Clinical trial NCT02709083
Conditions: Chronic Myelogenous Leukemia Chronic Myeloid Leukemia Leukemia
Sponsor: Emory University
Start date: 2016-10-01; Completion date: 2018-07-01
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well dasatinib, nilotinib, and imatinib mesylate works in treating patients with newly diagnosed, previously untreated chronic myeloid leukemia in which fewer than 10% of the cells in the blood and bone marrow are blast cells (immature blood cells) (chronic phase). Dasatinib, nilotinib, and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess incidence of major molecular response (MMR) at 12 months.

SECONDARY OBJECTIVES:

I. To assess progression free survival (PFS) at 12 and 24 months.

II. To assess accelerated phase (AP) or blast phase (BP) transformation-free survival at 12 and 24 months.

III. To assess incidence of deep MRs (≥ MR⁴) at 12 months and 24 months.

IV. To assess safety.

V. To assess patient reported outcomes (PRO).

TERTIARY OBJECTIVES:

I. To assess prognostic significance of detecting aberrant myeloid or lymphoid markers on diagnostic bone marrow.

II. To assess ability to enroll subjects who maintain deep molecular remissions in tyrosine kinase inhibitors (TKIs) discontinuation trials.

OUTLINE:

Patients receive dasatinib orally (PO) once a day (QD) or nilotinib PO twice a day (BID) at the discretion of the treating hematologist. Patients achieving either a 1 log reduction at 3 months or a 2 log reduction at 6 months in their breakpoint cluster region-abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) transcript levels may switch to imatinib mesylate PO QD.

After completion of study treatment, patients are followed up at 2 weeks and then up to 60 months.

Arms: arm 1: Patients receive dasatinib orally (PO) once a day (QD) or nilotinib PO twice a day (BID) at the discretion of the treating hematologist. Patients achieving either a 1 log reduction at 3 months or a 2 log reduction at 6 months in their breakpoint cluster region-abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) transcript levels may switch to imatinib mesylate PO QD.
Interventions: intervention 1: Dasatinib intervention 2: Imatinib Mesylate intervention 3: Nilotinib
Intervention descriptions: intervention 1: Given orally intervention 2: Given orally intervention 3: Given orally

Protocol documents:
Prot_SAP_000.pdf: 
Study Title:  
First-Line Dasatinib or Nilotinib Followed by Response Guided Switch to Imatinib 
in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia. 
Study Phase:  
Phase 2    
Study Site:  
Emory Healthcare (Winship Cancer Institute)  
                     
GA CORE approved centers across State of Georgia 
PI: 
Vamsi Kota  
 
Assistant Professor  
 
Division of Hematology 
 
Department of Hematology and Oncology 
 
Winship Cancer Institute of Emory University 
Statistician: 
 
Zhengjia Chen 
 
 
 
Research Associate Professor,  
                                        Department of Biostatistics and Bioinformatics 
                                        Rollins School of Public Health & Biostatistics Shared Core Resource 
                                         Winship Cancer Institute of Emory University, 
Product Name:  
Dasatinib, Nilotinib, Imatinib. 
IND Reference Number:  N/A 
Sponsor:  
 
Vamsi Kota, MD 
Version Number:  
Version 4.0  
Version Date:  
06/21/2017 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation   
 
 
 
Term 
AE  
 
 
 
 
 
Adverse event 
AP  
 
 
 
 
 
Accelerated phase 
BCR-ABL 
Fusion transcript or protein resulting from the 9;22 chromosomal 
translocation responsible for formation of the Philadelphia 
Chromosome 
BP  
 
 
 
 
 
Blast phase 
CBC   
 
 
 
 
Complete blood count 
CCyR   
 
 
 
 
Complete cytogenetic response 
CHR   
 
 
 
 
Complete hematologic response 
CML   
 
 
 
 
Chronic myelogenous leukemia 
CMR   
 
 
 
 
Complete molecular response 
CNS  
 
 
 
 
 
Central nervous system 
CP  
 
 
 
 
 
Chronic phase 
ECG   
 
 
 
 
Electrocardiogram 
eCRF   
 
 
 
 
Electronic case report form 
ENESTnd (trial)  
Evaluating Nilotinib Efficacy and Safety in Clinical Trials 
Newly Diagnosed Philadelphia Chromosome Positive (trial) 
FDA   
 
 
 
 
Food and Drug Administration 
GCP  
 
 
 
 
 
Good clinical practice 
ICF  
 
 
 
 
 
Informed consent form 
ICH 
 
 
 
 
 
 International Conference on Harmonization 
IDMC   
 
 
 
 
Independent data monitoring committee 
IRB/IEC  
Institutional review board/Independent ethics committee 
IRIS 
International Randomized Study of Interferon versus STI571  
IS  
 
 
 
 
 
International scale 
ITT  
 
 
 
 
 
Intent-to-treat 
MCyR   
 
 
 
 
Major cytogenetic response 
MMR   
 
 
 
 
Major molecular response 
NCCN   
 
 
 
 
National Comprehensive Cancer Network 
PCR 
 
 
 
 
 
 Polymerase chain reaction 
Ph+  
 
 
 
 
 
Philadelphia chromosome positive 
PK  
 
 
 
 
 
Pharmacokinetics 
PPI  
 
 
 
 
 
Proton pump inhibitors 
QoL  
 
 
 
 
 
Quality of life 
qRT-PCR  
Quantitative reverse transcriptase polymerase chain reaction 
SAE  
 
 
 
 
 
Serious adverse event 
SAP  
 
 
 
 
 
Statistical analysis plan 
TEAE   
 
 
 
 
Treatment-emergent adverse event 
TKI  
 
 
 
 
 
Tyrosine kinase inhibitor 
 
 
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PROTOCOL SYNOPSIS 
Study drugs 
Imatinib (IM), Nilotinib (NIL), Dasatinib (DAS) 
Study Title 
First-Line DAS or NIL Followed by Response Guided Switch 
to IM in Newly Diagnosed Chronic Phase Chronic Myeloid 
Leukemia (CP-CML) 
Phase 
Phase 2 
Eligible Population 
CP-CML 
Summary and Study Rationale 
IM, NIL and DAS are FDA-approved for upfront treatment in 
CP-CML. DAS and NIL are very potent agents and lead to fast 
molecular responses (MR), but have so far not shown survival 
benefits as compared to  IM. The long term safety profile of IM 
compares favorably with DAS and NIL. A switch to IM in 
patients with optimal response to NIL or DAS can reduce long-
term toxicities while maintaining the benefits of a faster initial 
response and possibly at a lower cost. 
Study Design 
Prospective open label, single-arm trial  
Study Objectives 
Primary Objective: To assess incidence of major molecular 
response (MMR) at 12 months. 
Secondary: To assess  
• 
 Progression free survival (PFS) at 12 and 24 months. 
• 
Accelerated phase (AP) or blast phase (BP) transformation-
free survival at 12 and 24 months 
• 
Incidence of deep MRs (>MR4) at 12 months and 24 
months 
• 
Safety  
• 
 Patient reported outcomes (PRO)  
Exploratory : To assess 
• 
 Prognostic  significance of detecting  aberrant myeloid or 
lymphoid markers   on diagnostic bone marrow  
• 
Ability to enroll subjects who maintain deep molecular 
remissions in TKIs discontinuation trials 
 
Diagnosis and Main Inclusion Criteria 
CP-CML 
Number of Patients 
100 
Duration of Patient Participation 
5 years 
Approximate Duration of Study 
7 years 
Dosage and Administration 
IM 400 mg/d, DAS 100 mg/d, NIL 300 mg bid 
 
Concomitant Medications/treatment 
No contraindicated drugs. Caution with drugs known to interact 
with each tyrosine kinase inhibitor (TKI) 
 
Study Endpoints  
Primary Endpoint:  
The proportion of subjects who achieve MMR at 12 months 
will be determined. Only MMR at 12 months will be 
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considered, MMR achieved before the 12 months and then 
subsequently lost will not be considered. 
Secondary Endpoints: 
i. 
PFS will be measured from the time of CML diagnosis 
to the time of loss of MMR or loss of hematologic 
response 
ii. 
AP or BP free survival will be measured from the time 
of CML diagnosis to the time of transformation to AP 
or BP 
iii. 
The number of subjects with  BCR-ABL1 transcript 
levels  < MR4 at any time will be determined 
iv. 
Safety will be evaluated by the assessment of 
laboratory and clinical adverse events (AEs) using the 
CTCAE v4.03 criteria. Safety will be assessed by the 
frequency, duration, and severity of AEs and SAEs, 
and clinical evaluations and changes in clinical 
laboratory blood samples 
v. 
The PRO score extracted from the MDASI-CML will 
be determined and intra and inter subject changes will 
be compared at the different study-defined time points 
Exploratory Endpoints:  
i. 
 Outcomes of subjects with and without detectable cells 
with aberrant lymphoid or myeloid markers at 
diagnosis will be compared  
ii. 
The proportion of subjects who achieve and maintain 
deep MR for 2 years and therefore qualify or enroll on 
a TKI discontinuation trial will be determined. 
Outcomes following TKI discontinuation will be 
collected 
Statistical Analysis 
Primary end point is MMR at 12 months. Assuming that 
subjects able to switch from DAS or NIL to IM at 3-6 months 
will achieve at 12 months the same rate of MMR achieved with 
continuous DAS or NIL i.e. 55%(P1) but not less than 40% 
(P0) which is achieved with upfront IM, 85 subjects will be 
needed to achieve 80% power to detect a difference (P1-P0) of 
0.1500 using a one-sided binomial test. The target significance 
level is 0.0500. The actual significance level achieved by this 
test is 0.0449. These results assume that the population 
proportion under the null hypothesis is 0.4000. With an 
assumption that up to 15% of subjects who start DAS or NIL 
will not be able to switch to IM and will not be included in the 
efficacy analysis, but will be included in the safety and 
outcome analysis at 5 years, the total sample size will be 100 
subjects. 
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TABLE OF CONTENTS 
 
 
 
