidomide.  Females with irregular 
menstruation must have a pregnancy test weekly 
for the first 4 weeks and then every 14 days while 
on therapy (including breaks in therapy), at 
discontinuation of pomalidomide and at Day 14 and 
Day 28 post the last dose of pomalidomide (see 
Appendix 1: Pomalidomide Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods ). 
 
4 If clinically indicated   
5 If needed to confirm response. 
6 CBC to be done weekly for the first cycle or until on a stable dose of 
pomalidomide, then day 1 of each cycle.  
7 All subjects must be registered into the POMALYST REMS™ program of Celgene 
Corporation, which provides education and counseling on the risks of fetal 
exposure, blood clots and reduced blood counts.  Counseling must be provided by 
the according to the POMALYST REMS™ program prior to each new prescription. 
See Appendix 1:  Pomalidomide Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods and Appendix 1:  Pomalidomide 
Education and Counseling Guidance Document. 
8 For responders, follow-up exams should take place every three months until 
disease progression.  Following disease progression, follow-up evaluations should 
take place annually. 
∞ Evaluations to be done every three cycles while on study drug. 
 
 


 
          Page 11 of 66  
Pomalidomide  
                         Protocol:  
Protocol version 5/11/15 
3 Background and Rationale 
3.1 Introduction 
The dependence of tumor growth and metastasis on angiogenesis has been well 
characterized and has led to exploration of the role of anti-angiogenic drugs (both small 
molecules and monoclonal antibodies) in the treatment of solid tumors.  Such agents have 
shown promise in both animal models and in preliminary studies of solid carcinomas in 
humans– including SCLC and non-SCLC [1,2].  Among these studies, three sets of 
investigators have performed preliminary evaluations of thalidomide (an anti-angiogenic 
drug in the IMiD class) in combination with conventional induction chemotherapy and/or as 
mono-therapeutic, post-induction maintenance therapy in subjects with newly diagnosed 
SCLC [3,4,5].  In each of these studies, some benefit with thalidomide use was detected – an 
increase in median survival (about 3 months overall) and/or 1- and 2-year survival relative 
to either parallel administration of or historic institutional control using equivalent 
conventional induction chemotherapy alone. 
Recently, the relative roles of enhanced expression/production of the inflammatory 
cytokines, including both cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha 
(TNF-alpha), in the up-regulation of lung cancer growth, the stimulation of metastasis, the 
inhibition of apoptosis and in the occurrence of paraneoplastic syndromes have been 
identified and investigated [6,7,8].   As a result of in vitro and in vivo studies on lung and 
other carcinomas, inhibition of TNF-alpha and COX-2 have been identified, along with 
inhibition of angiogenesis, as therapeutic targets for limiting the growth, metastasis and 
neuro-endocrine complications of various solid carcinomas. 
The emergence of immunomodulatory agents, such as thalidomide, lenalidomide and more 
recently CC-4047 (pomalidomide), as effective therapies has altered the therapeutic 
paradigm for multiple myeloma (MM). Following the approval and establishment of 
thalidomide-containing regimens, such as melphalan, prednisone and thalidomide (MPT) 
and Thal/Dex, as the standard first-line therapy for newly diagnosed MM (NDMM), 
lenalidomide in combination with standard high-dose dexamethasone (RD) was approved 
for the treatment of subjects with previously treated MM. However, even with the newly 
approved agents including thalidomide, lenalidomide and proteasome inhibitor such as 
bortezomide, MM remains an incurable disease and most subjects will eventually relapse 
and progress after multiple lines of different therapeutic regimens.  
 
In addition, thalidomide, especially when combined with a corticosteroid, is effective in 
other diseases related to AL-amyloid including Waldentroms macroglobulinemia, 
Castleman disease and POEMS (polyneuritis, organomegaly, endocrinopathy, M-protein 
and osteosclerosis) syndrome.  Substantial data indicate thalidomide combined with a 
corticosteroid with or without an alkylating drug is active in newly-diagnosed and 
progressive AL-amyloidosis with responses rates of 20-75 percent.  Preliminary data 
indicate lenalidomide and corticosteroids are active in AL-amyloidosis including subjects 
failing melphalan (at all doses) and corticosteroids and also thalidomide and corticosteroids.  
 


 
          Page 12 of 66  
Pomalidomide  
                         Protocol:  
Protocol version 5/11/15 
 
3.2 Pomalidomide 
Pomalidomide, a thalidomide analogue, is an immune-modulatory agent that, among other 
anti-tumor properties, on an equimolar basis in vitro, displays equivalent anti-angiogenic 
activity, about 8-fold greater activity in stimulation of apoptosis, at least 10-fold greater 
activity in inhibition of cellular COX-2 production and over 4,000-fold greater activity in 
inhibition of cellular TNF-alpha production relative to thalidomide [9,10].   Pomalidomide 
has also been shown to stimulate antibody-dependent cytotoxic T-cell activity (ADCC) [9].   
At tolerated doses (MTD = 2 mg QD and 5 mg QOD), pomalidomide has been shown to be 
active in subjects with relapsed or refractory multiple myeloma (MM) (study CC-4047-00-
001) [9,11,12].  In 45 subjects who received doses of pomalidomide ranging, by cohort, up 
to 10 mg daily, the most commonly occurring dose-limiting toxicity (DLT) was reversible 
neutropenia.  As with other IMiDs administered to subjects receiving concomitant systemic 
steroids, deep vein thrombosis (DVT) was seen (in 1subject each in this study and in its 
subsequent named subject supply rollover program) [9,13]. 
Recently, preliminary efficacy and safety data from an ongoing phase II study, led by 
Martha Lacy, et al, at Mayo Clinic, were published [14].  Sixty subjects with relapsed or 
refractory multiple myeloma were enrolled.  Pomalidomide (CC-4047) was given orally at a 
dose of 2 mg daily on days 1-28 of a 28-day cycle and dexamethasone was given orally at a 
dose of 40 mg daily on days 1, 8, 15, 22 of each cycle.  Subject also received aspirin 325 mg 
once daily for thromboprophylaxis.  The study endpoints were the response rate in subjects 
taking pomalidomide plus dexamethasone including subjects with lenalidomide resistant 
refractory multiple myeloma, and safety of pomalidomide plus dexamethasone. Responses 
were recorded using the criteria of the International Myeloma Working Group. Thirty eight 
subjects achieved objective response (63%) including CR in 3 subjects (5%), VGPR in 17 
subjects (28%), and PR in 18 subjects (30%).   The CR + VGPR rate was 33%.  Grade 3 or 
4 hematologic toxicity occurred in 23 subjects (38%) and consisted of anemia in three 
subjects (5%), thrombocytopenia in two subjects (3%) and neutropenia in 21 (35%).  
Among those that developed grade 3/4 neutropenia, all first experienced the neutropenia in 
cycle 1-3; no new subjects experienced grade 3/4 neutropenia in cycle 4 or later.  The most 
common non-hematological grade 3/4 toxicities were fatigue (17%) and pneumonia (8%).  
Other grade 3/4 non-hematological toxicities that occurred in less than 5% included 
diarrhea, constipation, hyperglycemia, and neuropathy.  One subject (1.6%) had a 
thromboembolic event of deep vein thrombosis.   
Similarly, pre-clinical data and the prior experience with thalidomide and lenalidomide in 
the treatment of subjects with myelofibrosis with myeloid metaplasia (MMM) provide the 
rationale for the use of pomalidomide in subjects with MMM. This is further supported by 
the results of a Celgene sponsored trial (MMM-001) which indicated that pomalidomide 
therapy at 0.5 mg or 2 mg/day +/- an abbreviated course of prednisone is well tolerated in 
subjects with myelofibrosis and active in the treatment of anemia [15]. 
 
 


 
          Page 13 of 66  
Pomalidomide  
                         Protocol:  
Protocol version 5/11/15 
Pomalidomide has been studied in AL amyloidosis at the Mayo clinic. Thirty-one subjects 
with previously-treated AL amyloidosis are enrolled and the data on 29 evaluable subjects 
were presented at ASH meeting in December 2010. Overall hematologic response rate is 
38% with 8 subjects achieving PR and 3 VGPR, including subjects failing prior 
lenalidomide and/or thalidomide. One year overall and progression free survival are 77% 
and 56% respectively. Twenty one of 29 subjects experienced > grade -3 AEs possibly 
attributed to treatment. The conclusions were that pomalidomide could provide a safe and 
effective therapy in previously treated subjects with AL amyloidosis, including those failing 
lenalidomide and/or thalidomide.  
Complete and updated adverse events are available in the Investigational Drug Brochure and 
the IND Safety Letters. 
3.3 Rationale 
AL amyloidosis is a variant plasma cell disorder in which clonal bone marrow plasma cells 
produce immunoglobulin light chains that misfold into fibrils that are deposited in visceral 
organs, leading to organ dysfunction and failure.  Untreated, the disease has a median 
survival of only about one year. Oral treatment with melphalan and dexamethasone 
produces improvement in survival, with hematologic remissions and improvement in organ 
function. Aggressive treatment with high dose intravenous melphalan with autologous stem 
cell transplantation (HDM/SCT) produces complete hematologic responses (CR) in about 
40% of subjects and partial responses in a similar proportion; these are frequently 
accompanied by stabilization or improvement in organ function. Unfortunately only about 
half of referred subjects are eligible for HDM/SCT. Furthermore, it has been observed by us 
as well as other groups that achievement of a hematologic complete response after treatment 
with oral melphalan and dexamethasone as well as HDM/SCT is associated with improved 
survival, QOL, and clinical/organ response. Thus, we continue to seek more effective 
regimens for subjects ineligible for aggressive treatment with HDM/SCT or not achieving a 
complete hematologic response to HDM/SCT or other modalities.  
 
The advent of novel agents in the treatment of multiple myeloma has changed the 
therapeutic landscape of plasma cell dyscrasias. Thalidomide has been studied as a single 
agent and in combination with dexamethasone for the treatment of AL amyloidosis. 
Unfortunately, thalidomide is poorly tolerated with 50-65% of subjects experiencing grade 3 
and 4 toxicities, leading to drug withdrawal in approximately half of the subjects. 
 
We are concluding a phase II study of lenalidomide alone and in combination with 
dexamethasone for subjects with AL amyloidosis. This study included untreated as well as 
relapsed subjects after HDM/SCT. Interim analysis of the first 34 subjects suggests 
achievement of a complete hematologic response CR in ~30% subjects and of partial 
hematologic response in ~40% subjects, with most responses occurring with the 
lenalidomide/dexamethasone combination. A variety of toxicities have been observed, 
including leukopenia, rash, venous thrombosis, and intolerance to the dexamethasone. This 
report indicated better tolerability than thalidomide, however, 20% of subjects still stopped 
treatment with lenalidomide due to toxicities. We have extended our study to subjects on 
dialysis, using attenuated doses, with good preliminary results. A study using lenalidomide 


 
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in combination with melphalan and dexamethasone is ongoing; this study is not suitable for 
subjects with significant prior exposure to alkylator agent.  
 
