Clinical trial NCT01460160
Conditions: Leukemia, Pediatric
Sponsor: Bristol-Myers Squibb
Start date: 2012-04-13; Completion date: 2021-06-01
Enrollment: 106 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether Dasatinib when added to standard chemotherapy is effective and safe in the treatment of pediatric philadelphia chromosome positive acute lymphoblastic leukemia

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Dasatinib
Intervention descriptions: intervention 1: Tablets, Oral, 60 mg/m2, Once daily, 2 years or until unacceptable toxicity

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
CA180372
IND Number:
66,971
Ex-US
Non-IND
EUDRACT Number
2011-001123-20 
Date:
01-Jun-2011
Revised Date:
28-Oct-2013
Clinical Protocol CA180372
A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib Added to Standard 
Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive 
Acute Lymphoblastic Leukemia
Revised Protocol Number: 05
Incorporates Amendment 04
Study Director 
Medical Monitor
M. Brigid Bradley-Garelik, MD
Co-Principal Investigator
Co-Principal Investigator
 
24-hr Emergency Telephone Number
Bristol-Myers Squibb Research and Development
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Dasatinib
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This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved.
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Date: 28-Oct-2013
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 05
28-Oct-2013
Incorporates Amendment 04
Amendment 04
28-Oct-2013
The key purposes of this amendment are to incorporate the following 
changes:
1) Add mandatory supportive care measures during the 3 High Risk Blocks
2) Provide updates to the WOCBP language to harmonize this language with 
the current BMS directives for WOCBP.
Revised 
Protocol 04
31-Jul-2013
Incorporates Amendment 03 
Amendment 03
31-Jul-2013
The key purposes of this amendment are to incorporate the following key 
changes:
1) Increase the number of treated subjects from 75 to at least 75 and up to 90.
2) Modify language regarding pregnancy prevention.
3) Incorporate recommendations for subject management and supportive care 
during High Risk (HR) Blocks 1-3.
4) Provides for clarifications, fixes inconsistencies across sections of the 
protocol and corrects various typographical errors.
Revised 
Protocol 03
07-Dec-2012
Incorporates Amendment 02 
Amendment 02
07-Dec-2012
The key purposes of this amendment are to incorporate the following key 
changes:
1) Introduce a new pediatric formulation of dasatinib.
2) Address lack of availability of native-asparaginase in the United States and 
allow use of Peg-Asparaginase upfront in such instances as well as provide 
more detailed instruction for dose modifications of the various asparaginase 
formulations.
3) Indicate that the BCR-ABL mutation status will be reported for baseline 
and at time of progression as a secondary objective instead of as an 
exploratory objective.
4) Allow Philadelphia chromosome positivity from peripheral blood to be
acceptable for study entry.
5) Expand the window for screening activities to 21 days.
6) Modify the definition of high risk group and low/standard risk group in 
response to Induction 1A treatment.
7) Provides for clarifications, fixes inconsistencies across sections of the 
protocol and corrects various typographical errors.
Revised 
Protocol 02
20-Sep-2011
Incorporates Amendment 01
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Document
Date of Issue
Summary of Change
Amendment 01
20-Sep-2011
The following amendment was developed to incorporate two key changes 
including:
1) Changing the statistical design of the trial to allow comparison to historical 
external controls. Specifically, the 3-year event free survival (EFS) of 
dasatinib plus chemotherapy will be compared to the 3-year EFS of 
chemotherapy alone from the Associazione Italiana di Ematologia Pediatrica -
Berlin-Frankfurt-Muenster ALL
2000 (AIEOP BFM 2000) trial and the 3-year EFS of imatinib plus 
chemotherapy from the European intergroup Study on post induction 
treatment of Philadelphia positive Acute Lymphoblastic Leukemia 
(EsPhALL). This analysis will improve the ability to interpret the safety and 
efficacy of dasatinib added to chemotherapy among
other treatment options for this pediatric leukemia.
2) Incorporating additional supportive care options for chemotherapy to 
accommodate the standard of care at sites in the United Kingdom (UK).
Additionally, typographical errors were also corrected. 
Revised 
Protocol 01
22-Jun-2011
Incorporates Administrative Letter 01
Administrative 
Letter 01 
22-Jun-2011
Corrects typographical errors.  These corrections make the text consistent 
with other protocol sections in which this text appears.
Original 
Protocol
01-Jun-2011
Not applicable.
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SYNOPSIS
Clinical Protocol CA180372
Title of Study: A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib Added to Standard 
Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute 
Lymphoblastic Leukemia
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Dasatinib 60 mg/m2 orally, once daily, for 2 years
Study Phase: 2
Research Hypothesis: Dasatinib added to chemotherapy will demonstrate a superior 3-year event free survival 
(EFS) rate compared to chemotherapy alone in the external historical control trial Associazione Italiana di 
Ematologia Pediatrica - Berlin-Frankfurt-Muenster ALL 2000 (AIEOP-BFM 2000) and non-inferior 3-year EFS 
compared to continuous imatinib added to chemotherapy in the external historical control trial of the amended 
European intergroup Study on post induction treatment of Philadelphia positive Acute Lymphoblastic Leukemia
(EsPhALL).
Primary Objective: Compare the 3-year event-free survival (EFS) with the external historical controls of the 
AIEOP-BFM 2000 and EsPhALL trials.
Study Design: Children and adolescents with newly diagnosed Ph+ ALL will be eligible for this open-label, 
single-arm study and will receive dasatinib added to successive blocks of standard multiagent chemotherapy 
(AIEOP-BFM ALL 2000 regimen) for a maximum duration of 2 years. 
Design: After diagnosis of acute lymphoblastic leukemia (ALL), subjects will begin standard induction 
chemotherapy (Block IA). Since the diagnosis of ALL typically requires urgent treatment and it takes up to 
10-14 days to determine which patients have Philadelphia chromosome positive (Ph+) ALL, frontline induction 
chemotherapy (Block IA) will start prior to enrollment in this trial (approximately 2 weeks) and will be based upon 
the investigator’s institutional standard of care. Enrollment on this study will occur prior to day 15 of Induction 
Block IA.  At day 15, dasatinib treatment shall begin and continue without planned interruption until the completion 
of therapy (102 weeks). The components of treatment are divided into blocks as follows: Induction IA (4-5 weeks), 
induction IB (28 days, 4 weeks), recovery period (2 - 4 weeks), consolidation blocks 1, 2, and 3 (21 days, 3 weeks 
each), reinduction block 1, including phase IIa and IIb (63 days, 9 weeks), interim maintenance (29 days, 4 weeks, 
overlaps 2 weeks with end of reinduction block 1), reinduction block 2 (63 days, 9 weeks), and continuation therapy 
(62 weeks).
Chemotherapeutic agents utilized in this regimen include: cyclophosphamide, cytarabine, 
6-mercaptopurine, 
methotrexate, 
leucovorin, 
dexamethasone, 
vincristine, 
asparaginase, 
hydrocortisone, 
daunorubicin, ifosfamide, etoposide, doxorubicin, and thioguanine. 
Subjects who meet pre-defined criteria may receive a hematopoietic stem cell transplant (HSCT). The use of 
dasatinib after transplantation is optional in all HSCT recipients, at the discretion of the treating physician. Subjects 
may receive 12 additional months of post-HSCT dasatinib.  Subjects with CNS3 disease at diagnosis will receive 
cranial irradiation during the Interim Maintenance period.
The total duration of the trial to determine the primary and secondary endpoints will be approximately 6 years.
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Figure 1:
Schematic Study Design
Study Population: 
Select Inclusion Criteria (See Section 3.3.1 for full criteria):

Philadelphia chromosome-positive ALL 

Induction chemotherapy approximately 14 days according to institutional standard of care

Performance status (Karnofsky or Lansky) 60%

Adequate liver, renal, and cardiac function

Age > 1 year and < 18 years at initial diagnosis of ALL
Select Exclusion Criteria (See Section 3.3.2 for full criteria):

Prior treatment with a BCR-ABL inhibitor (eg, imatinib) 

Biopsy proven Ph+ ALL extramedullary involvement of the testicles

Clinically significant cardiovascular disease or disorder of platelet function (eg, von Willebrand’s disease)

Active systemic infection 

Patients who are pregnant or breastfeeding or likely to become pregnant.

Men whose partner is unwilling or unable to avoid pregnancy.
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Study Assessments and Primary Endpoint: Event Free Survival (EFS) is defined as the time from first dasatinib
treatment until one of the following events: lack of complete response (induction and consolidation failure), relapse 
at any site, development of second malignant neoplasm, or death.  
External Data Safety Monitoring Board: An independent Data Safety and Monitoring Board will provide 
oversight of trial to ensure protection of the research participants.
Statistical Methods: The sample size comprises at least 75 treated subjects. A minimum of 20 treated subjects will 
be distributed in each of the age ranges of 1 - 11 years and 12 < 18 years, respectively. 
The primary analysis will compare the 3-year EFS of dasatinib plus chemotherapy with external historical controls 
in hierarchical order.  The trial will be considered positive if at least the first two comparisons are statistically 
significant. The comparisons will be as follows:
1)
Superiority over chemotherapy alone of AIEOP-BFM 2000
2)
Non-inferiority to continuous imatinib plus chemotherapy of the amended EsPhALL trial
3)
Superiority over continuous imatinib plus chemotherapy of the amended EsPhALL trial
For the analysis of the primary endpoints, a hierarchical testing procedure will be used so that the overall 
experiment-wise one-sided type I error rate is preserved at 0.05. 
The differences in 3-year EFS rates will be computed using binomial proportions.  The differences in event rates 
along with exact 2-sided 90% Clopper-Pearson CI’s will be provided. Test for difference in event rates will be 
carried out using a two-sided 2 test. Non-inferiority testing against the study treatment in the amended EsPhALL 
trial will be carried out using the corresponding 2-sided 90% CI for the treatment difference and comparing the 
lower confidence limit to the non-inferiority margin of -5%. This margin corresponds to 1/4 of the effect size of 
18% anticipated in the amended EsPhALL trial over the chemotherapy-only control of the original EsPhALL trial. 
All of the above tests will be performed at the 0.05 (one-sided) significance level. 
Secondary endpoints include safety and feasibility of dasatinib added to chemotherapy, an estimate of the EFS of 
dasatinib added to chemotherapy (including 3 and 5-year rates), complete remission rates at end of induction
compared with AIEOP BFM 2000 and the Amended EsPhALL trials, minimal residual disease levels by PCR for 
immunoglobulin and T-cell receptor gene rearrangement and BCR-ABL mutation status at baseline and time of 
progression or relapse. Adverse events and laboratory results will be graded utilizing the National Cancer 
Institute-Common Terminology Criteria (NCI-CTCAE) Version 4.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objective .................................................................................... 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent/Assent.................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.1.1 Prohibited Treatments: ................................................................... 
3.4.1.2 Restricted Treatments: .................................................................... 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.3 Supportive Care Guidelines ..................................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
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4 TREATMENTS ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Noninvestigational Product ..................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Full Treatment Plan ................................................................................. 
4.3.1.1 Induction Therapy Phase IA ........................................................... 
4.3.1.2 Induction Therapy Phase IB ........................................................... 
4.3.1.3 Consolidation Block 1 (HR1) .......................................................... 
4.3.1.4 Consolidation Block 2 (HR2) .......................................................... 
4.3.1.5 Consolidation Block 3 (HR3) .......................................................... 
4.3.1.6 First Reinduction (Protocol II) ....................................................... 
4.3.1.7 Interim Maintenance ....................................................................... 
4.3.1.8 Second Reinduction (Protocol II) ................................................... 
4.3.1.9 Continuation Therapy ..................................................................... 
4.3.1.10 Completion of Treatment .............................................................. 
4.3.1.11 Hematopoietic Stem Cell Transplant (HSCT) ............................... 
4.3.2 Dose Modifications .................................................................................. 
4.3.2.1 Dasatinib ......................................................................................... 
4.3.2.2 Asparaginase [PEG, E.coli, or Erwinia] ........................................ 
4.3.2.3 Cyclophosphamide .......................................................................... 
4.3.2.4 Cytarabine (Ara-C) ......................................................................... 
4.3.2.5 Daunorubicin or Doxorubicin ........................................................ 
4.3.2.6 Etoposide......................................................................................... 
4.3.2.7 Ifosfamide ........................................................................................ 
4.3.2.8 High-Dose Methotrexate (HD MTX) and Leucovorin Rescue ........ 
4.3.2.9 Intrathecal Methotrexate / Triple Intrathecal Therapy .................. 
4.3.2.10 PO Methotrexate (MTX) and 6-Mercaptopurine (MP) ................ 
4.3.2.11 Steroids (Dexamethasone and Prednisone) .................................. 
4.3.2.12 Thioguanine .................................................................................. 
4.3.2.13 Vincristine ..................................................................................... 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Physical Examination .............................................................................. 
5.3.2 Laboratory Test Assessments ................................................................... 
5.3.2.1 Serum Hematology Tests................................................................. 
5.3.2.2 Serum Chemistry Tests .................................................................... 
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5.3.2.3 CSF examination ............................................................................. 
5.3.2.4 Pregnancy Test................................................................................ 
5.3.3 Long-term Growth and Development and Bone Mineral Content ........... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.4.1.1 Bone Marrow Assessment ............................................................... 
5.4.2 Secondary Efficacy Assessments .............................................................. 
5.4.2.1 Overall Survival and Secondary Malignancy ................................. 
5.4.3 Mutation Analysis .................................................................................... 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.6 Pharmacodynamics Assessments ...................................................................... 
5.7 Pharmacogenomic/Pharmacogenetic Assessments ........................................... 
5.8 Outcomes Research Assessments ..................................................................... 
5.9 Other Assessments ............................................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Abnormalities ......................................................................... 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoint Definitions ......................................................................................... 
8.3.1 Primary Endpoint..................................................................................... 
8.3.2 Secondary Endpoints ............................................................................... 
8.3.2.1 Safety and Feasibility ...................................................................... 
8.3.2.2 Event Free Survival (EFS) .............................................................. 
8.3.2.3 Minimal Residual Disease (MRD) .................................................. 
8.3.2.4 Complete Remission Rate ............................................................... 
8.3.2.5 BCR-ABL Mutation ......................................................................... 
8.3.3 Exploratory Endpoints ............................................................................. 
 
 
 
 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Event Free Survival (EFS) .............................................................. 
 
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8.4.2.3 Complete Remission Rate ............................................................... 
 
8.4.2.5 Mutation Analysis ........................................................................... 
 
8.4.3 Safety Analyses......................................................................................... 
8.4.3.1 Growth and development and bone mineral content ...................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Pharmacodynamic Analyses .................................................................... 
8.4.6 Pharmacogenomic Analyses .................................................................... 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.8 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 MONITORING OF MTX SERUM LEVELS AND 
INTENSIFICATION OF LCV RESCUE BASED ON ESPHALL PRACTICES . 
APPENDIX 2 HD-MTX INFUSION AND RESCUE GUIDELINES AND FLOW 
CHART BASED ON COG PRACTICES .............................................................. 
APPENDIX 3 MEDICATIONS WHICH MAY CAUSE QTC PROLONGATION 
AND TORSADE DE POINTES (NOT ALL INCLUSIVE) .................................. 
APPENDIX 4 COMMON CYP3A4 SUBSTRATES (NOT ALL INCLUSIVE) ........ 
APPENDIX 5 COMMON CYP3A4 INHIBITORS (NOT ALL INCLUSIVE) .......... 
APPENDIX 6 COMMON CYP3A4 INDUCERS (NOT ALL INCLUSIVE) ............. 
APPENDIX 7 DEFINITIONS OF TANNER STAGES .............................................. 
APPENDIX 8 FOR PERFORMANCE STATUS SCALES ........................................ 
APPENDIX 9 DASATINIB DISPERSED TABLET DOSING INSTRUCTIONS..... 
APPENDIX 10 DEFINITION OF CNS LEUKEMIA AT DIAGNOSIS .................... 
APPENDIX 11 EXAMPLE INDUCTION THERAPIES PHASE IA ......................... 
APPENDIX 12 OPTIONAL SUPPORTIVE TREATMENT GUIDELINES.............. 
APPENDIX 13 DASATINIB ORAL SUSPENSION RECONSTITUTION 
INSTRUCTIONS .................................................................................................... 
APPENDIX 14 DASATINIB ORAL SUSPENSION DOSING ADMINISTRATION
................................................................................................................................. 
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1.2
Research Hypothesis 
Dasatinib added to chemotherapy will demonstrate a superior 3-year event free survival (EFS)
rate compared to chemotherapy alone in the external historical control trial Associazione Italiana 
di Ematologia Pediatrica - Berlin-Frankfurt-Muenster ALL 2000 (AIEOP-BFM 2000) and 
non-inferior 3-year EFS compared to continuous imatinib added to chemotherapy in the external 
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historical control trial of the amended European intergroup Study on post induction treatment of 
Philadelphia positive Acute Lymphoblastic Leukemia (EsPhALL).
1.3
Objectives
1.3.1
Primary Objective
The primary analysis will compare the 3-year EFS of dasatinib plus chemotherapy with external 
historical controls in hierarchical order. The trial will be considered positive if at least the first 
two comparisons are statistically significant. The comparisons will be as follows:
1) Superiority over chemotherapy alone of AIEOP-BFM 2000
2) Non-inferiority to continuous imatinib plus chemotherapy of the amended EsPhALL trial
3) Superiority over continuous imatinib plus chemotherapy of the amended EsPhALL trial
1.3.2
Secondary Objectives
The key secondary objectives are to determine: 
1. The safety and feasibility of dasatinib added to standard chemotherapy 
2. Estimate the EFS of dasatinib plus chemotherapy (including 3 and 5-year rates)
3. Complete remission rates (< 5% blasts in bone marrow and no peripheral blasts) at end of 
induction compared with AIEOP BFM 2000 and the Amended EsPhALL trials 
Other secondary objectives are to estimate:
1. The difference in 3-year EFS rate with the 3-year EFS rate of available historical controls 
such as the COG AALL0031 study
2. MRD levels (defined by PCR detection of clone-specific immunoglobulin and T-cell receptor 
gene rearrangements)
3. BCR-ABL mutation status at baseline and time of disease progression or relapse
1.3.3
Exploratory Objectives
 
 
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1.4
Product Development Background
Detailed background information on preclinical pharmacology, preclinical pharmacokinetics, 
preclinical toxicology, and clinical studies of dasatinib may be found in the dasatinib Investigator 
Brochure 1026.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonization (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s).
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials/process 
(eg, advertisements), and any other written information to be provided to subjects. The 
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investigator or sponsor should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling, information to be provided to subjects and any updates. 
The investigator or sponsor should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent/Assent
Investigators must ensure that subjects, or, in those situations where consent cannot be given by 
subjects, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent and assent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent and assent forms will adhere to the
ethical principles that have their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent and assent forms and written information about the study in 
the language in which the subject is most proficient prior to clinical study participation. 
The language must be non-technical and easily understood. 
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study
3) Obtain an informed consent and assent signed and personally dated by the subject or the 
subject's legally acceptable representative and by the person who conducted the informed 
consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
and assent form and any other information to be provided to the subjects, prior to the 
beginning of the study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or 
legal guardian, and the subject subsequently becomes capable of making and 
communicating their informed consent during the study, then consent must additionally 
be obtained from the subject.
6) Revise the informed consent and assent whenever important new information becomes 
available that is relevant to the subject's consent. The investigator, or a person designated 
by the investigator, should fully inform the subject or the subject's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. 
This communication should be documented. 
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
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For minors, according to local legislation, one or both parents or a legally acceptable 
representative must be informed of the study procedures and must sign the informed consent 
form approved for the study prior to clinical study participation. The explicit wish of a minor 
who is capable of forming an opinion and assessing this information to refuse participation in, or 
to be withdrawn from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
Children and adolescents with newly diagnosed Ph+ ALL will be eligible for this open-label, 
single-arm study and will receive dasatinib added to successive blocks of standard multiagent 
chemotherapy (AIEOP-BFM ALL 2000 regimen)15 for a maximum duration of 2 years. The 
study sample size is at least 75 treated patients. 
Design
After diagnosis of acute lymphoblastic leukemia (ALL) via cytogenetics, FISH or PCR (via local 
laboratory), subjects will begin standard induction chemotherapy (Block IA). Since the diagnosis 
of ALL typically requires urgent treatment and it takes up to 10-14 days to determine which 
patients have Philadelphia chromosome positive (Ph+) ALL, frontline induction chemotherapy 
(Block IA) will start prior to enrollment in this trial (approximately 2 weeks) and will be based 
upon the investigator’s institutional standard of care. Enrollment on this study will occur prior to 
day 15 of Induction Block IA. At day 15, dasatinib treatment shall begin and continue without 
planned interruption until the completion of therapy (102 weeks). 
Subjects who meet pre-defined criteria at specific time points in treatment may receive a 
hematopoietic stem cell transplant (HSCT). Subjects will have the option to receive 12 additional 
months of post-HSCT dasatinib (not mandatory). Subjects with CNS3 disease at diagnosis will 
receive cranial irradiation during the Interim Maintenance period. 
A schematic of the study design is shown in Figure 3.1.
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Figure 3.1:
Schematic Study Design
The components of treatment are divided into blocks as follows:

Induction IA (4 - 5 weeks)

Induction IB (28 days, 4 weeks)

Recovery period (Dasatinib continues, No chemotherapy given) (2 - 4 weeks)

Consolidation blocks 1, 2, and 3 (21 days, 3 weeks each)

Reinduction block 1, including phase IIa and IIb (63 days, 9 weeks)

Interim maintenance (29 days, 4 weeks)

Reinduction block 2 (63 days, 9 weeks)