1. Background _________________________________________________________ 8 
    1.1 Chronic Myeloid Leukemia ________________________________________________ 8 
    1.2 Measuring Response to therapy in CML: Molecular Response (MR) _______________ 8 
    1.3 Efficacy of First Line Tyrosine Kinase Inhibitors in CP-CML _____________________ 8 
          1.3.1 Imatinib _______________________________________________________________ 8 
          1.3.2 Dasatinib ______________________________________________________________ 8 
          1.3.3 Nilotinib _______________________________________________________________ 9 
    1.4 Safety of First Line Tyrosine Kinase Inhibitors in First Line Use CP-CML __________ 9 
          1.4.1 Imatinib _______________________________________________________________ 9 
          1.4.2 Dasatinib ______________________________________________________________ 9 
          1.4.3 Nilotinib _______________________________________________________________ 9 
    1.5 Prognostic significance of MR ____________________________________________ 10 
          1.5.1 MMR at 3 months ______________________________________________________ 10 
          1.5.2 MR at 6 months ________________________________________________________ 10 
          1.5.3 Deep MR _____________________________________________________________ 10 
    1.6 Outcomes of Patients who switch from 2G-TKIs to IM _________________________ 11 
    1.7 Rationale for the study __________________________________________________ 11 
2. Study Objectives and Hypothesis _____________________________________________ 12 
    2.1 Objectives ____________________________________________________________ 12 
    2.2 Hypothesis ____________________________________________________________ 12 
3. Investigational Plan ________________________________________________________ 12 
   3.1 Overall Study Design and Plan ____________________________________________ 12 
   3.2 Endpoints _____________________________________________________________ 13 
   3.3 Description of Treatment _________________________________________________ 14 
4. Selection of Study Population ________________________________________________ 15 
   4.1 Inclusion Criteria _______________________________________________________ 15 
   4.2 Exclusion Criteria _______________________________________________________ 15 
5. Study Procedures _____________________________________________________ 15 
   5.1 Schedule of Events ______________________________________________________ 15 
   5.2 Description of Study Visits _______________________________________________ 17 
             5.2.1 Visit 1 (Day-14 to -1): Screening1.3.1 Imatinib ________________________________ 17 
         5.2.2 Visit 2 (Day 1): Initiation of Treatment ______________________________________ 17 
             5.2.3 Disease Response Evaluation Visits (Months 3,6,9 and 12 ± 7 days) ________________ 18 
         5.2.4 Visits 15-23 (once patient is in MMR, every 6 months ± 7 days) __________________ 18 
         5.2.5 Unscheduled Visits ______________________________________________________ 18 
         5.2.6 End of Treatment Visit (± 14 days) _________________________________________ 18 
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   5.3 Subject Registration and Identification ______________________________________ 18 
          5.3.1 Screen Failure _________________________________________________________ 18 
          5.3.2 Early Discontinuation ___________________________________________________ 18 
  5.4 Study Duration _________________________________________________________ 19 
  5.5 Withdrawal Criteria ______________________________________________________ 19 
  5.6 Study Termination _______________________________________________________ 19 
6. Safety Assessments ____________________________________________________ 19 
7. PRO Questionnaire ___________________________________________________ 20 
8. Study Treatment _____________________________________________________ 20 
 8.1 Dose Selection, Treatment Administration, Compliance, and Dose Modifications ______ 20 
 8.2 Allocation of Treatment ___________________________________________________ 20 
 8.3 Concomitant Medications __________________________________________________ 20 
 8.4 Treatment Supply ________________________________________________________ 20 
          8.4.1 Formulation, Packaging and Labeling _______________________________________ 20 
          8.4.2 Treatment Storage, Dispensing and Accountability _____________________________ 21 
          8.4.3 Disposition of used and unused supplies _____________________________________ 21 
9. Adverse Event Reporting _______________________________________________ 21 
 9.1 Adverse Events __________________________________________________________ 21 
              9.1.1 Adverse Event Definition ________________________________________________ 21 
          9.1.2 Abnormal Laboratory Tests _______________________________________________ 21 
          9.1.3 Performing Adverse Event Assessment ______________________________________ 22 
          9.1.4 Reporting Period _______________________________________________________ 22 
          9.1.5 Adverse Event Severity __________________________________________________ 22 
          9.1.6 Causality _____________________________________________________________ 22 
          9.1.7 Expectedness __________________________________________________________ 23 
9.2 Serious Adverse Events ____________________________________________________ 23 
             9.2.1 Serious Adverse Event Definition __________________________________________ 23 
         9.2.2 Reporting Serious adverse Events __________________________________________ 24 
         9.2.3 Follow-up Information of Serious Adverse Events _____________________________ 24 
9.3 Other Safety Issues _______________________________________________________ 24 
             9.3.1 Pregnancy _____________________________________________________________ 24 
         9.3.2 Overdose ______________________________________________________________ 25 
10. Statistical Considerations ______________________________________________ 25 
10.1 General Considerations ___________________________________________________ 25 
10.2 Analysis Population ______________________________________________________ 25 
10.3 Study Endpoints ________________________________________________________ 25 
10.4 Determination of Sample Size ______________________________________________ 26 
10.5 Safety and Efficacy Analysis ______________________________________________ 26 
10.6 Interim Analysis ________________________________________________________ 26 
10.7 Protocol Deviations and Violations __________________________________________ 26 
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11. Quality Control and Quality Assurance and Study Monitoring _________________ 27 
12. Ethical Conduct of the Study ___________________________________________ 27 
 12.1 Institutional Review Boards Approval _______________________________________ 27 
 12.2 Subject Information and Consent ___________________________________________ 28 
 12.3 Subject Confidentiality ___________________________________________________ 28 
 12.4 Data Safety Monitoring Committee _________________________________________ 28 
13. Data Handling and Record Keeping ______________________________________ 29 
 13.1 Case Report Forms and Study Records ______________________________________ 29 
 13.2 Source Documents ______________________________________________________ 29 
 13.3 Retention of Data _______________________________________________________ 29 
 13.4 Study Termination ______________________________________________________ 29 
References ____________________________________________________________ 30 
Appendix A      Definition of Response in CP-CML _____________________________ 31 
Appendix B      Timing of Molecular Monitoring:ELN guidelines __________________ 32 
Appendix C      Management of Adverse Events _______________________________ 33 
Appendix D      MDASI-CML PRO Questionnaire _____________________________ 35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. Background: 
1.1 
Chronic Myeloid Leukemia:  
Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the presence 
of a signature hybrid oncogene, the BCR-ABL1 [1]and a unique triphasic clinical course. The majority of patients 
(~80%) are diagnosed during the early phase, or chronic phase (CP), however, and without effective treatment, 
CML invariably progresses to the advanced phases of the disease: AP phase (AP) or blast phase (BP). The 
Philadelphia chromosome (Ph+), the driving leukemogenic mechanism in CML, is a reciprocal translocation 
between chromosome 9 and 22 that juxtaposes two genes involved in cell signaling, signal transduction, and cell 
proliferation: BCR and ABL1. The ABL1 gene encodes non-receptor tyrosine kinases which become deregulated 
and constitutively active by the juxtaposition of BCR. BCR-ABL1 is central in controlling downstream pathways 
involved in cell proliferation, regulation of cellular adhesion and apoptosis. The understanding of the 
pathophysiology of CML led to development of drugs that specifically target the tyrosine kinase activity in BCR-
ABL1. These tyrosine kinase inhibitors (TKI) became the mainstay of modern therapy in CML[2] and have 
revolutionized patients outcomes. Indeed, treatment of patients with CML with TKIs is ranked as one of the great 
medical success stories of the past 30 years and for a new patient with CP-CML receiving IM, complete 
cytogenetic response (CCyR) are achieved in approximately 80% which translates into life spans 
indistinguishable from those of similar persons without leukemia. Imatinib (IM, GleevecR, Novartis), dasatinib 
(DAS, SprycelR, Bristol-Meyers Squibb) and nilotinib (NIL, TasignaR Novartis) are approved by the FDA as first-
line TKIs for the treatment of CML.  
1.2 Measuring Response to therapy in CML: Molecular Response (MR): 
Detection of BCR-ABL1 by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) is feasible 
on blood as well as marrow samples and is now a widely accepted method for monitoring response to therapy.[3] 
An excellent correlation exists between blood qRT-PCR and marrow cytogenetics and qRT-PCR. Response is 
measured by a decrease in BCR-ABL1 levels on a logarithmic scale. A 1 log reduction is a drop to below 10%, 
while a major molecular response (MMR) is defined as a 3 log reduction (0.1%).  Deep MR includes transcripts 
levels BCR-ABL1< 0.01% (MR4), < 0.0032% (MR4.5) and < 0.001% (MR5).[4] Transcripts levels < MR4.5 define 
complete MR (CMR). In the absence of universal standards or reagents for PCR assays, the International Scale 
(IS) was developed to harmonize MR across laboratories by applying a laboratory specific conversion factor.  
Practically, all laboratories are currently reporting PCR results using the IS, which permits the avoidance of 
regional variabilities.[5] Therefore blood monitoring by qRT-PCR for BCR-ABL1 can be done reliably 
using the IS at local laboratories to assess response to therapy in CML. 
 