Pomalidomide (CC4047), a third generation immunomodulatory agent, has shown 
promising activity in phase II trial in combination with low-dose dexamethasone for 
relapsed or refractory multiple myeloma as well as AL amyloidosis. Furthermore, responses 
were seen in 50% of subjects who were refractory to prior IMiD in AL amyloidosis.  
 
Given these promising results of pomalidomide in plasma cell dyscrasia, we propose a study 
of pomalidomide and low dose dexamethasone in the treatment of subjects with previously 
treated AL amyloidosis.  
4 Study Objectives and Endpoints 
4.1 Objectives 
4.1.1 Primary objectives 
 Determine dose-limiting toxicity (DLT) and the maximal tolerated dose (MTD) of 
pomalidomide combined with dexamethasone in subjects with previously- treated 
light-chain (AL)-amyloidosis 
4.1.2 Secondary objectives 
 Determine the following at the MTD: 
 Hematological complete (CR) very good partial (VGPR) and partial 
(PR) rates 
 duration of response 
 organ response 
 Time–to-event 
 Survival 
4.1.3 Exploratory study objectives 
 To investigate the relationship of changes in the levels of the biomarkers BNP and 
troponin I to frequency of specific adverse events and the occurrence of DLT 
4.2 Endpoints 
4.2.1 Primary Endpoint 
 Maximum tolerated dose 


 
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4.2.2 Secondary Endpoints 
 Hematological CR and PR 
 Response-duration 
 Organ response 
 Time–to-event 
 Survival 
4.2.3 Exploratory study Endpoint 
 The relationship of changes in the levels of the biomarkers BNP and troponin I to 
frequency of specific adverse events and the occurrence of DLT 
5 Investigational Plan 
5.1 Overall design 
 
STUDY DESIGN: 
Phase I/II dose-escalation study of pomalidomide and dexamethasone in persons with 
previously-treated AL-amyloidosis.  During the Phase I portion the MTD will be determined 
based on DLT in the first cycle.  At the MTD an expanded cohort of 12 subjects will be 
evaluated to estimate efficacy. 
The study includes a screening period, a treatment (dose escalation) period, and a follow-up 
period for survival.  After giving written informed consent, subjects will be evaluated for 
eligibility for enrollment in the study and baseline evaluations will be performed.  Subjects 
who satisfy all inclusion and exclusion criteria will begin study drug treatment with dose 
escalation.  Standard dose escalation rules will be used. 
Subjects will be monitored every cycle for safety, hematological status, and organ function 
during therapy or until the occurrence of progressive disease (PD).   
Treatment Group Assignments and Subject Replacement 
This is a dose-escalation study and dose escalation will proceed through 3 dose-levels 
according to standard rules in which dose levels are started sequentially after complete 
evaluation of the occurrence of DLT.  Based on the dose escalation scheme, as many as 30 
subjects could be enrolled in the study.  Subjects who discontinue pomalidomide for reasons 
other than DLT before completing at least 2 treatment cycles are to be replaced. 
Subpopulations 
An additional 12 subjects will be enrolled in an expanded cohort for analysis of efficacy at 
each schedule studied. 
Subjects in this cohort will be treated at the dose defined as the MTD for that schedule. 


 
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Schema: 
Phase I: 
Pomalidomide 2 mg/day D1-21 – dose escalation to 4 mg/day by 1 mg units* 
Dexamethasone 10-20 mg D1, 8, 15, 22 
 
* Pomalidomide dosing for Phase I cohorts 1 and 2 given on days 1-28 of a 28-day cycle and changed to Days 
1-21 of a 28 day cycle with Cohort 3. 
 
This cycle will be repeated every 28 days. 
 
Subjects will take aspirin 325 mg/day to prevent venous thrombosis whilst on-study. 
 
A proton pump inhibitor will be used for GI prophylaxis. 
 
Phase II: 
 
Pomalidomide [MTD] mg/day D1-21  
Dexamethasone 10-20 mg D1, 8, 15, 22 
 
This cycle will be repeated every 28 days. 
 
Subjects will take aspirin 325 mg/day for prophylaxis against venous thrombosis while on 
study. A proton pump inhibitor will be used for GI prophylaxis. 
      
Subjects will have a toxicity evaluation, physical examination, and blood work performed 
according to schedule 2 while on therapy before each cycle. All subjects will return to 
Boston Medical Center prior to each of the first 3 cycles of therapy.  The screening 
evaluation covers this requirement for cycle 1. A full disease evaluation will be performed 
at Boston Medical Center after every three cycles to determine response to treatment. 
Following cycle 3, subjects that are stable, may return every three months.  Only one month 
of study drug may be supplied at a time for each cycle.  A complete study calendar can be 
found in Section 2. Interim CBC may be performed locally.  All results will be transmitted 
to the Clinical Trials Office for review. 
5.1.1 Investigational Drug  
5.1.1.1 Pomalidomide 
Pomalidomide, 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1’-one)-1,3-dione, belongs to 
the IMiDs class of compounds.  The Chemical Abstract Service (CAS) registry number for 
CC-4047 is 19171-19-8.  The chemical structure of the active pharmaceutical ingredient 
(API) is as follows:  


 
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Pomalidomide has an asymmetric carbon atom and can therefore exist as the optically active 
forms S (-) and R (+).  Pomalidomide is being developed as a racemate.  
5.1.1.2 CLINICAL PHARMACOLOGY 
Mechanism of Action:  
Pomalidomide is an IMiD analogue of thalidomide that, among other anti-tumor properties, 
on an equimolar basis in vitro, displays equivalent anti-angiogenic activity, about 8-fold 
greater activity in stimulation of apoptosis, at least 10-fold greater activity in inhibition of 
cellular COX-2 production and over 4,000-fold greater activity in inhibition of cellular 
TNF-alpha production relative to thalidomide [9,10].   Pomalidomide has also been shown 
to stimulate antibody-dependent cytotoxic T-cell activity (ADCC) [11].   
5.1.1.3 Dose and tolerability: 
Pomalidomide was safe at doses of up to 50 mg in a Phase I single dose study in normal, 
healthy male volunteers and up to 5 mg QOD or 2 mg QD in a Phase I multidose clinical 
study in subjects with relapsed or refractory multiple myeloma; DLTs seen in subjects 
receiving higher doses were predominantly hematopoetic (i.e., neutropenia), and lower 
grade, self-limited neutropenia was also seen in some of the 1 and 2 mg QD and 5 mg QOD 
recipients. In a multidose, Phase II clinical study of subjects with prostate cancer, 2 mg QD 
dosing was well tolerated and, unlike the multiple myeloma subjects who received 1 and 2 
mg QD doses, only an overall shift to lower neutrophil counts was noted. No clinically 
relevant neutropenic AEs were observed, and no grade 3 or 4 neutropenic events occurred. It 
is, therefore, likely that subjects with solid tumors that do not extensively involve the bone 
marrow will have a higher pomalidomide MTD than subjects with hematologic 
malignancies. 
5.1.1.4 Supplier(s) 
Celgene Corporation will supply pomalidomide. 
5.1.1.5 Dosage form 
Pomalidomide will be supplied as 1.0 mg and 2.0 mg capsules for oral administration.   


 
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5.1.1.6 Packaging 
Pomalidomide will be shipped to the pharmacy at the study site in individual bottles.   
Bottles will contain a sufficient number of capsules to last for one cycle of dosing. Study 
drug must be dispensed in the original packaging with the label clearly visible.  . 
5.1.1.7 Labeling 
Pomalidomide investigational supplies are dispensed to the subjects 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. Pomalidomide should 
not be handled by FCBP unless wearing gloves.  All bottles will contain the following 
warning label:  “WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS.” 
 The study drug label must be clearly visible.  Additional labels must not cover the Celgene 
label. 
5.1.1.8 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.   
5.1.1.9 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. 
5.1.1.10 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.   
5.1.1.11 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.   


 
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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. 
5.1.1.12  Dexamethasone (Decadron) 
 
We will be using the oral formulation, which is available from any pharmacy.  Each 
tablet, for oral administration, contains 0.25 mg, 0.5 mg, 0.75 mg, 1.5 mg, 4 mg or 6 mg of 
dexamethasone. 
 
Dexamethasone (Decadron) is a synthetic adrenocortical steroid and is readily absorbed 
from the gastrointestinal tract.  Chemically, dexamethasone is 9-fluoro-11b, 17, 21-
trihydroxy-16a-methyl-pregna-1, 4-diene-3, 20-dione. 
5.2 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.  
Approximately 30 subjects with previously treated AL amyloidosis will be screened for 
enrollment and must meet the eligibility criteria below. 
 
Pregnancy Testing    
Must follow pregnancy testing requirements as outlined in the POMALYST REMS™ 
program. 
5.2.1 Inclusion Criteria 
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. 
Inclusion criteria  
1. Understand and voluntarily sign an informed consent form. 
2. Age 18 years at the time of signing the informed consent form. 
3. Able to adhere to the study visit schedule and other protocol requirements. 
4. Biopsy proven tissue amyloid deposits or positive fat aspirate 
5. Proof of AL type (either a or b suffices) 
6. Measurable plasma cell dyscrasia (a or b) AND c of the following required: 
a. Monoclonal protein in the serum or urine by immunofixation electrophoresis 
b. Plasmacytosis of bone marrow (< 30% plasma cells) with monoclonal 
staining for kappa or lambda light-chain isotype 


 
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c. dFLC > 50 mg/L (dFLC=difference in involved and uninvolved serum free 
light-chain levels) 
7. Must have received ≥1 prior treatment for AL amyloidosis, if it is intensive 
chemotherapy and an autotransplant it must be at least 3-6 months prior to 
enrollment on this study 
8. Subjects must have recovered from the reversible side effects of any prior therapy; 
permanent and stable side effects/changes are acceptable. Prior treatment for AL 
amyloidosis with chemotherapy, thalidomide, lenalidomide or steroids is not an 
exclusion. 
9. SWOG performance status of  2 at study entry (see Appendix 2). 
10. Laboratory test results within these ranges: 
d. Neutrophil  1.5 x10e9/L; 
e. Platelets 100x10e9/L; 
f. Total bilirubin < 1.5 mg/dL 
g. AST (SGOT) and ALT (SGPT) < 2 x ULN  
h. Serum creatinine < 3.0 mg/dL 
11. Disease free of prior malignancies for  5 years with exception of currently treated 
basal cell, squamous cell carcinoma of the skin, or carcinoma “in-situ” of the cervix 
or breast.  
12. 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 pomalidomide 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 28 days before she starts taking 
pomalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must 
agree to use a latex condom during sexual contact with a FCBP even if they have 
had a vasectomy.  All subjects must be counseled at a minimum of every 28 days 
about pregnancy precautions and risks of fetal exposure. See Appendix: 1 Risks of 
Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods, AND also Appendix 1:  Education and Counseling Guidance Document. 
                                               
 
† 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). 
 