Continuation therapy (62 weeks) 
Subjects who meet pre-defined MRD criteria prior to the start of the first consolidation block 
(HR1) or after the completion of the third consolidation block (HR3) of chemotherapy and have 
a genotype-matched donor (9/10 or 10/10) will receive a hematopoietic stem cell transplant 
(HSCT) instead of continuing the AIEOP-BFM ALL 2000 regimen. The timing of HSCT would 
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be following the consolidation block 3 (HR3). Subjects should continue on protocol specified 
chemotherapy until HSCT. If alternative chemotherapy is preferred, the subject must be 
discontinued from the study treatment but must continue to be followed per protocol for the long 
term growth assessments. If a subject goes off-treatment to receive a different chemotherapy, 
dasatinib will no longer be provided via this study. Subjects who do not meet the HSCT criteria 
are not recommended to receive HSCT. During the HSCT, subjects will not receive dasatinib. 
Following adequate engraftment of the HSCT, the use of dasatinib is optional at the discretion of 
the treating investigator. Subjects may receive 12 additional months of post-HSCT dasatinib See 
section 4.3.1.11 for additional details. Criteria for HSCT eligibility will be based on MRD 
response at key early timepoints in therapy. MRD will be assessed by quantitative polymerase 
chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes according to 
standardized criteria46. For subjects with uninformative PCR for Ig/TCR gene rearrangement 
known at baseline, RQ-PCR for BCR-ABL fusion transcripts or flow cytometry will be 
substituted (see section 4.3.1.11).
Key criteria for HSCT include:
1) MRD at end of IB/start of consolidation block 1 (HR1) ≥0.05% (5 x 10-4) as 
measured by Ig/TCR PCR
a.
For subjects that do not have informative results of Ig/TCR PCR, see 
section 4.3.1.11.
OR
2) MRD at end of IB/start of consolidation block 1 (HR1) 0.005-0.05% (5 x 10-5 to 5 x 
10-4)* as measured by Ig/TCR PCR and MRD at end of consolidation block 3 
(HR3)/start of reinduction block 1 remains positive at any detectable level (providing 
the assay limit is at least 0.1%).
*This includes if MRD at end of IB is positive but less than the quantifiable 
range (POS<QR) with QR not at least 0.005% (5 x 10-5)
a.
For subjects that do not have informative results of Ig/TCR PCR, see section 
4.3.1.11.
Subjects with CNS3 disease at diagnosis will receive cranial irradiation during the Interim 
Maintenance period. Subjects with testicular involvement with Ph+ ALL will not be eligible for 
this trial as testicular radiation will not be part of the therapy (see Section 4.3.1.7).
Duration
The total duration of the trial will be approximately 6 years and includes an estimated 
recruitment period of 3 years and a minimum follow-up of 3 years for the primary and secondary 
endpoints. The 3 year recruitment period is based upon the average historical accrual rates in the 
pediatric Ph+ ALL population13, 47, 48. Three years of additional follow-up would ensure that all 
subjects have sufficient follow-up to assess the primary and secondary endpoints. Subjects 
recruited near the beginning of the accrual period would have up to 6 years of follow-up while 
subjects recruited near the end of accrual would have at least 3 years of follow-up. Subjects who 
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remain in follow-up beyond the study duration of 6 years would enter an extension phase of the 
protocol and continue receiving long-term follow-up to assess exploratory endpoints.
Individual subjects will have up to 7 years of follow-up in this study, including the time during 
treatment. The total intended duration of treatment (including chemotherapy and dasatinib) will 
be approximately 104 weeks (2 years). Subjects will be followed (including time on treatment) 
for at least 3 years for event-free survival and other secondary endpoints, 5 years for overall 
survival and 7 years (2 years of treatment + 5 years after completion of treatment) for 
 
 and other exploratory endpoints. 
3.2
Post Study Access to Therapy
At the end of the treatment period, the sponsor will not continue to supply study drug to 
subjects/investigators unless the sponsor chooses to extend the study. The investigator should 
ensure that the subject receives appropriate standard of care to treat the condition under study.
It is expected that subjects who complete the full 104 weeks of treatment will be considered in a 
complete continuous remission. The use of dasatinib after transplanation is optional in subjects 
who complete HSCT at the discretion of the treating investigator. Additional dasatinib may be 
given for up to 12 months post-HSCT. 
3.3
Study Population
The intended population is children and adolescents with newly diagnosed Ph+ ALL who are 
candidate for standard multiagent chemotherapy (AIEOP-BFM ALL 2000 regimen).
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1) Signed Written Informed Consent
a.
Written informed consent from subject or from parents or legal guardians for minor 
subjects must be obtained according to local law and regulation. Assent should be 
obtained according to local law and regulation and if the child is mentally capable.
2) Target Population
a.
Philadelphia chromosome-positive ALL
i.
Documented presence of t(9;22) determined by cytogenetics or BCR-ABL fusion 
via RT-PCR or FISH (local laboratory)
b. Induction chemotherapy approximately 14 days according to institutional standard of 
care
c.
Performance status 60% (See Appendix 8)
i.
Karnofsky for patients >16 years of age and Lansky for patients younger 
1-16 years of age.
d. Adequate Liver Function defined as (See Table 5.1A for timing of assessments):
i.
Direct bilirubin 3 times the upper limit of normal (ULN) for age
ii.
ALT and AST 10 times the upper limit of normal (ULN) for age
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e.
Adequate Renal Function defined as (See Table 5.1A for timing of assessments):
i.
Serum creatinine 1.5 times the institutional upper limit of normal for age/gender 
or creatinine clearance or GFR 80 ml/min/1.73m2
f.
Adequate Cardiac Function defined as (See Table 5.1A for timing of assessments):
i.
QTc < 450 msec on baseline electrocardiogram as measured by the Frederica or 
Bazett formula (must be performed within 21 days prior to study enrollment)
ii.
LVEF 50% by gated radionuclide study/echocardiogram or shortening fraction 
27% by echocardiogram (not required to be repeated if performed prior to 
induction).
g. For COG sites (excluding DFCI Consortium sites), subjects must be enrolled in the COG 
Classification Trial (AALL08B1 or successor).
3) Age and Reproductive Status
a.
Males and females, Age > 1 year (365 days) and < 18 (17 years and 364 days) years at 
diagnosis
b. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of the study drug.
c.
Women must not be breastfeeding.
d. Sexually active WOCBP must agree to follow instructions for method(s) of contraception 
starting at the time of enrollment for the duration of treatment with study drug dasatinib 
plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment 
completion.
e.
Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug dasatinib plus 
90 days (duration of sperm turnover) for a total of 90 days post-treatment completion.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP 
on the use of highly effective methods of contraception. Highly effective methods of 
contraception have a failure rate of < 1% per year when used consistently and correctly.
At a minimum, sexually active WOCBP must agree to the use of two methods of 
contraception, with one method being highly effective and the other method being either 
highly effective or less effective as listed below:
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HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 

Male condoms with spermicide

Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena®
by WOCBP subject or male subject’s WOCBP partner.

Nonhormonal IUDs, such as ParaGard

Tubal ligation 

Vasectomy.

Complete Abstinence*
*Complete abstinence, defined as complete avoidance of heterosexual intercourse, is an 
acceptable form of contraception for all study drugs. Female subjects who choose complete 
abstinence are not required to use a second method of contraception, but female subjects must 
continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception 
must be used in the event that the subject chooses to forego complete abstinence
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal sponge

Progestin only pills by WOCBP subject or male subject’s WOCBP partner

Male condom without spermicide

Female condom*

* A male and female condom must not be used together
f.
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However the WOCBP must still undergo 
pregnancy testing as described in these sections.
3.3.2
Exclusion Criteria
1) Target Disease Exceptions 
a.
Prior treatment with a BCR-ABL inhibitor (eg. imatinib) 
b. Biopsy proven Ph+ ALL extramedullary involvement of the testicles
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2) Medical History and Concurrent Diseases 
a.
Active systemic infection in conjunction with septic shock syndrome that require either 
vasopressor support or mechanical ventillation. Other infections, resulting in delay of 
standard chemotherapy until resolution, would not exclude the subject.
b. Known clinically-significant disorder of platelet function (eg von Willebrand’s disease) 
c.
Clinically significant cardiovascular disease including ANY one of the following: 
i.
Congenital long QT syndrome
ii.
History of ventricular arrhythmias or heart block
d. Down syndrome (constitutional trisomy 21)
e.
Prior stem cell transplant
f.
Ph+ ALL occurring as a second malignant neoplasm after treatment of a prior 
malignancy
3) Allergies and Adverse Drug Reaction
a.
Subjects who have experienced hypersensitivity to any of the excipients in dasatinib 
tablets including: lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hydroxypropyl cellulose, magnesium stearate, hypromellose, titanium dioxide, 
and polyethylene glycol.
4) Sex and Reproductive Status
a.
Patients who are pregnant or breastfeeding or likely to become pregnant.
b. Men whose partner is unwilling or unable to avoid pregnancy.
5) Other Exclusion Criteria
a.
Prisoners or subjects who are involuntarily incarcerated 
b. Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and to ensure that the results of the study can be used. It is imperative that subjects fully 
meet all eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) includes any female who has experienced menarche 
and who has not undergone successful surgical sterilization (hysterectomy, or bilateral 
oophorectomy) or is not postmenopausal. 
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3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
3.4.1.1
Prohibited Treatments:
Prohibited treatments should not be used concomitantly with trial therapy and will constitute a 
relevant protocol deviation as one that can have a major impact on the interpretation of the trial. 
No other therapy for the treatment of Ph+ ALL other than the AIEOP-BFM ALL 2000 
chemotherapy regimen, HSCT (including preparative regimen) and dasatinib are allowed during 
the treatment phase of the trial. Subjects in follow-up after treatment discontinuation may receive 
additional treatment for relapsed ALL as medically indicated.
Medications associated with QT interval prolongation are prohibited. Please refer to the 
Appendix 3 for a website of “Drugs with Risk of Torsades de Points.” This list includes:

quinidine, procainamide, disopyramide

amiodarone, sotalol, ibutilide, dofetilide

erythromycins, clarithromycin, azithromycin

chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, 
levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
3.4.1.2
Restricted Treatments:
Restricted medications should be limited as concomitant medications during protocol therapy. 
These medications may create drug-drug interactions. These medications are allowed but must 
be prescribed with caution and with careful management of potential drug-drug interactions. Use 
of restricted medications will not be considered a protocol deviation. 
Caution should be exercised if subjects are required to take medications that inhibit platelet 
function or anticoagulants. Antiplatelet agents or anticoagulants should be avoided in the setting 
of Grade 3 or 4 thrombocytopenia. If a subject requires anticoagulation for treatment of a 
thrombus, the platelet count should be adequately maintained to minimize the risk of bleeding.
Ideally, subjects enrolled in this study should not take other medications known to prolong the 
QT interval. Reference to a list of medications known to prolong the QT interval is found in 
Appendix 3. While “Drugs with Risk of Torsades de Points” are prohibited, “Drugs with a 
Possible Risk or Conditional Risk of Torsades de Points” may be given concomitantly should the 
investigator believe that beginning therapy with a potentially QT prolonging medication (other 
than the ones explicitly prohibited) is vital to an individual subject’s care. Additional ECG(s) 
will be done at the investigator’s discretion to ensure the subject’s safety. If such a medication is 
considered important to a subject’s care, the situation should be discussed with the Study 
Director.
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Caution is warranted when administering dasatinib to subjects taking drugs that are highly 
dependent on CYP3A4 for metabolism and have a narrow therapeutic index. See Appendix 4 for 
a list of common CYP3A4 substrates with a narrow therapeutic index. Systemic exposures to 
these medications could be increased while receiving dasatinib49. 
Additionally strong to moderate CYP3A4 inhibitors
(eg, ketoconazole, itraconazole, 
erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin) may significantly increase concentrations of dasatinib and should be used with 
caution when administered concurrently with dasatinib. Strong to moderate CYP3A4 inducers
(eg, rifampicin) may decrease the concentration of dasatinib and should be used with caution 
when administered concurrently with dasatinib. See Appendix 5 and 6 for a list of CYP3A4 
inhibitors and inducers respectively.
Dasatinib may have decreased solubility and absorption at pH > 4. Subjects should avoid 
concomitant use of proton pump inhibitors or H2 antagonists. In a population of 13 subjects, 
Cmax and AUC were reduced by 42% and 46%, respectively when a single dose of dasatinib 
100 mg once daily was administered in the presence of 40 mg omeprazole compared to dasatinib 
alone, although there was significant intrapatient variability. If proton pump inhibitors or H2 
antagonist administration is considered in the best interest of the subject (eg during high dose 
corticosteroid administration), they may be used. However, based upon the high interpatient 
variability of dasatinib pharmacokinetics, some subjects may have a reduction and some subjects 
may have no reduction in the plasma concentration of dasatinib when concomitantly taken with 
these agents. Short-acting antacid agents (eg aluminum or magnesium hydroxide) may be 
administered without affecting dasatinib pharmacokinetics, but not within 2 hours of the 
dasatinib dose. 
3.4.2
Other Restrictions and Precautions
Based on pre-clinical data and clinical data, dasatinib might increase the likelihood of bleeding. 
Hence, subjects undergoing surgical procedures, including dental procedures should be 
instructed to inform their doctors of this potential increased risk.
3.4.3
Supportive Care Guidelines
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive 
care are to be used as medically indicated.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and noninvestigational product at the 
discretion of the investigator) for any of the following reasons:

Withdrawal of informed consent (subject’s decision to withdraw for any reason)

Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject
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
Pregnancy

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Unacceptable toxicity despite dose modifications as per Section 4.3.1

The subject has an event (see Section 8.3.1) including: 1) lack of response by the completion 
of consolidation block 3 (HR3), 2) relapse at any site, 3) development of second malignancy, 
and 4) death without relapse.
All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in Section 5. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page.
4
TREATMENTS
All protocol-specified investigational and noninvestigational products are considered study drug.
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4.1
Study Treatments
Table 4.1:
Product Description: Open Label
Product Description 
and Dosage Form
Potency
Primary Packaging
(Volume)/ Label Type
Secondary Packaging
(Qty) /Label Type
Appearance
Storage Conditions
(per label)
Dasatinib Tablet
20 mg
30 tablets per bottle / 
open label
NA
film coated tablets, 
biconvex, round, white 
to off-white in 
appearance with “20” 
or “BMS”debossed on 
one side and “527” on 
the other side
15°C - 25°C 
(59°F - 77°F) 
Dasatinib Tablet
50 mg
30 tablets per bottle / 
open label
NA
film coated tablets, 
biconvex, oval, white 
to off-white in 
appearance with “50” 
or “BMS” debossed on 
one side and “528” on 
the other side
15°C - 25°C 
(59°F - 77°F) 
Dasatinib Tablet
5 mg
30 tablets per bottle / 
open label
NA
film coated tablets, 
plain, round, white in 
appearance.
15°C - 25°C 
(59°F - 77°F) 
Dasatinib Powder for 
Oral Suspension
10 mg/ml in suspension
33 grams Dasatinib 
blend per bottle 
(990mg Dasatinib per 
bottle)
90 mL bottle volume
White to off-white 
powder that may 
contain lumps which 
forms a white to off-
white opaque 
suspension
15°C - 25°C 
(59°F - 77°F)
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4.1.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as follows:
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical study, including products already with a marketing authorization but used or assembled 
(formulated or packaged) in a way different from the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational product(s) is/are: 

Dasatinib 
This medication will be provided by Bristol-Myers Squibb. See Table 4.1.
Dasatinib will be delivered as a tablet, as an oral dispersed tablet or as an oral suspension from a 
powder (Powder for oral suspension (PFOS). For children and adolescents capable of 
swallowing tablets, the existing tablets, in strengths of 5, 20 and 50 mg, are considered a suitable 
pharmaceutical form and sufficient to cover the anticipated dose range. For children not able to 
swallow tablets, the dispersed tablet or powder for oral suspension are suitable alternatives. 
Dasatinib tablets may be dispersed in 100% preservative free juice (ie, orange or apple juice or 
lemonade). Complete details of the dispersion procedures can be found in Appendix 9. Once 
constituted with purified water, the PFOS has a mixed berry flavor. The PFOS bottle contains 
33 grams of Dasatinib blend (containing 990mg active Dasatinib API). The site constitutes with 
77 ml Purified water or Sterile Water for Injection. This generates a total volume of 99ml. The 
bottle is labeled for 90ml to assume a 10% overage. Once constituted, the Dasatinib suspension 
is 10mg/ml. Complete details for the preparation of the PFOS can be found in Appendices 13 
and 14. These same preparations may be used for administration via a nasogastric or g-tube.
It is not recommended to use a gel-cap to facilitate administration of the tablet as it is unknown if 
the gel-cap will alter the pharmacokinetics of the investigational product. 
If the subject vomits after administration of the dasatinib tablet, the subject should not be redosed 
unless the tablet was still intact.
4.1.2
Noninvestigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as noninvestigational products. 
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This study utilizes the standard Associazione Italiana di
Ematologia Pediatrica -
Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 chemotherapeutic protocol50.
In this protocol, noninvestigational product(s) are listed in Table 4.1.2 below by block of 
therapy. Chemotherapy will be obtained by the investigating site’s standard prescribing 
procedures according to country availability and specific regulatory requirements. 
Table 4.1.2:
Non-investigational Products
Phase
Chemotherapy 
Regimen
Phase
Chemotherapy Regimen
1.
Induction Block IB
Cyclophosphamide
Mercaptopurine 
Cytarabine
Methotrexate
5)
1st Reinduction Block 
(R1)
Dexamethasone
Vincristine 
Doxorubicin
L-Asparaginase
Cyclophosphamide
Cytarabine 
Thioguanine 
Methotrexate
2.
High Risk Block 1 
(HR1)
Dexamethasone
Vincristine
Methotrexate
Leucovorin
Cytarabine
Hydrocortisone
Cyclophosphamide
L-Asparaginase
6)
Interim 
Maintenance 
(IM)
Mercaptopurine
Methotrexate
3.
High Risk Block #2 
(HR2)
Dexamethasone
Vincristine
Methotrexate
Leucovorin
Ifosfamide 
Cytarabine
Hydrocortisone 
Daunorubicin
L-Asparaginase
7)
2nd Reinduction Block 
(R2)
Dexamethasone
Vincristine
Doxorubicin
L-Asparaginase
Cyclophosphamide
Cytarabine
Thioguanine
Methotrexate
4.
High Risk Block #3 
(HR3)
Dexamethasone
Cytarabine
Etoposide
L-Asparaginase
Methotrexate
Hydrocortisone
8)
Continuation Therapy
Mercaptopurine
Methotrexate
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the sponsor. If 
concerns regarding the quality or appearance of the study drug arise, do not dispense the study 
drug and contact the sponsor immediately.
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Dasatinib
4.2
Method of Assigning Subject Identification
After informed consent and subject assent has been obtained as per local guidelines, the patient 
must be enrolled into the study by calling an interactive voice response system (IVRS) to obtain 
the subject number. Instructions on the use of the IVRS will be provided to the study site.
4.3
Selection and Timing of Dose for Each Subject
The summary of the treatment plan is shown below in Figure 4.3 and Table 4.3A. Subjects will 
receive up to 24 months of treatment during this trial. Since subjects with Ph+ ALL often 
experience delays in treatment due to toxicities associated with therapy, delays in starting 
treatment blocks are expected. Therefore, all start dates for the initiation of all treatment blocks 
are estimates, and should not be considered as strict requirements.
As patients newly diagnosed with Ph+ ALL require urgent treatment, initial therapy for their 
disease will start outside the protocol with a chemotherapy regimen that is standard at the 
investigative center (referred to as induction therapy IA). Dasatinib (IMP) at a dose of 60 mg/m2
once daily will be introduced on day +15 from initiation of treatment or no later than when the 
day 15 induction chemotherapy is administered in all subjects in addition to ongoing 
chemotherapy (approximately until day + 29 to 33). From the start of induction therapy IB, all 
subjects will follow the same treatment plan shown in Table 4.3A. A key for abbreviations is 
found at the end of the table. If commercial shortages of protocol specified chemotherapy agents 
occur then sites are to use their best clinical judgment in consultation with the BMS Medical 
Monitor regarding an appropriate substitution. A summary of hematological counts prior to the 
start of each block of therapy is presented in Table 4.3B.
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CA180372
BMS-354825
Dasatinib
Figure 4.3:
Treatment Plan Summary
Table 4.3A:
Treatment Plan Summary
Phase
Drug/Administration 
Route
Dose
Day
Induction Therapy 
Phase IA
(Until Day 29 - 33)
All patients will receive 
first induction according to 
institutional standard of 
care.
Dasatinib/po
60 mg/m2 once daily
Start day 15 from beginning 
of IA or no later than when 
the day 15 induction 
chemotherapy is 
administered Continuously
Induction Therapy 
Phase IB
Starts no sooner than day 
33
Dasatinib/po
60 mg/m2 once daily
Continuously
CPM/iv (1h)
1000 mg/m2
1, 28
6-MP/po
60 mg/m2/d
1-28
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Dasatinib
Table 4.3A:
Treatment Plan Summary
Phase
Drug/Administration 
Route
Dose
Day
(Phase lasts 28 days)
ARA-C/iv or sc
75 mg/m2/d
3-6, 10-13, 17-20, 24-27
MTX/it
Dose by age
(Table 4.3.1.2)
3, 17
Recovery period (Dasatinib continues, No chemotherapy given) (2 - 4 weeks)
Eligible for hematopoietic Stem Cell Transplant if MRD at end of IB/start of consolidation block 1 0.05% (see 
section 4.3.1.11 for subjects know to have uninformative PCR for Ig/TCR gene rearrangement assessment)
Consolidation Block 1 
(HR-1)
Starts when ANC 500/l 
(0.5 x 109/L) and 
platelets 50,000/l (50 
x 109/L) (Day 78 of 
therapy). 
HR-1 lasts 21 days. 
Dasatinib/po
60 mg/m2 once daily
Continuously
DEXA/po or iv
20 mg/m2/d
1-5
MTX/it
ARA-C/it
HC/it
Dose by age
(Table 4.3.1.3)
1
HD-MTX/iv (24h)
5 g/m2
1
CF-Rescue/iv or po
Levo Form: 
7.5 mg/m2 (not 
available in U.S.)
Racemic form: 
15 mg/m2
42, 48, 54 h after start of 
HD-MTX
VCR/iv
1.5 mg/m2/d
(max 2 mg)
2, 6
CPM/iv (1h)
200 mg/m2
(q12h x 5)
2-4
HD-ARA-C/iv (3h)
2 g/m2 (q12h x 2)
5
ASP/iv (1-2h) or im
Dose based on 
preparation 
(Section 4.3.1.3)
6
G-CSF/sc or iv
5 ug/kg/day or 
pegfilgrastim 100 
µg/kg s.c given once
Start anytime between day 7-
11 until WBC > 3000 mm3
Consolidation Block 2 
(HR-2)
Starts when ANC 500/l 
(0.5 x 109/L) and 
platelets 50,000/l (50 
Dasatinib/po
60 mg/m2 once daily
Continuously
DEXA/po or iv
20 mg/m2/d
1-5
MTX/it
ARA-C/it
HC/it
Dose by age
(Table 4.3.1.4)
1
HD-MTX/iv (24h)
5 g/m2
1
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CA180372
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Dasatinib
Table 4.3A:
Treatment Plan Summary
Phase
Drug/Administration 
Route
Dose
Day
x 109/L) 
HR-2 lasts 21 days.
CF-Rescue/iv or po
Levo Form: 
7.5 mg/m2 (not 
available in U.S.)
Racemic form: 
15 mg/m2
42, 48, 54 h after start of 
HD-MTX
VCR/iv
1.5mg/m2
(max 2 mg)
2, 6
IFO/iv (1h)
800 mg/m2
(q12h x 5)
2-4
DNR/iv (24h)
30 mg/m2
5
ASP/iv (1-2h) or im
Dose based on 
preparation
(Section 4.3.1.5)
6
G-CSF/sc or iv
5 ug/kg/day or 
pegfilgrastim 100 
µg/kg s.c given once
Start anytime between day 7-
11 until WBC > 3000 mm3
Consolidation Block 3 
(HR-3)
Starts when ANC 500/l 
(0.5 x 109/L) and 
platelets 50,000/l (50 
x 109/L) 
HR-3 last 21 days.
Dasatinib/po
60 mg/m2 once daily
Continuously
DEXA/po or iv
20 mg/m2/d
1-5
HD-ARA-C/iv (3h)
2 g/m2 x 4 (q12h x 
4)
1, 2
Etop/iv (1h)
100 mg/m2
(q12h x 5)
3-5
MTX/it
ARA-C/it
HC/it
Dose by age
(Table 4.3.1.5)
5
ASP/iv (1-2h) or im
Dose based on 
preparation
(Section 4.3.1.5)
6
G-CSF/sc iv
5 ug/kg/day or 
pegfilgrastim 100 
µg/kg s.c given once
Start anytime between day 7-
11 until WBC > 3000mm3
Eligible for hematopoietic Stem Cell Transplant if MRD at end of IB/start of consolidation block 1 (HR1) 
0.005-0.05% by Ig/TCR PCR and MRD at end of consolidation block 3 (HR3)/start of reinduction block 1 
remains positive at any detectable level (providing the assay limit is at least 0.1%). (see section 4.3.1.11 for 
subjects known to have uninformative PCR for Ig/TCR gene rearrangement assessment)
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CA180372
BMS-354825
Dasatinib
Table 4.3A:
Treatment Plan Summary
Phase
Drug/Administration 
Route
Dose
Day
1st Reinduction (Protocol 
II) 
Protocol IIa (days 1-35)
Protocol IIb (days ~36-63)
1st Reinduction starts after 
completion of HR-3 and 
lasts 63 days.
Starts when ANC 
(500/l; 0.5 x 109/L) 
and platelet counts (
50,000/l; 50 x 109/L)
Dasatinib/po
60 mg/m2 once daily
Continuously
DEXA/po
10 mg/m2/d
1-7, 15-21
MTX/it
Dose by age
(Table 4.3.1.6)
1, 38, 45
VCR/iv
1.5 mg/m2
(max 2 mg)
8, 15, 22, 29
DOX/ADR/iv (1h)
25 mg/m2
8, 15, 22, 29
ASP/iv (1-2h) or im
Dose based on 
preparation
(Section 4.3.1.6)
Schedule base on preparation
CPM/iv (1h)
1000 mg/m2
36
ARA-C/sc or iv
75 mg/m2/d
38-41, 45-48
6-TG/po
60 mg/m2/d
36-49
Interim Maintenance
This phase starts after 
completion of the 1st
Reinduction and lasts 
29 days.
Starts when ANC 
(750/l; 0.75 x 109/L) 
and platelet counts 
(75,000/l; 75 x 109/L)
Dasatinib/po
60 mg/m2 once daily
Continuously
6-MP/po
50 mg/m2/d
1-28
MTX/po
20 mg/m2
1, 8, 15, 22
Cranial irradiation
18Gy
CNS3 Only
2nd Reinduction 
Protocol IIa (days 1-35)
Protocol IIb (days ~36-63)
This phase starts 
immediately after Interim 
Maintenance and lasts 
63 days.
Starts when ANC 
(500/l; 0.5 x 109/L) 
and platelet counts 
(50,000/l; 50 x 109/L)
Dasatinib/po
60 mg/m2 once daily
Continuously
DEXA/po
10 mg/m2/d
1-7, 15-21
MTX/it
(Omit in CNS3 given 
cranial irradiation)
Dose by age
(Table 4.3.1.8)
1, 38, 45
VCR/iv
1.5 mg/m2
(max 2 mg)
8, 15, 22, 29
DOX/ADR/iv (1h)
25 mg/m2
8, 15, 22, 29
ASP/iv (1-2h) or im
Dose based on 
preparation
(Section 4.3.1.8)
Schedule base on preparation
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Clinical Protocol
CA180372
BMS-354825
Dasatinib
Table 4.3A:
Treatment Plan Summary
Phase
Drug/Administration 
Route
Dose
Day
CPM/iv (1h)
1000 mg/m2
36
ARA-C/sc or iv
75 mg/m2/d
38-41, 45-48
6-TG/po
60 mg/m2/d
36-49
Continuation Therapy
Starts after completion of 
the 2nd reinduction and 
continues for 
approximately 62 weeks 
(until a total of 2 years 
treatment is complete).
Starts when ANC 
(750/l; 0.75 x 109/L) 
and platelet counts 
(75,000/l; 75 x 109/L)
6-MP/po
50 mg/m2/d
Daily
MTX/po
20 mg/m2 weekly
Weekly
MTX/it
(Omit in CNS3 given 
cranial irradiation)
Dose by age
(Table 4.3.1.8)
Every 6 weeks
x 6 doses
Dasatinib/po
60 mg/m2 once daily
Continuously
CPM = cyclophosphamide, ARA-C = cytosine arabinoside, 6-MP = 6-mercaptopurine, MTX = methotrexate, DEXA 
= dexamethasone, VCR = vincristine, HD-ARA-C = high dose cytosine arabinoside, HD-MTX = high dose 
methotrexate, CF = citrovorum factor (folinic acid, calcium folinate, or leucovorin), ASP = asparaginase, G-CSF = 
granulocyte-colony stimulating factor, DNR = daunorubicin, IFO = ifosfamide, Etop= etoposide, DOX = 
doxorubicin, ADR = adriamycin, 6-TG = 6-thioguanine, HC = hydrocortisone, po = oral, iv = intravenous, sc = 
subcutaneous, it = intrathecal, im = intramuscular
Table 4.3B:
Hematological Criteria Prior to Each Treatment Block
Treatment block
Count criteria
Induction IA
None
Induction IB
ANC > 0.5 x 109/L and plt > 50 x 109/L
Consolidation blocks; HR1, HR2 and HR3
ANC > 0.5 x 109/L and plt > 50 x 109/L
First Reinduction IIa
ANC > 0.5 x 109/L and plt > 50 x 109/L
First Reinduction IIb
ANC > 0.5 x 109/L and plt > 50 x 109/L
Interim maintenance
ANC > 0.75 x 109/L and plt >75 x 109/L
Second Reinduction IIA
ANC > 0.5 x 109/L and plt > 50 x 109/L
Second Reinduction IIB
ANC > 0.5 x 109/L and plt > 50 x 109/L
Continuation
ANC > 0.75 x 109/L and plt >75 x 109/L
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CA180372
BMS-354825
Dasatinib
4.3.1
Full Treatment Plan
4.3.1.1
Induction Therapy Phase IA
All patients will receive the first induction according to the institutional standard of care. See 
Appendix 11 for examples of induction phase IA regimens.
Dasatinib 60 mg/m2 daily will be introduced on day 15 from the start of induction IA, or no later 
than when the day 15 chemotherapy is administered to accommodate any delays for toxicity or 
scheduling/logistics. Dasatinib will be given continuously until the end of therapy (2 years).
Dasatinib should only be interrupted for toxicity. Induction IA will last approximately 29 to 
33 days depending on the institutional standard of care. The dasatinib dose may be rounded up to 
the nearest 5 mg dose. The dasatinib dose will be recalculated based on BSA every 12 weeks, or 
more often if necessary.
4.3.1.2
Induction Therapy Phase IB
Pneumocystis 
(jirovecii) 
pneumonia 
(PCP) 
prophylaxis 
is 
recommended 
with 
trimethoprim/sulfamethoxazole, cotrimoxazole or other appropriate agent against Pneumocystis 
jirovecii according to the institutional standard of care. Note that pentamidine use is prohibited in 
this trial due to potential interaction with dasatinib (see Section 3.4.1.1)
Induction IB therapy should begin no sooner than day 33 or when parameters noted below are 
met.
Requirements for beginning of phase IB: 