1.3  
Efficacy of First Line Tyrosine Kinase Inhibitors in CP-CML:  
1.3.1 Imatinib:  
IM is the first TKI approved by the FDA as first-line therapy in CP- CML in 2002, and is very effective. Indeed, 
survival of CP-CML at 8 years is 85% (93% when only CML-related deaths are considered). Once a complete 
cytogenetic response (CcyR) is achieved, survival for CML patients treated with IM becomes indistinguishable 
from the general population.[6] IM is therefore a very safe and effective treatment for CP-CML.  
1.3.2 Dasatinib: 
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DAS was approved in 2010 for use as first-line treatment for CP-CML following results from a phase 3 
randomized trial (DASISION) that compared DAS 100 mg/d to IM 400 mg/d. At 12 months, higher rates of CcyR 
and MMR were observed with DAS as compared to IM (77 vs. 66% and 46 vs.28%).[7] Long term (5year) follow 
up has so far not shown a difference in progression-free survival (PFS, 85 vs 86%) or overall survival (OS,91 vs 
90%).  
1.3.3 Nilotinib: 
NIL was approved for first-line treatment of CP-CML in 2010 following results from a phase 3 randomized trial 
(ENESTnd) that compared NIL 300 mg or 400 mg twice daily to IM 400 mg once daily. At 12 months, MMR was 
44% for 300mg and 43% for 400 mg of NIL and 22% for IM. CcyR was also higher in the NIL arms 80% and 
78% respectively, vs 65% with IM.[8] With 4 years of follow-up and despite the faster and deeper responses with 
NIL there was no survival advantage for NIL as compared to IM. OS at 4 years was 94.3% and 96.7% in the NIL 
arms as compared to 93.3% in the IM arm. [8]  
1.4 Safety of First Line Tyrosine Kinase Inhibitors in First Line Use CP-CML:  
TKI therapy is associated with both class-specific and drug-specific short term and long term side-effects.  
1.4.1 Imatinib: 
After short term exposure, the most common non-hematological adverse events (AEs) seen in more than 10% of 
patients were fluid retention (42%), gastrointestinal  (GI) AEs (10-20%), myopathy (10%) and rash (10%). The 
majority of these AEs were grades 1-2 AEs. The discontinuation rate due to early AEs is <5%.[7] 
Long term safety data with up to 9 years of follow-up is available for patients treated with IM.[6] IM appears well 
tolerated with no new AEs reported with long-term exposure.  
1.4.2 Dasatinib:  
After short term exposure, the most common non-hematological AEs occurring in more than 10% of patients 
included fluid retention (19%), pleural effusion (10%), GI AEs (17%), myopathy (11%) and rash (10%). The 
discontinuation rate was 5% with these short term AEs.[7] 
Long term treatment with DAS is safe in the majority of patients, but reports of pulmonary AEs with prolonged 
use are emerging. Pleural effusions and fluid retention appear to be increasing with 5 year follow-up studies 
reporting up to 30% incidence of pleural effusions.[9] Reports of pulmonary hypertension are also emerging with 
more than 1 year of exposure to the drug. A French registry study reported an incidence of 0.45% in DAS-treated 
patients.[10] 
1.4.3 Nilotinib: 
After short term exposure to NIL, the most common non-hematological AEs  occurring in more than 10% of 
patients include elevated liver enzymes (40-60%), hyperglycemia (35%), lipase (24%), skin rash(31%), headache 
(14%), myalgias (10%). Although QT interval prolongation occurs in less than 10%, FDA's approval of NIL 
includes a black box warning for possible life-threatening QT prolongation and possible sudden death. . The 
discontinuation rate was 5% with these short term AEs.[8]  
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Long term treatment with NIL has shown increased risks of peripheral arterial disease (PAD). Clinically evident 
PAD as measured by ankle brachial indices was observed in higher frequency in NIL than in IM-treated patients 
(~30 vs 6%)[11]. Other large studies also confirm an increased incidence of  PAD in 3-7%[10, 12] NIL is 
administered twice daily, and therefore non-adherence is more commonly observed than with IM and DAS which 
are administered once daily.[12, 13] 
Drug: 
Non hematological Early 
AEs in > 10% 
Early discontinuation 
due to AEs 
Long-term AEs 
Imatinib 400 mg/d 
Fluid retention (43%) 
Myalgia (39%) 
Diarrhea (21%)[7] 
4.3 % 
None[6] 
Dasatinib 
100 
mg/d  
Fluid retention (25%) 
Diarrhea (19%) 
Myalgia (13%)[7] 
 
5 % 
Pleural effusion 30%[9] 
Pulmonary 
Hypertension 
0.45%  
[10]5 years 
Nilotinib 300 mg 
bid 
Biochemical abnormalities 
(40%) 
Rash (30 %) 
Headache (10%) [8] 
5 % 
Peripheral 
vascular 
problems (6-30%) [12] 
4 year 
 
1.5 Prognostic significance of MR  
1.5.1 MMR at 3 month: 
Early MR is predictive of progression free survival. The 3 month 1 log reduction can be predictive of 
MMR at 12 months as well with approximately 55% of patients on 2nd Generation(2G)-TKIs achieving 
MMR as compared to 40% on IM.[14]  In another  study, transcript levels below 10% by qRT-PCR at 3 
months was associated with a 8-year OS of 93.3% as compared to 56.9% if qRT-PCR was > 10% (p < 
.001).[15] These results were independently confirmed and are widely accepted.[16, 17]  
1.5.2 MR at 6 months:  
In addition to patients who achieve the 1 log reduction in transcript levels at 3 months, patients achieving 
2 log reduction at 6 months have excellent prognosis. A qRT-PCR level of less than 1% at 6 months 
predicts CcyR at 2 years and CMR at the same time point. In fact, European Leukemia Net (ELN) 
guidelines define treatment failure as a qRT-PCR greater than 10% at 6 months.[16]  
 
1.5.3 Deep MR: 
 
Attaining deep MR may increase the number of patients discontinuing TKIs.[4]. Indeed treatment free 
remission is now considered an important goal in CML therapy, and the success of TKI discontinuation is 
linked to the achievement of deep MR.  
 
Table 1: Short-term and long-term AEs associated with IM, DAS and NIL. 
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 Table 2: Early and deep MR achieved with IM, DAS and NIL.   
1.6 Outcomes of Patients who switch from 2G-TKIs to IM:  
We identified 12 patients with CP CML diagnosed between 08/2013 and 06/2015 who received first line therapy 
with DAS (9), NIL (2), and ponatinib (PON, 1) and subsequently switched to IM. Reasons for switching to IM 
included: TKI toxicity, physicians’ preference, drug availability and closure of a clinical trial. Response to TKI 
was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for BCR-ABL1. 
Response to these >2G-TKIs at 3 months was as follows: CHR (n=12), 1 log (<10%, n=12), 2 log (<1%, n=8), 
and 3 log (MMR, <0.1%, n=3) reductions of BCR-ABL1 transcripts. Median qRT-PCR at 3 months was 0.77% 
(range 0-7%).  
Median time to discontinuation of >2G-TKIs and initiation of IM was 106 days (range, 92 – 203) from diagnosis.  
IM was started at 400 mg/d and was well tolerated except in 2 patients who discontinued due to grade 2 skin rash 
(1) and grade 2 anxiety (1). Both patients switched back to DAS at 54 and 228 days after initiation of IM 
respectively. All patients that switched to IM were evaluable with a follow up of at least 3 months. These patients 
have shown a continuous response with 12/12(100%) achieving a 2 log reduction at 6 months, and 5/7(70%) 
achieving MMR at 12 months. With up to 30 months follow-up (median 12 months), all patients showed 
continuous decrease in their transcripts (Figure 1) 
and no losses of MMR or progression to BP were 
observed.  With a median follow-up of 12 months 
(range 5-30 months), 5 patients achieved CMR.  
 
This retrospective analysis shows that IM 
can be safely and effectively administered 
following optimal response to >2G-TKIs.  
 
1.7 Rationale for the study: 
Based on the short-term safety and high early MRs associated with front-line 2G-TKIs and our preliminary data 
showing continuous responses in patients who switch to IM following optimal responses, we propose a study 
testing the safety and efficacy of starting DAS or NIL in newly diagnosed CP-CML patients followed by a switch 
to IM after early MR. This strategy aims to combine the benefits of faster deep MR achieved with DAS or NIL 
and the safety of prolonged exposure to IM.   
Given that the majority of CML patients are diagnosed and managed in private Oncology practices, this trial will 
be conducted both at Emory and through the Georgia Center for Oncology Research and Education (CORE). 
Drug 
1 log reduction in 
qRT-PCR 
at 
3 
month 
MMR at any time in 12 
month  
Deep MR at 4 years 
Imatinib 
400 mg  
64%[8] 
28%[8] 
23% [18] 
Dasatinib 
100 mg 
84%[17] 
46%[7] 
42 % [7]  
Nilotinib 
300 
mg 
BID 
91% [14] 
51%[8] 
40 %[14] [19] 
Version 4 dated 06/21/2017                                                                                                                            Page 11 
 


Georgia CORE is a public private partnership dedicated to generating collaborative resources for cancer 
prevention, care, research and education. One of the goals of Georgia CORE is to expand access to cutting-edge 
therapies in Georgia through cancer clinical trials. Georgia CORE’s network includes 24 academic or community 
oncology practices, with 9/10 of Georgia’s oncologists belonging to this organization. Georgia CORE plays a role 
in facilitating regulatory requirements for sites that use a central IRB, and also monitors the IRB interactions for 
the sites using local IRBs. A partnership with the community through Georgia CORE will allow rapid accrual of 
CML patients on the proposed trial.  
 