 


 
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13. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (subjects 
intolerant to ASA may use warfarin or low molecular weight heparin or direct factor 
Xa inhibitors or newer anticoagulants, per preference of the patient and investigator). 
14. 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. 
5.2.2 Exclusion criteria   
1. Subjects with secondary or familial amyloidosis 
2. Subjects with multiple myeloma (≥30% plasma cells in a bone marrow biopsy 
specimen or lytic bone lesions) 
3. Cytotoxic chemotherapy or radiation therapy ≤4 weeks of initiation of study therapy. 
4. Subjects with symptomatic cardiac arrhythmias or O2-dependent restrictive 
cardiomyopathy  
5. Dialysis-dependent 
6. Subjects with untreated or uncontrolled infections. 
7. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
8. Pregnant or breast feeding females. (Lactating females must agree not to breast feed 
while taking pomalidomide). 
9. 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. 
10. Use of any other experimental drug or therapy within 28 days of initiation of study 
therapy. 
11. Known intolerance to steroids. 
12. Known hypersensitivity to thalidomide or lenalidomide. 


 
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13. The development of erythema nodosum if characterized by a desquamating rash 
while taking thalidomide or similar drugs. 
14. Concurrent use of other anti-cancer agents or treatments. 
15. Known HIV positivity is not an exclusion, unless CD4 counts <200/mcL and/or 
patient has multi-drug resistant HIV infections and/or other concurrent AIDS-
defining conditions.  HIV b-DNA < 75 copies/mL.   
5.3 Visit schedule and assessments 
Screening Assessments and all on study scheduled visits and assessments are outlined in 
Section 2 Table of Study Assessments.  
 
At treatment discontinuation, subjects will undergo off study evaluations per the Schedule 
of Assessments, Section 2.   In addition, a safety assessment will be done approximately 30 
days post the last dose of study drug.  Follow-Up contact with the subjects should occur at a 
minimum of every 3 months until progression, then annually. 
5.4 Drug Administration 
5.4.1 Treatment assignments 
The Phase I portion of the study will be aimed at determining the safety profile and the 
MTD of Pomalidomide. A 3+3 dose escalation scheme will be implemented. Subjects will 
receive escalating doses of Pomalidomide orally on D1-21 in a 28-day cycle* in the absence 
of disease progression or unacceptable toxicity. DLTs will be assessed in Cycle 1 only. 
Dose escalation of Pomalidomide will continue until MTD has been identified or a 
maximum planned dose (4 mg/day D1-21) is determined to be safe. 
 
* Pomalidomide dosing for Phase I cohorts 1 and 2 given on days 1-28 of a 28-day cycle and changed to Days 
1-21 of a 28 day cycle with Cohort 3. 
 
The Phase II portion of the study will begin after determination of the MTD and evaluation 
of the safety profile at the MTD in at least 6 subjects. The dose for administration will be 
informed by the results of the Phase I portion of the study. In the Phase II, eligible subjects 
will receive Pomalidomide at the MTD or the maximum planned dose from D1-21.  
Once the MTD is defined during Phase I, patients currently receiving treatment may discuss 
the option with the treating investigator to continue on their current dose, or increase to the 
MTD, if they have not achieved a complete response. 
 
5.4.2 Dosing regimen 
The initial planned dose of pomalidomide for investigation is 2 mg/day, orally on days 1 - 
21 (28 day cycle).*  Dosing will be in the evening at approximately the same time each day, 


 
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either 2 hours before or 2 hours after food ingestion.  Participants will be instructed to avoid 
smoking, as smoking can decrease the efficacy of pomalidomide.  Only enough 
pomalidomide for one cycle of therapy will be supplied to the subject each cycle. 
 
* Pomalidomide dosing for Phase I cohorts 1 and 2 given on days 1-28 of a 28-day cycle and changed to Days 
1-21 of a 28 day cycle with Cohort 3. 
The planned dose levels of Pomalidomide are presented below in Table 15-1 table. 
 
Table 15-1 Planned Study Drug Doses 
Dose 
Group 
Pomalidomide 
Dose (mg/dose) 
Enrollment (Number of Subjects) 
Initial 
Additional  
(if 1 of Initial 3 has DLT) 
Expanded at 
MTDa 
 
1 
2 
3b 
3 
12 
2 
3 
3 
3 
3 
4 
3 
3 
a. Twelve additional subjects are to be enrolled in an expanded cohort for analysis of 
efficacy and treated at the MTD for each dosing schedule. 
b. If the first 2 subjects enrolled experience DLT then this cohort is closed and further 
subjects will be evaluated at 1mg/day dose and the cohort expanded at that dose. 
The dose escalation rules will follow the standard Fibonacci method. 


 
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Dose escalation algorithm 
 
At least 3 subjects are to be enrolled in each dose group, beginning with the 2 mg/dose.  
Within each dose group, 3 subjects are to complete at least 2 treatment cycles.  It is noted 
that if the first 2 subjects in the first cohort develop DLT, then the cohort at the 1 mg/dose 
dose will be defined as the MTD. 
Dose escalation within a cohort is not allowed. 
If after all 3 subjects complete 1 treatment cycle: 
No subject experiences DLT, then enrollment at the next planned dose level may 
commence. 
One subject experiences DLT, then 3 additional subjects are to be enrolled at the current 
dose level. 
If 1 of 6 subjects experiences DLT, then enrollment at the next planned dose level 
may commence. 
If 2 or more of 6 subjects experience DLT, then the previous dose is declared the 
MTD.   


 
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Two or more subjects experience DLT, then the previous dose is declared the MTD.   
Dose escalation continues through the 3 dose levels in order to define the MTD 
based on the occurrence of DLT in the first cycle.  Definitions of DLT and MTD 
are as follows: 
DLT 
Based on the first cycle; toxicity considered by the investigator to be related to 
Pomalidomide; Grade 4 thrombocytopenia or neutropenia;  Grade 3 non-
hematologic toxicity  
MTD 
The dose level at which DLT occurs in no more than 1 of 6 subjects (ie, the 
dose level below that at which DLT was established). 
 
Subjects will take aspirin 325 mg/day to prevent venous thrombosis while on 
pomalidomide. 
 
A proton pump inhibitor will be used for GI prophylaxis. 
Pomalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.   Pomalidomide should be taken without food, at least 2 hours before or 2 hours 
after a meal. 
If a dose of pomalidomide 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 as usual 
at the next scheduled time. 
Subjects who take more than the prescribed dose of pomalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately.   
Subjects experiencing adverse events may need study treatment modifications (See section 
5.5). 
5.4.3 Special Handling Instructions 
Females of childbearing potential should not handle or administer pomalidomide unless they 
are wearing gloves. 
5.4.4 Record of administration 
Accurate records will be kept of all study drug administration (including dispensing and 
dosing) will be made in the source documents.   
5.5 
Dose Continuation, Modification and Interruption    
Subjects will be evaluated for AEs at each visit with the NCI CTCAE v4.0 (Appendix 3: 
NCI CTCAE v4.0) used as a guide for the grading of severity.  Refer to Sections 6.5.1, 6.5.2 


 
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and 6.5.3 for instructions on beginning a new cycle of therapy and dose-modifications 
during a cycle of therapy.    
 
5.5.1  Dose-Modification Guidelines 
During the study, the focus of the evaluations is on the assessment of toxicity to document 
the occurrence of DLT. Although DLTs may occur at any point during treatment, only 
DLTs occurring during Cycle 1 of treatment must influence decisions regarding dose-
escalation, expansion of a dose level, or evaluation of intermediate dose levels. However, 
DLTs occurring in later cycles may be taken into consideration for dose-escalation 
decisions, at the discretion of the investigators. Unless a DLT is documented to have 
occurred, no dose modification is allowed during Cycle 1.  
 
In the event that a patient experiences DLT during Cycle 1, treatment should be held and the 
event will be counted toward the assessment of MTD for the given cohort. Patients 
experiencing DLTs in Cycle 1 may be restarted following recovery from toxicity at the 
discretion of the investigator according to the guidelines provided in Section 5.5.2. If a 
decision is made to restart study therapy following a DLT, the pomalidomide dose must be 
reduced 1 dose level. The patient will be evaluated weekly for possible toxicities that may 
have occurred after the previous dose(s). If multiple toxicities are noted, the dose 
adjustments and/or delays should be made according to the most severe toxicity guidelines. 
5.5.2 Dose-Reduction Steps 
Dose-reduction steps are below: 
 
Table 1: Pomalidomide Dose Reduction Steps for Phase I and II 
 
Starting Dose 
MTD (as determined in Phase I portion) mg 
daily on Days 1-28 every 28 days 
 
Dose Level – 1 
Decrease by 1 mg daily from MTD on Days 1-21 
every 28 days* 
Dose Level – 2 
Decrease by 2 mg daily from MTD on Days 1-21 
every 28 days* 
Dose Level – 3 
Decrease by 3 mg daily from MTD on Days 1-21 
every 28 days* 
* Pomalidomide dosing for Phase I cohorts 1 and 2 given on days 1-28 of a 28-day cycle and changed to Days 
1-21 of a 28 day cycle with Cohort 3. 
 
Table 2: DEXAMETHASONE Dose Reduction Steps  for Phase I and II 
Starting Dose 
20 mg QD once weekly every 28 days 
Dose Level –1 
10 mg QD once weekly every 28 days 
 
Dose Level –2 
4 mg QD once weekly every 28 days 
 
 


 
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Dosing will be adjusted as needed by study investigators as outlined in the tables in Section 
5.5.3.  If dexamethasone is permanently discontinued, the patient will continue with single 
agent Pomalidomide. 
 
5.5.3 Instructions for initiation of a New Cycle  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
 The ANC is ≥ 1,000/mm³;  
 The platelet count is ≥ 50,000/mm³;  
 Any pomalidomide-related rash, neuropathy or cardiac event that may have occurred 
has resolved to ≤ grade 1 severity; 
 Any other pomalidomide-related adverse events that may have occurred have 
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 treatment will not be initiated until the toxicity has resolved as 
described above.  If pomalidomide dosing was held during the previous cycle and was 
restarted with a one-level dose reduction without requiring an interruption for the remainder 
of the cycle, then that reduced dose level will be initiated on Day 1 of the new cycle. If 
pomalidomide dosing was omitted due to an attributable toxicity (see table 3) for the 
remainder of the previous cycle or if the new cycle is delayed due to attributable 
toxicity newly encountered on the scheduled Day 1, then the new cycle will be started 
with a one-level dose reduction of pomalidomide.  If pomalidomide is permanently 
discontinued, the subject will be removed from study.   If dexamethasone is permanently 
discontinued, the subject may continue on single-agent pomalidomide.   
5.5.4 Instructions for dose modifications or interruptions during a cycle. 
 