Good general condition without serious infections; 

Creatinine level within normal limits according to age; 

ANC > 500/l (> 0.5 x 109/L); platelets > 50,000/l (> 50 x 109/L)
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
CYCLOPHOSPHAMIDE (CPM): 1000 mg/m2/dose i.v. (1 hour) days 1, 28. (There are no 
blood count requirements for the initiation of day 28 cyclophosphamide. Please see Appendix 12 
for optional hydration guidelines.
Please consider adequate anti-emetic supportive therapy according to standard institutional 
guidelines
6-MERCAPTOPURINE (6-MP): 60 mg/m2/day p.o., to be taken in the evening on an empty 
stomach (1 hour before or after dinner), not together with milk, days 1 - 28 (total 28 days). Once 
6-MP is started in this block it should continue, regardless of hematologic counts. If initiation of 
ARA-C cycle is delayed due to inadequate blood counts or the cycle is interrupted, then 6-MP 
should also be delayed/interrupted.
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CA180372
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Dasatinib
CYTOSINE ARABINOSIDE (ARA-C): 75 mg/m2/day s.c. or i.v. in one daily dose, days 3 - 6, 
10 - 13, 17 - 20, 24 - 27. 
The 4-day cycles that begin on days 10, 17, and 24 should be started when WBC > 500/μl 
(> 0.5 x 109/L) and platelets > 30,000/μl (>30 x 109/L); each cycle when started should not be 
stopped unless for acute infection (please consider that fever might be also induced by the drug).
Note: For the cycle starting on day 3, the WBC and platelet counts do not need to be rechecked if 
adequate to begin this Induction 1B block.
INTRATHECAL METHOTREXATE: days 3, 17 (start with the 4-day cycle of ARA-C in 
cycles 1 and 3), age-dosed: 
Table 4.3.1.2:
Intrathecal Methotrexate Therapy Dose by Age
AGE
Methotrexate
1 year < 2 years
8 mg
2 years < 3 years
10 mg
3 years
12 mg
4.3.1.3
Consolidation Block 1 (HR1)
If MRD at end of IB/start of consolidation block 1 (HR1) 0.05% (5 x 10-4) according to 
RQ-PCR of rearranged immunoglobulin/T-cell receptor genes, then see Section 4.3.1.11
regarding HSCT. See section 4.3.1.11 for subjects known to have uninformative PCR for 
Ig/TCR gene rearrangement assessment at baseline.
Consolidation therapy will start at least 14 days after the end of Phase IB, provided the patient is 
in good general condition and adequate ANC (500/l; 0.5 x 109/L) and platelet counts 
(50,000/l; 50 x 109/L) are documented (rising counts). Subjects must wait until day 78 even 
if their blood counts are adequate prior to day 78. Dasatinib administration will not be 
interrupted between the end of phase IB and the beginning of the first HR block. The interval 
between each block element should be no less than 21 days ( counting from day 1 of HR-1 
to day 1 of HR-2).
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
DEXAMETHASONE (DXM): 20 mg/m2/day p.o. or i.v. in 3 doses, days 1-5 (no tapering). See 
Section 3.4.1.2 regarding the use of proton pump inhibitors and H2 blockers.
VINCRISTINE (VCR): 1.5 mg/m2/day i.v. (max dose: 2 mg), day 2 and 6. (Dose may be 
administered via i.v. push over 1 minute, or infusion as per institutional standard of care) 
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Dasatinib
HIGH-DOSE METHOTREXATE (HD-MTX): 5 g/m2/dose i.v. over 24 hours on day 1 
(1/10 in 30 minutes, the remaining 9/10 in 23.5 hour-infusion ). Suggested hyperhydration: 
3,000 ml/m2 over 24 hours: Gluc. 5%(D5W)+ NaCl 0,45%+ 90 mEq/m2KCl+NaHCO3 
90 mEq/m2. Urine pH > 7.0 over the time of infusion. 
MTX dosing is based upon BSA and the dose should not be capped.
Serum levels of MTX must be determined at hours 24, 42, 48 from start of MTX infusion. For 
monitoring of MTX serum levels and intensification of LCV rescue, see Appendix 1 or 2.
Alternatively, the HD-MTX infusion guidelines in Appendix 2 may be followed in place of the 
above guidelines.
CITROVORUM FACTOR (CF) (Folinic acid, calcium folinate, or leucovorin): 7.5 mg/m2 
i.v (Levo form; levoleucovorin, not available in the U.S.) or 15 mg/m2 i.v or po (Racemic form; 
leucovorin) at hours 42, 48, and if needed 54 hours from start of HD-MTX. For monitoring of 
MTX serum levels and intensification of LCV rescue, see Appendix 1 or 2. 
Starting from hour 60, Citrovorum Factor is needed only if serum levels at hour 48 exceed 
0.5 μmol/l. In this case, see the nomogram for therapeutic adjustments (Appendix 1 or 2). 
CYCLOPHOSPHAMIDE (CPM): 200 mg/m2 i.v. in 1 hour q 12 hours x 5 doses, days 2-4. 
Start immediately after the completion of HD-MTX infusion. See Appendix 12 for optional 
MESNA guidelines. 
HIGH-DOSE ARA-C (HD-ARA-C): 2 g/m2/iv in 3-hour infusion, given every 12 hours for a 
total of 2 doses on day 5. The use of corticosteroid eye drops is suggested. 
HIGH-DOSE L-ASPARAGINASE (HD-L-ASP) or PEG-ASPARAGINASE (PEG-ASP):
First-line therapy consists of native E. coli asparaginase. If native E. coli asparaginase is not 
available or for centers in the United Kingdom (UK), Peg-asparaginase should be used as 
first-line therapy. 

E. coli (medac or Kidrolase or Elspar): 25,000 IU/m2/dose, over 2 hours i.v. or i.m., 3 hours 
after completion of the infusion of the second dose of HD-ARA-C. 

Peg-Asp: In non-United Kingdom locations, use 2,500 IU/m2 over 1-2 hours i.v. or i.m.

Peg-Asp: In the United Kingdom, use 1000 IU/m2 over 1 hour i.v. or i.m.
In subjects developing an allergic reaction to PEG-ASP during Induction IA, neither E.coli ASP 
or PEG ASP should given. In such subjects, Erwina, if available, should be used.
If an allergic reaction occurs following administration of native asparaginase or Peg-asp during 
Consolidation therapy, the algorithm specified in section 4.3.2.2 should be used for replacement.
INTRATHECAL THERAPY: Day 1 and should be given 2 hours after start of HD-MTX 
(window of -6 to + 6 hours in relation to start of HD-MTX is acceptable), dose according to age: 
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CA180372
BMS-354825
Dasatinib
Table 4.3.1.3:
Intrathecal Dose by Age
AGE
Methotrexate
Ara-C
Hydrocortisone
1 year < 2 years
8 mg
20 mg
8 mg
2 years < 3 years
10 mg
26 mg
10 mg
3 years
12 mg
30 mg
12 mg
SUPPORTIVE CARE: The 3 High Risk Consolidation blocks are profoundly myelosuppressive 
and also include 5 days of high dose dexamethasone, which can blunt clinical signs of infection:
therefore the following precautions are to be taken for all subjects during each High Risk block: 

Mandatory blood counts with differential every 2 days after completion of chemotherapy 
until there is evidence of marrow recovery. These blocks are highly myelosuppressive.
Recovery is defined as ANC > 0.2 x109/L (200/µl) and platelet transfusion independence.

Mandatory myeloid growth factor support: G-CSF 5µg/kg/day s.c. or i.v. starting anytime 
from 7 to 11 days the from the start of the block (eg, at least 24 hours after completion of the 
chemotherapy in each HR block), until the WBC count is > 3.0 x109/L (>3000/mm3). The 
option of pegfilgrastim 100µg/kg s.c. given once during the 7-11th day from the start of the 
block may be considered as an alternative. Myeloid growth factor support is routinely 
included in these blocks in BFM and EsPhALL trials.

Although not required, STRONGLY consider hospitalizing patients for close observation 
after each intensive block of chemotherapy, particularly during the period of profound 
myelosuppression, until there is evidence of blood count recovery because this is the 
intervention most likely to reduce the death rate.  

Because clinical signs of infection can be blunted following high dose dexamethasone 
therapy, a very low threshold should be used for institution of empiric antimicrobial therapy.
4.3.1.4
Consolidation Block 2 (HR2)
Consolidation therapy will begin 21 days after the start of HR1, provided the patient is in good 
general condition and adequate ANC (500/l; 0.5 x 109/L) and platelet counts (50,000/l; 
50 x 109/L) are documented (rising counts) and at least 21 days have elapsed since the start of 
HR1.
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
DEXAMETHASONE (DEXA): 20 mg/m2/day p.o. or i.v. in 3 doses, days 1-5 (no tapering). 
See Section 3.4.1.2 regarding the use of proton pump inhibitors and H2 blockers. 
VINCRISTINE: 1.5 mg/m2/day i.v. (max dose: 2 mg), day 2 and 6
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Clinical Protocol
CA180372
BMS-354825
Dasatinib
HIGH-DOSE METHOTREXATE (HD-MTX): 5 g/m2/dose i.v. on day 1 over 24 hours 
(1/10 in 30 minutes, the remaining 9/10 over a 23.5 hour-infusion). Suggested hyperhydration: 
3,000 ml/m2 over 24 hours: Gluc. 5%(D5W)+ NaCl 0,45%+ 90 mEq/m2KCl+NaHCO3 
90 mEq/m2. Urine pH > 7.0 over the time of infusion. 
MTX dosing is based upon BSA and the dose should not be capped.
Serum levels of MTX must be determined at hours 24, 42, 48 from infusion start. For monitoring 
of MTX serum levels and intensification of LCV rescue, see Appendix 1 or 2.
Alternatively, the HD-MTX infusion guidelines in Appendix 2 may be followed in place of the 
above guidelines.
CITROVORUM FACTOR (CF) (Folinic acid, calcium folinate, or leucovorin): 7.5 mg/m2 
i.v (Levo form; levoleucovorin, not available in the U.S.) or 15 mg/m2 i.v or po (Racemic form; 
leucovorin) at hours 42, 48, and if needed 54 hours from start of HD-MTX. For monitoring of 
MTX serum levels and intensification of LCV rescue, see Appendix 1 or 2.
Starting from hour 60, CF is needed only if serum levels at hour 48 exceed 0.5 μmol/l. In this 
case, see nomogram for therapeutic adjustments (Appendix 1 or 2). 
IFOSFAMIDE (IFO): 800 mg/m2 i.v. over 1-hour infusion, q 12 hours x 5 total doses, days 
2 - 4. Start immediately after completion of HD-MTX infusion. See Appendix 12 for optional 
MESNA administration.

Post hydration after HD-MTX(given on Day 1 of this cycle) as detailed in 
Appendix 1(EsPhALL based) or 2 (COG based) provides adequate hydration on days of 
ifosfamide administration. However, if MTX level meets criteria for leucovorin to be 
stopped, total fluids should remain at 125 mL/m2/hour until at least 12 hours after the last 
dose of ifosfamide.
HIGH-DOSE L-ASPARAGINASE (HD-L-ASP) or PEG-ASPARAGINASE (PEG-ASP): 
First-line therapy consists of native E. coli asparaginase. If native E. coli asparaginase is not 
available or for centers in the United Kingdom (UK), Peg-asparaginase should be used as 
first-line therapy. 

E. coli (medac or Kidrolase or Elspar): 25,000 IU/m2/dose, over 2 hours i.v. or i.m., on 
day 6. 

Peg-Asp: In non-United Kingdom locations, use 2,500 IU/m2 over 1-2 hours i.v. or i.m.

Peg-Asp: In the United Kingdom, use 1000 IU/m2 over 1 hour i.v. or i.m. 
In subjects developing an allergic reaction to PEG-ASP during Induction IA, E. coli Asp or 
Peg-Asp should not be given. In such subjects, Erwina, if available, should be used.
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If an allergic reaction occurs following administration of native asparaginase or Peg-asp during 
Consolidation therapy, the algorithm specified in section 4.3.2.2 should be used for replacement.
DAUNORUBICIN (DNR): 30 mg/m2 over 24-hour infusion on day 5.
INTRATHECAL THERAPY: day 1, 2 hours after start of HD-MTX (window of -6 to + 
6 hours in relation to start of HD-MTX is acceptable), according to age: 
Table 4.3.1.4:
Intrathecal Dose by Age
AGE
Methotrexate
Ara-C
Hydrocortisone
1 year < 2 years
8 mg
20 mg
8 mg
2 years < 3 years
10 mg
26 mg
10 mg
3 years
12 mg
30 mg
12 mg
SUPPORTIVE CARE: The 3 High Risk Consolidation blocks are profoundly myelosuppressive 
and also include 5 days of high dose dexamethasone, which can blunt clinical signs of infection:
therefore the following precautions are to be taken for all subjects during each High Risk block: 

Mandatory blood counts with differential every 2 days after completion of chemotherapy 
until there is evidence of marrow recovery. These blocks are highly myelosuppressive. 
Recovery is defined as ANC > 0.2 x109/L (200/µl) and platelet transfusion independence.

Mandatory myeloid growth factor support: G-CSF 5µg/kg/day s.c. or i.v. starting anytime 
from 7 to 11 days the from the start of the block (eg, at least 24 hours after completion of the 
chemotherapy in each HR block), until the WBC count is > 3.0 x109/L (>3000/mm3). The 
option of pegfilgrastim 100µg/kg s.c. given once during the 7-11th day from the start of the 
block may be considered as an alternative. Myeloid growth factor support is routinely 
included in these blocks in BFM and EsPhALL trials.

Although not required, STRONGLY consider hospitalizing patients for close observation 
after each intensive block of chemotherapy, particularly during the period of profound 
myelosuppression, until there is evidence of blood count recovery because this is the 
intervention most likely to reduce the death rate.

Because clinical signs of infection can be blunted following high dose dexamethasone 
therapy, a very low threshold should be used for institution of empiric antimicrobial therapy.
4.3.1.5
Consolidation Block 3 (HR3)
Consolidation therapy will start provided the patient is in good general condition and adequate 
ANC (500/l; 0.5 x 109/L) and platelet counts (50,000/l; 50 x 109/L) are documented 
(rising counts) and at least 21 days have elapsed since the start of HR2.
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DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
DEXAMETHASONE (DEXA): 20 mg/m2/day p.o. or i.v. in 3 doses, days 1-5 (no tapering). 
See Section 3.4.1.2 regarding the use of proton pump inhibitors and H2 blockers.
HIGH-DOSE ARA-C (HD-ARA-C): 2 g/m2 i.v. in 3-hour infusion, q 12 hours x 4 total doses, 
days 1-2. The use of corticosteroid eye drops is suggested.
ETOPOSIDE: 100 mg/m2 i.v. in 1 hour, q 12 hours, 5 total doses, days 3 - 5. 
HIGH-DOSE L-ASPARAGINASE (HD-L-ASP) or PEG-ASPARAGINASE (PEG-ASP):
First-line therapy consists of native E. coli asparaginase. If native E. coli asparaginase is not 
available or for centers in the United Kingdom (UK), Peg-asparaginase should be used as 
first-line therapy. 

E. coli (medac or Kidrolase or Elspar): 25,000 IU/m2/dose, over 2 hours i.v. or i.m., on 
day 6. 

Peg-Asp: In non-United Kingdom locations, use 2,500 IU/m2 over 1-2 hours i.v. or i.m.

Peg-Asp: In the United Kingdom, use 1000 IU/m2 over 1 hour i.v. or i.m. 
In subjects developing an allergic reaction to PEG-ASP during Induction IA, E.coli Asp or 
Peg-Asp should not be given. In such subjects, Erwina, if available, should be used.
If an allergic reaction occurs following administration of native asparaginase or Peg-asp during 
Consolidation therapy, the algorithm specified in section 4.3.2.2 should be used for replacement.
INTRATHECAL THERAPY: day 5, dose according to age:
Table 4.3.1.5:
Intrathecal Dose by Age
AGE
Methotrexate
Ara-C
Hydrocortisone
1 year < 2 years
8 mg
20 mg
8 mg
2 years < 3 years
10 mg
26 mg
10 mg
3 years
12 mg
30 mg
12 mg
SUPPORTIVE CARE: The 3 High Risk Consolidation blocks are profoundly myelosuppressive 
and also include 5 days of high dose dexamethasone, which can blunt clinical signs of infection:
therefore the following precautions are to be taken for all subjects during each High Risk block: 

Mandatory blood counts with differential every 2 days after completion of chemotherapy 
until there is evidence of marrow recovery. These blocks are highly myelosuppressive. 
Recovery is defined as ANC > 0.2 x109/L (200/µl) and platelet transfusion independence.

Mandatory myeloid growth factor support: G-CSF 5µg/kg/day s.c. or i.v. starting anytime 
from 7 to 11 days the from the start of the block (eg, at least 24 hours after completion of the 
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chemotherapy in each HR block), until the WBC count is > 3.0 x109/L (>3000/mm3). The 
option of pegfilgrastim 100µg/kg s.c. given once during the 7-11th day from the start of the 
block may be considered as an alternative. Myeloid growth factor support is routinely 
included in these blocks in BFM and EsPhALL trials.

Although not required, STRONGLY consider hospitalizing patients for close observation 
after each intensive block of chemotherapy, particularly during the period of profound 
myelosuppression, until there is evidence of blood count recovery because this is the 
intervention most likely to reduce the death rate.

Because clinical signs of infection can be blunted following high dose dexamethasone 
therapy, a very low threshold should be used for institution of empiric antimicrobial therapy
4.3.1.6
First Reinduction (Protocol II)
If MRD at end of IB/start of consolidation block 1 (HR1) 0.005-0.05% (5 x 10-5 - 5 x 10-4) or 
POS<QR with QR not at least 0.005% (5 x 10-5) and MRD at end of consolidation block 3 
(HR3)/start of reinduction block 1 remains positive at any detectable level (providing the 
assay limit is at least 0.1%) according to RQ-PCR of rearranged immunoglobulin/T-cell 
receptor genes, then see Section 4.3.1.11 regarding HSCT. See section 4.3.1.11 for subjects 
known to have uninformative PCR for Ig/TCR gene rearrangement assessment at baseline.
The first re-induction with protocol II starts at least 21 days from the start of HR3 block, 
provided the patient is in good general condition and adequate ANC (500/l; 0.5 x 109/L) and 
platelet counts (50,000/l; 50 x 109/L) are documented. Protocol II comprises two phases, IIa 
and IIb.
Phase IIa
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
DEXAMETHASONE (DXM): 10 mg/m2/day p.o. or i.v. in 3 doses, days 1-7 and 15-21. See 
Section 3.4.1.2 regarding the use of proton pump inhibitors and H2 blockers.
VINCRISTINE (VCR): 1.5 mg/m2/dose i.v. (maximum dose 2.0 mg/dose), day 8, 15, 22, 29. 
DOXORUBICIN (DOX)/ADRIAMYCIN (ADR): 25 mg/m2/dose i.v. to be infused in up to 
1 hour or according to institutional standards on days 8, 15, 22, and 29.
L-ASPARAGINASE 
(L-ASP) 
E. 
coli 
(medac 
or 
Kidrolase 
or 
Elspar)
or 
PEG-ASPARAGINASE (PEG-ASP):
First-line therapy consists of native E. coli asparaginase. If native E. coli asparaginase is not 
available or for centers in the United Kingdom (UK), Peg-asparaginase should be used as 
first-line therapy. 