2. Study Objectives and Hypothesis 
2.1   Objectives:  
• 
Primary Objective: To assess incidence of MMR at 12 months. 
 
• 
Secondary: To assess  
o  PFS at 12 and 24 months. 
o AP or BP transformation-free survival at 12 and 24 months 
o Incidence of deep MR (>MR4) at 12 months and 24 months 
o Safety  
o  Patient reported outcomes (PRO)  
• 
Exploratory : to assess 
o The prognostic  significance of detecting  aberrant myeloid or lymphoid markers on diagnostic bone 
marrow  
o Ability to enroll subjects who maintain deep molecular remissions in TKI discontinuation trials 
2.2 Hypothesis:  
We hypothesize that patients with newly diagnosed CP-CML who achieve a 1 log reduction in BCR-ABL1 
transcript level at 3 months or a 2 log reduction at 6 months following front-line treatment with DAS or NIL will 
show continuous MR following a switch to IM. . We also hypothesize that the TKIs DAS, NIL, and IM will be 
safe and well-tolerated, that the incidence of MMR at 12 months in subjects who switch to IM will be comparable 
to the incidence reported with continuous treatment with DAS or NIL (Table 2) [7, 8], and that subjects will 
achieve and maintain deep MR which will  offer them the opportunity to enroll in TKI discontinuation trials. We 
also hypothesize that loss of response and progression to advanced phases CML following a switch to IM will be 
comparable to the incidence reported with continuous treatment with DAS or NIL.[7, 8] We also hypothesize that 
PRO using the MD Anderson Symptom Inventory (MDASI-CML, appendix D) assessed at study-specific time 
points will reflect a more favorable profile with IM as compared to DAS or NIL. We also hypothesize that 
marrow flow cytometry performed at diagnosis will predict early progression to advanced phases of the disease. 
3. Investigational Plan  
3.1. Overall Study Design and Plan: 
This is an open-label multicentric phase 2 study that will enroll newly diagnosed previously untreated CP-CML 
patients. A standard of care diagnostic bone marrow aspirate will be required to confirm the diagnosis of CP-
CML.  Eligible patients who sign consent will start front-line DAS at 100 mg once a day or NIL at 300mg twice a 
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day at the discretion of the treating hematologist. Response will be assessed through measurements of BCR-
ABL1 transcripts by qRT-PCR (IS) using local laboratories at time points recommended by the ELN guidelines 
(Appendix B). Drug compliance will be measured by obtaining prescription fill information from the pharmacy. 
These are drugs are being filled by specialty pharmacies and obtaining a prescription fill information at the end of 
one year is a much better way to assess compliance. A study-dedicated research coordinator or the investigator 
will contact subjects on predefined time points using telephone or video conferencing to provide education about 
CML and common side-effects of TKIs, provide reminders to complete MDASI-CML forms when due, assess 
compliance, and address questions related to CML response. Should subject report new AEs during these 
communications, the research nurse will ask subjects to contact the local hematologist, who may then consult with 
the investigator. Results of response monitoring done at local laboratory will be collected by research nurse and 
discussed with the investigator. A study-specific letter interpreting the qRT-PCR according to the ELN guidelines 
will then be generated and transmitted to both subjects and treating hematologist. Subjects with  BCR-ABL1 
levels < 10% at 3 months or < 1% at 6 months, will switch to IM at 400 mg once a day. Subjects not achieving 
these landmark responses will be taken off study but will continue treatment per standard of care guidelines. 
Patients and physicians may opt not to switch but the information regarding the reasons and follow up information 
will continue to be collected unless patient prefers to come off the study.The study primary endpoint (MMR) will 
be assessed by blood qRT-PCR at 12 months. Study duration is 2 years and all subjects will be offered to enroll in 
the long-term follow-up part of the study.  
3.2      Endpoints:  
Primary Endpoint:  
The proportion of subjects who achieve MMR at 12 months will be determined. Only MMR at 12 months will be 
considered, MMR achieved before the 12 months and then subsequently lost will not be considered. 
Secondary Endpoints: 
i. 
PFS will be measured from the time of CML diagnosis to the time of loss of MMR or loss of 
hematologic response 
ii. 
AP or BP free survival will be measured from the time of CML diagnosis to the time of 
transformation to AP or BP 
iii. 
The number of subjects with  BCR-ABL1 transcript levels  < MR4 at any time will be determined 
iv. 
Safety will be evaluated by the assessment of laboratory and clinical adverse events (AEs) using 
the CTCAE v4.03 criteria. Safety will be assessed by the frequency, duration, and severity of AEs 
and SAEs, and clinical evaluations and changes in clinical laboratory blood samples 
v. 
The PRO score extracted from the MDASI-CML will be determined and intra and inter subject 
changes will be compared at the different study-defined time points 
 
Exploratory Endpoints:  
i. 
 Outcomes of subjects with and without detectable cells with aberrant lymphoid or myeloid 
markers at diagnosis will be compared  
ii. 
The proportion of subjects who achieve and maintain deep MR for 2 years and therefore qualify 
or enroll on a TKI discontinuation trial will be determined. Outcomes following TKI 
discontinuation will be collected 
 
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3.3  
Description of Treatment:  
All newly diagnosed CP-CML patients will be offered to participate in the study. The primary hematologist (co-
investigator) will discuss the study and counsel both patient and care-giver. The objectives of the study, 
procedures, alternative therapies and potential risks and benefits of participation will be explained. Preliminary 
data suggesting that the detection of lymphoblasts by flow cytometry on the diagnostic marrow may be a marker 
for early blast transformation will be disclosed to the patient. Patient will be given the time to read the consent 
and the opportunity to ask questions before signing the consent form approved by the local or central Institutional 
Review Board (IRB). Within 48 hours of consenting, protocol registration procedures will be completed. 
Eligibility checklist form will be verified by the investigator prior to enrollment. Subjects will then start DAS at 
100 mg once a day or NIL at 300 mg twice a day at the treating hematologist discretion. After initiation of TKI, 
subjects will be monitored by their local hematologists according to the standard of care. Response to therapy will 
be assessed through measurements of BCR-ABL1 transcripts by qRT-PCR (IS) using local laboratories at time 
points recommended by the ELN guidelines (Appendix B). Subjects who achieve either a 1 log reduction (<10%) 
at 3 months or a 2 log reduction (1%) at 6 months in their BCR-ABL1 transcript levels, will be offered to switch 
to IM at 400 mg once a day. Subjects with qRT-PCR above 10% at 6 months will be taken off study and managed 
according to standard of care, but will be followed for survival. Eligible subjects who decline to switch to IM will 
come off treatment and continue to be followed for safety and survival. All subjects will be followed for a total of 
60 months from the time of last subject’s enrollment on the study. 
A study-dedicated research coordinator will contact subjects every 3 months in the first six months after initiating 
treatment, then every 6 months thereafter, using telephone or video conferencing to provide education about CML 
and common side-effects of TKIs, provide reminders to complete MDASI-CML forms when due, assess 
compliance, and address questions 
related to CML response. The nurse 
will 
also 
provide 
educational 
resources available on the internet. 
(http://www.cmladvocates.net/education, http://www.nationalcmlsociety.org/side-effects ). Research nurse will 
also collect documentation of AEs and reports of qRT-PCR collected every 3 months from the treating 
hematologist. The nurse will also review results of the qRT-PCR with the investigator, generate and transmit a 
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standardized report that summarizes response to treatment using ELN guidelines. Study schema is shown in 
Figure 2. 
Local hematologists will manage AEs and dose modifications according to the NCCN guidelines (Appendix C). 
AEs and dose modifications will be collected by the research nurse. Should the local hematologist decide to 
discontinue the first-line TKI due to intolerance, a switch the 2G-TKI to complete the first 3 months of therapy 
will be encouraged after discussion with the investigator. Subjects with intolerance or inadequate response to IM 
will be switched back to the 2G-TKI they received prior to initiating IM after discussion with the investigator.  
 4. 
Selection of Study Population  
4.1 
Inclusion Criteria: 
1. Newly diagnosed, previously untreated CP-CML (by WHO definition)  (hydroxyurea permitted up to 7 days 
prior to enrollment)  
2. Age > 16 years 
3. Able to give written informed consent and comply with all study visits and procedures. 
 
4.2 
Exclusion Criteria: 
1. 
 CML in AP or BP  
2. 
Unable to  receive TKI for insurance reasons (uninsurable) 
3. 
Refuse or unable to perform telephone or video conferences with research nurse 
4. 
Subjects who are pregnant, breast feeding or sexually active and unwilling to use effective birth control 
while on treatment with TKI  
5. 
Clinically significant gastrointestinal disease, digestive dysfunction, or surgery that would compromise 
absorption of oral administration of medications 
6. 
Any medical or psychological condition that, in the opinion of the Investigator, might interfere with the 
subject’s participation in the trial, poses any additional risk for the subject, or confounds the assessment of 
the subject 
 
5. Study Procedures  
5.1 Schedule of Events: The required procedures for the study and data collection process are shown in Table 3. 
 
 Table 3. Schedule of 
Events: study 
requirements. 
Screening 
± 14days 
Day1 
Evaluations at 
3 and 6 
momths 
± 14 days  
Evaluations at 
3, 6, 9, and 12 
months  ± 2 
days  
Evaluations q 
6 months  ± 7 
days after 12 
months  
End of 
Treatment 
1Informed Consent  
X 
 
 
 
 
 
2History and Demographics 
X 
 
 
 
 
 
3CML history  
X 
 
 
 
 
 
4Physical Examination 
X 
 
 
X 
X 
X 
5Concomitant medications 
X 
 
 
X 
X 
X 
6CBC, differential and 
Serum Chemistries,  
X 
 
 
X 
X 
X 
7Urine HCG 
X 
 
 
 
 
 
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8 Blood qRT-PCR for BCR-
ABL1  
 
 
 
X 
X 
X 
9 Compliance  
 
 
X 
X 
X 
X 
10Adverse Events  
 
 
X 
X 
X 
X 
11 Nurse Telemonitoring  
 
X 
 
X 
X 
X 
 12 PRO 
 
 
X* 
X** 
 
 
* between first and second month only 
** between third and fourth month, (1 month after starting IM) and at 12 months only if switched to imatinib 
1Informed Consent: All subjects must take part in the informed consent process prior to any study related activity. 
During the consent process, the person obtaining consent must inform the subject of all elements of informed 
consent. Adequate time must be allowed for questions and for the subject to make a voluntary decision. No 
protocol-specific procedures are to be performed until the subject has signed and dated the IRB approved 
informed consent form. Each subject's participation in the trial begins with the signing and dating of the informed 
consent form. 
2Medical/Surgical History and Demographics: Medical/surgical history that includes diagnoses and therapies as 
well as demographic information that consists of the subject’s age, gender, race, and ethnicity will be recorded. 
3CML History: The initial presentation history and pathology including date of first onset of leukocytosis, CBC 
with differential, serum chemistries and LDH, spleen size and extra-medullary disease, diagnostic bone marrow 
aspirate and biopsy (overall marrow cellularity, morphologic number of blasts, cytogenetic findings with number 
of metaphases, FISH for BCR-ABL1, qRT-PCR for BCR-ABL1, and percentage of aberrant cells if flow 
cytometry performed must be recorded 
4Vital signs and Physical Examination: Vital signs including temperature, pulse, and blood pressure, and complete 
physical examination, including weight, must be performed at screening, every 3 months in the first year, then 
biannually as part of standard of care unless new AEs. 
 5Concomitant medications: All prescribed, over the counter, and supplemental/herbal medications, including 
route of administration (oral, topical, intravenous, rectal, subcutaneous, etc.), frequency, and duration will be 
recorded.  
6Complete Blood Count (CBC), differential and Serum Chemistries: CBC with automated differential and serum 
chemistries will be obtained at screening, every 3 months in the first year, then biannually as part of standard of 
care unless new AEs.  
7Urine human chorionic gonadotropin (HCG): HCG will only be performed in pre-menopausal women of 
childbearing age with no history of hysterectomy or bilateral tubal ligation. 
8Blood qRT-PCR for BCR-ABL1: Blood qRT-PCR for BCR-ABL1 will be obtained every 3 months until MMR, at 
12 months, and then bi-annually thereafter will be done as part of standard of care. 
9 Compliance: will be obtained by getting the prescription filling information from the specialty pharmacy that the 
patient used. 
10Adverse event assessments: All AEs will be collected by research nurse quarterly regardless if the event is 
considered related to the treatment or not. The AEs documented on the diary card will also be collected. 
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11Nurse/Coordinator Telemonitoring: Research nurse will communicate with subject on day1, monthly in the first 
6 months, then biannually unless new AEs 
12 PRO: subjects will receive the MDASI-CML questionnaire at the referring hematologist’s office. Questionnaire 
will be obtained between first and second month 1 month after starting TKI,  and between third and fourth 
month(1 month after starting IM) and at 12 months. The nurse will educate and remind subjects to complete forms 
when due 
End of Treatment or Early Termination Procedures: The End-of-Treatment (or early termination) Visit should be 
performed within 2 weeks (14 days) of the subject/investigator decision to end treatment. ABL1 domain mutation 
will be obtained as part of standard of care in case of progressive disease. Subjects will be followed for up to 60 
months. Reasons for coming off treatment will be documented.  
Long Term Follow-up:  
- 
Safety: All AEs ongoing or starting within 30 days after the End-of-Treatment must be recorded on the case 
report form (CRF). After this time, ongoing AEs thought to be at least possibly study-drug related and all 
ongoing serious adverse events (SAE) should be followed at least every 4 weeks until they resolve to baseline 
(or CTCAE grade ≤1), stabilize, or are considered to be chronic or irreversible.  
- 
Relapse-free Survival: After enrollment on a TKI discontinuation trial or if subjects withdraw from study for 
toxicity or any reason,  information on disease status (qRT-PCRs) will be collected every 6 months for up to 
60 months from the time the last subject is registered on study. 
 