 


 
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Table 3: Pomalidomide Dose Modifications for toxicities attributable to Pomalidomide  
NCI CTCAE Toxicity 
Grade 
Onset Day 2-14 of Cycle 
Onset ≥ Day 15 of Cycle 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia ¥ 
 
Hold (interrupt) pomalidomide 
dose. 
 
Follow CBC weekly. 
 
If neutropenia has resolved to ≤ 
grade 2 prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue the cycle.  If 
neutropenia is the only toxicity for 
which a dose reduction is 
required. G-CSF may be used 
and the pomalidomide dose 
maintained ¥ 
 
Omit pomalidomide for remainder 
of cycle 
 
See Instructions for Initiation of a 
New Cycle and reduce the dose of 
pomalidomide by 1 dose level.  If 
neutropenia is the only toxicity for 
which a dose reduction is 
required. G-CSF may be used and 
the pomalidomide dose 
maintained for the next cycle at 
the investigators discretion.¥ 
Thrombocytopenia 
≥Grade 3 (platelet count 
< 50,000/mm³) 
 
Hold (interrupt) pomalidomide 
dose. 
 
Follow CBC weekly 
 
Hold prophylactic anticoagulation 
for thrombocytopenia (grade 3 or 
4) or bleeding. Prophylactic 
anticoagulation can be resumed 
when platelet count >50k (<2 
grade) and no sign of bleeding. 
 
If thrombocytopenia resolves to ≤ 
grade 2 prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue the cycle. 
 
 
Omit pomalidomide for remainder 
of cycle 
 
See Instructions for Initiation of a 
New Cycle and reduce the dose of 
pomalidomide by 1 dose level. 
 
Hold prophylactic anticoagulation 
for thrombocytopenia (grade 3 or 
4) or bleeding. Prophylactic 
anticoagulation can be resumed 
when platelet count >50k (<2 
grade) and no sign of bleeding. 
Non-blistering rash 
Grade 3 
 
 
 
 
             Grade 4 
 
If Grade 3, hold (interrupt) 
pomalidomide dose.  Follow 
weekly. 
 
If the toxicity resolves to ≤ grade 
1 prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue the cycle. 
 
 
 
 
Discontinue pomalidomide.  
Remove subject from study. 
 
Omit pomalidomide for remainder 
of cycle.  
 
See Instructions for Initiation of a 
New Cycle and reduce the dose of 
pomalidomide by 1 dose level. 
 
 
Discontinue pomalidomide.  
Remove subject from study. 
Desquamating 
(blistering) rash- any 
Grade  
 
Discontinue pomalidomide.  
Remove subject from study. 
 
Discontinue pomalidomide.  
Remove subject from study. 
Neuropathy 
 
Grade 3 
 
 
 
 
Grade 4 
 
 
Hold (interrupt) pomalidomide 
dose.  Follow at least weekly. 
 
If the toxicity resolves to ≤ grade 
1 prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue the cycle. 
 
 
 
 
Discontinue pomalidomide.  
Remove subject from study. 
 
Omit pomalidomide for the 
remainder of the cycle. 
 
See Instructions for Initiation of a 
New Cycle and reduce the dose of 
pomalidomide by 1 dose level. 
 
 
Discontinue pomalidomide.  
Remove subject from study. 


 
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Table 3: Pomalidomide Dose Modifications for toxicities attributable to Pomalidomide  
NCI CTCAE Toxicity 
Grade 
Onset Day 2-14 of Cycle 
Onset ≥ Day 15 of Cycle 
Venous 
thrombosis/embolism 
≥ Grade 3 
 
Hold (interrupt) pomalidomide 
and start anticoagulation; restart 
pomalidomide at investigator’s 
discretion (maintain dose level). 
 
Omit pomalidomide for remainder 
of cycle. See Anticoagulation 
Consideration (Section 5.6.1.2) 
other non-hematologic 
toxicity ≥ Grade 3 
 
Hold (interrupt) pomalidomide 
dose.  Follow at least weekly. 
 
If the toxicity resolves to ≤ grade 
2 prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue the cycle. 
 
Omit pomalidomide for remainder 
of cycle.  
 
See Instructions for Initiation of a 
New Cycle and reduce the dose of 
pomalidomide by 1 dose level. 
 
Hyperthyroidism or 
hypothyroidism  
≥ Grade 2 
 
Omit pomalidomide for remainder 
of cycle, evaluate etiology, and 
initiate appropriate therapy.  
 
If the toxicity resolves to ≤ grade 
1 prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue the cycle. 
 
Omit pomalidomide for remainder 
of cycle, evaluate etiology, and 
initiate appropriate therapy.  
 
See Instructions for Initiation of a 
New Cycle and reduce the dose of 
pomalidomide by 1 dose level. 
Any attributable or non-
attributable 
hospitalization or 
toxicity grade < 2 
 
Pomalidomide may be held or 
continued at the discretion of the 
treating investigator.   
 
 
Once resumed, maintain dose 
level. 
 
Pomalidomide may be held or 
continued at the discretion of the 
treating investigator.   
 
If held, see Instructions for 
Initiation of a New Cycle and  
maintain dose level. 
 
¥ 
As stated in the table, pomalidomide should be held for occurrence of grade 3 
neutropenia with fever or grade 4 neutropenia attributable to Pomalidomide. Follow 
CBC weekly.  
If neutropenia has resolved to ≤ grade 2 prior to Day 21, restart pomalidomide at next 
lower dose level and continue the cycle.  If neutropenia is the only toxicity for which a 
dose reduction is required, G-CSF may be used and the pomalidomide dose can be 
maintained. In case of second occurrences of Grade 4 neutropenia or Grade 3 
neutropenia with fever in the setting of GCSF, pomalidomide will be held and if 
neutropenia has resolved to ≤ grade 2 prior to Day 21, restart pomalidomide at next 
lower dose level with addition of G-CSF 
 
Dose Modifications for Dexamethasone 
Table 4: Non-hematological toxicity attributable to dexamethasone 
 
Grade 1-2 
Grade 3-4 
Dyspepsia / GI 
Start H2-blocker or Proton Pump 
Inhibitor if not already on one of 
these. 
Hold dexamethasone and start H2-
blocker or Proton Pump Inhibitor if not 
already on one of these. Once toxicity 
has decreased to Grade 0-2, resume 
Dex at one dosing level lower with 
continued H2B or PPI. If Grade 3-4 
toxicity persists for more than 14 


 
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days,endoscopy or other UGI 
evaluation is encouraged. 
Edema 
May add diuretic 
Decrease dex by one dosing level, and 
add diuretics 
Confusion/Mood Alteration 
For Grade 2, decrease 
dexamethasone by one dosing 
level without holding dose 
Hold dex until severity decreases to 
Grade 0-2, then resume dex at next 
lower dosing level. 
Myopathy 
For Grade 2-4, decrease dexamethasone by one dosing level without 
holding dose 
Hyperglycemia 
For Grade 2, add oral 
hypoglycemic agents and/or 
insulin to control blood sugar. If 
hyperglycemia not able to be 
easily controlled, decrease 
dexamethasone by one dosing 
level without holding dose. 
Add oral hypoglycemic agents and/or 
Insulin, and decrease dosing level by 
one. 
 
Other 
For Grade 2, decrease 
dexamethasone by one dosing 
level without holding dose 
Hold dex until severity decreases to 
Grade 0-2, then resume dex at next 
lower 
 
 
5.5.3 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 and empty study drug containers 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.   
5.6 Concomitant therapy   
5.6.1 Recommended concomitant therapy   
Subjects should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate.  
 
5.6.1.2 Anti-coagulation Consideration   
Pomalidomide increases 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.  
Subjects will take aspirin 325 mg/day to prevent venous thrombosis while on 
pomalidomide. Low molecular weight heparin may be utilized in subjects that are intolerant 
to ASA. Coumadin should be used with caution and close monitoring of INR. 
5.6.2 Prohibited concomitant therapies 
Concomitant use of sargramostim (GM-CSF), other anti-cancer therapies, including 
radiation, thalidomide, or other investigational agents is not permitted while subjects are 


 
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receiving study drug during the treatment phase of the study.  G-CSF is not allowed during 
Phase I, Cycle 1 while evaluating for DLT.  However, G-CSF is allowed for Phase II 
participants or following cycle 1 for Phase I participants. 
5.7 Discontinuation of Study-Treatment  
Treatment will continue until the occurrence of any of the following events.   
 Disease progression  
 Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of the treatment regimen. 
 Major violation of the study protocol. 
 Withdrawal of consent 
 Lost to follow up 
 Death 
 Suspected pregnancy 
 
5.8 
Follow-Up   
Subjects who discontinue treatment for any reason, will be followed every 3 months until 
disease progression, then annually for survival, as clinically indicated. At treatment 
discontinuation, subjects will undergo a safety assessment approximately 30 days post the 
last dose of study drug.  In addition off study evaluations per the Schedule of Assessments, 
Section 2 will be done. 
6 Adverse events 
6.1 Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 

Results in death 

Is life-threatening1 

Requires in-patient hospitalization or prolongation of existing 
hospitalization 

Results in persistent or significant disability or incapacity2 

Is a congenital anomaly or birth defect 

Is an important medical event3 


 
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
Suspected positive Pregnancy 
 
 1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused death 
if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred.  Important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the definition 
above should also usually be considered serious.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalization, or the development of drug dependency or 
drug abuse.  A new diagnosis of cancer during the course of a treatment should be considered as 
medically important.  
6.2 Adverse Drug Reaction Reporting 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  
A copy of the CTCAE Version 4.0 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 4.0.  All adverse clinical experiences, whether observed by the 
investigator or reported by the subject, must be recorded, with details about the duration and 
intensity of each episode, the action taken with respect to the test drug, and the subject’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 subject’s 
outcome. 
 
AEs and SAEs will be reported from the first dose of study drug through 30 days after 
administration of the last dose of study drug or the start of subsequent therapy for 
amyloidosis, whichever occurs first. All SAEs should continue to be monitored until they 
are resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).   
 
Pregnancies 
Pregnancies occurring while the subject is on pomalidomide or within 4 weeks after the 
subject’s last dose of pomalidomide are considered expedited reportable events.  If the 
subject is on pomalidomide, it is to be discontinued immediately and the subject is to be 
instructed to return any unused portion of pomalidomide to the Investigator.  The pregnancy 
must be reported 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. 
 


 
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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 Expedited Reporting of SAEs to Celgene (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). 
 