L-Asp: 10,000 IU/m2/dose, over 1 hour i.v. or i.m., days 8, 11, 15 and 18, 
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
Peg-Asp: In non-United Kingdom locations, use a single dose of 2,500 IU/m2 over 1-2 hours 
i.v. or i.m. on day 8 in place of the 4 doses of native asparaginase

Peg-Asp: In the United Kingdom, use a single dose of 1,000 IU/m2 over 1 hour i.v. or i.m. on 
day 8 in place of the 4 doses of native asparaginase
In case of an allergic reaction follow the algorithm specified in section 4.3.2.2 for replacement.
INTRATHECAL METHOTREXATE: day 1, dose according to age. See Table 4.3.1.6
Phase IIb 
This portion of treatment starts on day 36 of protocol II provided the patient is in good general 
condition and adequate ANC (500/l; 0.5 x 109/L) and platelet counts (50,000/l; 50 x 
109/L) are documented. 
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
CYCLOPHOSPHAMIDE (CPM): 1000 mg/m2/dose i.v. (1 hour) day 36. 
See Appendix 12 for optional MESNA guidelines.
Please consider adequate anti-emetic supportive therapy.
6-THIOGUANINE (6-TG): 60 mg/m2/day p.o., taken in the evening on an empty stomach 
without milk (1 hour before or after dinner), days 36 - 49 (total 14 days). If 6-thioguanine is not 
available, then an option to substitute 6-mercaptopurine 60 mg/m2/day p.o. taken in the evening 
on an empty stomach without milk (1 hour before or after dinner), days 36-49 (total 14 days) is 
permitted. If initiation of ARA-C cycle is delayed due to inadequate blood counts or the cycle is 
interrupted, then 6-TG should also be delayed/interrupted.
CYTOSINE ARABINOSIDE (ARA-C): 75 mg/m2/day s.c. or i.v. in one daily dose, days 
38 - 41 and 45 - 48. 
The 4-day cycle that begins on day 45 should be started when WBC > 500/l (> 0.5 x 109/L) and 
platelets > 30,000/l (> 30 x 109/L); each cycle when started should not be stopped unless for 
acute infection (please consider that fever might be also induced by the drug). 
Note: For the cycle starting on day 38, the WBC and platelet counts do not need to be rechecked 
if adequate to begin this protocol IIb block (day 36 of first reinduction).
INTRATHECAL METHOTREXATE: days 38 and 45 (together with ARA-C cycles on days 
38 and 45), dose according to age: 
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Table 4.3.1.6:
Intrathecal Methotrexate Therapy Dose by Age
AGE
Methotrexate
1 year < 2 years
8 mg
2 years < 3 years
10 mg
3 years
12 mg
4.3.1.7
Interim Maintenance
This short phase is aimed to allow administration of cranial irradiation during 
antimetabolite-based non-intensive chemotherapy. It will start 2 weeks after completion of the 
last chemotherapy of the previous phase (day 49 of protocol II, ie 64 days after the start of First 
Reinduction) and will last 4 weeks (ie the time comprised between the first and the second 
administration of protocol II) provided the patient is in good general condition and adequate 
ANC (750/l; 0.75 x 109/L) and platelet counts (75,000/l; 75 x 109/L). Dasatinib 
administration will not be interrupted between the end of protocol II and the beginning of interim 
maintenance. 
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
6-MERCAPTOPURINE (6-MP): 50 mg/m2/day p.o., taken in the evening on the empty 
stomach without milk (1 hour before or after dinner), days 1 - 28.
METHOTREXATE (MTX): 20 mg/m2/dose p.o. once a week days 1, 8, 15, and 22. 
In selected cases it could be necessary to start the two drugs with increasing doses according to 
the patient’s compliance and/or hematological reconstitution. 
CRANIAL IRRADIATION: During interim maintenance cranial irradiation will be given to 
patients with CNS3 leukemia at diagnosis (See Appendix 10 for definition). Only subjects 
36 months of age, not receiving a HSCT should receive cranial irradiation during interim 
maintenance. Cranial irradiation will be administered at the dose of 18 Gy in 10 fractions. It will 
begin on day 1 of interim maintenance. 
CNS3 patients that receive HSCT should receive a total cranial irradiation dose of 18 Gy. This is 
usually given as a cranial boost during the HSCT preparative regimen. If a non-TBI preparative 
regimen is used, then a cranial boost of 18 Gy should be considered prior to or following HSCT.
Radiation Therapy Guidelines
Equipment and Calibration
X-ray beams with a nominal energy of 4 or 6 MV. IMRT is not allowed. 
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Target Volume
The target volume consists of the entire brain and meninges, including the frontal lobe as well as 
the posterior halves of the globes of the eyes, with the optic disk and nerve superior to the vertex 
and posterior to the occiput. The caudal border will be below the skull base to at least the C2 
vertebral level.
Target Dose
The prescription point in each target volume is at or near the center. For multi-convergent beams, 
the prescription point is usually at the intersection of the beam axes. The absorbed dose is 
specified in centigray (cGy)-to-muscle. No corrections for bone attenuation will be made.
The daily dose to the prescription points for the cranial volume will be 1.8 Gy for patients with 
CNS3 leukemia at diagnosis. The total dose to the prescription point shall be 18 Gy in 
10 treatments for patients with CNS3 leukemia at diagnosis.
Fractionation
All radiation fields shall be treated once each day; the treatment shall be given 5 days a week.
Treatment Interruptions 
No corrections will be made for treatment interruptions less than 7 days. For any interruptions 
greater than 7 days, contact the study director.
Dose Uniformity 
The dose variations in each target volume shall be within +7%, -5% of the prescription-point 
dose. 
Treatment Technique
The patient can be treated prone or supine. The cranial volume is treated with 2 lateral, equally 
weighted photon beams. The fields shall extend at least 1 cm beyond the periphery of the scalp. 
Field-shaping shall be done with blocks which are at least 5 HVL thick. See Figure 4.3.1.7. 
Multi-leaf collimators are also acceptable provided coverage is adequate.
Figure 4.3.1.7:
Example of radiation simulation radiograph with cerrobend block 
design (left) and megavoltage portal film (right) for cranial 
irradiation volume.
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Eye protection 
A simple method to minimize lens irradiation, while irradiating the posterior halves of the eyes, 
is to let the central axes of the horizontal cranial beams go through both orbits. The anterior 
edges of the beams are defined by an external block or by an independently controlled collimator 
and meet at a point 1 cm anterior to the frontal lobe meninges. Shielding blocks cover the 
anterior halves of the eyes and protect the nose and mouth. Essentially the same geometry can be 
achieved with the central axes through the center of the head by angling the lateral fields so that 
the rays through the eyes lie in the same horizontal plane. It is also acceptable to use a 
parallel-opposed beam-pair, without such angling, with shielding blocks that cover the anterior 
half of the proximal eye. The dose to the contralateral lens will be higher.
4.3.1.8
Second Reinduction (Protocol II)
It will start immediately after the interim maintenance provided the patient is in good general 
condition and adequate ANC (500/l; 0.5 x 109/L) and platelet counts (50,000/l; 50 x 
109/L) are documented. 
Phase IIa 
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
DEXAMETHASONE (DEXA): 10mg/m2/day p.o. or i.v. in 3 doses, days 1 - 7 and 15 - 21. See 
Section 3.4.1.2 regarding the use of proton pump inhibitors and H2 blockers.
VINCRISTINE (VCR): 1.5 mg/m2/dose i.v. (maximum dose 2.0 mg/dose), day 8, 15, 22, and 
29. 
DOXORUBICIN (DOX)/ADRIAMYCIN (ADR): 25 mg/m2/dose i.v. to be infused in up to 
1 hour or according to institutional standards on days 8, 15, 22, and 29. 
L-ASPARAGINASE 
(L-ASP) 
E. 
coli 
(medac 
or 
Kidrolase
or 
Elspar)
or 
PEG-ASPARAGINASE (PEG-ASP):
First-line therapy consists of native E. coli asparaginase. If native E. coli asparaginase is not 
available or for centers in the United Kingdom (UK), Peg-asparaginase should be used as first-
line therapy. 

L-Asp: 10,000 IU/m2/dose, over 1 hour i.v. or i.m., days 8, 11, 15 and 18. 

Peg-Asp: In non-United Kingdom locations, use a single dose of 2,500 IU/m2 over 1-2 hours 
i.v. or i.m. on day 8 in place of the 4 doses of native asparaginase

Peg-Asp: In the United Kingdom, use a single dose of 1,000 IU/m2 over 1 hour i.v. or i.m. on 
day 8 in place of the 4 doses of native asparaginase
In case of an allergic reaction follow the algorithm specified in section 4.3.2.2 for replacement.
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INTRATHECAL METHOTREXATE: day 1, dose according to age. See Table 4.3.1.8.
Phase IIb
This portion of treatment starts on day 36 of protocol II provided the patient is in good general 
condition and adequate ANC (500/l; 0.5 x 109/L) platelet counts (50,000/l; 50 x 
109/L) are documented.
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
CYCLOPHOSPHAMIDE (CPM): 1000 mg/m2/dose i.v. (1 hour) day 36. 
See Appendix 12 for optional MESNA guidelines.
Please consider adequate anti-emetic supportive therapy.
6-THIOGUANINE (6-TG): 60 mg/m2/day p.o., taken in the evening on the empty stomach 
without milk (1 hour before or after dinner), days 36 - 49 (total 14 days). If 6-thioguanine is not 
available, then an option to substitute 6-mercaptopurine 60 mg/m2/day p.o. taken in the evening 
on an empty stomach without milk (1 hour before or after dinner), days 36-49 (total 14 days) is 
permitted. If initiation of ARA-C cycle is delayed due to inadequate blood counts or the cycle is 
interrupted, then 6-TG should also be delayed/interrupted.
CYTOSINE ARABINOSIDE (ARA-C): 75 mg/m2/day s.c. or i.v. in one daily dose, days 38 -
41 and 45 - 48. 
The 4-day cycle that begins on day 45 should be started when WBC > 500/ml (> 0.5 x 109/L) 
and platelets > 30,000/ml (> 30 x 109/L); each cycle when started should not be stopped unless 
for acute infection (please consider that fever might be also induced by the drug.
Note: For the cycle starting on day 38, the WBC and platelet counts do not need to be rechecked 
if adequate to begin this protocol IIb block (day 36 of second reinduction).
INTRATHECAL METHOTREXATE: days 38 and 45 (together with ARA-C cycles on days 
38 and 45).
Omit intrathecal MTX in CNS3 subjects who received cranial irradiation.
Dose according to age: 
Table 4.3.1.8:
Intrathecal Methotrexate Therapy Dose by Age
AGE
Methotrexate
1 year < 2 years
8 mg
2 years < 3 years
10 mg
3 years
12 mg
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4.3.1.9
Continuation Therapy
Continuation therapy will start after completion of second reinduction (protocol II) provided the 
patient is in good general condition with adequate ANC (750/l; 0.75 x 109/L) and platelet 
counts (75,000/l; 75 x 109/L). The duration of treatment in this block is approximately 
62 weeks. 
DASATINIB: 60 mg/m2 once daily orally continuously (held only for toxicity). The dasatinib 
dose may be rounded up to the nearest 5 mg dose.
6-MERCAPTOPURINE (6-MP): 50 mg/m2/day p.o., taken in the evening on the empty 
stomach without milk (1 hour before or after dinner).
INTRATHECAL METHOTREXATE: Every 6 weeks x 6 doses. The first dose should be 
administered on Day 1 of Continuation.
Omit intrathecal MTX in CNS3 subjects who received cranial irradiation. 
Dose according to age (Table 4.3.1.9A): 
Table 4.3.1.9A:
Intrathecal Methotrexate Therapy Dose by Age
AGE
Methotrexate
1 year < 2 years
8 mg
2 years < 3 years
10 mg
3 years
12 mg
METHOTREXATE (MTX): 20 mg/m2/weekly p.o. 
The aim is to adjust doses to maintain the ANC between 750 and 1500/l (0.75 and 1.5 x 109/L) 
and the platelet count between 75,000 and 150,000/l (75 and 150 x 109/L).
Start maintenance at 100% doses and DO NOT give higher doses at the start of continuation 
therapy even if the subject tolerated higher doses throughout interim maintenance.
During continuation therapy, if the ANC is > 1500/l (1.5 x 109/L) and platelets > 150,000/l 
(150 x 109/L) for 8 weeks, the dose of mercaptopurine should be escalated by 25%. Otherwise 
keep at 100% of dose.
If the subsequent monthly ANC is > 1500/l (1.5 x 109/L):
1) Keep mercaptopurine at the 125% dose and increase oral methotrexate by 25% to a dose of 
25 mg/m2.
2) Continue to increase the mercaptopurine and oral methotrexate dose in 25% steps 
alternatively every eight weeks as outlined above if ANC > 1500/l (1.5 x 109/L) and 
platelets > 150,000/l (150 x 109/L) persists. There are no maximum doses for 
mercaptopurine and methotrexate.
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Dose Reduction for Falling Neutrophil Counts
If the neutrophil count falls to between 500/l (0.5 x 109/L) and 750/l (0.75 x 109/L):

HALVE the dose of mercaptopurine and oral methotrexate
If neutrophil count is < 500/l (0.5 x 109/L):

STOP mercaptopurine and methotrexate. ONLY RESTART when the count is over 750/l 
(0.75 x 109/L). Restart at 100% of last dose when neutrophil > 750/l (0.75 x 109/L).
If counts fluctuate significantly when restarting at 100% of last dose, starting at 50% and titrating 
upwards is permissible to avoid frequent interruptions of mercaptopurine exposure
(this maneuver is often not necessary).
Dose Reduction for Falling Platelet Counts
If the platelet count is < 75,000/l (75 x 109/L):

HALVE the dose of mercaptopurine and methotrexate.
If the platelet count is <50,000/l (50 x 109/L):

STOP mercaptopurine and methotrexate. ONLY RESTART when the count is greater than 
75,000/l (75 x 109/L). Restart at 100% of last dose when platelet count > 75,000/l (75 x 
109/L).
If counts fluctuate significantly when restarting at 100% of last dose, starting at 50% and titrating 
upwards is permissible to avoid frequent interruptions of mercaptopurine exposure
(this maneuver is often not necessary).
4.3.1.10
Completion of Treatment
Total duration of chemotherapy will not exceed 24 months. Upon treatment completion, confirm 
CR by bone marrow aspirate and CSF examination.
4.3.1.11
Hematopoietic Stem Cell Transplant (HSCT)
All subjects will be screened for an HLA-identical family or unrelated donor. 
Criteria for HSCT are:
1) MRD at end of IB/start of consolidation block 1 (HR1) 0.05% (5 x 10-4) as measured by 
Ig/TCR PCR 
a.
For subjects that do not have informative results of Ig/TCR PCR, the criteria for 
HSCT will be a less than 3-log reduction in MRD as measured by RQ-PCR for 
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BCR-ABL. In the rare circumstance that both Ig/TCR and BCR-ABL PCR are 
uninformative, flow cytometry results may be utilized with the same criteria as the 
Ig/TCR PCR.
OR
2) MRD at end of IB/start of consolidation block 1 (HR1) 0.005-0.05% (5 x 10-5 to 5 x 10-4)* as 
measured by Ig/TCR PCR and MRD at end of consolidation block 3 (HR3)/start of 
reinduction block 1 remains positive at any detectable level (providing the assay limit is at 
least 0.1%). 
*This includes if MRD at the end of IB is positive but less than the quantifiable range 
(POS<QR) with QR not at least 0.005% (5X10-5)
a.
For subjects that do not have informative results of Ig/TCR PCR, a positive MRD 
level as measured by RQ-PCR for BCR-ABL. In the rare circumstance that both 
Ig/TCR and BCR-ABL PCR are uninformative, flow cytometry results may be 
utilized with the same criteria as the Ig/TCR PCR.
MRD will be assessed by quantitative polymerase chain reaction (RQ-PCR) of rearranged 
immunoglobulin/T-cell receptor genes according to standardized criteria51. Subjects that fulfill 
the above criteria and have a genotype-matched donor (9/10 or 10/10) will receive hematopoietic 
stem cell transplant (HSCT) instead of continuing the AIEOP-BFM ALL 2000 regimen. The 
timing of HSCT would be following the consolidation block 3 (HR3). Subjects should continue 
on protocol specified Reinduction chemotherapy until HSCT. If alternative chemotherapy is 
preferred, the subject must be discontinued from the study treatment but must continue to be 
followed per protocol for the long term growth assessments. If a subject goes off-treatment to 
receive a different chemotherapy, dasatinib will no longer be provided via this study. Subjects
who do not meet the above criteria should not receive HSCT. Subjects may receive additional 
dasatinib until the start of the HSCT preparation regimen or until within a 2 week window for 
HSCT. During the preparative regimen and HSCT, subjects will not receive dasatinib. Subjects 
with CNS3 disease at diagnosis who are proceeding to HSCT should also receive a cranial boost 
of radiation to a total of 18 Gy.
The preparative regimen prior to HSCT and the treatment for the HSCT will be according to the 
institutional standard of care. Subjects who proceed to HSCT will not continue to report AEs or 
conmeds during the preparation, procedure or recovery period unless considered related to the 
investigational product. Subjects who proceed to HSCT will continue to be followed on-study for 
the primary endpoint (ie events), and exploratory endpoints of 
 