5.2  
Description of Study Visits 
5.2.1  Visit 1 (Day -14 to -1): Screening 
- 
Obtain written informed consent 
- 
Record demographic data including age, gender, and race 
- 
Obtain and Review medical, surgical, and CML history as described above. 
- 
Record prior and concomitant medications including start/stop dates, indication, dose and frequency taken 
within 7 days of Day 1. 
- 
Record results of CBC with differential count and CP Comp which is part of standard of care 
- 
Collect urine for pregnancy test for female patients who are not postmenopausal or surgically sterile which is 
part of standard of care. If positive, repeat and confirm results prior to Visit 2. A second positive test will 
result in exclusion of the patient from the study. 
- 
Obtain and record height in cm, weight in kg, vital signs, body temperature, systolic/diastolic BP and pulse 
rate. Obtain and record physical examination with spleen size in cm below the costal margin, and any extra 
medullary disease, as a part of standard of care. 
 5.2.2 
Visit 2 (Day 1): Initiation of Treatment 
- 
Review and document all inclusion and exclusion criteria to ensure that subjects meet all inclusion criteria 
and none of the exclusion criteria. 
- 
First nurse telemonitoring   
- 
MDASI-CML questionnaire 
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5.2.3 
Disease response evaluation Visits (Months 3, 6, 9 and 12 ±14 days) 
- 
Collect and record results of blood qRT-PCR of BCR-ABL1 
- 
remind subjects of dosing instructions, and obtain drug diary card 
- 
Assess  TKI compliance by collecting prescription fill information from the pharmacy at 6 and 12 month visit 
only. 
- 
Collect AEs and SAEs 
- 
MDASI-CML questionnaire between  3rd and 4th month (1 month after starting IM) and at 12 months. 
5.2.4 
Visits (once patient is in MMR, every 6 months ± 14 days) 
- 
Collect and record blood qRT-PCR of BCR-ABL1 
- 
Assess  TKI compliance by completing MMAS-8 at each telecommunication 
 
5.2.5 
Unscheduled Visits: 
Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical and laboratory 
measurements performed based on AEs or other findings. 
       5.2.6  
End of Treatment Visit (±14 days) 
The end of treatment visit will be at the time of last study monitoring or visit coinciding with loss of response or 
disease progression visit and should be completed as soon as possible after an end of study event. Only 
information about AEs and SAEs will be collected at this visit. 
5.3 Subject Registration and Identification: 
Demographic information on all subjects who sign the Informed Consent Form will be recorded on the master 
subject log. Those subjects who complete screening procedures and meet all eligible criteria may be enrolled. At 
the time of enrollment, the subject will be assigned a unique identification number, consisting of a study site 
number and a unique consecutive number. 
5.3.1 Screen Failure: 
Subjects who have signed informed consent and subsequently fail to meet the inclusion and/or exclusion criteria 
are defined as screen failures. For all screen failures, the Investigator is to maintain a screening log that 
documents the subject initials and reason(s) for screen failure. A copy of the log will be retained in the 
Investigator’s study files.  
5.3.2 Early Discontinuation: 
In the event that a subject is withdrawn from the study, every effort will be made by the Investigator to document 
and report the reasons for withdrawal as thoroughly as possible. The reason(s) for termination must be clearly 
reported in the subject’s CRF. An End-of-Treatment reason for discontinuation must be recorded for any subject 
who is registered. In the event that the subject fails to return for the necessary visit(s), an effort must be made to 
contact the subject to determine the reason, and this information should be recorded in the appropriate source 
record and the end-of-treatment CRF. 
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5.4 Study Duration: 
The total estimated duration of the study is 7 years, including 24 months to accrue subjects, with 5 year for follow 
up for the last subject. TKIs will not be supplied to subjects as this is standard of care treatments and all drugs are 
approved for first line use in CML. 
5.5 Withdrawal Criteria: 
Subjects will be discontinued from further study if any of the following occur:  
• 
Blast phase transformation 
• 
Loss of  MR (>1%) after initial achievement of MMR  
• 
Significant deviation from the protocol or eligibility criteria 
• 
Noncompliance with study or follow-up procedures 
• 
Pregnancy 
• 
Subject withdrawal of consent and decision to discontinue participation 
• 
Termination of the trial  
• 
Any other reason that, in the opinion of the Investigator, would justify removal of the subject from the study 
5.6 Study Termination: 
If the investigator, Data Monitoring Committee, or regulatory agencies discover conditions during the study that 
indicate that the study should be terminated, this action may be taken after appropriate consultation between the 
investigator, and Data Monitoring Committee. Conditions that may warrant termination of the study include, but 
are not limited to: 
• 
Incidence of MMR at 12 months <28% at the first interim analysis  
• 
Submission of knowingly false information from the research facility to the regulatory authorities 
• 
Insufficient adherence to protocol requirements 
Study termination and follow-up will be performed in compliance with the conditions set forth in the guidelines 
for GCP, International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. 
6. Safety Assessments: 
Safety Assessments: Safety will be assessed by routine physical and laboratory evaluations according to the 
schedule (Table 3) and as medically indicated. AEs will be recorded and the severity will be graded according to 
the NCI CTCAE v.4.0.  
Adverse Events: Type, incidence, severity (graded in accordance with the NCI CTCAE v.4.0), timing, seriousness 
and relatedness, outcome, action taken with drug, and treatment will be assessed and documented by the 
investigator continuously throughout the study. Baseline malignancy-related signs and symptoms will be recorded 
as AEs during the study if they worsen in severity or increase in frequency. Procedures for following AEs at the 
end of treatment and beyond are outlined in Section 5.1. 
 
 
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7. PRO Questionnaire: 
PRO assessments will be obtained using the MDASI-CML questionnaire. PRO generally encompass symptoms, 
multi-dimensional quality of life and functional status. Collection of PRO data offers the most powerful method to 
understand the subject experience with treatments by offering a more holistic approach to clinical response 
because the subjects’ response can provide a richer picture of the treatment effects, both good and bad. In 
addition, minimizing symptoms and improving quality of life are increasingly being recognized as important 
goals in clinical studies. Changes in a person’s physical, emotional, social and functional well-being are best 
measured by directly asking subjects about these areas using validated questionnaires, interviews or subject 
diaries. Non-English speaking subjects require validated survey in their languages. Subjects are required to 
complete the questionnaire in either English or Spanish whichever is their preference. MDASI-CML is a validated 
questionnaire derived from the MD Anderson symptom inventory questionnaires and  consists of 13 symptom 
related questions and 7 CML specific questions in part 1. The second part consists of 6 questions that address the 
effects on subjects’ quality of life. This is the only validated questionnaire in CML. The estimated time to 
completion is 5 minutes and the ease of completion has been validated by patient groups.[20] 
8. Study Treatment: 
All drugs are standard of care and no experimental drug will be given to subjects. The choice of treatment will be 
at the discretion of the treating physician. IM, DAS and NIL are all approved for first line use in CML. Subjects 
will be started on DAS or NIL as first line treatment. 
 