Any suspected fetal exposure to pomalidomide must be reported to Celgene within 24 hours 
of being made aware of the event.  The subject 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 pomalidomide should also be reported. 
In the case of a live “normal” birth, Celgene Corporation Worldwide Drug Safety 
Surveillance (WWDSS) should be advised as soon as the information is available. 
 
6.2.1 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:  
drugsafety@celgene.com 
 
 
6.3 Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
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 


 
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be filed in the study's Regulatory Binder, and a copy provided 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 subject 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. 
6.3.1 Expedited reporting by investigator to Celgene 
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-AMYL-PI-0024) 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.  
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.   
6.3.2 Investigator 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 investigator/physician 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 


 
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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. 
6.4 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 (see Section 11.4 for records retention information). 
7 Response-Criteria 
Efficacy assessments are scheduled to occur every three months while on therapy. 
  
7.1 
Hematologic Response Criteria 
 
CR 
Negative serum and urine immunofixation electrophoresis, normal serum free light 
chain ratio 
 
VGPR dFLC <40 mg/L, dFLC = difference in involved and uninvolved serum free light-
chain levels 
 
PR 
dFLC reduction >50%, dFLC = difference in involved and uninvolved serum free 
light-chain levels 
 
SD 
Meets neither criteria for CR, VGPR, PR or PD 
 
PD 
From CR, an increase in serum M-protein to > 0.5 g/dL, an increase in the urine 
M-protein to > 200 mg/day, or an increase in the serum monoclonal free light 
chain by > 10 mg/dL (100 mg/L). From VGPR, PR or SD, an increase in the serum 
M-protein from the lowest level by > 50%, as long as the absolute magnitude of 
this increase is > 0.5 g/dL; or an increase in the urine M-protein from the lowest 
level by 50%, as long as the absolute magnitude of this increase is > 200 mg/day; 
or an increase in the serum or urine monoclonal free light chain by > 50% from the 
lowest level, as long as the absolute magnitude is > 10 mg/dL (100 mg/L). 
 
Measurable disease to enter on the clinical trial 


 
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dFLC of 50 mg/L, dFLC = difference in involved and uninvolved serum free light 
levels 
 
7.2 
Organ Response-Criteria: 
 
A subject will be said to have had an organ response in an involved organ if any of the 
following criteria are met, and none of the criteria in Section 10.4 are met. 
 
Kidney: 50% reduction in 24-hour urine protein excretion in the absence of progressive 
renal insufficiency (defined as a 25% increase in serum creatinine, as long as that is > to an 
absolute increase of 0.5 mg/dL). In the case of nephrotic syndrome: a decrease in proteinuria 
to < 1g/24h and an improvement in one of 2 extrarenal features – normalization of serum 
albumin or resolution of edema and/or discontinuation of diuretics in response to 
improvement in edema. 
 
Heart: ≥ 2 mm reduction in the interventricular septal (IVS) thickness by echocardiogram, 
improvement of ejection fraction by ≥ 20% (echocardiogram must be performed at the same 
institution), or decrease in 2 NYHA classes without increase in diuretic need (see Appendix 
E for class definitions). 
 
Liver: ≥ 50% decrease in normalization of an initially elevated alkaline phosphatase level or 
reduction in the size of the liver by at least 3 cm (determined by US or CT). 
 
Neuropathy: While neurotoxicity is acceptable for determining organ involvement, it will 
not be adequate for assessing organ response; organ response will be indeterminable for 
subjects in which neurotoxicity is the only site of organ involvement. 
 
Gastrointestinal Tract: While GI involvement is acceptable for determining organ 
involvement, it will not be adequate for assessing organ response: organ response will be 
indeterminable for subjects in which GI is the only site of organ involvement. 
 
8 Protocol Amendments/Deviations 
8.1 Protocol amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed and approved by Celgene.  Amendments should only be submitted to IRB/EC after 
consideration of Celgene review.  Written verification of IRB approval will be obtained 
before any amendment is implemented.   


 
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8.2 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 in writing of such deviation from protocol. 
Non-emergency minor deviations from the protocol will be permitted with approval of the 
Principal Investigator.  
9 Data Management 
9.1 Analyses and Reporting 
Data will be analyzed and reported after study is completed or meaningful endpoints are 
reached. All subsequent data collected will be analyzed and reported in a follow-up clinical 
report.  
9.2 Data Monitoring Committee 
Toxicity and accrual monitoring will be performed on a routine basis by the study 
investigators as well as the multidisciplinary members of the Amyloid Treatment and 
Research Program at Boston University, which has over 40 years’ experience in the 
treatment of AL amyloidosis.  Subjects will undergo toxicity assessment, performance status 
assessment and laboratory tests before beginning each new cycle.  Response assessment will 
be conducted every three cycles.  The clinical status and laboratory reports of the study 
participants will be reviewed routinely by the co-investigators at the weekly meetings of the 
Stem Cell Transplant Program and reviewed by the Amyloid Program at weekly meetings.  
Dose modifications/interruptions or discontinuation will be implemented according to 
Section 5.5.  
 
In addition, the BMC Cancer Center’s Internal Data and Safety Monitoring Committee 
(DSMC) will review the protocol, and will determine review frequency based on level of 
risk.  The protocol will be reviewed at least annually by the DSMC. Please see full DSMB 
Charter in Appendix 4. 
 
 


 
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9.3 
Study monitoring and auditing 
9.3.1 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 onto CRFs or other data collection system.  The 
Investigator will permit study-related monitoring visits and audits by 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 the Celgene representative so that the accuracy 
and completeness may be checked. 
10   Statistical Plan 
10.1 Overview 
This is a Phase I/II study. Responses and toxicity will be compared informally to those 
reported lenalidomide and dexamethasone combined. 
 
The Phase I portion of the study will be aimed at determining the safety profile and the 
MTD of pomalidomide. A 3+3 dose escalation scheme will be implemented. Subjects will 
receive escalating doses of pomalidomide orally on D1-21 in a 28-day cycle in the absence 
of disease progression or unacceptable toxicity.* Pomalidomide has been safely given to 
persons with relapsed/refractory myeloma subjects at 2 mg/day continuously in a small 
Phase II study. Therefore, the estimated safe starting dose of pomalidomide will be 2 
mg/day continuously. DLTs will be assessed in Cycle 1 only. Dose escalation of 
pomalidomide will continue until MTD has been identified or a maximum planned dose (4 
mg/day continuously) is determined to be safe. 
 
* Pomalidomide dosing for Phase I cohorts 1 and 2 given on days 1-28 of a 28-day cycle and changed to Days 
1-21 of a 28 day cycle with Cohort 3. 
 


 
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10.2 Datasets to be analyzed 
Data for safety analysis will be obtained utilizing the NCI Common Terminology Criteria 
for Adverse Events v4.0. 
DLT 
Based on the first cycle; toxicity considered by the investigator to be related to 
pomalidomide; Grade 4 thrombocytopenia or neutropenia; > Grade 3 non-hematologic 
toxicity  
MTD The dose level at which DLT occurs in no more than 1 of 6 subjects (ie, the dose 
level below that at which DLT was established). 
Data to be included in the analysis for the hematologic response endpoint include evaluation 
of serum free light chain assay, monoclonal protein in serum or urine by immunofixation 
electrophoresis, percentage of plasma cells and presence of clonal dominance of kappa or 
lambda isotope on bone marrow biopsy.    
Data for the secondary endpoint of organ response will include creatinine and 24 hour urine 
protein, liver span and liver function tests, mean left ventricular wall thickness, NYHA heart 
failure class, orthostatic vital signs and symptoms, GI symptoms and evaluation of 
peripheral neuropathy. 
Data for the exploratory endpoint include BNP and troponin I levels. 
10.3 Statistical Methodology 
Determination of Sample Size 
Based on the dose escalation scheme, as many as 30 subjects may be enrolled in this study. 
 
The number of subjects enrolled will depend on the outcome of the actual dose escalation process.  
The dose-escalation phase consists of 3 cohorts, each with 2 to 6 subjects enrolled depending on 
when DLT occurs.  Therefore, a minimum of 2 and a maximum of 18 subjects will be enrolled in 
this phase. 
 
An additional 12 subjects will be enrolled in an expanded cohort for efficacy at each 
schedule.  Therefore, an additional 12 subjects could potentially be enrolled. 
 
It is expected that approximately 30 patients will be enrolled in the phase I/II portions of this 
study.  The endpoints measured in the protocol will be overall response rate (ORR) 
determined by either CR, VGPR or PR and response of one or more organs.    It is estimated 
by the principle investigator’s approximate frequency of response in 18 patients (6 patients 
will be dosed at the MTD during the phase I portion of this trial plus the additional 12 
patients at this MTD dose during the phase II portion).   Using the adjusted Wald’s 
confidence interval for the proportion and the corresponding point estimates for hypothetical 
data, it is expected that if 6 out of 18 have ORR then the estimated response rate would be 
35.57% with a 90% confidence interval between 18.21% and 52.81% with similar estimates 
for organ response.  


 
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Randomization and Stratification 
This is not a randomized study. 
 
Populations for Analysis 
The safety population will include all subjects who received at least 1 dose of study drug. 
 
The additional 12 subjects enrolled in the expanded cohort for efficacy will comprise the efficacy 
population. 
 
Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed.  Standard clinical monitoring and data 
management practices will be used to ensure the integrity of data. 
 
General Methodology 
In general, summary tabulations will be presented by dose group showing the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous variables, 
and the number and percent (calculated using non-missing values) per category for categorical data. 
 
Safety Analysis 
 
 Determination of MTD 
 
The determination of MTD will be achieved by the results of a deterministic algorithm; thus, 
statistical hypothesis testing is not intended. 
 
The evaluation of MTD will be based on data from subjects who receive pomalidomide and whose 
data are interpretable in the context of study drug-specific toxicity (ie, subjects should have had 
sufficient safety assessments performed to determine whether DLT occurred and should not have 
received alternate antineoplastic therapies through cycle 1).  Subjects who are withdrawn from the 
study for reasons other than DLT before completing cycle 1 and are replaced consequently will not 
be included in the analysis of MTD.  Subjects will be analyzed according to the dose actually 
received. 
 
Pharmacokinetics/Pharmacodynamics 
Not applicable. 
 
Efficacy Analysis 
The efficacy analysis will be based on confirmed hematological response and confirmed organ 
response.  The analysis of response data at the MTD will be descriptive, consisting of 2-sided 90% 
confidence intervals. 
 
Additional analyses of efficacy data at the MTD will consist of evaluations of time to hematologic 
response, duration of hematologic response, and time to worsening of hematologic and/or organ 
function.  These analyses will also be descriptive in nature. 
 


 
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Analysis of the rates of responders for each of the other dose levels will also be presented, without 
calculation of confidence intervals. 
 