. Follow-up for these endpoints could also continue if 
subjects proceed to second line therapy.
Use of dasatinib after stem cell transplantation
The use of dasatinib after transplantation is optional in all HSCT recipients at the discretion of 
the treating physician. There are several reports that the use of dasatinib post-transplant appears 
safe52,53.It is recommended that a subject continuing dasatinib treatment post-HSCT may start at 
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an initial dose of 48 mg/m2 daily once the subject has a satisfactory engraftment with stable 
ANC, PTL and WBC count (ANC > 0.5 x 109/L for at least 28 days, PTL > 50 x 109/L; WBC 
> 1.5 x 109/L. If the initial dose is deemed tolerable by the treating physician, the dose of 
dasatinib may be escalated to 60 mg/m2. For those subjects who opt for post-HSCT dasatinib,
administration is suggested throughout the first year post-transplantation until day +365 from 
HSCT. The dasatinib dose may be rounded up to the nearest 5 mg dose. If dasatinib treatment is 
re-started then all data for adverse events, serious adverse events, concomitant medications and 
all other medical and diagnostic procedures must be recorded in the eCRF.
4.3.2
Dose Modifications
Dose interruptions or reductions for adverse events are described in the following tables below. 
Dose modifications should be made for adverse events considered related to the specific drug 
being modified. Relatedness of an adverse event to a particular drug is determined by the 
investigator.
For an individual subject, dose interruptions, reductions and treatment 
discontinuation may be more or less conservative than indicated below in Table 4.3.2.1, through 
4.3.2.13 based on the clinical judgment of the investigator.
4.3.2.1
Dasatinib 
Table 4.3.2.1:
Dose Modifications for Dasatinib
Dasatinib 
Related Event 
and Severity
Dasatinib
Hematologic
Grade 1-4
No Dose Interruption/Reduction
If neutropenia 
and/or 
thrombocytop
enia result in 
delay of next 
block of 
treatment 
> 14 days 
Interrupt dasatinib and resume at the same dose level once the next block of treatment is 
continued. If neutropenia and/or thrombocytopenia persist and the next block of treatment is 
delayed another 7 days, a bone marrow assessment will be performed to assess the cellularity 
and percentage of blasts. If marrow cellularity is < 10%, dasatinib must be held until ANC 
> 500/µL (0.5 x 109/L) at which time treatment may be resumed at full dose. If marrow 
cellularity if > 10%, consider resumption of dasatinib. If necessary, repeat the bone marrow 
assessment every 7-10 days until treatment continues.
Gr3 anemia
No dose reductions.
Subjects developing anemia may be transfused or prescribed erythropoietin at the 
investigator’s discretion.
Non-Hematologic
Grade 1-2
No Dose Interruption/Reduction
Grade 2
If does not resolve despite symptomatic treatment, consider interrupting dasatinib
Resume at 60 mg/m2 after recovery to Grade 1
Consider reduction to 48 mg/m2 for recurrent events
Grade 3
Hold therapy until grade 1
Resume at 48 mg/m2 after recovery to Grade 1
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Dasatinib
Table 4.3.2.1:
Dose Modifications for Dasatinib
Dasatinib 
Related Event 
and Severity
Dasatinib
Liver Function Tests
Direct 
Bilirubin > 5x 
institutional 
ULN
Hold until direct bilirubin levels have returned to baseline or < 1.5x institutional ULN.
Resume at 60 mg/m2
Reduce to 48 mg/m2 if recurrent event
AST/ALT 
> 15x 
institutional 
ULN
Hold until AST/ALT levels have returned to baseline or < 2.5 x institutional ULN
Resume at 60 mg/m2
Reduce to 48 mg/m2 if recurrent event
Bleeding
Any bleeding 
or 
hemorrhage
Subjects who have evidence of bleeding or hemorrhage of any grade at any site may have dose 
adjustments or interruption at the discretion of the investigator
4.3.2.2
Asparaginase [PEG, E.coli, or Erwinia]
Table 4.3.2.2:
Dose Modifications for Asparaginase
Event
Asparaginase
Allergy
In case of allergy to an asparaginase formulation,:
•
COG members and sites in Italy should use the algorithm in Table 4.3.2.2a should 
be used.
•
United Kingdom sites should use the algorithm in Table 4.3.2.2b
Coagulopathy
If symptomatic, hold asparaginase until symptoms resolve, then resume with the next 
scheduled dose. Consider factor replacement (FFP, cryoprecipitate, factor VIIa). Do not 
withhold dose for abnormal laboratory findings without clinical symptoms.
Hyperbilirubinemia
L-asparaginase may need to be withheld in patients with an elevated direct bilirubin, 
since asparaginase has been associated with hepatic toxicity.
Hyperglycemia
Do not modify dose. Treat hyperglycemia as medically indicated
Hyperlipidemia
Do not modify dose
Ketoacidosis
Hold asparaginase until blood glucose can be regulated with insulin
Pancreatitis 
Hold asparaginase for mild pancreatitis until symptoms and signs subside, and amylase 
levels return to normal and then resume. Permanently discontinue asparaginase in the 
presence of hemorrhagic pancreatitis or severe pancreatitis (abdominal pain > 72 hours 
and > Grade 3 amylase elevation (> 2 x ULN) or pancreatic pseudocyts).
Thrombosis
Withhold asparaginase until resolved, and treat with appropriate anti-thrombotic 
therapy, as indicated. Upon resolution of symptoms consider resuming asparaginase, 
while continuing low molecular weight heparin or anti-thrombotic therapy. Do not 
withhold dose for abnormal laboratory findings without clinical correlate.
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Dasatinib
Table 4.3.2.2:
Dose Modifications for Asparaginase
Event
Asparaginase
CNS Events (bleed, 
thrombosis, infarct)
Hold asparaginase. Treat with FFP, factors or anticoagulation as appropriate. Resume at 
full dose when all symptoms have resolved (and evidence of recanalization in case of 
thrombosis by CT/MRI).
Table 4.3.2.2a:
Asparaginase Substitutions for COG and Italy
Peg-Asparaginase
During HR1-HR3 blocks
Substitute 1 dose of PEG-ASP (Oncaspar) in a single dose 
of 2500 IU/m2 over 1-2 hours i.v. or i.m. according to the 
institutional standard of care.
During First or Second 
Reinduction Blocks
For full course substitution: substitute one dose of PEG-
ASP (2500 IU/m2) given on day 8 for the four doses of E. 
Coli asparaginase.
For substitution after E. coli asparaginase given on day 8 
or day 11 of reinduction, give a single dose of PEG-ASP 
(2500 IU/M2) to replace the remaining scheduled doses of 
E.coli asparaginase.
Substitution after a dose of E.coli asparaginase given at 
day 15 or day 18 of reinduction, is not recommended 
Erwinia
Known allergy to PEG-
ASP
In case of an allergy to PEG-ASP during induction therapy 
before entry on this trial or on this trial, then Erwinia 
asparaginase should be substituted (if available). 
If Erwinia asparaginase is not available, then the doses 
should be omitted.
During HR1 to HR3 
blocks
Substitute 3 doses of Erwinia asparaginase (25,000 IU/m2) 
given on a Monday/ Wednesday/ Friday schedule for the single 
dose of E.coli asparaginase scheduled during HR1 to HR3 
blocks.
During first or second 
reinduction block 
(Protocol II)
Substitute 6 doses of Erwinia asparaginase (25,000 IU/m2) 
given on a Monday/ Wednesday/ Friday schedule starting 
at day 8 for the 4 doses of E.coli asparaginase given during 
the first or second reinduction block (Protocol II).
If a reaction occurs to PEG-ASP given on day 8 of the first 
or second reinduction block, then six doses of Ewinia 
asparaginase should be administered as above, starting 
1-2 days after the dose of PEG-ASP.
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Dasatinib
Table 4.3.2.2b:
Asparaginase Substitutions for United Kingdom
Erwinia
Known 
allergy 
to 
PEG-ASP
In case of an allergy to PEG-ASP during induction therapy 
before entry on this trial or on this trial, then Erwinia 
asparaginase should be substituted (if available).
If Erwinia asparaginase is not available, then the doses should 
be omitted.
During HR1 to HR3 
blocks
Substitute 3 doses of Erwinia asparaginase (25,000 IU/m2) 
given on a Monday/ Wednesday/ Friday schedule for during 
each of the HR1 to HR3 blocks.
During first or second 
reinduction 
block 
(Protocol II)
Substitute 6 doses of Erwinia asparaginase (25,000 IU/m2) 
given on a Monday/ Wednesday/ Friday schedule starting at 
day 8 during the first or second reinduction block (Protocol II).
If a reaction occurs to PEG-ASP given on day 8 of the first or 
second reinduction block, then six doses of Ewinia 
asparaginase should be administered as above, starting 1-2 days 
after the dose of PEG-ASP
4.3.2.3
Cyclophosphamide
Table 4.3.2.3:
Dose Modification for Cyclophosphamide
Event
Cyclophosphamide
Hematuria
Omit cyclophosphamide in the presence of macroscopic hematuria. If there is a 
history of previous significant hematuria, consider the use of MESNA as outlined 
in Section 4.3.1
CrCl < 10 mL/min/1.73 m2
Reduce cyclophosphamide by 50%. 
4.3.2.4
Cytarabine (Ara-C)
Table 4.3.2.4:
Dose Modifications for Cytarabine (Cytosine Arabinoside)
Event
Cytarabine
Fever
Do not withhold Ara-C for fever if it is likely to have been caused by the Ara-C. 
Grade 3-4 rash
Withhold until resolved. Make up missed doses and consider concurrent treatment with 
hydrocortisone or dexamethasone.
Grade 3-4 
conjunctivitis
Withhold until resolved. Make up missed doses and consider concurrent treatment with 
corticosteroid ophthalmic drops (optional).
Severe infection 
Withhold until resolved. Make up missed doses.
CrCl 
< 60 mL/min/1.73 m2
Withhold until resolved and omit if recovery requires > 3 weeks
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Dasatinib
Table 4.3.2.4:
Dose Modifications for Cytarabine (Cytosine Arabinoside)
Event
Cytarabine
Grade 2 or higher 
neurotoxicity 
(including ataxia, 
nystagmus, dysarthria, 
dysmetria, seizures, 
encephalopathy)
Hold high-dose cytarabine and do not give any further doses of high-dose cytarabine 
(HR1 and HR3 blocks). Low-dose cytarabine may be given in patients who have 
experienced neurotoxicity with high-dose cytarabine.
4.3.2.5
Daunorubicin or Doxorubicin
Table 4.3.2.5:
Dose Modification for Daunorubicin or Doxorubicin
Event
Daunorubicin or Doxorubicin
EF < 50% or SF < 
27%
Skip scheduled dose. Future doses may be given if cardiac function documented to be 
acceptable.
Severe infection or 
mucositis (grade 3-4) 
and ANC < 500/μL 
(0.5 x 109/L)
Delay during phases other than Induction. During induction, continue administration. 
Subsequent doses should be given at full dose.
Direct Bilirubin 
1.2-3 mg/dL
50% dose reduction
Direct Bilirubin 
3.1-5 mg/dL
75% dose reduction
Direct Bilirubin 
> 5 mg/dL
Withhold dose and administer next scheduled dose if toxicity has resolved. Do not 
make up missed doses. 
4.3.2.6
Etoposide
Table 4.3.2.6:
Dose Modifications for Etoposide
Event
Etoposide
Allergic Reaction
Premedicate with diphenhydramine or similar antihistamine (1-2 mg/kg slow IV push). 
If symptoms persist, add hydrocortisone 100-300 mg/m2. Continue to use 
premedication before etoposide in future. Also consider substituting an equimolar 
amount of etoposide phosphate, in the face of significant allergy and/or hypotension.
Hypotension
If diastolic or systolic blood pressure (BP) falls 20 mm Hg during infusion, reduce 
infusion rate by 50%. Start a simultaneous infusion of NS 10 mL/kg if BP fails to 
recover or falls further. Stop infusion if BP does not recover, continue NS. If the patient 
has had any episode of hypotension, prehydrate with 0.9% NaCl at 10 mL/kg/hr for 
2 hours prior to any subsequent infusion.
Creatinine clearance 
10-50 mL/min/1.73 m2
Dose reduce by 25%
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Dasatinib
Table 4.3.2.6:
Dose Modifications for Etoposide
Event
Etoposide
Creatinine clearance 
< 10 mL/min/1.73 m2,
Dose reduce by 50%
Direct bilirubin is 
> 2 mg/dL
Dose reduce by 50%
Direct bilirubin is 
> 5 mg/dL
Hold dose.
4.3.2.7
Ifosfamide
Table 4.3.2.7:
Dose Modification for Ifosfamide
Event
Ifosfamide
Gross hematuria
For persistent gross hematuria occurring during the ifosfamide cycle, withhold further 
ifosfamide. 
Grade 4 neurotoxicity
Consider administration of methylene blue at 2 mg/kg [Maximum dose: 50 mg] on the 
day this occurs. The methylene blue dose may be repeated at 4 hours and 8 hours after 
ifosfamide administration, following which ifosfamide should be discontinued and no 
further ifosfamide will be administered. Hypersensitivity, renal impairment and 
glucose-6-phosphate dehydrogenase (G-6PD) deficiency are contraindications to 
administer methylene blue.
4.3.2.8
High-Dose Methotrexate (HD MTX) and Leucovorin Rescue
Review of methotrexate dosing on AIEOP-BFM-based protocols indicated that excessive 
methotrexate toxicity has not been encountered in patients > 2 m2 who receive more than 
10 grams of methotrexate. The investigator should base the methotrexate on the patient's 
meter-squared dosing and not cap at 10 grams of methotrexate.
Blood samples for the determination of creatinine and ALT values must be drawn immediately 
within 72 hours prior to a course of intravenous MTX. Blood samples for ALT should not be 
drawn immediately following the MTX infusions as 100% of patients are expected to have 
significant elevations at that time.
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Dasatinib
Table 4.3.2.8:
Dose Modification of High-Dose Methotrexate
Event
High-Dose Methotrexate
Creatinine is > 1.5 x 
baseline or creatinine 
clearance 
< 65 mL/minute/1.73m2
Postpone course. If renal function does not recover, omit MTX. Do not give HD 
MTX to a patient with this degree of renal impairment, assuming that prolonged 
excretion can be managed with glucarpidase.
ALT 10 – 20 X ULN
Give HDMTX without modification. If problem recurs with next course of HDMTX 
consider discontinuing TMP/SMX and delay HDMTX until ALT <10 X ULN.
ALT 10 – 20 X ULN for 
2 consecutive cycles
Discontinue TMP/SMX
Hold therapy until ALT < 10 X ULN, then resume at full doses at point of 
interruption.
Do not skip doses.
ALT > 20 X ULN
Discontinue TMP/SMX.
Hold therapy until ALT < 10 X ULN, then resume at full doses at point of 
interruption. 
Do not skip doses.
ALT > 20 X ULN for 
> 2 weeks
Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, total protein, and 
hepatitis A, B, C, CMV, and EBV serologies.
Consider liver biopsy before additional therapy given. 
Direct 
hyperbilirubinemia of 
> 2.0 mg/dL
Hold IV MTX
Grade 3-4 mucositis
Hold IV MTX. Increase leucovorin rescue following the next course from 3 to 5 
doses on a q6 hr schedule. If subsequent course is not associated with Grade 3-4 
mucositis, attempt to decrease the leucovorin. If mucositis recurs despite the extended 
leucovorin, decrease the dose of MTX by 25%, increase hydration to 200 mL/m2/hr 
and continue increased leucovorin as above.
4.3.2.9
Intrathecal Methotrexate / Triple Intrathecal Therapy
Table 4.3.2.9:
Dose Modification for Intrathecal Methotrexate / Triple Intrathecal 
Therapy
Event
Methotrexate / Triple Intrathecal Therapy
Systemic Toxicity 
(myelosuppression, 
mucositis)
No dose reduction. Leucovorin may be used at a dose of 5 mg/m2/dose every 12 hours 
x 2 doses, beginning 48 hours after the IT therapy has been delivered.
Acute neurotoxicity
Consider holding the next dose of IT therapy, or substituting IT Ara-C for one dose of 
IT MTX or triple IT therapy.
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Dasatinib
Table 4.3.2.9:
Dose Modification for Intrathecal Methotrexate / Triple Intrathecal 
Therapy
Event
Methotrexate / Triple Intrathecal Therapy
Hydrocephalus, 
microcephaly or 
known abnormality of 
CSF flow precluding 
intrathecal 
chemotherapy via LP
Ommaya catheter may be used in place of IT therapy. Intraventricular chemotherapy 
should be given according to the same schedule but at 50% of the corresponding 
age-based doses that would be given by LP.
Viral, bacterial or 
fungal meningitis
Omit until resolved.
4.3.2.10
PO Methotrexate (MTX) and 6-Mercaptopurine (MP)
Doses may be interrupted during Induction Ib and the 2 applications of protocol IIb but doses 
should not be modified unless there is evidence of TPMT polymorphisms.

If homozygous deficient for TPMT, administer 10% of the original dose.

If heterozygous for TPMT, administer 30-50% of the original dose and escalate to 100% 
dose as tolerated.

If wild type, continue at original dose.
During Interim Maintenance and Continuation blocks the aim is to adjust doses to maintain the 
ANC between 750 and 1500/l (0.75 and 1.5 x 109/L) and the platelet count between 75,000 and 
150,000/l (75 and 150 x 109/L).
Start maintenance at 100% doses and DO NOT give higher doses at the start of continuation 
therapy even if the subject tolerated higher doses throughout interim maintenance.
During continuation therapy, if the ANC is > 1500/l (1.5 x 109/L) and platelets > 150,000/l 
(150 x 109/L) for 8 weeks, the dose of mercaptopurine should be escalated by 25%. Otherwise 
keep at 100% of dose.
If the subsequent monthly ANC is > 1500/l (1.5 x 109/L):
1) Keep mercaptopurine at the 125% dose and increase oral methotrexate by 25% to a dose of 
25 mg/m2.
2) Continue to increase the mercaptopurine and oral methotrexate dose in 25% steps 
alternatively every eight weeks as outlined above if ANC > 1500/l (1.5 x 109/L) and 
platelets > 150,000/l (150 x 109/L) persists. There are no maximum doses for 
mercaptopurine and methotrexate.
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Dasatinib
Dose Reduction for Falling Neutrophil Counts
If the neutrophil count falls to between 500/l (0.5 x 109/L) and 750/l (0.75 x 109/L):

HALVE the dose of mercaptopurine and oral methotrexate
If neutrophil count is < 500/l (0.5 x 109/L):

STOP mercaptopurine and methotrexate. ONLY RESTART when the count is over 750/l 
(0.75 x 109/L). Restart at 100% of last dose when neutrophil > 750 l (0.75 x 109/L).
If counts fluctuate significantly when restarting at 100% of last dose, starting at 50% and titrating 
upwards is permissible to avoid frequent interruptions of mercaptopurine exposure
(this maneuver is often not necessary).
Dose Reduction for Falling Platelet Counts
If the platelet count is < 75,000/l (75 x 109/L):

HALVE the dose of mercaptopurine and methotrexate.
If the platelet count is <50,000/l (50 x 109/L):

STOP mercaptopurine and methotrexate. ONLY RESTART when the count is greater than 
75,000/l (75 x 109/L). Restart at 100% of last dose when platelet count > 75,000/l (75 x 
109/L).
If counts fluctuate significantly when restarting at 100% of last dose, starting at 50% and titrating 
upwards is permissible to avoid frequent interruptions of mercaptopurine exposure 
(this maneuver is often not necessary).
4.3.2.11
Steroids (Dexamethasone and Prednisone)
Table 4.3.2.11:
Dose Modifications for Dexamethasone
Event
Dexamethasone
Hypertension
Dose should not be reduced.
Hyperglycemia
Dose should not be reduced.
Pancreatitis
Do not modify dose for asymptomatic elevations of amylase and/or lipase. Hold steroids, 
except for stress doses, in the presence of hemorrhagic pancreatitis or severe pancreatitis 
(abdominal pain >72 hours and > Grade 3 amylase elevation (> 2x ULN). Consider 
resuming once improved. Do not make up missed doses.
Severe psychosis
Dexamethasone dose may be decreased by 50% for severe psychosis or switch to 
prednisone.
Osteonecrosis
Do not modify corticosteroid therapy for osteonecrosis Grade 1 (clinically 
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Dasatinib
Table 4.3.2.11:
Dose Modifications for Dexamethasone
Event
Dexamethasone
asymptomatic, radiographic finding only). For ≥ Grade 2 avoid prolonged treatment 
with dexamethasone for 6 months and until joint symptoms have resolved and any MRI 
findings have improved (if applicable).
4.3.2.12
Thioguanine
Doses may be interrupted during the 2 applications of protocol IIb but doses should not be 
modified unless there is evidence of TPMT polymorphisms.

If homozygous deficient for TPMT, administer 10% of the original dose.

If heterozygous for TPMT, administer 30-50% of the original dose and escalate to 100% 
dose as tolerated.

If wild type, continue at original dose.
4.3.2.13
Vincristine
Table 4.3.2.13:
Dose Modification for Vincristine
Event
Vincristine
Grade 3 neuropathic 
pain
Hold dose(s). When symptoms subside, resume at 50% previous dose (maximum dose: 
1 mg), then escalate to full dose as tolerated.
Vocal cord paralysis
Hold dose(s). When symptoms subside, resume at 50% previous dose (maximum dose: 
1 mg), then escalate to full dose as tolerated.
Grade 3 motor 
neuropathy
Consider holding dose(s). When symptoms subside, consider resuming at 50% previous 
dose (maximum dose: 1 mg), then escalate to full dose as tolerated.
Jaw pain
Do not modify dose.
Direct bilirubin 
3.1 - 5 mg/dL
50% dosage decrease (maximum dose: 1 mg)
Direct bilirubin 
5.1 - 6 mg/dL
75% dosage decrease (maximum dose: 0.5 mg)
Direct bilirubin 
> 6 mg/dL
Withhold dose and administer next scheduled dose if toxicity has resolved. Do not 
make up missed doses.
Grade 3 constipation 
or ileus
Consider holding dose(s). When symptoms subside, resume at 50% previous dose 
(maximum dose: 1 mg), then escalate to full dose as tolerated.
4.4
Blinding/Unblinding
Not applicable for this open-label study.
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Dasatinib
4.5
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the patient’s 
medication diary, medical record and eCRF.
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be destroyed 
on site, it is the investigator’s responsibility to ensure that arrangements have been made for the 
disposal, procedures for proper disposal have been established according to applicable 
regulations, guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. The unused study drugs can only be destroyed after being inspected and 
reconciled by the responsible BMS Study Monitor.
4.6.2
Return of Study Drug
Study drug will not be returned. All unused and/or partially used study drug may be destroyed on 
site providing the site has an applicable standard operating procedure on file.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Key to Abbreviations: IA - Induction A; IB - Induction B; HR1-HR3 - High Risk Blocks; R1 - Reinduction #1; IM - Interim 
Maintenance; R2 - Reinduction #2; C - Continuation; EOT - End of Treatment; F/U - Follow-up
Table 5.1A:
Protocol CA180372 Flow Chart/Time and Events Table
Procedure
Screeninga
IA
IB
HR1
HR2
HR3
End I/HR Blocks
R1
IM
R2
C
HSCT 
Subjectsb
EOTc
F/Ud
Notes
WITH post-
HSCT 
Dasatinib
Informed Consent
X
Inclusion/Exclusi
on Criteria
X
Medical History
X
Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam includes vital signs (heart rate, respiratory 
rate, blood pressure), height and weight, performance status, 
and extramedullary assessment prior to the start of each 
block. End of I/HR blocks perform extramedullary exam 
only for disease assessment.
Assessment of 
adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
HSCT Summary
X
For subjects who receive a HSCT, summary data will be 
collected.
Chest X-Ray
X
12-Lead ECG
X
X
X
Prior to the start of each indicated block and as clinically 
indicated.
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Table 5.1A:
Protocol CA180372 Flow Chart/Time and Events Table
Procedure
Screeninga
IA
IB
HR1
HR2
HR3
End I/HR Blocks
R1
IM
R2
C
HSCT 
Subjectsb
EOTc
F/Ud
Notes
WITH post-
HSCT 
Dasatinib
Echocardiogram
or MUGA as per 
local practice
X
X
X
Prior to the start of each indicated block and as clinically 
indicated.
CBC & 
Differential
X
X
X
X
X
X
X
X
X
X
X
X
Prior to the start of each block and as indicated
NOTE: In HR1, HR2 and HR3 every 2 days after 
completion of chemotherapy until recovery as defined in 
sections 4.3.1.3-4.3.1.5.
Serum Chemistry
X
X
X
X
X
X
X
X
X
X
X
Chemistry panel includes: BUN (or UREA), creatinine, 
HCO3, ALT, AST, total bilirubin, direct bilirubin (at 
screening and if clinically indicated), LDH, Na, K, Cl, Mg, 
PO4, total serum or ionized Ca and uric acid. Prior to the 
start of each block and as clinically indicated
Pregnancy Test
X
X
X
X
X
X
X
X
X
X
X
X
For women of childbearing potential pregnancy tests must 
be performed monthly. The pregnancy test at screening 
must be performed within 24 hours prior to the start of 
dasatinib.
CSF sample and 
analysis
X
X
X
X
X
X
X
X
Cell count including RBC and WBC and cytopathology 
including blast cells performed at each intrathecal dose
Mutation analysis 
X
X
Mutation testing performed at baseline and if evidence of 
relapse during follow-up. Mutation testing at baseline will 
be performed off of previously banked diagnostic samples.
Bone marrow is preferred specimen, peripheral blood is also 
acceptable.
Bone Marrow 
Blast %
X
X
X
X
X
X
And as clinically indicated to confirm relapse
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Table 5.1A:
Protocol CA180372 Flow Chart/Time and Events Table
Procedure
Screeninga
IA
IB
HR1
HR2
HR3
End I/HR Blocks
R1
IM
R2
C
HSCT 
Subjectsb
EOTc
F/Ud
Notes
WITH post-
HSCT 
Dasatinib
Cytogenetic or 
Molecular 
analysis for
Philadelphia 
Chromosome 
status
X
To be performed via local practice
Bone Marrow 
MRD Assessment
X
X
X
X
X
X
X
Bone marrow MRD assessments will be assessed via: 1) 
PCR for Ig/TCR gene rearrangement, 2) PCR for BCR-ABL 
ratio, and 3) multiparameter flow cytometry. Bone marrow 
samples prior to each indicated treatment block should be 
obtained once peripheral blood counts have recovered. 
Subjects with HSCT and post-HSCT dasatinib should have 
a bone marrow MRD assessment at 3 and 12 months after 
transplant. Additional assessments as clinically indicated. If 
a bone marrow cannot be obtained, assessment could be 
done from peripheral blood provided the peripheral blood
percentage of blasts is 40%. See Lab Manual for details.
Assessment of 
survival and 
second 
malignancies
X
All subjects should be contacted by phone every 3 months if 
not seen at the site. 
Assessment must be performed at the 3 and 5 year 
milestones following 1st dose of dasatinib. A visit window 
of one month after each of these milestones is acceptable.
In subjects remaining event free at 3 and 5 years, 
assessments at 3 and 5 years should include at a minimum: 
CBC with diff, PE for extramedullary relapse and second 
malignancy.
Any death or second malignancy should be reported within 
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Table 5.1A:
Protocol CA180372 Flow Chart/Time and Events Table
Procedure
Screeninga
IA
IB
HR1
HR2
HR3
End I/HR Blocks
R1
IM
R2
C
HSCT 
Subjectsb
EOTc
F/Ud
Notes
WITH post-
HSCT 
Dasatinib
1 and 4 weeks, respectively, of the investigator or study 
personnel being informed while the subject is on study.
See Section 3.1 for details.
Cranial Irradiation
X
Cranial irradiation during interim maintenance for patients 
with CNS3 disease only
Dispense 
Dasatinib
X
X
X
X
X
X
X
X
X
X
a Screening activities should be conducted within 21 days prior to treatment with dasatinib, except the screening CBC, and serum chemistries which should be 
performed within 72 hours prior to the start of dasatinib therapy. The pregnancy test at screening must be performed within 24 hours prior to the start of 
dasatinib. If test results for these assessments are available within the above time periods, repeat testing is not necessary. Screening bone marrow MRD and 
mutation detection assessments will be performed on samples that have been previously banked prior to this study. No additional bone marrow sample needs 
to be collected at screening.
b Subjects who receive post-HSCT dasatinib should be assessed monthly while receiving dasatinib. Subjects who undergo HSCT and opt not to receive post-
HSCT dasatinib may proceed to the EOT assessment.
c All subjects will be followed for a minimum of 30 days after the last dose of dasatinib to assess dastinib related adverse events. Additional follow-up visits 
will be required every 4 weeks until all dasatinib related toxicities resolve to baseline values (or CTC Grade 1), stabilize, or are deemed irreversible. Refer to 
Section 5.3 for timing for the end of treatment procedures.
d Assessments yearly for up to 5 years after the completion of therapy with dasatinib for all subjects, with or without HSCT. Mutation analysis in the blood and 
bone marrow assessment for % blasts and MRD should only be performed to document relapse if clinically indicated. Adverse event assessment during 
follow-up is only for ongoing dasatinib related toxicities until resolved to baseline values (or CTC Grade 1), stabilize, or are deemed irreversible.
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Table 5.1B:
Long-Term Growth & Development and Bone Mineral Content
Assessments
Baselinea
Annually 
During 
Treatment
Annually for 
5 years after 
completing 
dasatinib
Notes
Height / Weight
X
X
X
X-ray of Left Hand & Wrist for 
assessment of bone-age
X
X
X
Pubertal status (Tanner Stage)
X
X
X
Visual exam only (See Appendix 7). Done at baseline and then yearly 
until 5 years after completion of therapy with dasatinib. Assessments 
performed 1 year from start of treatment for HSCT patients and 
annually for 5 years following dasatinib completion.
Free T4, TSH
X
X
X
FSH, LH in children 8 years of age
X
X
X
IGF-1, IGFbeta-3
X
X
X
Electrolytes
X
X
X
Urinary N-Telopeptide
X
X
X
Bone Alkaline Phosphatase
X
X
X
Bone densitometry (DXA scans)
X
X
X
For children < 5 years of age, DXA scanning may be omitted. Once a 
child is 5 years of age, DXA scanning required yearly until 5 years 
after completion of therapy with dasatinib. See section 5.3.3.
a Baseline assessments should be performed within 3 weeks before starting dasatinib except DXA scans and bone age x-rays which can be done within a 
window of 3 weeks prior or 4 weeks after starting dasatinib.
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5.2
Study Materials
Study sites will receive the following additional study material: 