8.1 Dose Selection, Treatment Administration, Compliance, and Dose Modifications: 
DAS will be started at 100 mg once a day and NIL at 300 mg twice a day. Any dose reductions and dose 
interruptions will be noted. Subjects will be managed by the local oncologist with help from the PI or Co-Pi if 
requested. Dose modifications will be per the treating hematologist and as suggested by guidelines provided in 
Appendix C. Once subjects achieve a 1 log reduction in BCR-ABL1 at 3 months or 2 logs at 6 months , DAS or 
NIL will be discontinued and  IM 400 mg once a day will begin. Dose modification of TKI will be done at the 
treating physician’s discretion and will be per standard of care guidelines.(Appendix C) These events will be 
captured by the research nurse . 
8.2 
Allocation of Treatment: 
The results of screening assessments for each subject will be reviewed by the investigator, who will approve each 
subject’s enrollment. The choice of DAS and NIL will be at the discretion of the treating physician based on 
subject’s location and the physician’s choice.  
8.3 
Concomitant Medications: 
All concomitant medications administered will be reviewed and standard guidelines will be followed for any 
medications with known drug interactions. 
8.4 Treatment Supply:  
8.4.1 Formulation, Packaging and Labeling:  
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Subjects will obtain the medication as per practice patterns which would be from pharmacies after insurance 
approval or after subject assistance programs that are available. 
8.4.2 Treatment Storage, Dispensing, and Accountability 
Subjects will be taking the medication at home and they will be responsible for the storage of the drug. Subjects 
will be counselled on the importance of adhering to the treatments. RN will contact the subject at diagnosis, 
monthly in the first 6 months and every 6 months for 60 months from start of treatment (Table 3). RN will ensure 
education is provided to the subject regarding compliance and will also ensure subject is completing the 
compliance diary. Compliance will be assessed by getting the prescription fill information from the pharmacy at 
12 month intervals  
8.4.3 Disposition of used and unused supplies 
N/A. 
9. Adverse Event Reporting  
9.1 
Adverse Events 
9.1.1 
Adverse Event Definition 
An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An 
AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product whether or not considered related to the medicinal 
product. Any worsening of a preexisting condition, which is temporally associated with the use of the drug (i.e., 
occurs after the first dose of drug), is also an AE. AEs include:  
• 
Abnormal test findings  
• 
Changes in physical exam findings 
• 
Other untoward medical events, regardless of their relationship to the drug, such as injury, events that require 
surgery, accidents, or apparently unrelated illnesses, and hypersensitivity 
• 
AEs may include signs or symptoms resulting from: drug overdose, drug withdrawal, drug abuse, drug 
misuse, drug interactions, drug dependency, and, in utero drug exposure  
9.1.2 
Abnormal Laboratory Tests 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
• 
Test result is associated with accompanying symptoms that are considered clinically significant in the opinion 
of the investigator 
• 
Test result requires additional diagnostic testing (other than merely repeating an abnormal test) or 
medical/surgical intervention 
• 
Test result leads to a change in drug dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy 
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• 
Test result is considered to be an AE by the investigator  
9.1.3 
Performing Adverse Event Assessment 
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship to the 
investigational product, will be reported as described in the following sections. For all AEs, the investigator must 
pursue and obtain information adequate to determine the outcome of the AE and to assess whether it meets the 
criteria for classification as a serious AE requiring immediate notification to the appropriate regulatory agencies. 
9.1.4 
Reporting Period 
For all enrolled subjects, AEs (serious and non-serious) should be recorded on the CRF beginning on day 1 and 
concluding 30 days following the last dose of the assigned study treatment or the investigator/subject decision to 
discontinue treatment, whichever occurs later. Any ongoing AEs thought to be at least possibly study-drug related 
and all ongoing SAEs after this time should be followed at least every 4 weeks until they resolve to baseline (or 
CTCAE grade ≤ 1), stabilize, or are considered to be chronic/irreversible. 
9.1.5 
Adverse Event Severity 
The severity of AEs will be assessed according to the CTCAE, v.4.0. If the AE is not defined in the CTCAE, the 
investigator will determine the severity of the AE based on the following definitions: 
• 
Mild (grade 1): The AE is noticeable to the subject but does not interfere with routine activity. The AE does 
not require discontinuing administration or reducing the dose of the drug 
• 
Moderate (grade 2): The AE interferes with routine activity but responds to symptomatic therapy or rest. The 
AE may require reducing the dose, but not discontinuing administration of the drug 
• 
Severe (grade 3): The AE significantly limits the subject’s ability to perform routine activities despite 
symptomatic therapy. In addition, the AE leads to discontinuing administration or reducing the dose of the 
drug 
• 
Life-Threatening (grade 4): The AE requires discontinuing administration of the drug. The subject is at 
immediate risk of death 
• 
Death (grade 5): The subject dies as a direct result of the complication or condition induced by administration 
of the drug 
9.1.6 
Causality 
The investigator’s assessment of causality must be provided for all AEs (serious and non-serious). An 
investigator’s causality assessment is the determination of whether exists a reasonable possibility that the 
investigational product caused or contributed to the AE. In addition, if the investigator determines an SAE is 
associated with study procedures, the investigator must record this causal relationship in the source documents 
and on the SAE form and report such an assessment in accordance with the SAE reporting requirements. The 
investigator will use medical consideration and use the following categories of causality to determine the 
relatedness of an AE with the drug based on the following definitions. Not all criteria in each category of 
relatedness must be present. 
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• 
Definitely Not Related (not drug related):  The subject did not receive drug, OR the temporal sequence of the 
AE onset relative to the administration of the drug is not reasonable, OR there is another obvious cause of the 
AE 
• 
Probably Not Related (not drug related): there is evidence of exposure to drug, there is another more likely 
cause of the AE, dechallenge (if performed) is negative or ambiguous, rechallenge (if performed) is negative 
or ambiguous 
• 
Possibly Related (drug related): there is evidence of exposure to drug, the temporal sequence of the AE onset 
relative to administration of the drug is reasonable, the AE could have been due to another equally likely 
cause, dechallenge (if performed) is positive 
• 
Probably Related (drug related): there is evidence of exposure to drug, the temporal sequence of the AE onset 
relative to administration of the drug is reasonable, the AE is more likely explained by the drug than by 
another cause 
• 
Definitely Related (drug related): there is evidence of exposure to drug, the temporal sequence of the AE 
onset relative to administration of the drug is reasonable, dechallenge is positive, rechallenge (if feasible) is 
positive, the AE shows a pattern consistent with previous knowledge of the test drug or a test drug class 
9.1.7 
Expectedness 
The expectedness of an SAE is assessed by the Investigator in the overall classification of SAEs for regulatory 
reportability. Side effect profile for all the drugs is well known and subjects will be counselled on the expected 
side effects from the drugs they are taking.  
9.2 
Serious Adverse Events 
The definitions and reporting requirements of ICH Guidelines for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting, Topic E2A, will be adhered to. 
9.2.1 
Serious Adverse Event Definition 
An AE is considered an SAE if at least one of the following conditions applies: 
• 
Death: An AE that results in death is any subject death within 30 days of the last dose of drug 
administration. The cause of death or AE that resulted in a fatal outcome is the SAE 
• 
Life-threatening AE: An AE that places the subject, in the view of the investigator or the sponsor, at 
immediate risk of death from the event as it occurred (i.e., this does not include an event that had it 
occurred in a more severe form might have caused death) 
• 
Results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions: Any substantial disruption of a person’s ability to conduct normal life functions 
• 
Inpatient hospitalization or prolongation of existing hospitalization: Hospitalization refers to admission of 
a subject into a hospital for any length of time 
• 
A congenital anomaly/birth defect: A fixed, permanent impairment established at or before birth 
• 
Cancer: Occurrence or diagnosis of a new cancer during the study is considered an SAE. A new cancer is 
a cancer that is histopathologically different than the cancer under study in the trial (i.e., does not include 
metastatic or progressive disease) 
• 
Overdose: Occurrences of overdose must be reported as an SAE 
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• 
Important medical event: Medical and scientific judgment should be exercised in determining whether an 
event is an important medical event. An important medical event may not result in death, be life-
threatening, or require hospitalization. However, if it is determined that the event may jeopardize the 
subject and/or may require intervention to prevent one of the other outcomes listed in the definition 
above, the important medical events should be reported as serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalization; or the development of drug dependency or drug abuse. 
AEs (reported from clinical studies) that require hospitalization or prolongation of hospitalization are considered 
serious. Any initial admission (even if less than 24 hours) to a health care facility meets these criteria. Adverse 
events that require emergency room care that do not result in hospital admission are not SAEs unless assessed by 
the investigator to be an important medical event. Hospitalization does not include the following: Hospice 
facilities, Respite care, skilled nursing facilities, Nursing home, Routine emergency room admissions, and same 
day surgeries (as outpatient/same day/ambulatory procedure) 
Hospitalization or prolongation of hospitalization in the absence of a precipitating AE is not in itself an SAE. 
Examples include: social admission (e.g., subject has no place to sleep), optional admission not associated with a 
precipitating AE (e.g., for elective cosmetic surgery that was planned prior to study enrollment [appropriate 
documentation is required for these cases]), hospitalization or prolongation of hospitalization for scheduled 
therapy of the target malignancy of the study is not considered an SAE 
9.2.2 
Reporting Serious Adverse Events 
All SAEs will be reviewed and assessed by study investigators. SAEs will be reported to the IRB of record for 
each site according to their IRB’s policies.  
9.2.3 
Follow-up Information of Serious Adverse Events 
Appropriate diagnostic tests should be performed and therapeutic measures, as medically indicated, should be 
instituted. Appropriate consultation and follow-up evaluations should be carried out until the event has resolved 
or is otherwise explained by the investigator. For all SAEs, the investigator is obligated to pursue and provide 
information to the appropriate regulatory agencies. There should be routine follow-up through and including 30 
days after the last administration of assigned study treatment or the investigator/subject decision to discontinue 
treatment, whichever occurs later, in all subjects in order to monitor for the occurrence of SAEs. If an SAE 
continues after the 30-day evaluation period, then the subject must be followed until the event resolves or returns 
to baseline. The medical monitor may specify a longer period of time if required to assure the safety of the 
subject. 
9.3 
Other Safety Issues 
9.3.1 
Pregnancy 
Females of childbearing potential and fertile males will be informed as to the potential risk of conception while 
participating in this treatment and will be advised that they must use effective contraception as is the standard of 
care. If a subject is confirmed pregnant during the trial, appropriate counseling should be provided and the follow 
up will continue per standard of care recommendations.  
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9.3.2 
Overdose  
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as an SAE. 
These adverse events will be monitored as instructed in the schedule of events and as clinically indicated. 
10. Statistical Considerations  
10.1 
General Considerations 
For the purposes of this protocol and all analyses, a month of treatment is defined as 30 days, and will be the same 
length as a cycle of treatment.  
10.2 
Analysis Population Intention to treat (ITT) population: The ITT population includes all subjects 
who are enrolled in the study.  
Safety Population: The safety population includes all subjects who have received at least 1 dose of TKIs.  
Per-protocol Population: The per-protocol population includes all subjects who are enrolled, receive at least one 
dose of drug, and have no major protocol violations that could be expected to impact response data, such as: 
failure to satisfy one or more eligibility criteria, administration of other anti-cancer therapy concurrent with drug, 
and administration of incorrect drug dose. Major protocol violations will be finalized and documented prior to 
final data analysis. 
10.3 
Study Endpoints 
Primary Endpoint: The primary objective is to determine the proportion of subjects who achieve MMR at 12 
months will be determined. Only MMR at 12 months will be considered, MMR achieved before the 12 months 
and then subsequently lost will not be considered. 
Secondary Endpoints: 
i. 
PFS will be measured from the time of CML diagnosis to the time of loss of MMR or loss of 
hematologic response 
ii. 
AP or BP free survival will be measured from the time of CML diagnosis to the time of 
transformation to AP or BP 
iii. 
The number of subjects with  BCR-ABL1 transcript levels  < MR4 at any time will be determined 
iv. 
Safety will be evaluated by the assessment of laboratory and clinical adverse events (AEs) using 
the CTCAE v4.03 criteria. Safety will be assessed by the frequency, duration, and severity of AEs 
and SAEs, and clinical evaluations and changes in clinical laboratory blood samples 
v. 
The PRO score extracted from the MDASI-CML will be determined and intra and inter subject 
changes will be compared at the different study-defined time points.  
 