Exploratory Analysis 
An exploratory analysis will be conducted to investigate the relationship of changes in the 
levels of the biomarkers brain natriuretic peptide (BNP) and troponin I to the frequency of 
specific AEs and the occurrence of DLT.  Additionally, the benefit, if any, of using these 
measures in addition to routine monitoring by ECG and echocardiogram will be explored.  
The frequency of conversion in immunofixation results from positive to negative will be 
explored and the disappearance of free light chain.  Efficacy at additional doses may be 
explored for potential use in future Phase II clinical trials. 
 
Interim Analysis 
Interim analyses will be performed following each cohort during the Phase I portion of the 
study.  No interim analysis is planned for the Phase II portion. 
10.4 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(s) and had this 
confirmed, will not be evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever 
possible.  
10.5 Interim analyses  
10.5.1 Interim analysis strategy 
Accrual will be placed on hold during interim analyses during the Phase I portion while 
cohort toxicities are evaluated. 
10.5.2 Efficacy 
If none of the first four subjects treated at the MTD experience a response, consideration 
will be made to terminate the study.  Accrual will not be placed on hold during efficacy 
evaluation. 
10.5.3 Safety 
Interim analysis will be performed following each cohort during the Phase I portion of the 
study. 


 
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10.6 Sample size and power considerations 
11 
Regulatory Considerations 
11.1 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. 
11.2 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 Investigator’s 
study files. 
11.3 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 


 
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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. 
11.4 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 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; SAE reports, 
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. 
11.5 Premature discontinuation of study 
11.5.1 Single center 
The responsible local clinical Investigator as well as Celgene has 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. 
11.5.2    Study as a whole 
Celgene reserves the right to terminate this clinical study at any time for reasonable medical 
or administrative reasons. 


 
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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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12 
References 
1. Yano, S., Muguruma, H., Matsumori, Y., et al.; “Antitumor vascular strategy for 
controlling experimental spread of human small-cell lung cancer cells with ZD6474 
in natural killer cell-depleted severe combined immunodeficiency mice”; Clin. 
Cancer Res. 11 (24 pt. 1): 8789 – 8798, 15 Dec. 2005. 
2. Johnson, DH, Fehrenbacher, L, Novotny, WF, et al. “Randomized Phase II Trial  
Comparing Bevacizumab plus Carboplatin and Paclitaxel with Carboplatin and 
Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-
Small-Cell Lung Cancer”;  J. Clin. Oncology 22 (11): 2184 – 2191; 1 June 2004. 
3. Lee, SM, James, LE, Mohamed-Ali, V, et al. “A phase II study of carboplatin / 
etoposide with thalidomide in small cell lung cancer (SCLC)”; ASCO 38th meeting, 
2002; abstract # 1251 in Proceedings of the American Society of Clinical Oncology 
21: 313a, 2002. 
4. Cooney, M, Subbaya, S, Chapman, R, et al.  “Phase II trial of maintenance daily oral 
thalidomide in patients with extensive stage small cell lung cancer (ES-SCLC) in 
remission”; ASCO 41st meeting, 2005; abstract # 7166; Proceedings of the 
American Society of Clinical Oncology, 2005. 
5. Pujol, J, Breton, J, Gervals, R, et al.; “A prospective randomized phase III, double-
blind, placebo-controlled study of thalidomide in extended-disease (ED) SCLC 
patients after response to chemotherapy (CT)”; 11th World Conference on Lung 
Cancer; 3-6 July 2005, Barcelona, Spain; Lung Cancer 49 (supplement 2):  S54, July 
2005; abstract O-159. 
6. Sheski, FD, Natarajan, V and Pottratz, ST; “Tumor necrosis factor-alpha stimulates 
attachment of small cell lung carcinoma to endothelial cells” J. Lab. Clin. Med. 
133(3): 265 – 273, March 1999. 
7. Haley, KJ, Patidar, K, Zhang, F, et al.; “Tumor necrosis factor induces 
neuroendocrine differentiation in small cell lung cancer cell lines”; Am. J. Physiol. 
275(2 Pt. 1): L311 – L321, 1998. 
8. Han, S, Sidell, N, Roser-Page, S and Roman, J; “Fibronectin stimulates human lung 
carcinoma cell growth by inducing cyclooxygenase-2 (COX-2) expression”; Int. J. 
Cancer 111(3): 322-331, 1 Sept. 2004. 
9. Data on file: Celgene Corp.; Summit, NJ. 
10. Payvandi, F., Wu, L., Haley, M, et al.  “Immunomodulatory drugs inhibit expression 
of cyclooxygenase-2 from TNF-alpha, IL-1 beta, and LPS-stimulated human PBMC 
in a partially IL-10-dependent manner”; Cell Immunol. 230(2): 81-88, Aug. 2004. 
11. Schey, SA, Fields, P, Bartlett, JB, et al.  “Phase I study of an immunomodulatory 
thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma”; J. Clin. 
Oncol. 22(16): 3269-3276, 15 Aug 2004. 


 
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12. Suppiah, R, Srkalovic, JG, and Hussein, MA. “Immunomodulatory analogues of 
thalidomide in the treatment of multiple myeloma”; Clin. Lymphoma Myeloma 6(4): 
301-305, Jan. 2006. 
13. McCarthy, DA, Macey, MG, Streetly, M, et al. “The neutropenia induced by the 
thalidomide analogue CC-4047 in patients with multiple myeloma is associated with 
an increased percentage of neutrophils bearing CD64”; Int. Immunopharmacol. 6(7): 
1194-1203, Jul. 2006 (Epub 29 Mar. 2006). 
14. Lacy, MQ, et al. “Pomalidomide (CC4047) Plus Low-Dose Dexamethasone As 
Therapy for Relapsed Multiple Myeloma.” Journal of Clinical Oncology. 2009 Aug 
31: Epub ahead of print. 
15. Tefferi, A, Verstovsek, S, Barosi, G, et al. “Pomalidomide Therapy in Anemic 
Patients with Myelofibrosis: Results from a Phase-2 Randomized Multicenter 
Study,”; Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 663. 
 
 


 
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13  Appendices 
 


 
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Appendix I 


 
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Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods  
Risks Associated with Pregnancy 
Pomalidomide was found to be teratogenic in a developmental study in rabbits.  
Pomalidomide is an analogue of thalidomide.  Thalidomide is a known human teratogen that 
causes severe life-threatening human birth defects.  If Pomalidomide is taken during 
pregnancy, it may cause birth defects or death to an unborn baby. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who: 
1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (ie, has had menses at any time in the 
preceding 24 consecutive months). 
Counselling 
For a female of childbearing potential, pomalidomide is contraindicated unless all of the 
following are met (ie, all females of childbearing potential must be counselled concerning 
the following risks and requirements prior to the start of pomalidomide study therapy):  
 She understands the potential teratogenic risk to the unborn child 
 She understands the need for effective contraception, without interruption, 28 
days before starting study treatment, throughout the entire duration of study 
treatment, dose interruption and 28 days after the end of study treatment 
 She should be capable of complying with effective contraceptive measures 
 She is informed and understands the potential consequences of pregnancy and 
the need to notify her study doctor immediately if there is a risk of pregnancy 
 She understands the need to commence the study treatment as soon as study drug 
is dispensed following a negative pregnancy test 
 She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol 
 She acknowledges that she understands the hazards and necessary precautions 
associated with the use of pomalidomide 
The investigator must ensure that females of childbearing potential: 
 Comply with the conditions for pregnancy risk minimization, including 
confirmation that she has an adequate level of understanding 
 Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, pomalidomide is contraindicated unless all of 
the following are met (ie, all females NOT of childbearing potential must be counselled 
concerning the following risks and requirements prior to the start of pomalidomide study 
therapy):  


 
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 She acknowledges that she understands the hazards and necessary precautions 
associated with the use of pomalidomide 
The effect of pomalidomide on spermatogenesis is not known and has not been studied. 
Therefore, male subjects taking pomalidomide must meet the following conditions (ie, all 
males must be counselled concerning the following risks and requirements prior to the start 
of pomalidomide study therapy): 
 Understand the potential teratogenic risk if engaged in sexual activity with a 
pregnant female or a female of childbearing potential 
 Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or a female of childbearing 
potential.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual contact during the following time periods related to this study: 1) for at least 28 
days before starting study drug; 2) while participating in the study; 3) dose interruptions; 
and 4) for at least 28 days after study treatment discontinuation.  
The two methods of reliable contraception must include one highly effective method and 
one additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and 
additional effective methods of contraception:   
 Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
 Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Because of the increased risk of venous thromboembolism in subjects with multiple 
myeloma taking pomalidomide and dexamethasone, combined oral contraceptive pills are 
not recommended. If a subject is currently using combined oral contraception the subject 
should switch to another one of the effective methods listed above. The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. 
The efficacy of contraceptive steroids may be reduced during co-treatment with 
dexamethasone.  


 
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Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic 
antibiotics should be considered particularly in subjects with neutropenia.  
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of  25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential 
who commit to complete abstinence, as outlined below. 
Before starting study drug 
Female Subjects: 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
starting study drug.  The first pregnancy test must be performed within 7 days prior to the 
start of study drug and the second pregnancy test must be performed within 24 hours prior to 
the start of study drug.  The subject may not receive study drug until the study doctor has 
verified that the results of these pregnancy tests are negative. 
Male Subjects: 
Must practice complete abstinence or  agree to use a condom during sexual contact with a 
pregnant female or a female of childbearing potential while participating in the study, during 
dose interruptions and for at least 90 days following study drug discontinuation, even if he 
has undergone a successful vasectomy.   
During study participation and for 28 days following study drug discontinuation  
Female Subjects: 
 FCBP with regular or no menstrual cycles must agree to have pregnancy tests 
weekly for the first 28 days of study participation and then every 28 days while 
on study, at study discontinuation, and at day 28 following study drug 
discontinuation. If menstrual cycles are irregular, the pregnancy testing must 
occur weekly for the first 28 days and then every 14 days while on study, at 
study discontinuation, and at days 14 and 28 following study drug 
discontinuation.   
 At each visit, the Investigator must confirm with the FCBP that she is continuing 
to use two reliable methods of birth control.   
 Counselling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days.  
 If pregnancy or a positive pregnancy test does occur in a study subject, study 
drug must be immediately discontinued. 
 Pregnancy testing and counselling 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. 
 Females must agree to abstain from breastfeeding during study participation and 
for at least 28 days after study drug discontinuation. 


 
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Male Subjects: 
 Counselling about the requirement for complete abstinence or condom use 
during sexual contact with a pregnant female or a female of childbearing 
potential and the potential risks of fetal exposure to pomalidomide must be 
conducted at a minimum of every 28 days.   
 If pregnancy or a positive pregnancy test does occur in the partner of a male 
study subject during study participation, the investigator must be notified 
immediately. 
Additional precautions 
 Subjects should be instructed never to give this medicinal product to another 
person and to return any unused capsules to the study doctor at the end of 
treatment. 
 Subjects should not donate blood during therapy and for at least 28 days 
following discontinuation of study drug. 
 Male subjects should not donate semen or sperm during therapy or for at least 90 
days following discontinuation of study drug. 
 Only enough study drug for one cycle of therapy may be dispensed with each 
cycle of therapy.  
 