NCI CTCAE v 4.0 booklets for grading criteria 

Dasatinib Investigator Brochure

Instruction Manual for IVRS

Instructional manual and/or kits for collection, processing and shipment of blood and tissue 
samples

Instructional manual and requisition forms for submission of local safety laboratory data

Medication diary
5.3
Safety Assessments
Informed consent must be obtained prior to any study screening procedures that would not have 
been performed as part of normal subject care. Screening activities should be conducted within 
3 weeks prior to treatment with dasatinib, except the screening CBC, and serum chemistries and 
which should be performed within 72 hours prior to the start of dasatinib therapy. The pregnancy 
test at screening must be performed within 24 prior to the start of dasatinib. Collection of 
samples for long term growth and bone mineral content should be performed within 3 weeks 
before starting dasatinib. DXA scans and bone age x-rays can be done within a window of 
3 weeks prior or 4 weeks after starting dasatinib. If test results for these assessments are 
available within the above time periods, repeat testing is not necessary.
End of treatment procedures must be completed within 30 days after the last dose of dasatinib. 
The end of treatment visit will depend on a subject’s course of treatment and will be performed 
after:

Completion of 104 weeks of chemotherapy in subjects who do not receive a HSCT

Completion of 12 months of post-HSCT dasatinib in subjects who receive a HSCT and 
post-HSCT dasatinib

Completion of at least consolidation block 1 or 3 (HR1 or HR3) in subjects who received a 
HSCT but opt for no post-HSCT dasatinib

Subject withdrawal from the study as per any of the reasons listed in Section 3.5
All subjects will be followed for a minimum of 30 days after the last dose of dasatinib to assess 
dasatinib-related adverse events. Additional follow-up visit(s) will be required every 4 weeks 
until all dasatinib related toxicities resolve to baseline values (or CTC Grade 1), stabilize, or 
are deemed irreversible. 
Any additional medical testing and procedures, whether more frequent or in addition to 
those described, should be performed as medically indicated.
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5.3.1
Physical Examination
Physical exam includes vital signs (heart rate, respiratory rate, blood pressure), height and 
weight, performance status, and extrameduallary assessment. Extramedullary assessment of 
disease outside of the bone marrow and CNS, including hepatosplenomegaly by palpation or 
other extramedullary involvement proven by biopsy.
After completion of treatment, 
extramedullary assessment must be performed 3 and 5 years following the first dose of dasatinib 
in subjects remaining free of any evidence of progression. A visit window of 1 month after but 
not before each of these milestones is acceptable.
5.3.2
Laboratory Test Assessments
All laboratory assessments should follow the schedule as detailed in Table 5.1A and Table 5.1B. 
5.3.2.1
Serum Hematology Tests 
Serum hematology tests include CBC and full differential counts. Hematology tests should be 
conducted according to Table 5.1A and as clinically indicated when relapse/progression is 
suspected.
5.3.2.2
Serum Chemistry Tests 
Chemistry panel includes: BUN (or urea), creatinine, HCO3, ALT, AST, total bilirubin, direct 
bilirubin (at screening and if clinically indicated), LDH, Na, K, Cl, Mg, PO4, total serum or 
ionized Ca and uric acid.
During the long-term follow up period (5 years after completion of dasatinib therapy) serum 
chemistries need only include the electrolyte parameters (Na, K, CL, Mg, PO4, serum or ionized 
Ca).
5.3.2.3
CSF examination
CSF sampling should occur at the same time that subjects receive intrathecal therapy (IT) and 
CSF cell counts should be assessed according to the schedule in Table 5.1A.
5.3.2.4
Pregnancy Test
For women of child-bearing potential, a serum or urine pregnancy test should have a minimum 
sensitivity of 25 IU/L or equivalent units of βHCG. All on-study pregnancy testing should follow 
the schedule detailed in Table 5.1A. 
5.3.3
Long-term Growth and Development and Bone Mineral Content 
Assessments for bone growth, development and bone mineral content should follow the schedule 
detailed in Table 5.1B. The physical exam, laboratory and radiological assessments are further 
summarized in Table 5.1B.
See Appendix 7 for details regarding the Tanner staging. Bone age will be assessed by an 
anteroposterior radiograph of the left hand and wrist. 
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DXA Scanning
Bone mineral content and density will be evaluated with dual-energy-x-ray absorptiometry 
(DXA). Bone mineral content, density and bone area will be evaluated with dual energy x-ray 
absorptiometry (DXA) utilizing pediatric normal reference ranges and pediatric-specific scanner 
software. If possible, subjects should be scanned on the same make and model of DXA scanner 
throughout the study. For subjects below the age of 20 years, scans of the posterior-anterior (PA) 
lumbar spine (L1-L4) and if feasible total body less head (TBLH) should be performed. Subjects 
in long-term follow-up who reach the age of 20 years should have scans of posterior-anterior 
(PA) lumbar spine (L1-L4), total hip and femoral neck performed54. The decision to administer 
sedation medication to reduce ancillary movement and alleviate distress to the subject should be 
carefully considered.
5.4
Efficacy Assessments
5.4.1
Primary Efficacy Assessment
5.4.1.1
Bone Marrow Assessment
A bone marrow aspirate (biopsy optional) will be utilized in determining the primary endpoint of 
the trial and is one of the most critical elements of data for collection. A bone marrow 
assessment will be performed for cytology, conventional cytogenetics and MRD assessment as 
outlined in Table 5.1A. Since these assessments are critical in determining EFS, a bone marrow 
aspirate should be performed as clinically indicated if relapse is suspected in order to document 
an event for the primary endpoint of this trial.
Detailed instructions for the processing and shipment of samples for MRD assessment will be 
provided to all study sites in a separate manual.
5.4.2
Secondary Efficacy Assessments
5.4.2.1
Overall Survival and Secondary Malignancy
Overall survival and secondary malignancies should be assessed according to the schedule in 
Table 5.1A. As these data contribute to the analysis of the primary endpoint and the key 
secondary endpoint of safety, timely reporting of these events is important. Deaths and second 
malignancies should be reported in the case report form within 1 and 4 weeks, respectively of the 
investigator or study personnel being informed.
To fulfill the objective of reporting the 3 year and 5 year EFS rates, all subjects should have a 
follow-up visit performed at the 3 year and 5 year timepoint (or within 1 month thereafter)
following first dose of dasatinib. For subjects remaining free of any evidence of progression, this 
visit should include an assessment for secondary malignancies.
5.4.3
Mutation Analysis
Detailed instructions for the processing and shipment of samples for mutation analysis will be 
provided to all study sites in a separate manual.
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5.5
Pharmacokinetic Assessments
Not Applicable.
5.6
Pharmacodynamics Assessments
Not Applicable.
5.7
Pharmacogenomic/Pharmacogenetic Assessments
Not Applicable.
5.8
Outcomes Research Assessments
Not Applicable.
5.9
Other Assessments 
Not Applicable.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A serious AE (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
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Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) 
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE.
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these 
events must be handled as SAEs. (See Section 6.1.1 for reporting pregnancies).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life 
threatening)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)

medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative).
6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 5 half lives of dasatinib (ie 24 hours) of discontinuation of dosing. If applicable, 
SAEs must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin 
biopsy).
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure.
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy, or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
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SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on 
a Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports 
are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): See Contact Information 
list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. As noted in section 
4.3.1.11, AEs do not need to be reported for subjects going on to HSCT unless considered related 
to the investigational product.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on the 
nonserious AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
All adverse events, including those that are serious, will be graded according to the NCI CTCAE 
version 4.0.
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The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used for all BMS clinical study AEs:

Related - There is a reasonable causal relationship to study drug administration and the AE. 

Not Related - There is not a reasonable causal relationship to study drug administration and 
the AE.
The expression "reasonable causal relationship" is meant to convey in general that there are facts 
(eg evidence such as de-challenge/re-challenge) or other arguments to suggest a positive causal 
relationship.
6.3
Laboratory Test Abnormalities
The following laboratory abnormalities should be captured on the nonserious AE CRF page or 
SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted
It is expected that wherever possible, the clinical, rather than the laboratory term would be used 
by the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half lives after product administration, the investigator must 
immediately notify the BMS (or designee) Medical Monitor of this event and complete and 
forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours and in accordance 
with the SAE reporting procedures described in Section 6.1.1
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug, after a thorough 
discussion of benefits and risk with the subject.
Protocol required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
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Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form.
6.5
Overdose
An overdose is defined as the accidental or intentional ingestion or infusing or any dose of a 
product that is considered both excessive and medically important. All occurrences of overdose 
must be reported as an SAE (see Section 6.1.1 for reporting details).
6.6
Other Safety Considerations
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
An independent Data Safety Monitoring Board (DSMB) is in place for this trial. The DSMB was
initiated prior to the start of the study and will review data for all patients starting from the date 
each subject signs informed consent. The DSMB will review safety data to determine if 
unacceptable toxicity rates warrant a recommendation to discontinue the study due to excessive 
and unacceptable toxicities. Specifics of DSMB activities will be detailed in the DSMB charter. 
An interim analysis will be performed for the DSMB members to review data. Guidelines for 
stopping the study based on excess mortality are pre-specified.
The independent DSMB will communicate their recommendation regarding the continuation of 
the trial to the Sponsor, COG and EsPhALL. The accrual will continue during the review of the 
data.
Schedules of analyses and meeting of the DSMB will be specified in the DSMB charter.
Guidelines for stopping the trial will be used to ensure that the study be terminated as early as 
possible if its application is associated with a treatment related mortality higher than acceptable 
with standard treatments. In the standard treatment, the rates of deaths that will be considered 
acceptable are rates lower than 3% in the induction period or 7% during any further study time 
point, excluding deaths after HSCT.
The DSMB may recommend to stop the trial if there is a high observed to expected rate of death 
over this acceptable limit. 
The tables below show the minimum number of treatment related deaths in induction (after day 
15) and in continuous complete remission (CCR), excluding deaths after HSCT, at which the 
DSMB and the study steering committee should evaluate stopping the study. The method applied 
for developing these guidelines follows a Bayesian approach, extending that of Metha and 
Caine55, 56. In these guidelines, the maximum acceptable level of probability of treatment related 
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deaths in induction (IND) and in CCR were pIND = 3% and pCCR = 7% respectively. The 
number of failures is assumed to be taken from a binomial distribution. The prior distribution for 
the probability of the endpoint of interest was taken as a beta (1,1), corresponding to an 
uninformative uniform distribution. The stopping bounds reported in Table 7A and Table 7B
below are the experimental results that give a posterior probability of 90% or more, of observing 
pIND 3% and pCCR 7%, respectively. 
Table 7A:
Guidelines for Early Stopping Due to Treatment Related 
Mortality in Induction
No. of subjects on treatment
No. of Death Events
11-36
2
37-58
3
59-82
4
83-106
5
Table 7B:
Guidelines for Early Stopping Due to Treatment Related 
Mortality in CCR
No. of Subjects on Treatment
No. of Death Events
11 - 15
2
16 - 25
3
26 - 35
4
36 - 45
5
46 - 56
6
57 - 67
7
68 - 78
8
79 - 90
9
91 - 101
10
Interim Monitoring for Inferior Event-Free survival 
Assumptions specific to efficacy are presented in Section 8.1 Interim analysis will be conducted 
to protect against poor EFS. Under the exponential assumption, three-year EFS of 78% (lower 
limit the 95% confidence interval for an observed 88% EFS rate) translates to a hazard rate of 
0.083. Interim analysis will be based on the estimated hazard rate, testing the alternate 
hypothesis that the hazard rate is > 0.083 (at an alternative of 0.119 which corresponds to a 
3-year EFS of 70%). 
Testing H0: S(3) 0.78 vs. H1: S(3) < 0.78 where S(3) is the 3-year EFS rate.
Test statistics:
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Z_i = (lambda_hat – lambda_0) / sqrt (lambda_0 / T_i)
Where 
Z_i = value of the test statistic at the time of the ith interim analysis
Lambda_hat = estimate of hazard rate at the time of ith interim analysis 
Lambda_0 = estimate of hazard rate under the null hypothesis 
T_i = Total time at risk for patients at the time of ith interim analysis
The t2 spending function will be used to maintain an overall one-sided Type I error rate of 10%. 
The total number of expected events is 26. Interim analyses will be performed as close as 
possible to when 33%, 66%, 100% of the expected information (events), respectively have been 
observed. The corresponding critical values (boundaries) are Z_c: 2.29, 1.76, and 1.37. 
At the time of interim monitoring, if Z_i > Z_c, then the monitoring boundary would be crossed 
and the study will be stopped for inferior EFS.
8
STATISTICAL CONSIDERATIONS
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.2
Populations for Analyses
The following data sets will be used in this study:

All treated/evaluable subjects: Subjects who received at least one dose of dasatinib. 
Demographic, baseline characteristics, safety, efficacy and bone growth and maturation 
assessments will be performed on all treated/evaluable subjects.

Mutation Data Set: All treated subjects who have mutation data available will be included in 
the mutation data set.
8.3
Endpoint Definitions
8.3.1
Primary Endpoint
The 3-year event-free survival (EFS) rate is the primary endpoint where EFS is defined as the 
time from the starting date of dasatinib until an event and will be computed using binomial 
proportions.
Events for EFS are defined as ANY first one of the following: 

Lack of complete response in bone marrow (see below definition)

Relapse at any site 

Development of second malignant neoplasm

Death from any cause
The primary analysis will compare the 3-year EFS rate of dasatinib plus chemotherapy with the 
following historical controls:
1. 3-year EFS rate of chemotherapy alone from the AIEOP-BFM 2000 trial
2. 3-year EFS rate of continuous imatinib added to chemotherapy from the amended 
EsPhALL trial.
Response Criteria for EFS
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Criteria for Response in Bone marrow (BM) are: 

M1: < 5% lymphoblasts (Complete Response in BM)

M2: 5 - 25% lymphoblasts

M3: > 25% lymphoblasts
For the primary analysis, complete response (CR) in the bone marrow will be assessed between 
the start of dasatinib and completion of consolidation block 3 (HR3)/start of first reinduction 
(Protocol II). Those subjects who reach CR within this window will be considered at risk for 
relapse or death without relapse.
Those who do not reach CR (ie, M1 bone marrow) between the start of dasatinib and the last day 
of consolidation block HR3/start of first reinduction (Protocol II) will be considered as an event 
(resistant). For subjects who undergo HSCT, the date of the HSCT will not be considered as an 
event. These subjects will continue to be followed for an event during and after HSCT.
The primary analysis will be performed once the last subject treated has passed the 3-year 
follow-up period to ensure all subjects have the opportunity for 3-year EFS assessments.
Subjects without an event and lost to follow-up before their 3-year assessments will not be 
considered as an event in the primary analysis, however, will be considered an event in the 
sensitivity analysis. The term “lost to follow-up” should be interpreted as discontinuation from 
the study resulting in a stop of any further data collection.
Relapse Criteria for EFS
Relapse is defined as any recurrence of disease, whether in the marrow or extramedullary site: 

CNS relapse: Positive cytomorphology and 5 or more WBC/µL in CSF, or any signs of CNS 
leukemia such a facial nerve palsy, brain/eye involvement, or hypothalamic syndrome.

Testicular relapse: Must be documented by testicular biopsy, in the absence of concomitant 
bone marrow or CNS relapse.

Bone marrow relapse: Patients with an M3 marrow (>25% blasts) after first CR has been 
achieved
Relapse should be histopathologically determined.
All BM samplings, CSF evaluations, physical examinations and death information subsequent to 
achievement of a CR will be utilized to determine relapse, second malignancy and death for EFS 
analysis.
Sensitivity analysis of the primary endpoint of EFS will include stratification of subjects by high 
risk and low/standard risk57,58. These risk groups are defined as follows:
Definition of high risk group:  MRD at end of Induction 1A 0.01%
Definition of low/standard risk: MRD at end of Induction 1A of < 0.01%
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8.3.2
Secondary Endpoints
8.3.2.1
Safety and Feasibility
Treatment related mortality shall define the endpoint of safety and feasibility. A minimum 
number of treatment related deaths in induction (after day 15) and in continuous complete 
remission (CCR) will be pre-specified in the stopping rules. Subjects in CCR are patients who 
reach CR and do not have an event (relapse, death or second malignant neoplasm).
Adverse events and laboratory results will be graded according to the Common Terminology 
Criteria (CTCAE) Version 4.0. Additional laboratory results that are not graded by CTCAE 
Version 4.0 will be presented according to the following categories: below normal limits, within 
normal limits, and above normal limits.
8.3.2.2
Event Free Survival (EFS)
The EFS endpoint is also considered for secondary/sensitivity analyses, including:
1. HSCT considered as an event if the subject discontinues
2. Lost to follow-up considered as an event (at the date of last contact)
3. Induction failures considered as an event at time 0
4. Stratified subgroup analysis of 3-year EFS rates for HSCT status looking at 3 groups: 
subjects who had HSCT, subjects who were eligible to have HSCT but did not, and 
subjects who were ineligible for HSCT.
5. Using Kaplan-Meier estimates of EFS probabilities (for overall EFS estimation including 
the 3-year and 5-year Kaplan-Meier estimates)
6. Stratified by high versus low/standard risk (as defined in Section 8.3.1)
7. Comparing 3-year EFS with results in COG AALL0031 (with alignment of EFS 
definition)
8.3.2.3
Minimal Residual Disease (MRD)
The MRD levels are the proportion of leukemic cells in a sample at a specific time point. The 
method of reference is the quantitative PCR detection of clone-specific immunoglobulin and 
T-cell receptor gene rearrangements (Ig/TCR). The limit of detection of this assay will be 
approximately 10-4 - 10-5 or 0.01% - 0.001%.
PCR for BCR-ABL will be expressed as a ratio of BCR-ABL transcripts compared to a control 
gene (eg ABL) with log reduction compared to baseline. 
8.3.2.4
Complete Remission Rate
Complete remission will be defined as < 5% lymphoblasts in the bone marrow (ie, M1 bone 
marrow) and CSF with no evidence of other extra medullary disease.
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8.3.2.5
BCR-ABL Mutation
A BCR-ABL mutation is defined as the presence of a detectable amino acid substitution in the 
ABL kinase domain.
8.3.3
Exploratory Endpoints
 
 
 
 
 
 
 
 
 
 
 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized using descriptive statistics.
8.4.2
Efficacy Analyses
8.4.2.1
Event Free Survival (EFS)
Comparison of 3-Year EFS Rates with Historical, External Controls
The primary analysis will compare the 3-year EFS of dasatinib plus chemotherapy with external 
historical controls in hierarchical order. The trial will be considered positive if at least the first 
two comparisons are statistically significant. The comparisons will be as follows:
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1. Superiority over chemotherapy alone of AIEOP-BFM 2000
2. Non-inferiority to continuous imatinib plus chemotherapy of the amended EsPhALL trial
3. Superiority over continuous imatinib plus chemotherapy of the amended EsPhALL trial
For the analysis of the primary endpoints, a hierarchical testing procedure will be used so that the 
overall experiment-wise one-sided type I error rate is preserved at 0.05. The difference with the 
3-year EFS rate from the chemotherapy alone control arm will be tested first. If that test is 
significant in favor of dasatinib, then non-inferiority against imatinib plus chemotherapy in the 
amended EsPhALL trial will be tested second. If that test is significant and non-inferiority of 
dasatinib is declared, then superiority testing of the difference with the 3-year EFS rate in the 
continuous imatinib added to chemotherapy arm from the amended EsPhALL trial will be tested 
last. 
The differences in 3-year EFS rates will be computed using binomial proportions of subjects who 
are free of event at 3 years over all treated subjects. Subjects lost to follow-up without an event 
will be considered event free in the primary analysis. All subjects will have the opportunity to be 
followed for 3 years prior to the analysis and the denominator will include all treated/evaluable
subjects.
The differences in event rates along with exact 2-sided 90% Clopper-Pearson CI’s will be 
provided. Test for difference in event rates will be carried out using a two-sided χ2 test. 
Non-inferiority testing against the study treatment in the amended EsPhALL trial will be carried 
out using the corresponding 2-sided 90% CI for the treatment difference and comparing the 
lower confidence limit to the non-inferiority margin of -5%. This margin corresponds to 1/4 of 
the effect size of 18% anticipated in the amended EsPhALL trial over the chemotherapy-only 
control of the original EsPhALL trial.
All of the above tests will be performed at the 0.05 (one-sided) significance level. Analyses will 
be conducted in the treated population (ie, subjects enrolled but never treated with study drug 
will not be part of the co-primary endpoints).
The difference in 3-year EFS rate with the 3-year EFS rate of available historical controls such as 
COG AALL0031 will be computed using binomial proportions as a secondary objective. When 
comparing with these controls, the definition of event in EFS may be modified in order to align 
the endpoints for a relevant comparison.
Overall EFS
Overall estimation of EFS is one of the key secondary endpionts. Overall estimation of the EFS 
of dasatinib plus chemotherapy will be performed utilizing the Kaplan-Meier (KM) Product 
Limit method. The medians will be provided with their 2-sided 95% CI computed using the 
method of Brookmeyer and Crowley. The 3-year and 5-year EFS rates will be computed with the 
corresponding 95% CI's using Greenwood's formula for computing the standard error will be 
provided. Analyses of EFS will include KM plots with number of patients at risk.
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In the secondary endpoint of overall EFS estimation via the KM method, subjects who neither 
relapse nor die or who are lost to follow-up will be censored on the date of their last bone 
marrow, CSF assessment or physical exam, whichever occurs last.
Additionally, sensitivity analyses will be performed on the primary endpoint, EFS as described 
in section 8.3.2.2.
 
 
 
 
8.4.2.3
Complete Remission Rate
Complete remission will be assessed between the start of dasatinib and the last day of induction 
IA in all treated subjects.
 
 
 
 
 
 
 
 
 
 
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Rates
The rates of MRD negative subjects will be computed for each of the time points, and defined as 
the number of MRD negative among all treated subjects. In order to include all treated subjects
in the MRD rate analysis, those without any valid Ig/TCR assessment (eg. missing data) will be 
considered as MRD positive (ie non-responders) for response rates computations. The exact 
2-sided 95% Clopper-Pearson Confidence Interval will be used.
MRD Levels as a Prognostic Factor for EFS Methods 
For the 3 methods of MRD evaluation, Kaplan-Meier plots will be used to estimate the time from 
the MRD assessment until the event given the category of MRD levels (landmark analyses for 
MRD-negative, very low positive, low positive and high positive). The medians will be provided 
with their 2-sided 95% CI computed using the method of Brookmeyer and Crowley.
Comparison Between MRD Methods
Concordance tables between the reference test (Ig/TCR) and each of the 2 other methodologies 
will be done for each of the MRD time points and for 3 different thresholds (0.1 %, 0.01 %, no 
leukemia cells detected). 
McNemar tests will be done on 2 x 2 tables (subjects with < 0.1% vs. subjects with 0.1%; 
subjects with < 0.01% vs. subjects with 0.01%; subjects with no cells detected vs. subjects with 
cells detected).
Kappa coefficients will be computed on 4 x 4 tables (0.1 %; 0.01 - 0.1 %; detected with a level 
< 0.01%; undetectable).
To describe the correlation between the methods, Pearson correlation coefficient and graphical 
methods (Ig/TCR vs. BCR-ABL and Ig/TCR vs. flow cytometry) will be used. 
8.4.2.5
Mutation Analysis
BCR-ABL mutation status will be analyzed at baseline and at disease progression or relapse. The 
specific type and frequency of mutations in BCR-ABL kinase domain will be summarized using 
descriptive statistics.
 