Exploratory Endpoints:  
i. 
 Outcomes of subjects with and without detectable cells with aberrant lymphoid or myeloid 
markers at diagnosis will be compared  
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ii. 
The proportion of subjects who achieve and maintain deep MR for 2 years and therefore qualify 
or enroll on a TKI discontinuation trial will be determined. Outcomes following TKI 
discontinuation will be collected 
10.4 
Determination of Sample Size: 
Subjects that switch to IM will only be included in the analysis to assess the number of subjects that achieve 
MMR at 12 months which is the primary end point for the study. We assume that 15% will not achieve a 1 log 
reduction at 3 months or 2 log reduction at 6 months and therefore will not switch to IM. Assuming that the 
subjects switched to IM will have the same rate of MMR of 55%(P1) [8,14] at 12 months but not less than 
40%(P0)as obtained with IM alone, a sample size of 85 achieves 80% power to detect a difference (P1-P0) of 
0.1500 using a one-sided binomial test. The target significance level is 0.0500. The actual significance level 
achieved by this test is 0.0449. These results assume that the population proportion under the null hypothesis is 
0.4000. We estimate that up to 15% of subjects started on DAS or NIL will not be able to switch to IM and will 
not be included in the analysis but will be included in the safety and outcome analysis at 5 years. The total sample 
size required will be 100 subjects to achieve the 85 subjects required for analysis towards the primary end point. 
 
10.5 
Safety and Efficacy Analysis  
All subjects receiving at least 1 dose of drug will be considered evaluable for safety. Listings of laboratory test 
results will also be generated, and descriptive statistics summarizing the changes in laboratory tests over time will 
be presented. Exposure to drug over time will also be summarized. The AE incidence rates, as well as the 
frequency of occurrence of overall toxicity, categorized by toxicity grades (severity) will be described as obtained 
from subject forms and subject communications. Descriptive statistics will summarize the changes in BCR-ABL1 
testing over time will be presented. Loss of MMR is defined as an increase in BCR-ABL1 by qRT-PCR test 
above 0.1% that is both confirmed within a month and associated with a rise in the qRT-PCR on a confirmatory 
test obtained 4 weeks later (ELN definition). For the primary and secondary efficacy endpoints, subgroup 
analyses will be performed by baseline potential prognostic factors. Subgroups will include: age, gender, race, 
underlying diagnosis, and other disease-related prognostic factors (disease status).  
10.6  
Interim Analysis 
Interim analysis will be done after 50% of subjects that are enrolled and switched to IM have a 12 month follow 
up. The estimated 12 month MMR for DAS and NIL is 55%. The study hypothesizes that the rate of MMR will be 
similar to that of first line DAS or NIL and better than that seen with IM. Hence an MMR of less than 40% seen 
with IM alone would be taken as grounds for stopping the trial. 
10.7 
Protocol Deviations and Violations 
To be protocol-compliant, a subject must not have any major protocol deviations during the study period. Protocol 
deviations will be identified prior to final analysis and will be listed by treatment group in the clinical study 
report. 
 
 
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11. 
Quality Control and Quality Assurance and Study Monitoring 
The investigator is responsible for performing quality control and assurance checks. Before enrolling any subjects 
into this study, the investigator will review the protocol, the CRFs and instructions for their completion, the 
procedure for obtaining informed consent, and the procedure for reporting AEs with all personnel listed on the 
delegation of authority. All the regulatory documents will be collected by Emory study PI with the assistance of 
Georgia CORE.  The investigator will perform monthly evaluation of the conduct of the trial and perform the 
following: 
• 
Review information recorded in the CRFs and verify against source documents 
• 
Review data for safety information and to identify missing data   
• 
Review protocol violations, out-of-range data, and other data inconsistencies 
Emory PI will set up monthly teleconference with GA CORE study sites investigators who have enrolled patients 
to provide oversight to the study. Data source documents (in the forms of patient medical records) from all 
consented subjects will be sent to and stored at Emory University from Georgia Core approved outside facilities. 
The data source documents will be used to complete case report forms by the Emory PI and his designee.  The 
Emory PI and his designee will also be responsible for collecting all the study visits telecommunications to 
complete study case report forms.  
Data gathered after the subjects sign the consent forms will be uploaded onto Oncore and information maintained 
in a database that will be accessible only by the Emory IRB approved personnel.  
The Multi-Site Coordinator from Winship Cancer Institute of Emory University will be responsible for 
conducting remote monitoring visits annually. 
This study will also be monitored by the DSMB Winship Committee.  
12. Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical standards that have their origin in the Declaration of 
Helsinki and that are consistent with GCP guidelines and the applicable regulatory requirements. 
12.1 
Institutional Review Boards Approval 
The protocol and the informed consent document must have the initial and at least annual approvals of the IRB. 
The signed IRB approval letter must identify the documents approved (i.e., list the investigator’s name, the 
protocol number and title, the date of the protocol and informed consent document, and the date of approval of the 
protocol and the informed consent document). Any advertisements used to recruit subjects should also be 
reviewed by the IRB. Approval will be obtained from Emory IRB initially and the protocol will be submitted to 
GA CORE IRB to run this trial across the state of Georgia. Any amendments will need to be approved by both the 
IRBs once the trial is active.   
Per Georgia Core SOP: Interactions with the Institutional Review Board (IRB),  Georgia CORE communicates 
with the central IRB on behalf of the Georgia CORE network sites who use a central IRB throughout the research 
process in order to ensure compliance with the regulations and to protect the safety and well-being of study 
subjects.  Georgia CORE network sites that use a local IRB are responsible for following their standard operating 
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procedures for interacting with the IRB. Georgia CORE will monitor the IRB interactions of the sites using local 
IRBs In addition, Georgia CORE will be providing the study sponsor with a periodic investigator trial report for 
sponsor to review.   
12.2 
Subject Information and Consent 
The study informed consent form will follow regulations that provide protection for human subjects in clinical 
investigations and to describe the general requirements for informed consent. The informed consent document 
will contain all of the elements of the informed consent specified in the regulations. Nothing in this protocol or 
the regulations is intended to limit the authority of a physician to provide emergency medical care under 
applicable regulations. In addition, regulatory agencies will be granted permit to conduct inspections and review 
records pertaining to this clinical investigation. 
12.3 
Subject Confidentiality 
Throughout the course of the study, all PHI record will be kept securely using password protected computer 
terminals. Access to the data will be on a need to know basis, therefore, only those investigators listed in the 
protocol will have access to the data. A high premium will be placed on ensuring that identifying information is 
not made available to staff engaged in routine care of the subject unless if necessary for the safe performance of 
their duties. For this reason, all research-related samples and clinical data will be de-identified using assigned 
study-specific registration numbers for such non-standard of care procedures as much as possible. 
The investigator agrees to keep all information in strict confidence and to request similar confidentiality from 
his/her staff and the IRB. Study documents (investigators' brochures and other material) will be stored 
appropriately to ensure their confidentiality. The information provided to the investigator may not be disclosed to 
others without direct written authorization, except to the extent necessary to obtain informed consent from 
subjects who wish to participate in the trial.  
12.4 
Data Safety Monitoring Committee 
Subject safety, study efficacy and compliance will be reviewed on a quarterly basis. The Data and Safety 
Monitoring Committee (DSMC) of the Winship Cancer Institute will also oversee the conduct of this study. This 
committee will review pertinent aspects of study conduct including subject safety, compliance with protocol, data 
collection and efficacy. Initial study monitoring will occur within 1 year from the date of the first subject accrued, 
with 2 of the first 5 subjects being reviewed.  Subsequent monitoring will occur in routine intervals per the 
Winship Data and Safety Monitoring Plan (DSMP) version 1-16-2015.   
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with the protocol, data 
collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute Internal Monitors assigned to the 
DSMC may verify informed consent, eligibility, data entry, accuracy and availability of source documents, 
AEs/SAEs, and essential regulatory documents.  Following the monitoring review, monitors will provide a 
preliminary report of monitoring findings to the Emory PI and other pertinent individuals involved in the conduct 
of the study.  The Emory PI is required to address and respond to all the deficiencies noted in the preliminary 
report.  Prior to the completion of the final summary report, monitors will discuss the preliminary report responses 
with the Emory sponsor and other team members (when appropriate).  A final monitoring summary report will 
then be prepared by the monitor.  Final DSMC review will include the final monitoring summary report with 
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corresponding Emory PI response, submitted CAPA (when applicable), Emory PI Summary statement, and 
available aggregate toxicity and safety data.   
The DSMC will render a recommendation and rating based on the overall trial conduct.  The Emory PI is 
responsible for ensuring that instances of egregious data insufficiencies are reported to the IRB.  Continuing 
Review submissions will include the DSMC recommendation letter.  Should any revisions be made to the 
protocol-specific monitoring plan after initial DSMC approval, the PI will be responsible for notifying the DSMC 
of such changes.  The Committee reserves the right to conduct additional audits if necessary.  
13. Data Handling and Record Keeping 
13.1 
Case Report Forms and Study Records 
Study-specific CRFs will be made available for the conduct of this study. Study data, contained in source 
documentation, will be entered into the CRFs for all subjects enrolled in the study. All pertinent data records will 
be maintained for 5 years after completion or termination of the study. 
 
13.2 
Source Documents 
The investigator agrees that qualified representatives of the sponsor and regulatory agencies will have the right, 
both during and after this study, to conduct inspections and to audit and review medical records pertinent to the 
clinical study as permitted by the regulations. Subjects will not be identified by name in any reports stemming 
from the study, and confidentiality of information in medical records will be preserved. The confidentiality of the 
subject will be maintained unless disclosure is required by regulations.  
13.3 
Retention of Data 
Trial documents (including correspondence related to this clinical study, subject records, source documents, 
CRFs, drug inventory records and IRB and sponsor correspondence pertaining to the study, original subject, 
laboratory, and drug inventory records relating to the study) will be retained until 5 years after completion or 
termination of the study and according to the Clinical Trial Office policies. Thereafter, records will not be 
destroyed but stored at an offsite location. 
  