 
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  Pomalidomide Education and Counselling Guidance Document  
To be completed prior to each dispensing of study drug. 
Protocol Number: ____________________________________________ 
 
Subject Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
Female: 
⁯  
If female, check one: 
⁯
 
FCBP (Female of childbearing potential): sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (ie, has had menses at any 
time during the preceding 24 consecutive months) 
 
NOT FCBP 
Male: 
⁯ 
 
Do Not Dispense study drug if: 
 The subject is pregnant. 
 No pregnancy tests were conducted for a FCBP. 
 The subject states she did not use TWO reliable methods of birth control 
(unless practicing complete abstinence of heterosexual contact) [at least 28 
days prior to therapy, during therapy and during dose interruption]. 
FCBP: 
1.    I verified that the required pregnancy tests performed are negative. 
2.    I counselled FCBP regarding the following: 
 Potential risk of fetal exposure to pomalidomide:  If pomalidomide is taken 
during pregnancy, it may cause birth defects or death to any unborn baby.  
Females are advised to avoid pregnancy while taking pomalidomide. The 
teratogenic potential of pomalidomide in humans cannot be ruled out.  FCBP 
must agree not to become pregnant while taking pomalidomide.  
 Using TWO reliable methods of birth control at the same time or complete 
abstinence from heterosexual contact [at least 28 days prior to therapy, during 
therapy , during dose interruption and 28 days after discontinuation of study 
drug]. 
 That even if she has amenorrhea she must comply with advice on contraception   


 
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 Use of one highly effective method and one additional method of birth control 
AT THE SAME TIME. The following are examples of highly effective and 
additional effective methods of contraception:   
 Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
 Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
 Pregnancy tests before and during treatment, even if the subject agrees not to 
have reproductive heterosexual contact.  Two pregnancy tests will be performed 
prior to receiving study drug, one within 7 days and the second within 24 hours 
of the start of study drug. 
 Frequency of pregnancy tests to be done: 
 Every week during the first 28 days of this study and a pregnancy test every 
28 days during the subject’s participation in this study if menstrual cycles are 
regular or every 14 days if cycles are irregular.   
 If the subject missed a period or has unusual menstrual bleeding.   
 When the subject is discontinued from the study and at day 28 after study 
drug discontinuation if menstrual cycles are regular.  If menstrual cycles are 
irregular, pregnancy tests will be done at discontinuation from the study and 
at days 14 and 28 after study drug discontinuation. 
 Stop taking study drug immediately in the event of becoming pregnant and to 
call their study doctor as soon as possible.  
 NEVER share study drug with anyone else. 
 Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
 Do not breastfeed a baby while participating in this study and for at least 28 days 
after study drug discontinuation. 
 Do not break, chew, or open study drug capsules. 
 Return unused study drug to the study doctor. 
3.     Provide Pomalidomide Information Sheet to the subject. 


 
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FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE 
FOR AT LEAST 24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR 
BILATERAL OOPHORECTOMY): 
1. 
I counselled the female NOT of childbearing potential regarding the following: 
 Potential risk of fetal exposure to pomalidomide (Refer to item #2 in FCBP) 
 NEVER share study drug with anyone else. 
 Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
 Do not break, chew, or open study drug capsules 
 Return unused study drug capsules to the study doctor. 
2. 
Provide Pomalidomide Information Sheet to the subject. 
MALE: 
1. 
I counselled the Male subject regarding the following: 
 Potential study drug fetal exposure to pomalidomide (Refer to item #2 in FCBP). 
 To engage in complete abstinence or use a condom when engaging in sexual 
contact (including those who have had a vasectomy) with a pregnant female or a 
female of childbearing potential,  while taking study drug, during dose 
interruptions and for 90 days after stopping study drug. 
 Males should notify their study doctor when their female partner becomes 
pregnant and female partners of males taking study drug should be advised to 
call their healthcare provider immediately if they get pregnant 
 NEVER share study drug with anyone else. 
 Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
 Do not donate semen or sperm while taking study drug and for 90 days after 
stopping study drug. 
 Do not break, chew, or open study drug capsules. 
 Return unused study drug capsules to the study doctor. 
2.    Provide Pomalidomide Information Sheet to the subject. 
Investigator/Counsellor Name (Print): ____________________ 
 
 (circle applicable) 
Investigator/Counsellor Signature: _______________________  
Date: 
_____/_____/_____ 
(circle applicable) 
**Maintain a copy of the Education and Counselling Guidance Document in the subject 
records.** 


 
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Appendix Ib: 


 
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Pomalidomide Information Sheet  
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Pomalidomide Information Sheet before you start taking study drug 
and each time you get a new supply. This Pomalidomide Information Sheet does not 
take the place of an informed consent to participate in clinical research or talking to 
your study doctor or healthcare provider about your medical condition or your 
treatment.   
What is the most important information I should know about 
pomalidomide? 
1. Pomalidomide may cause birth defects (deformed babies) or death of an 
unborn baby. Pomalidomide is similar to the medicine thalidomide. It is 
known that thalidomide causes life-threatening birth defects. Pomalidomide 
has not been tested in pregnant women but may also cause birth defects. 
Pomalidomide was found to cause birth defects when tested in pregnant 
rabbits.  If you are a female who is able to become pregnant: 
 Do not take study drug if you are pregnant or plan to become pregnant 
 You must either not have any sexual relations with a man or use two 
reliable, separate forms of effective birth control at the same time:  
 for 28 days before starting study drug 
 while taking study drug  
 during dose interruptions of study drug  
 for 28 days after stopping study drug  
 You must have pregnancy testing done at the following times: 
 within 10 – 14 days and again 24 hours prior to the first dose of study drug  
 weekly for the first 28 days 
 every 28 days after the first month or every 14 days if you have irregular 
menstrual periods 
 if you miss your period or have unusual menstrual bleeding 
 28 days after the last dose of study drug (14 and 28 days after the last dose if 
menstrual periods are irregular) 
 Stop taking study drug if you become pregnant during treatment 
 If you suspect you are pregnant at any time during the study, you must stop 
study drug immediately and immediately inform your study doctor. The 
study doctor will report all cases of pregnancy to Celgene Corporation.  
 Do not breastfeed while taking study drug 


 
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 The study doctor will be able to advise you where to get additional advice on 
contraception. 
If you are a female not of childbearing potential: 
In order to ensure that an unborn baby is not exposed to pomalidomide, your study 
doctor will confirm that you are not able to become pregnant. 
If you are a male: 
The effect of pomalidomide on sperm development is not known and has not been 
studied. The risk to the fetus in females of child bearing potential whose male 
partner is receiving pomalidomide is unknown at this time.   
1. Male patients (including those who have had a vasectomy) must 
either not have any sexual relations with a pregnant female or a 
female who can become pregnant, or must use a condom during 
sexual contact with a pregnant female or a female that can become 
pregnant: 
o While you are taking study drug  
o During dose interruptions of study drug  
o For 28 days after you stop taking study drug   
2. Male patients should not donate sperm or semen while taking 
study drug and for 28 days after stopping study drug.  
3. If you suspect that your partner is pregnant any time during the 
study, you must immediately inform your study doctor. The 
study doctor will report all cases of pregnancy to Celgene 
Corporation. Your partner should call their healthcare provider 
immediately if they get pregnant. 
2. Restrictions in sharing study drug and donating blood: 
1. Do not share study drug with other people. It must be kept out of 
the reach of children and should never be given to any other 
person. 
2. Do not donate blood while you take study drug and for 28 days after 
stopping study drug.  
3. Do not break, chew, or open study drug capsules. 
4. You will be supplied with no more than one cycle of study drug  
5. Return unused study drug capsules to your study doctor. 
Additional information is provided in the informed consent form and you 
can ask your study doctor for more information. 
 
 
 


 
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Appendix II – SWOG Performance Status Scale 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 


 
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Appendix 3 NCI CTCAE Version 4.0 
 
TOXICITY WILL BE SCORED USING NCI CTC VERSION 4.0 FOR TOXICITY 
AND ADVERSE EVENT REPORTING.  A COPY OF THE NCI CTCAE VERSION 
4.0 CAN BE DOWNLOADED FROM THE CTEP HOMEPAGE: 
HTTP://EVS.NCI.NIH.GOV/FTP1/CTCAE/ABOUT.HTML.  ALL APPROPRIATE 
TREATMENT AREAS HAVE ACCESS TO A COPY OF THE CTC VERSION  
 


 
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APPENDIX 4 
 
Cancer Research Center Data Safety Monitoring Charter 
 
Data Safety and Monitoring Program 
BU/BMC Cancer Center 
Boston, MA  02118 
617-638-8265 
 
Table of Contents: 
Mission ................................................................................................................................. 1 
Background .......................................................................................................................... 1 
Responsibilities .................................................................................................................... 2 
Membership ......................................................................................................................... 3 
Meeting Schedule ................................................................................................................ 3 
Procedures .......................................................................................................................... 4 
Appendix I: DSMC Form....................................................................................................... 5 
Figure 1…. .......................................................................................................................... .6 
 
Mission: 
The Cancer Center Data Safety Monitoring Committee (DSMC) functions to ensure the 
safety of participants in investigator-initiated, interventional clinical trials conducted by 
BUMC Cancer Center members by monitoring clinical trial progress and the collection, 
validity and integrity of the data collected on clinical trials under its jurisdiction.  The 
committee ensures compliance with FDA, NCI and IRB requirements. The policies and 
procedures of the Data and Safety Monitoring Committee follow NCI guidelines.  
 
Background: 
All cancer related interventional protocols from any department must be reviewed by the 
Cancer Center Scientific Review Committee (SRC).  This includes trials that are recruiting 
individuals to cancer prevention or detection; treatment of disease or symptoms; and 
studies of cancer survivors, i.e. people who have had a previous diagnosis of cancer.   
 
At the time it approves a new investigator-initiated, interventional protocol, the SRC assigns 
a category of risk that determines the level of monitoring required by the DSMC. The level 
of risk (low, moderate high) is based on a number of criteria, including the expected 
duration of the study based on the study design and a realistic estimate of the rate of 
enrollment; the nature of the study population (e.g., prisoners, pregnant women); 
procedures to ensure the safety of subjects in accordance with the degree of risk; the 
complexity of methods needed to ensure the validity and integrity of the data; and planned 
data management systems including case report forms, records and the plan for data 
collection. Multiple-site studies must also have an operational plan that describes the 
procedures for reporting serious adverse events to the Cancer Clinical Trials Program 
(CCTP), IRB, FDA, and NIH, as appropriate, and plans for notifying participants of trial 
results and communicating relevant study information to participants’ health providers (e.g., 
cessation of drugs, changes in dosage, etc.)  
 