 
 
 
 
8.4.3
Safety Analyses
Death rates during induction as well as in subjects in CCR will be monitored as per the stopping 
rules described in protocol Section 7.
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Overall safety analysis will include the frequency of all adverse events and laboratory 
abnormalities as well as frequency of dose interruptions, dose reductions and treatment 
discontinuations for study drug related toxicity. Toxicities will be coded using the most current 
version at the time of analysis of Medical Dictionary for Regulatory Activities (MedDRA) 
system organ classes.
In subjects opting to continue dasatinib post HSCT, the safety of dasatinib will be described 
separately.
 
 
 
 
 
 
 
 
 
8.4.4
Pharmacokinetic Analyses
Not Applicable.
8.4.5
Pharmacodynamic Analyses
Not Applicable.
8.4.6
Pharmacogenomic Analyses
Not Applicable.
8.4.7
Outcomes Research Analyses
Not Applicable.
8.4.8
Other Analyses 
Not Applicable.
8.5
Interim Analyses
Interim analyses of efficacy and safety will occur for the Data Safety and Monitoring Board 
(DSMB) review as described in section 7.
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9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

Bristol-Myers Squibb

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. 
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
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9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the sponsor, whichever is longer. The investigator must contact BMS prior to 
destroying any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by the sponsor) is maintained at each study site where 
study drug is inventoried and dispensed. Records or logs must comply with applicable 
regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label ID number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

non-study disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to the sponsor

retain samples for bioavailability/bioequivalence, if applicable 

dates 
and 
initials 
of 
person 
responsible 
for 
Investigational 
Product 
(IP) 
dispensing/accountability, as per the Delegation of Authority Form.
The sponsor will provide forms to facilitate inventory control if the investigational site does not 
have an established system that meets these requirements.
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9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data reported on the CRF that are derived from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. 
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by the sponsor. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by a qualified physician who is an investigator or subinvestigator. 
For electronic CRFs, review and approval/signature is completed electronically through the BMS 
electronic data capture tool. The investigator must retain a copy of the CRFs including records of 
the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by the sponsor. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected considering the following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (eg, among the top quartile of enrollers)

Involvement in trial design

Regional representation (eg, among top quartile of enrollers from a specified region or 
country)

Other criteria (as determined by the study team)
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The data collected during this study are confidential and proprietary to the sponsor. Any 
publications or abstracts arising from this study require approval by the sponsor prior to 
publication or presentation and must adhere to the sponsor’s publication requirements as set forth 
in the approved clinical trial agreement (CTA). All draft publications, including abstracts or 
detailed summaries of any proposed presentations, must be submitted to the sponsor at the 
earliest practicable time for review, but at any event not less than 30 days before submission or 
presentation unless otherwise set forth in the CTA. Sponsor shall have the right to delete any 
confidential or proprietary information contained in any proposed presentation or abstract and 
may delay publication for up to 60 days for purposes of filing a patent application.
In the event of any conflict between the publication provisions detailed above and those stated in 
the clinical trial agreement, the publication terms in the clinical trial agreement shall prevail.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator or 
the sponsor as related to the investigational product
Unexpected Adverse 
Reaction
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved investigational 
product)
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11
LIST OF ABBREVIATIONS
Term
Definition
ACI
As Clinically Indicated
ADR
Adriamycin
AE
Adverse Event
AIEOP
Associazione Italiana di Ematologia Pediatrica
ALL
Acute Lymphoblastic Leukemia
ALT
Alanine Aminotranferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ARA-C
Cytarabine Arabinoside
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BCR-ABL
Oncogene fusion protein 
BFM
Berlin-Frankfurt-Müenster Leukemia Backbone Therapy
βHCG
Beta Human Chorionic Gonadotropin
Bili
Bilirubin
BM
Bone Marrow
BMS
Bristol-Myers Squibb
BP
Blood Pressure
BP - CMP
Blast Phase Chronic Myeloid Leukemia
BUN
Blood Urea Nitrogen
C2
2nd Cervical Vertebrae
C
Continuation
Ca
Calcium
CBC
Complete Blood Count
cc
cubic centimeter
c-FMS
Macrophage Colony-Stimulating Factor
CF-Rescue
Citrovorum Factor (Leucovorin)
CCR
Complete Cytogenetic Response
CFR
Code of Federal Regulations
CHR
Complete Hematologic Remission
CI
Confidence Interval
Cl
Chloride
Cmax
Peak Serum Concentration
CML
Chronic Myeloid Leukemia
CMV
Cytomegalovirus
CNS
Central Nervous System 
COG
Children’s Oncology Group
CPM
Cyclophosphamide
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Term
Definition
CrCl
Creatinine Clearance
CRF
Case Report Form
CSF
Cerebrospinal Fluid
CT
Computerized Tomography
CTA
Clinical Trial Agreement
CYP3A4
Cytochrome P450 3A4
CxRT
Cranial Radiotherapy
DEXA/DXM
Dexamethasone
DFS
Disease Free Survival
DFCI Consortium
Dana Farber Cancer Institute Consortium
DLT
Dose Limiting Toxicity
dL
Deciliter
DNR
Daunorubicin
DOX
Doxorubicin
DSMB
Data Safety Monitoring Board
DXA
Dual-Energy-x-ray absorptiometry
EBV
Epstein - Barr Virus
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EFS
Event Free Survival
EMA
European Medicines Agency
EOT
End of Treatment
EsPhALL
European InterGroup Study on Post Induction Treatment of 
Philadelphia Positive Acute Lymphoblastic Leukemia
Etop
Etoposide
FFP
Fresh Frozen Plasma
FISH
Fluorescent in situ Hybridization
FSH
Follicle Stimulating Hormone
F/U
Follow-up
G
Glucose
G-CSF
Granulocyte Colony Stimulating Factor
GCP
Good Clinical Practice
GFR
Glomerular Filtrate Rate
GI
Gastrointestinal
G-6PD
Glucose-6-phosphate dehydrogenase
Gy
Gray (amount of radiation in photon radiation therapy)
H2
Histamine
HC
Hydrocortisone
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Term
Definition
HCO3
Bicarbonate
HD
High Dose
HD-ARA-C
High Dose Cytarabine
HD-MTX
High Dose Methotrexate
h or hr
Hour
HIV
Human Immunodeficiency Virus
HLA
Human Leukocyte Antigen
HMG COA
3-hydroxy-methyl-glutaryl COA
HR
Hour
HR 1
Consolidation High Risk Block 1 
HR 2
Consolidation High Risk Block 2
HR 3
Consolidation High Risk Block 3
HRT
Hormone Replacement Therapy
HSCT
Hematopoietic Stem Cell Transplant
HVL
Half Value Layer
Hyper-CVAD
Hyperfractionated doses of Cyclophosphamide, Vincristine, 
Adriamycin (Doxorubicin), and Dexamethasone (Methotrexate 
and Cytarabine also used)
IA
Induction Phase A
IB
Induction Phase B
ICH
International Conference of Harmonization
ID
Identification 
IEC
Independent Ethics Committee
IFO
Ifosfamide
IGF-1
Insulin Like Growth Factor - 1
IGFB-3
Insulin like Growth Factor Binding Protein - 3
Ig/TCR
Immunoglobulin and T-cell Receptor
IM
Interim Maintenance or Intramuscular
IMP
Investigational Medicinal Product
IMRT
Intensity Modulated Radiation
IND
Investigational New Drug
IP
Investigational Product
IRB
Institutional Review Board
IT
Intrathecal
IU
International Unit
IVRS
Interactive Voice Response System
IV
Intravenous
K
Potassium
KCl
Potassium Chloride
Kg
Kilogram
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Term
Definition
KM
Kaplan Meier
L
Liter
LAAM
Levo-alpha-acetyl-methadol
L-ASP
L-Asparaginase
LCV
Leucovorin
LDH
Lactate dehydrogense
LH
Luteinizing Hormone
LP
Lumbar Puncture
LVEF
Left Ventricular Ejection Fraction
MaHR
Major Hematologic Response
Max
Maximum
Min
Minute
Msec
Millisecond
MCyR
Major Cytogenetic Response
MEdDRA
Medical Dictionary for Regulatory Activities
MESNA
2-Mercaptoethane Sulfonate Sodium
mEq
Milliequivalents
meTIMP
Methythionosine-5-Monophosphate
Mg
Magnesium
Mg
Milligram
mm HG
Millimeters of Mercury
mL
Milliliter
6-MP
Mercatopurine
MRD
Minimum Residual Disease
MRI
Magnetic Resonance Imaging
MTX
Methotrexate
MV
Megavolt
N
Number or Sample Size
NA
Not Applicable
Na
Sodium
NaCL
Sodium Chloride
NaHCO3
Sodium Bicarbonate
NCI-CTCAE
National Cancer Institute Common Terminology Criteria 
non-TBI
non-total body irradiation
nM
Nanometer
NS
Normal Saline
OS
Overall Survival
OZ
Ounce
PA
Posterior-anterior
PEG-ASP
Polyethylene Glycol Asparaginase
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Term
Definition
Ph-
Philadelphia Chromosome Negative
Ph+
Philadelphia Chromosome Positive
pCCR
Probability in Continuous Complete Remission
PCR
Polymerase Chain Reaction
PDGFR
Platelet Derived Growth Factor Receptor
pH
Concentration of Hydronium Ions
pIND
Probability in Induction
PO
Orally
PT
Prothrombin Time
PTL
Platelet
PO4
Phosphate
Q
Every
qPCR
Quantitative Polymerase Chain Reaction
QT; QTc
QT interval; Corrected QT Interval
R1
Reinduction 1
R2
Reinduction 2
RANKL
Receptor Activator of Nuclear Factor Kappa B Ligand
RQ-PCR
Real Time Quantitative Polymerase Chain Reaction
RT-PCR
Real Time Polymerase Chain Reaction 
SAE
Serious Adverse Event
SC
Subcutaneous
SFK
Src Family Kinases
Src
Src Tyrosine Kinase
TBI
Total Body Irradiation
TBLH
Total Body Less Head
T-cell
Thymus Cell
6-TG
Thioguanine
TKI
Tyrosine Kinase Inhibitor
TMP/SMX 
Trimethoprim/sulfamethoxazole
TSH
Thyroid Stimulating Hormone
T4
Thyroxine
g
Microgram
L
Microliter
M
Micromolar
ULN
Upper Limit of Normal
VCR
Vincristine
WBC
White Blood Cell 
WOCBP
Women of Childbearing Potential
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12
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14 Schultz KR, Bowman WP, Aledo A, et al. Continuous Dosing Imatinib with Intensive 
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21 Talamonti MS, Roh MS, Curley SA, et al. Increase in activity and level of pp60c-src in 
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23 Pene-Dumitrescu T, Peterson LF, Donato NJ, Smithgall TE. An inhibitor-resistant mutant of 
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24 Porkka K, Koskenvesa P, Lundan T, et. al. Dasatinib crosses the blood-brain barrier and is an 
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25 Slayton W, Schultz K, Jones T, et. al. Continuous dose dasatinib is safe and feasible in 
combination with intensive chemotherapy in pediatric Philadelphia chromosome positive 
acute lymphoblastic leukemia (Ph+ ALL): Children's Oncology Group (COG) Trial 
AALL0622. Blood (ASH Annual Meeting Abstracts) 2012 120: Abstract 137.
26 Investigator Brochure Dasatinib BMS-354825, Version 10, Princeton, NJ: Bristol-Myers 
Squibb; 3 November 2010. BMS Document Control No. 930003494.
27 Ottmann O, Dombret H, Martinelli G, et. al. Dasatinib induces rapid hematological and 
cytogenetic responses in adult patients with Philadelphia chromosome positive acute 
lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 
2 study. Blood. 2007 Oct 1;110(7): 2309-15.
28 Lilly MB, Ottmann OG, Shah NP, et. al. Dasatinib 140 mg once daily versus 70 mg twice 
daily in patients with Ph-positive acute lymphblastic leukemia who failed imatinib: results 
from a phase 3 study. Am J Hematol. 2010 Mar; 85(3):164-70.
29 Ravandi F, O’Brien S, Thomas D, et. al. First report of phase 2 study of dasatinib with hyper-
CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) 
acute lymphblastic leukemia. Blood 2010 Sep 23;116 (12): 2070-7.
30 Aplenc R, Blaney SM, Strauss LC, et. al. Pediatric phase I trial and pharmacokinetic study of 
dasatinib: a report from the Children’s Oncology Group phase 1 consortium. J Clin Oncol. 
2011 Mar 1; 29(7): 839-44.
31 Chow EJ, Friedman DL, Yasui Y, et al. Decreased adult height in survivors of childhood 
acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study. J Pediatr 
2007; 150:370–75.
32 Atkinson SA, Halton JM, Bradley C, et al. Bone and mineral abnormalities in childhood 
lymphoblastic leukemia: Influence of disease, drugs and nutrition. Int J Cancer Suppl 1998; 
11:35-9.
33 Lee WY, Kang MI, Baek KH. The Skeletal Site-Differential Changes in Bone Mineral 
Density Following Bone Marrow Transplantation: 3-Year Prospective Study. J Korean Med 
Soc 2002; 17:749-54.
34 Baek KH, Lee WY, Oh KW, et al. Changes in the serum growth factors and osteoprotegerin 
after bone marrow transplantation: impact on bone and mineral metabolism. J Clin 
Endocrinol Metab 2004; 89:1246-54.
35 Chemaitilly W, Boulad F, Heller G, et. al. Final height in pediatric patients after 
hyperfractionated total body irratdiation and stem cell transplant. Bone Marrow Transplant 
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36 Sanders JE, Guthrie KA, Hoffmeister PA, et. al. Final adult height of patients who received 
hematopoietic cell tranplantation in childhood. Blood 2005 Feb 1;105(3): 1348-54.
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37 Millot F, Baruchel A, Guilhot J, et al. Imatinib is efficient but has a negative impact on 
growth in children with previously untreated chronic myelogenous leukemia (CML) in early 
chronic phase (CP): Results of the French national phase IV trial. Blood 2009; 114:356 
(abstract 863).
38 Mariani S, Giona F, Basciani S, et al. Low bone density and decreased inhibin-B/FSH ratio 
in a boy treated with imatinib during puberty. Lancet 2008; 372:111-2.
39 Kimoto T, Inoue M, Kawa K. Growth deceleration in a girl treated with imatinib. Int J 
Hematol 2009 Mar; 89(2):251-2. Epub 2009 Jan 20.
40 Berman E, Nicolaides M, Maki RG. Altered Bone and Mineral Metabolism in Patients 
Receiving Imatinib Mesylate. N Engl J Med 2006; 354:2006-13.
41 Barr RD. Imatinib mesylate in children and adolescents with cancer. Pediatr Blood Cancer 
2010; 55:18-25.
42 Alenshin A, Finn RS. SRC: a century of science brought to the clinic. Neoplasia. 2010 Aug; 
12(8): 599-607.
43 Brownlow N, Mol C, Hayford C. et. al. Dasatinib is a potent inhibitor of tumour-associated 
macrophages, osteoclasts and the FMS receptor. Leukemia. 2009 Mar; 23(3): 590-4.
44 Id Boufker H, Lagneaux L, Najar M, et. al. The Src inhibitor dasatinib accelerates the 
differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts. 
BMC Cancer. 2010 Jun 17;10:298.
45 Shah NP, Kantarjian HM, Kim DW, et. al. Intermittent target inhibition with dasatinib 100 
mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -
intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008 Jul 1;26(19): 3204-12.
46 Bruggemann M, Schrauder A, Raff T, et.al. Standarzied MRD quantification in European 
ALL trials: proceedings of the second international symposium on MRD assessment in Kiel, 
Germany, 18-20 September 2008. Leukemia 2010; 24: 521-535.
47 Cazzaniga G, Lanciotti M, Rossi V, et al. Prospective molecular monitoring of BCR/ABL 
transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in 
treatment response', British Journal of Haematology 2002; 119(2):445-53.
48 Schrappe M, Arico M, Harbott J, et al. Philadelphia chromosome-positive (Ph+) childhood 
acute lymphoblastic leukemia: good initial steroid response allows early prediction of a 
favorable treatment outcome. Blood 1998; 92:2730-41.
49 BMS-354825 Investigator Brochure, Version #5. Princeton, NJ: Bristol-Myers Squibb; 2005. 
Report No.: BMS Document Control No. 930003494.
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50 Conter V, Bartram CR, Valsecchi MG, et. al. Molecular Response to Treatment Redefines 
All Prognostic Factors in Children and Adolescents with B-cell Precursor Acute 
Lymphoblastic Leukemia: Results in 3184 Patients of the AIEOP-BFM ALL 2000 Study. 
Blood. 2010 Apr; 115 (16): 3206-3214.
51 Bruggemann M, Schrauder A, Raff T, et.al. Standarzied MRD quantification in European 
ALL trials: proceedings of the second international symposium on MRD assessment in Kiel, 
Germany, 18-20 September 2008. Leukemia 2010; 24: 521-535.
52 Klyuchnikov P, Schafhausen P, Kroger N, et. al. Second-generation tyrosine kinase inhibitors 
in the post-transplant period in patients with chronic myeloid leukemia or Philadelphia-
positive acute lymphoblastic leukemia. Acta Haemotol 2009; 122: 6-10.
53 Atallah E, Kantarjian H, De Lima M, et. al. The role of dasatinib in patients with 
Philadelphia positive acute lymphcytic leukemia and chronic myeloid leukemia relapsing 
after stem cell transplant. Blood. 2006; 108: 4520.
54 Gordon CM, Bachrach LJ, Carpenter TO, et. al. Dual Energy X-ray Absorptiometry 
Interpretation and Reporting in Children and Adolescents:  The 2007 ISCD Official 
Positions. J of Densitometry: Assessment of Skeletal Health, vol. 11 (1) 43-28, 2008.
55 Metha CR and Caine KC. Charts for the early stopping of pilot studies. J Clin Oncol 1984; 
2:676-82.
56 Mariani L and Marubini E. Design and analysis of phase II cancer trials: a review of 
statistical methods and guidelines for medical researchers. International Statistical Review 
1996; 64: 61 88.
57 Flor T, Schrauder A, Cazzaniga, G, et. al. Minimal residual disease-directed risk stratification 
using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene 
rearrangements in the international multicenter trial AIEOP-BFM 2000 for childhood acute 
lymphoblastic leukemia. Leukemia, 22:771-782, 2008. 
58 Borowitz, MJ, Devidas M, Hunger SP, Bowman WP, Carroll WL, Linda S, Martin PL, 
Pullen DJ, Visawanatha D, Willman CL, Winick N, Camitta BM. Clinical significance of 
minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to 
other prognostic factors. A Children's Oncology Group study. Blood, 111:5477-5485, 2008. 
Epub 2008 April 3. PMID: 18388178. 
59 Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist, 
2nd edition. Stanford, CA: Stanford University Press, 1959.
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APPENDIX 1
MONITORING OF MTX SERUM LEVELS AND INTENSIFICATION 
OF LCV RESCUE BASED ON ESPHALL PRACTICES
Guidelines for intravenous administration of high dose Methotrexate
Cotrimoxazole should be stopped 7 days before the start of the intravenous infusion and can be 
recommenced 7 days after.
Prehydration
Time: Start hydration at least 6 hours prior to the commencement of the intravenous 
methotrexate.
Fluid: 4% glucose with 0.18% normal saline. To each 500 mL add 25 mmol of sodium 
bicarbonate and 10 mmol of potassium chloride.
Infusion rate: 125 mL/m2/h (3 L/m2/day)
NB: Adjust the sodium bicarbonate concentration to maintain the urinary pH between 7 and 8. 
Do not start the infusion until a urinary pH of at least 7 has been achieved.
Dose of Methotrexate:
Dilute the methotrexate in an appropriate volume of saline (0.9%). Infuse 500 mg/m2 of 
methotrexate over 30 minutes and then 4,500 mg/m2 of methotrexate to be infused over 
23.5 hours. Note, even if the infusion is not complete at this time point, it must be stopped.
Hydration during Methotrexate infusion:
Fluid: 4% glucose with 0.18% normal saline. To each 500 mL add 25 mmol of sodium 
bicarbonate and 10 mmol of potassium chloride.
Infusion rate: Hydration needs to continue during the 24 hours of methotrexate infusion to 
maintain a combined infusion rate of 125 mL/h. This may be achieved either by using a 
Y extension set or using both lumens of the central venous line.
Post Methotrexate Hydration:
Continue hydration until Calcium folinate rescue is completed
Fluid: 4% glucose with 0.18% normal saline. To each 500 mL add 25 mmol of sodium 
bicarbonate and 10 mmol of potassium chloride. Infusion rate: 125 mL/m2/h (3 L/m2/day)
Methotrexate levels: Check plasma methotrexate level at 48 hours after start of the 
methotrexate infusion. If the level is 0.5 micromol/L (< 1 x 10-6 M or 0.227 mg/mL), then do 
not give more than three doses of Calcium folinate (42, 48 and 54 hours). If MTX levels at 
48 hours are > 0.5 micromol/L, then continue hydration and Calcium folinate rescue every 
6 hours until MTX levels are < 0.25 micromol/L as per nomogram.
Calcium folinate Rescue: 15 mg/m2 intravenously at 42, 48 and 54 hours and subsequently only 
if the plasma methotrexate level is high (see above). Subsequent doses maybe given orally if 
necessary. Intravenous hydration is stopped when the last dose of Calcium folinate is given.
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Intrathecal Methotrexate: This is ideally as close to 2 hours after the start of the methotrexate 
infusion as possible. The infusion must not be discontinued to carry out the intrathecal 
administration. Intrathecal methotrexate should not be given once the intravenous methotrexate 
infusion has been stopped at 24 hours.
Note: Maintain output at 400 mL/m2 at any 4 hour period.
Table for monitoring of MTX serum levels and intensification of LCV rescue 
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APPENDIX 2
HD-MTX INFUSION AND RESCUE GUIDELINES AND FLOW 
CHART BASED ON COG PRACTICES
When IT therapy and HD MTX are scheduled for the same day, deliver the IT therapy within 
6 hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the 
MTX bolus).
Hold TMP-SMX on the days of HDMTX infusion and for at least 72 hours after the start of the 
HD MTX infusion and until the MTX level is less than 0.4 μM. In the presence of delayed 
clearance continue to hold these medications until MTX level is less than 0.1 M.
For patient's allergic to or experiencing excessive myelosuppression with TMP/SMX, alternative 
prophylaxis with dapsone (1-2 mg/kg/day, maximum dose 100 mg/day), or atovaquone 
(30 mg/kg/day if 1-3 mo. or > 2 years, 45 mg/kg/day if between 3 mo. & 2 years) may be 
considered.
Hold any nonsteroidal anti-inflammatory medications, penicillin, proton pump inhibitors or 
aspirin-containing medications on the day of HD MTX infusion and for at least 72 hours after 
the start of the HD MTX infusion and until the MTX level is less than 0.4 M. In the presence of 
delayed clearance continue to hold these medications until MTX level is less than 0.1 M.
Recommended Prehydration with D5 ¼ NS with 30 mEq NaHCO3/L at 125 mL/m2/hour for at 
least 6 hours and until urine specific gravity is 1.010 and pH is 7 and 8. Ringers Lactate 
may be used as the initial fluid if a bicarbonate containing solution is unavailable. Adjust fluid 
volume and sodium bicarbonate to maintain urine specific gravity and pH at above parameters. 
Give a bicarbonate bolus (25 mEq/m2 over 15 min) to raise the urine pH relatively quickly, a 
normal saline bolus may also be helpful in facilitating hydration. Continue hydration and 
alkalinization throughout HD MTX infusion, and for a minimum of 48 hours after its 
completion. In patients with delayed MTX clearance, continue hydration until the plasma MTX 
concentration is below 0.1 M.
Hour 0: MTX 500 mg/m2 IV mixed in a final volume of 65 mL/m2 D5 ¼ NS with 30 mEq 
NaHCO3/L and infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m2
mixed in a final volume of 2935 mL/m2 D5 ¼ NS with 30 mEq NaHCO3/L given by continuous 
IV infusion over 23.5 hours at 125 mL/m2/hr. Be certain that the HD MTX infusion is completed 
in the 24 hour period. Unintentional prolongation to as long as 26 hours though not encouraged 
is acceptable.
Hours 24, (36), 42 and 48: Draw MTX level and serum creatinine; NOTE: 36 hour level is only 
drawn if needed (see below)
For MTX levels that exceed these expected values modify the rescue regimen as noted 
below and increase hydration to 200 mL/m2/hr, monitor urine pH to assure a value 7 and 
monitor urine output to determine if volume is 80% of the fluid intake, measured every 
4 hours. If serum creatinine rises significantly, at any time point, assure appropriate urine pH and 
urine volume as above and draw a 42 hour level. If urine output fails to continue at 80% of the 
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fluid intake, consider furosemide. Regardless of urine output, also consider glucarpidase 
(carboxypeptidase G2) (See below). For patients with delayed clearance during a previous 
course, begin the following course with the increased hydration (200 mL/m2/hr). If subsequent 
course is not associated with delayed clearance, attempt to use standard hydration.
If the 24 hour level is < 150 M draw the next level at hour 42 and refer to table below.  
If the 24 hour level is 150 M and/or creatinine > 125% baseline, repeat level if MTX 
contamination is possible. If the value is “real” refer to the changes in hydration, etc. described 
above and repeat the level with a serum Cr at hour 36. Then refer to the table below.
If the 42 and 48 hour levels are 1 and 0.4 M, respectively, give leucovorin (racemic form)
at 15 mg/m2 IV/PO at 42, 48 and 54 hours post the start of methotrexate loading dose. No 
additional levels are needed, nor is additional leucovorin.
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Table Appendix 2:
Leucovorin Dose Modifications Based Upon MTX Levels
(36 hr MTX level)
42 hr MTX level
48 hr MTX level
Leucovorin Rescuea
Only required if 
24 hr level 150 
µM. See guidelines 
belowb
1.01 to 9.9 µM
0.41 to 5.9 µM
Continue 15 mg/m2 q 6h until MTX level 
< 0.1 M (draw q12-24 h).
10 to 19.9 µM
6 to 9.9 µM
Increase to 15 mg/m2 q 3h until MTX level 
< 0.1 M (draw q 6-24 h).
Consider glucarpidase.
20 to 200 µM
10 to 100 µM
Increase to 100 mg/m2 q 6h until MTX level 
< 0.1 M (draw q 6-24 h). Consider 
glucarpidase.
> 200 µM
> 100 µM
Increase to 1000 mg/m2 q 6h until MTX level 
< 0.1 M (draw q 6-24 h). Consider 
glucarpidase.
a If the level is high at hour 36 or 42, but then the patient “catches up” and the level falls to the expected values of 
1 and/or 0.4 M at hours 42 and 48, respectively, resume standard leucovorin and hydration as long as urine 
output remains satisfactory.
b If the 36 hour level exceeds 3 micromolar, increase hydration to 200 mL/m2/hr, monitor urine pH to assure a 
value 7 and monitor urine output to determine if volume is 80% of the fluid intake, measured every 4 hours. If 
urine output fails to continue at 80% of the fluid intake, consider furosemide. Regardless of urine output, also 
consider glucarpidase if 36 hour MTX level exceeds 10 micromolar (see below).
NOTE: For patients who have markedly delayed MTX clearance secondary to renal dysfunction, 
consider using glucarpidase (carboxypeptidase G2). To obtain supplies of glucarpidase 
(carboxypeptidase G2, Voraxaze) in the US contact the Voraxane 24-hour Access Call Center. 
Additional 
information 
can 
be 
found 
at 
http://www.btgplc.com/products/speciality-
pharmaceuticals/voraxaze. Canadian sites can contact McKesson at (877)384-7425 for further 
information. 
 