13.4 
Study Termination 
The study will be terminated at any time for any of the following reasons: 
• 
Failure to enroll subjects 
• 
Protocol violations 
• 
Inaccurate or incomplete data 
• 
Unsafe or unethical practices 
• 
Questionable safety of the drug 
• 
Administrative decision 
In the event of the termination of the Study, a written statement describing why the study was terminated 
prematurely will be made available by the investigator. 
 
 
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References: 
 
1. 
Faderl, S., et al., The biology of chronic myeloid leukemia. N Engl J Med, 1999. 341(3): p. 164-72. 
2. 
Kantarjian, H.M., et al., New insights into the pathophysiology of chronic myeloid leukemia and imatinib 
resistance. Ann Intern Med, 2006. 145(12): p. 913-23. 
3. 
Lima, L., et al., Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, 
second-line agents, and beyond. Cancer, 2011. 117(6): p. 1245-1252. 
4. 
Falchi, L., et al., Significance of deeper molecular responses in patients with chronic myeloid leukemia in 
early chronic phase treated with tyrosine kinase inhibitors. Am J Hematol, 2013. 88(12): p. 1024-9. 
5. 
Muller, M.C., et al., Harmonization of molecular monitoring of CML therapy in Europe. Leukemia, 2009. 
23(11): p. 1957-63. 
6. 
Gambacorti-Passerini, C., et al., Multicenter independent assessment of outcomes in chronic myeloid 
leukemia patients treated with imatinib. J Natl Cancer Inst, 2011. 103(7): p. 553-61. 
7. 
Kantarjian, H., et al., Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid 
leukemia. N Engl J Med, 2010. 362(24): p. 2260-70. 
8. 
Saglio, G., et al., Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med, 
2010. 362(24): p. 2251-9. 
9. 
Latagliata, R., et al., Incidence, risk factors and management of pleural effusions during dasatinib 
treatment in unselected elderly patients with chronic myelogenous leukaemia. Hematol Oncol, 2013. 
31(2): p. 103-9. 
10. 
Montani, D., et al., Pulmonary arterial hypertension in patients treated by dasatinib. Circulation, 2012. 
125(17): p. 2128-37. 
11. 
Gora-Tybor, J., et al., Real-life comparison of severe vascular events and other non-hematological 
complications in patients with chronic myeloid leukemia undergoing second-line nilotinib or dasatinib 
treatment. Leuk Lymphoma, 2015. 56(8): p. 2309-14. 
12. 
Kim, T.D., et al., Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients 
treated with nilotinib or imatinib. Leukemia, 2013. 27(6): p. 1316-21. 
13. 
Yood, M.U., et al., Adherence to treatment with second-line therapies, dasatinib and nilotinib, in patients 
with chronic myeloid leukemia. Curr Med Res Opin, 2012. 28(2): p. 213-9. 
14. 
Hughes, T.P., et al., Early molecular response predicts outcomes in patients with chronic myeloid 
leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood, 2014. 123(9): p. 1353-60. 
15. 
Marin, D., et al., Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for 
predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J 
Clin Oncol, 2012. 30(3): p. 232-8. 
16. 
Hanfstein, B., et al., Early molecular and cytogenetic response is predictive for long-term progression-
free and overall survival in chronic myeloid leukemia (CML). Leukemia, 2012. 26(9): p. 2096-102. 
17. 
Jain, P., et al., Early responses predict better outcomes in patients with newly diagnosed chronic myeloid 
leukemia: results with four tyrosine kinase inhibitor modalities. Blood, 2013. 121(24): p. 4867-74. 
18. 
Preudhomme, C., et al., Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med, 
2010. 363(26): p. 2511-21. 
19. 
Larson, R.A., et al., Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-
positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia, 2012. 26(10): 
p. 2197-203. 
20. 
Williams, L.A., et al., Measuring the symptom burden associated with the treatment of chronic myeloid 
leukemia. Blood, 2013. 122(5): p. 641-7. 
21. 
Morisky, D.E., et al., Predictive validity of a medication adherence measure in an outpatient setting. J 
Clin Hypertens (Greenwich), 2008. 10(5): p. 348-54. 
 
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Appendices: 
Appendix A: Definition of Response in CP-CML: 
a. Hematological Response: 
 
Hematologic Response 
Definition 
Complete Hematological Response 
• 
WBC < 10 x 109/L 
• 
Basophils < 5% in blood 
• 
No 
myelocytes, 
promyelocytes, myeloblasts 
in the differential in blood 
• 
Platelet count < 450 x 109/L 
• 
Spleen not palpable 
 
 
b. Cytogenetic Response: 
Cytogenetic Response (based on 
analysis of at least 20 metaphases) 
% 
Philadelphia 
Chromosome 
Positive Cells 
None 
>95% 
Minimal 
66-95% 
Minor 
36-65% 
Partial 
1-35% 
Complete 
0% 
Major 
Complete + Partial responses 
 
c. Molecular Responses: 
Molecular response 
qRT-PCR BCR-ABL1/ABL ratio 
MR1 
< 10% ,    1 Log reduction 
MR2 
<1%,        2 Log reduction 
MR3, MMR or Major 
< 0.1%,    3 Log reduction 
MR4 
< 0.01%   4 log reduction 
Deep Molecular response 
 < 0.0032% or undetectable  
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Appendix B: Timing of molecular monitoring: ELN guidelines: 
Time Point 
 
At diagnosis 
Chromosomal analysis 
FISH for t (9:22) 
qRT-PCR 
During treatment 
qRT-PCR every 3 months till MMR 
then every 3-6 months and/or 
Chromosomal analysis at 3,6 and 12 
months till Ccyr then every 12 months 
Failure/progression 
qRT-PCR, 
chromosomal 
analysis, 
immunophenotype 
and 
mutation 
analysis 
 
 
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: 
Appendix C: Management of Adverse events  
Imatinib: 
Hematologic Toxicities 
• Chronic phase, absolute neutrophil count (ANC) <1.0 x 109/L, and/or platelets <50 x 109/L: Hold imatinib until 
ANC ≥1.5 x 109/L and platelets ≥75 x 109/L, then resume imatinib at the starting dose of 400 mg. If recurrence of 
ANC <1.0 x 109/L and/or platelets <50 x 109/L, hold drug until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L, 
then resume imatinib at reduced dose of 300 mg. 
• Growth factors can be used in combination with imatinib for patients with resistant neutropenia. 
• Grade 3-4 anemia: Check reticulocyte count, ferritin, iron saturation, B12, folate, and correct nutritional 
deficiencies if present. Transfusion support should be used if patient is symptomatic. 
 
Non-Hematologic Toxicities 
• Bilirubin >3 x institutional upper limit of normal (IULN) or liver transaminases >5 x IULN: hold imatinib until 
bilirubin <1.5 x IULN and transaminase levels <2.5 x IULN. Resume imatinib at a reduced daily dose (400 mg to 
300 mg, 600 mg to 400 mg, or 800 mg to 600 mg).  
• Severe hepatotoxicity or severe fluid retention: hold imatinib until the event has resolved. Treatment can be 
resumed as appropriate depending on the severity of the event. 
• Patients with moderate renal impairment (CrCL = 20–39 mL/min) should receive 50% decrease in the 
recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not 
recommended in patients with mild renal impairment (CrCL = 40–59 mL/min). For patients with moderate renal 
impairment, doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients 
with severe renal impairment. 
 
Specific Interventions 
• Fluid retention (pleural effusion, pericardial effusion, edema, and ascites): diuretics, supportive care, dose 
reduction, interruption, or discontinuation. Consider echocardiogram to check LVEF. 
• GI upset: Take medication with a meal and large glass of water. 
• Muscle cramps: calcium supplement, tonic water 
• Rash: topical or systemic steroids, dose reduction, interruption, or discontinuation 
 
Dasatinib: 
Hematologic Toxicities 
• ANC <0.5 x 109/L or platelets <50 x 109/L: Hold dasatinib until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L, 
then resume dasatinib at the starting dose if recovery occurs in ≤7 days. If platelets <25 x 109/L or recurrence of 
ANC <0.5 x 109/L for >7 days, hold drug until ANC ≥1.0 x 109/L and platelets ≥50 x 109/L, then resume 
dasatinib at reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg 
once daily. 
• Growth factors can be used in combination with dasatinib for patients with resistant neutropenia and 
thrombocytopenia. 
• Grade 3-4 anemia: Check reticulocyte count, ferritin, iron saturation, B12, folate, and correct nutritional 
deficiencies if present. Transfusion support should be used if patient is symptomatic. 
 
Non-Hematologic Toxicities 
• If a severe, non-hematologic, adverse reaction develops with dasatinib, treatment must be held until the event 
has resolved or improved. 
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Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of the 
event. 
 
Specific Interventions 
• Fluid retention events (ascites, edema, pleural and pericardial effusion): diuretics, supportive care. 
• Pleural/pericardial effusion: diuretics, dose interruption. If patient has significant symptoms, consider short 
course of steroids (prednisone 
20-50 mg/day x 3-4 days, may taper with 20 mg/day x 3-4 days); when resolved, reduce one dose level. 
• GI upset: Take medication with a meal and large glass of water. 
• Rash: topical or systemic steroids, dose reduction, interruption, or discontinuation 
 
Nilotinib: 
 
Hematologic Toxicities 
• ANC <1.0 x 109/L, and/or platelets <50 x 109/L: Hold nilotinib and monitor blood counts. Resume within 2 
weeks at prior dose if ANC >1.0 x 109/L and platelets >50 x 109/L. If blood counts remain low for >2 weeks, 
reduce dose to 400 mg once daily. 
 
Non-Hematologic Toxicities 
• Elevated serum lipase, amylase, bilirubin, or hepatic transaminases 
grade ≥3: hold nilotinib and monitor serum levels. Resume nilotinib at 400 mg once daily if serum levels return to 
grade ≤1. 
 
Specific Interventions 
• Rash: topical or systemic steroids, dose reduction, interruption, or 
discontinuation. 
• Growth factors can be used in combination with nilotinib for patients with resistant neutropenia and 
thrombocytopenia. 
• Grade 3–4 anemia: Check reticulocyte count, ferritin, iron saturation, B12, folate, and correct nutritional 
deficiencies if present. Transfusion support should be used if patient is symptomatic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix D: MDASI-CML PRO questionnaire:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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