Prior to implementation, all studies in need of internal monitoring must have a monitoring 
plan approved by the SRC, including frequency of reviews based on the level of risk and 
accrual target. Typically, high-risk studies are reviewed quarterly by the DSMC, moderate 


 
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risk studies are reviewed twice each year, and low risk studies are reviewed annually. 
However, each study is considered independently. Implementation of monitoring plans 
approved by the SRC is the responsibility of the DSMC. The DSMC Coordinator manages 
the logistics associated with DSMC sessions. 
 
Two months prior to a scheduled DSMC review, the PRMS Administrator informs the 
principal investigator and primary study coordinator of the upcoming review.  At this time, 
the research staff is requested to submit a completed DSMC Report Form (Appendix I) and 
associated documents to the PRMS Administrator (for each DSMC review).   
 
In addition to being monitored by the DSMC, clinical studies also undergo annual auditing 
by the SRC (see below).  Two months prior to an annual DSMC review, the PRMS 
Administrator informs the Principal Investigator and primary study coordinator to prepare 
protocol documents for audit and informs the PRMS Audit Committee that an audit is due.  
The Audit Committee audits 10% of charts for a given year, or a minimum of three charts, 
to assess fidelity to the approved protocol, study documentation, timeliness of adverse 
reporting, accuracy of data collection, and other variables.  The audit report, which lists all 
major and lesser deviations from protocol, is submitted to the Principal Investigator and to 
the DSMC.   
 
One month prior to the DSMC Meeting, the PRMS Administrator distributes pertinent 
documents to the Committee members, including.   
 Completed DSMC Form (Appendix I) 
 Electronic copy of the protocol 
 Spreadsheet including: date of enrollment, patient initials, patient number, gender, 
age, race, status on study (i.e., active, follow-up, completed, expired) 
 A copy of the Data Safety Monitoring Plan outlined in the INSPIR application. 
 SAE reports, follow-up reports, and outcome reports 
 Audit Committee Report (if annual review) 
 
Responsibilities of the DSMC 
 
Familiarize themselves with the research protocol(s) and review proposed plans for 
data safety monitoring, and protocol data submitted by the research staff. 
 
Review annual audit report from the PRMS Audit Committee to evaluate the 
appropriateness of the conduct of the study.   
 
When applicable, review interim analyses of toxicity data prepared by the study 
statistician according to the data safety monitoring plan and upon special request. 
Recommendations regarding study modification, or termination of study accrual based 
on these analyses can be made at that time by the DSMC. Modifications may include 
dropping a treatment arm based on toxicity results, dose adjustment, increasing or 
decreasing sample size, etc.   
 
Provide the PI and the Cancer Center Scientific Review Committee with a written 
report following each DSMC meeting summarizing its review of the trial as related to 
the cumulative toxicities observed and any relevant recommendations related to 
continuing, amending or terminating accrual to the trial. 


 
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  The Committee has the authority to require amendments, to recommend suspension 
or termination of any research activities that fall under its jurisdiction, and to institute 
other requirements to improve participant safety  
 
 Confidentiality 
Procedures: 
 
No 
communication 
of 
the 
deliberations 
or 
recommendations of the DSMC is allowed outside the DSMC, except as provided for in 
the DSM policy. It is also understood that industry studies are considered proprietary to 
the sponsor. Any outcome results are strictly confidential and must not be divulged to 
anyone who is not a member of the DSMC, except as specified in the policy. 
 
DSMC Membership 
 
The Chair of the DSMP is responsible for overseeing all aspects of data monitoring, 
ensuring the safety of participants in all clinical trials, particularly institutionally-sponsored, 
investigator-initiated trials, and verifying the validity and integrity of the data provided to the 
DSMC. 
 
Omar Eton, MD; Hematology and Oncology (DSMC Chair) 
Michael Stone, MD; Surgical Oncology 
Gustavo Mercier, MD Radiology 
Gregory Russo, MD, Radiation Oncology  
David Baribeault, Pharm D, Investigational Pharmacy 
Bhavesh Shah, Pharm D, Investigational Pharmacy 
Gail Wilkes, RN Nurse Educator 
Linda Frattura, BA Clinical Research Associate, Cancer Clinical Trials Program 
Mary-Tara Roth, Clinical Research Resources Office 
Natalie Erali, CCRP, PRMS Administrator 
Douglas Faller, MD, PhD, Director, Cancer Research Center (ex officio) 
 
Theodore Colton, ScD. Director of Cancer Biostatistics Resource (ad hoc) 
Jack Clark, PhD (Health Policy and Management) (ad hoc) 
 
 
The members of the multi-disciplinary DSMC include representatives from medical 
oncology, surgical oncology, radiology, radiation oncology, oncology nursing, pharmacy, 
health policy, the Boston University Clinical Research Resources Office, and the Cancer 
Clinical Trials Office and Pharmacy. 
 
 
Meeting Schedule 
DSMC meetings will be held at least every three months. Special meetings (in person, via 
telephone or electronic) may be convened when necessary, for urgent concerns regarding 
patient safety or data integrity. The PI or the Scientific Review Committee may request 
unplanned monitoring of a given study. Data will be collected and analyzed approximately 
four weeks before the DSMC meeting. A copy of all the analyses will be mailed to the 
DSMC members before the meeting. The timing for ending material will allow two (2) 
weekends for the DSMC members to review it. 
 


 
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Data and safety monitoring and study reviews take place until all subjects have completed 
any protocol-related activities and are beyond the time during which study-related adverse 
events may occur. 
 
 
DSMC Procedures 
 
The DSMC may vote to take one of the following actions for each protocol reviewed: 
 
Full Approval: enrollment may continue; no outstanding questions regarding toxicity or 
accrual. 
 
Conditional Approval: enrollment may continue conditional upon satisfactory response by 
the principal investigator to the DSMC concerns regarding toxicities and/or accrual and/or 
new information relevant to the trial. 
 
Suspension: enrollment immediately suspended pending principal investigator response to 
the DSMC concerns regarding toxicity and/or accrual patterns. 
 
Closure: study closed due to unacceptable toxicity and/or accrual patterns. The presence 
of three or more of the DSMC voting members constitutes a quorum. 
 
All DSMC decisions are conveyed in writing to the study principal investigator and the 
Scientific Review Committee. 
 
The CCTP Protocol Review and Monitoring System (PRMS) Administrator serves as 
recording secretary to the DSMC and is responsible for coordinating all meetings and 
communications. 
 
Study principal investigators may appeal DSMC decisions in writing to the chairman of the 
DSMC. 
 
Temporary or permanent suspension of any BMC investigator-initiated clinical trial by the 
DSMC will be reported immediately to the BUMC IRB and any relevant study collaborators 
(e.g. pharmaceutical companies). The monitoring plan is amended as to reflect any new 
monitoring requirements. 
 
If the suspension is temporary, the BUMC IRB and any relevant study collaborators will 
also be notified in a timely manner regarding the resolution of the issues that caused the 
suspension, and the date that the suspension was lifted. 
 
This committee was established in January, 2010 and its procedures will be continually 
reviewed and refined until a more permanent charter can be adopted. 


 
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BUMC Cancer Center Protocol Review and Monitoring System (PRMS) 
 
Please submit this form two weeks prior to the scheduled DSMC Meeting and attach the following documents: 
•  
Electronic copy of the protocol 
•  
Spreadsheet including: date of enrollment, pt initials, pt number, gender, age, race, status on study 
•  
A copy of the Data Safety Monitoring Plan outlined in the INSPIR application. 
•  
SAE reports, follow-up reports, and outcome reports 
 
 
BUMC PROTOCOL #: 
 
 
Activation DATE: 
 
STUDY STATUS: 
Open to Accrual 
DATE OF LAST REPORT: 
 
 
PROTOCOL TITLE 
 
10 
Principal Investigator; Primary Research Nurse/Associate 
 
11 
PROTOCOL ACTIVITY 
Planned Accrual Duration: 
 
 
 
Date First Patient Enrolled at BMC: 
 
Local Accrual to Date / Goal: 
National Accrual to Date / Goal: 
 /  
/  
# Consented Since Last Report: 
 
Accrual Since Last Report: 
 
# Eligible Since Last Report: 
 
# Ineligible Since Last Report: 
 
12 
Study Status:  (include # of Patients currently active, in follow-up, completed or expired.) 
13 
 
14 
 
15 
PROTOCOL-SPECIFIC INTERIM ANALYSIS (if applicable) 
16 
 
17 
 
18 
 
19 
SAE/UPSER REPORTING SINCE LAST REPORT: List event, causality attribution, expected/not 
expected, patient study ID number, date of occurrence (include cycle #, Day #), and date IRB 
notified.  Attach SAE reports, follow-up reports, and outcome reports. 
1] 
 
2] 
 
3] 
 
PATIENTS COMPLETED/OFF PROTOCOL SINCE LAST REPORT w Provide reason [progression, death (include cause), toxicity (specify), completed 
therapy, etc].  Provide detailed supplemental information for patients off study treatment due to toxicity or death. 
 
PROTOCOL DEVIATIONS/EXCEPTIONS SINCE LAST REPORT w Include both purposeful and accidental variances in the approved procedures outlined for 
a study in its IRB approved protocol; provide date reported to Regulatory or IRB.  Attach any protocol deviation forms.   
 
OTHER COMMENTS  
 
Investigator Signature & Date: 
 
Data Manager Signature 
& Date: 
 


 
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 Figure 1 shows the procedures involved in data and safety monitoring. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scientific Review Committee: 
Ensures that protocol has also been 
reviewed and approved by 
Biostatistical Shared Resource, IRB, 
and Institutional Biosafety 
Committee (if specimens are 
involved) 
The Data & Safety Monitoring 
Committee monitors study progress, 
patient safety, and data integrity 
consistent with approved plan, through 
study completion or termination 
Audit Team conducts annual audit 
through completion of study 
interventions or termination 
The Scientific Review Committee 
-Reviews and modifies/approves 
monitoring plan 
-Assigns risk level  
-Sets DSMC dates  
-Sets Audit date  
-Assigns Audit Team  
The Data & Safety Monitoring 
Committee determines disposition; 
recommends needed actions and 
revisions to monitoring plan; and 
notifies PI, IRB, and other appropriate 
bodies of results and actions 
Scientific Review Committee 
reviews the protocol and other 
required documents 
Revise or abort 
Approved? 
Revised protocol 
Yes 
No 
Protocol Review 
and Monitoring 
System Oversight 
Committee 
New Investigator-Initiated Study 
Data and Safety 
Monitoring Board