Sites 
in 
Australia 
and 
New 
Zealand 
should 
contact 
medialinformationAUS@hospira.com. Patients requiring glucarpidase rescue will remain on 
study.
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Figure Appendix 2: High Dose Methotrexate Flow Chart
All levels are timed from the start of the HDMTX infusion.
Draw 24-hr MTX level
& Creatinine
MTX < 150 µM
MTX 150 µM or
Cr > 125% baseline
Draw 36-hr MTX level++
(& Creatinine)
MTX > 3 µM
MTX > 10 µM
Consider glucarpidase
Increase hydration 
to 200 mL/m2/hr
Draw MTX level (& Creatinine)
at Hr 42++ & Hr 48
Continue standard hydration
(ie @ 125 mL/m2/hr)
MTX 3 
µM
Hr 42 1 µM
Hr 48 0.4 µM
LCV 15 mg/m2
at hrs 42, 48, & 
54, then stop 
LCV
- No further 
MTX levels 
required
LCV 15 mg/m2 at 
hrs 42, 48, & 54 
and continue 
q6hrs until MTX 
level < 0.1 µM-
Repeat MTX 
levels q12-24 hrs
Hr 42 = 10-19.9 µM 
Hr 48 = 6-9.9 µM
Hr 42 = 20-200 µM
Hr 48 = 10-100 µM
Hr 42 >200 µM
Hr 48 >100 µM
Hr 42 = 1.01-9.9 µM
Hr 48 = 0.41-5.9 µM
LCV 15 mg/m2
starting at hr 42 
and continue 
q3hrs, until MTX 
level < 0.1 µM
Repeat MTX 
levels q6-24 hrs
Consider 
glucarpidase
LCV 100 mg/m2 
starting at hr 42 
and continue 
q6hrs, until MTX 
level < 0.1 µM
Repeat MTX
levels q6-24 hrs
Consider 
glucarpidase
LCV 1000 mg/m2 
starting at hr 42 
and continue 
q6hrs, until MTX 
level < 0.1 µM
Repeat MTX 
levels q6-24 hrs
Consider
glucarpidase
++ If the level is high at hour 36 or 42, but then the patient “catches up” and the level falls to the expected values of 1 and/or 
0.4 µM at hours 42 and 48, respectively, resume standard leucovorin and hydration as long as urine output remains satisfactory.
Consider repeat 
MTX level to r/o 
contamination.
Increase 
hydration while 
awaiting result 
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APPENDIX 3
MEDICATIONS WHICH MAY CAUSE QTC PROLONGATION 
AND TORSADE DE POINTES (NOT ALL INCLUSIVE)
Refer to http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm
Patients are prohibited from taking medications listed in Category 1: Drugs with Risk of Torsade 
de Pointes. Caution is warranted when administering dasatinib to subjects taking drugs 
associated with prolongation of QTc listed in Category 2: Drugs with Possible Risk of Torsade 
de Pointes. 
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APPENDIX 4
COMMON CYP3A4 SUBSTRATES (NOT ALL INCLUSIVE)
The following lists describe medications which are common CYP3A4 substrates. This list should 
not be considered all inclusive. Consult individual drug labels for specific information on a 
compound’s propensity for metabolism by CYP3A4.
Macrolide Antibiotics:
clarithromycin
erythromycin
NOT azithromycin
Anti-arrhythmics:
quinidine
Benzodiazepines:
alprazolam
diazepam
midazolam
triazolam
Immune Modulators:
cyclosporine
tacrolimus (FK506)
HIV Antivirals:
indinavir
nelfinavir
ritonavir
saquinavir
Antihistamines:
astemizole
chlorpheniramine
terfenidine
Calcium Channel 
Blockers:
amlodipine
diltiazem
felodipine
lercanidipine
nifedipine
nisoldipine
nitrendipine
verapamil
HMG CoA Reductase 
Inhibitors:
atorvastatin
cerivastatin
lovastatin
NOT pravastatin
simvastatin
Steroid 6beta-OH:
estradiol
hydrocortisone
progesterone
testosterone
Others:
alfentanyl
buspirone
cafergot
caffeine
cocaine
dapsone
codeine-N-demethylation
dextromethorphan
eplerenone
fentanyl
finasteride
gleevec
haloperidol
irinotecan
LAAM
lidocaine
methadone
odanestron
pimozide
propranolol
quinine
salmetrerol
sildenafil
sirolimus
tamoxifen
taxol
terfenadine
trazodone
vincristine
zaleplon
zolpidem
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APPENDIX 5
COMMON CYP3A4 INHIBITORS (NOT ALL INCLUSIVE)
The following lists describe medications and foods which are strong to moderate inhibitors of 
CYP3A4. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A4.
Table Appendix 5:
CYP3A4 Inhibitors
Strong CYP3A4 Inhibitors
Moderate CYP3A4 Inhibitors
Weak CYP3A4 Inhibitors
5-fold increase in AUC
2 but < 5-fold increase in AUC
1.25 but < 2-fold increase in AUC
atazanavir, clarithromycin, 
indinavir, itraconazole, 
ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, 
telithromycins
amprenavir, aprepitant, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice(a), 
verapamil
cimetidine
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APPENDIX 6
COMMON CYP3A4 INDUCERS (NOT ALL INCLUSIVE)
The following lists describe medications which are common inducers of CYP3A4. This list 
should not be considered all inclusive. Consult individual drug labels for specific information on 
a compound’s propensity to induce CYP3A4.
HIV Antivirals:
efavirenz
nevirapine
Others:
barbiturates
carbamazepine
glucocorticoids
modafinil
phenobarbital
phenytoin
rifampin
St. John’s wort
troglitazone
pioglitazone
rifabutin
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APPENDIX 8
FOR PERFORMANCE STATUS SCALES
Table Appendix 8:
For Performance Status Scales
STATUS
SCALES
STATUS
KARNOFSKY
LANSKY
KARNOFSKY 
or LANSKY
ZUBROD 
(ECOG)
ZUBROD 
(ECOG)
Normal, no complaints
Fully active, normal
100
0
Normal activity
Able to carry on normal 
activities; minor signs or 
symptoms of disease
Minor restrictions in 
physically strenuous 
activity
90
1
Symptoms, but 
fully 
ambulatory
Normal activity with 
effort; some signs or 
symptoms of disease
Active, but tires more 
quickly
80
Cares for self. Unable to 
carry on normal activity or 
to do active work
Substantial restriction 
of, and less time spent, 
in play activity
70
2
Symptomatic, 
but in bed 
< 50% of the 
day.
Requires occasional 
assistance, but able to care 
for most of his needs
Out of bed, but minimal 
active play; keeps busy 
with quiet activities
60
Requires considerable 
assistance and frequent 
medical care
Gets dressed, but 
inactive much of day; 
no active play, able to 
participate in quiet play
50
3
Needs to be in 
bed > 50% of 
the day, but not 
bedridden
Disabled. Requires special 
care and assistance
Mostly in bed; 
participates in some 
quiet activities
40
Severely disabled. 
Hospitalization indicated 
though death non 
imminent
In bed; needs assistance 
even for quiet play
30
4
Unable to get 
out of bed
Very sick. Hospitalization 
necessary. Active 
supportive treatment 
necessary
Often sleeping; play 
limited to passive 
activities
20
Moribund
No play; does not get 
out of bed
10
5
Moribund
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APPENDIX 10
DEFINITION OF CNS LEUKEMIA AT DIAGNOSIS

CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, regardless 
of the number of white blood cells (WBCs).

CNS 2: In CSF, presence < 5/L WBCs and cytospin positive for blasts, or > 5/uL WBCs but 
negative by Steinherz/Bleyer algorithm:

CNS 2a: < 10/μL RBCs; < 5/L WBCs and cytospin positive for blasts;

CNS 2b: 10/μL RBCs; < 5/L WBCs and cytospin positive for blasts; and

CNS 2c: 10/μL RBCs; 5/L WBCs and cytospin positive for blasts but negative by 
Steinherz/Bleyer algorithm (see below).

CNS 3: In CSF, presence of 5/L WBCs and cytospin positive for blasts and/or clinical 
signs of CNS leukemia:

CNS 3a: < 10/μL RBCs; 5/L WBCs and cytospin positive for blasts;

CNS 3b: 10/μL RBCs, 5/L WBCs and positive by Steinherz/Bleyer algorithm 
(see below);

CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement 
or hypothalamic syndrome).
Method of Evaluating Traumatic Lumbar Punctures (Steinherz/Bleyer algorithm)
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and 
contains 5 WBC/μL and blasts, the following algorithm should be used to distinguish between 
CNS2 and CNS3 disease:
CSF WBC    >    2X
Blood WBC
CSF RBC 
Blood RBC
A patient with CSF WBC 5/μL, CSF RBC 10/μL, and cytospin positive for blasts, whose 
CSF WBC/RBC ratio is at least 2 X greater than the blood WBC/RBC ratio, has CNS3b disease 
at diagnosis. Otherwise, the patient has CNS2c disease.
Example: CSF WBC = 60/μL; CSF RBC = 1500/μL; blood WBC = 46000/μL; blood RBC = 3.0 
X 106/μL:
60      =   0.04   >   2X
46000      = 0.015    (patient has CNS3b disease)
1500 
3.0 X 106
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APPENDIX 11
EXAMPLE INDUCTION THERAPIES PHASE IA
Example Children’s Oncology Group Therapies for Induction 1A
Induction: Weeks 1 - 2 base upon patient subgroup:
Standard Risk B-cell precursor ALL (Age 1-9.99 years, WBC<50,000/l; 50 x 109/L)
Day 1
Intrathecal cytarabine (dose per age)
Day 1-14
Dexamethasone 6 mg/m2/day
Day 1,8
Vincristine 1.5 mg/m2
Day 4
Peg-asparaginase 2500 IU/m2
Day 8
Intrathecal methotrexate (dose per age)
High Risk B-cell precursor ALL (does not meet standard risk criteria above)
Day 1
Intrathecal cytarabine (dose per age)
Day 1-14
Dexamethasone 10 mg/m2/day (ages 1 - 9.99 years)
OR
Prednisone 60 mg/m2/day (ages 10+ years)
Day 1,8
Vincristine 1.5 mg/m2
Day 1,8
Daunorubicin 25 mg/m2
Day 4
Peg-asparaginase 2500 IU/m2
Day 8
Intrathecal methotrexate (dose per age)
T-Cell ALL
Day 1
Intrathecal cytarabine (dose per age)
Day 1-14
Prednisone 60 mg/m2/day
Day 1,8
Vincristine 1.5 mg/m2
Day 1,8
Daunorubicin 25 mg/m2
Day 4
Peg-asparaginase 2500 IU/m2
Day 8
Intrathecal methotrexate (dose per age)
Induction: Weeks 3 - 4
Begin Week 3 Induction therapy regardless of peripheral blood counts.
Do not interrupt Induction therapy for myelosuppression.
Day 15-28
Prednisone 60 mg/m2/day (all subjects will receive prednisone regardless 
of steroid use for first 14 days)
Day 15, 22
Vincristine 1.5 mg/m2
Day 15, 22
Daunorubicin 25 mg/m2
Day 29
Intrathecal methotrexate (dose per age; also on day 15 and 22 if CNS3)
Day 15-28
Dasatinib 60 mg/m2/day (continue after day 28)
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Age-based dosing:
Table Appendix 11A:
Cytarabine Intrathecal Chemotherapy Dosages
Age
ARA-C
1 to < 2
16 mg
2 to < 3
20 mg
3 to < 9
24 mg
9
30 mg
Table Appendix 11B:
Methotrexate Intrathecal Chemotherapy Dosages
Age
Methotrexate
1 to < 2
8 mg
2 to < 3
10 mg
3 to < 9
12 mg
9
15 mg
Alternative Example Dana-Farber Cancer Institute ALL Consortium Induction IA
Day 1
Intrathecal cytarabine (dose per age as below)*
Day 1-3
Methylprednisolone 32 mg/m2/day
Day 4-17
Methylprednisolone 32 mg/m2/day or Prednisone 40 mg/m2/day
Day 4,5
Doxorubicin 30 mg/m2 (with Dexrazoxane 300 mg/m2 in high risk 
subjects)
Day 4,11
Vincristine 1.5 mg/m2 (maximum dose 2 mg)
Day 5
Methotrexate 40 mg/m2
Day 7
PEG-asparaginase 2500 IU/m2
*IT cytarabine continued twice-weekly for CNS2 and CNS3 subjects until 3 consecutive clear CSF specimens
Day 18-32
Methylprednisolone 32 mg/m2/day or Prednisone 40 mg/m2/day
Day 18,25
Vincristine 1.5 mg/m2 (maximum dose 2 mg)
Day 18
IT Methotrexate/Cytarabine/Hydrocortisone (dose per age)
Day 32
IT Methotrexate (dose per age)
Day 15-32
Dasatinib 60 mg/m2/day (continue after day 32)
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Table Appendix 11C:
Intrathecal Dose by Age
AGE
Methotrexate
Ara-C
Hydrocortisone
1 year < 2 years
8 mg
20 mg
8 mg
2 years < 3 years
10 mg
26 mg
10 mg
3 years
12 mg
30 mg
12 mg
Example therapies for Induction IA in the United Kingdom (UK)
In the UK, at the time of being identified as having Ph+ALL, patients will be undergoing 
induction on either Regimen A or B of UKALL 2003. Those on Regimen B will continue 
induction as per the protocol. Those on Regimen A should move to the Regimen A to C 
induction switch. This is to ensure that all patients receive anthracyclines during induction.
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APPENDIX 12
OPTIONAL SUPPORTIVE TREATMENT GUIDELINES
Induction Therapy Phase IB:
Optional hydration guidelines during cyclophosphamide administration:

hyperhydration 3,000 ml/m2 over 24 hours: G 5%+ NaCl 0,45%+ 90 mEq/m2KCl 

MESNA (1/3 of CPM dose, hours 0, 4, 8 from CPM start). 

FUROSEMIDE 0.5-1 mg/kg i.v if input > output +400ml/ m2/12 h. 
Consolidation Block 1 (HR1):
Optional MESNA guidelines during cyclophosphamide administration:

MESNA 70 mg/m2 hours 0, 4 and 8 from start of CPM may be used.
Suggested corticosteroid eye drops with high-dose Ara-C:

Prednisolone eye drops every 2-3 hours to both eyes from the start of the cytarabine
infusion for a total of 5 days.
Consolidation Block 2 (HR2):
Optional MESNA guidelines during ifosfamide administration:

MESNA 300 mg/m2 i.v hour 0, 4 and 8 from start of infusion.
Hydration following ifosfamide administration: If a patient stops methotrexate hydration for 
whatever reason, need to continue until 12 hours post ifosfamide infusion.
Consolidation Block 3 (HR3):
Suggested corticosteroid eye drops with high-dose Ara-C:

Prednisolone eye drops every 2-3 hours to both eyes from the start of the cytarabine infusion 
for a total of 5 days.
First Reinduction (Protocol II), Phase IIb:
Optional hydration guidelines during cyclophosphamide administration:

hyperhydration 3,000 ml/m2 over 24 hours: G 5%+ NaCl 0,45%+ 90 mEq/m2KCl 

MESNA (1/3 of CPM dose, hours 0, 4, 8 from CPM start). 

FUROSEMIDE 0.5-1 mg/kg i.v if input > output +400ml/ m2/12 h.
Second Reinduction (Protocol II), Phase IIb:
Optional hydration guidelines during cyclophosphamide administration:
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
hyperhydration 3,000 ml/m2 over 24 hours: G 5%+ NaCl 0,45%+ 90 mEq/m2KCl 

MESNA (1/3 of CPM dose, hours 0, 4, 8 from CPM start). 

FUROSEMIDE 0.5-1 mg/kg i.v if input > output +400ml/ m2/12 h.
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Page:
1 
Protocol Number:
CA180372 
IND Number:
66,971 
EUDRACT Number
2011-001123-20 
 
Date:
20-Sep-2011 
Protocol CA180372: A Phase 2 Study of Dasatinib Added to Standard 
Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome 
Positive Acute Lymphoblastic Leukemia 
Amendment Number 01 
Site Number: All 
Study Director  
Medical Monitor 
 
 
 
 
 
M. Brigid Bradley-Garelik, MD 
 
 
 
 
 
 
Co-Principal Investigator 
Co-Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
24-hr Emergency Telephone Number: 
 
 
 
Bristol-Myers Squibb Research and Development 
  
 
 
This protocol amendment contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS).  
 
This amendment must be maintained with the referenced protocol. 
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Amendment Rationale: 
The following amendment was developed to incorporate two key changes including: 
1) Changing the statistical design of the trial to allow comparison to historical external 
controls.  Specifically, the 3-year event free survival (EFS) of dasatinib plus 
chemotherapy will be compared to the 3-year EFS of chemotherapy alone from the 
Associazione Italiana di Ematologia Pediatrica - Berlin-Frankfurt-Muenster ALL 
2000 (AIEOP BFM 2000) trial and the 3-year EFS of imatinib plus chemotherapy 
from the  European intergroup Study on post induction treatment of Philadelphia 
positive Acute Lymphoblastic Leukemia (EsPhALL).  This analysis will improve the 
ability to interpret the safety and efficacy of dasatinib added to chemotherapy among 
other treatment options for this pediatric leukemia. 
2) Incorporating additional supportive care options for chemotherapy to accommodate 
the standard of care at sites in the United Kingdom (UK). 
 
Additionally, typographical errors were also corrected.  This amendment impacts the 
study conduct (supportive care options with chemotherapy) and data analysis (primary 
endpoint).  The amendment applies to all subjects and should be implemented after 
IRB/IEC/HA review. 
Details regarding changes are outlined in sequential order of the protocol. 
1) Study title, research hypothesis and primary endpoint were modified to incorporate 
comparison to historical controls 
2) Complete remission rates added as a key secondary objective 
3) Changed vincristine dose from day 1 to day 2 in HR1 and HR2 blocks of treatment 
4) Included recommendation for pneumocystis pneumonia (PCP) prophylaxis 
5) Moved optional hydration guidelines with cyclophosphamide and ifosfamide to 
Appendix 12 (supportive care guidelines) 
6) Added additional option for alternative hydration and methotrexate infusion 
guidelines commonly used in the UK to Appendix 1 
7) Included “calcium folinate” and “leucovorin” as additional nomenclature for 
citrovorum factor (folinic acid) 
8) Clarified that corticosteroid eye drops are suggested with high dose Ara-C 
administration 
9) Clarified that G-CSF incorporated in HR1, HR2, and HR3 blocks are optional and 
incorporated into Appendix 12 (supportive care guidelines) 
10) Clarified that asparaginase formulation, PEG-ASP (ONCOSPAR), may be 
administered either i.v. or i.m. 
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11) Corrected timing of asparginase dose in HR2 and HR3 block as day 6 
12) Revised section 8.1, sample size determination to reflect revised primary endpoint of 
comparison with historical, external controls 
13) Included the definition of “high risk” and “low/standard risk” Ph+ ALL 
14) Incorporated the method of analysis for the added secondary endpoint of complete 
remission rate 
15) Incorporated standard induction IA regimens common in the UK as subjects will 
receive this therapy prior to consenting to this trial.  This was added in Appendix 11. 
16) Added Appendix 12 (supportive care guidelines) 
17) Included hematology lab parameters in SI units (Système International d’Unités) 
 
Changes to the Protocol: Cover Page, Title:  
Title modified to reflect the comparison to historical controls.  The Children’s 
Hospital name has been modified to reflect the institutional name change.  
2) Synopsis, Title of Study 
Title modified to reflect the comparison to historical controls  
3) Synopsis, Research Hypothesis 
Modified to reflect the comparison to historical controls.  Specifically, dasatinib 
added to chemotherapy will demonstrate a superior 3-year EFS rate compared to 
chemotherapy alone in the external historical control trial AIEOP BFM 2000 and 
superior 3-year EFS rate compared to imatinib added to chemotherapy in the external 
historical control trial EsPhALL Synopsis, Primary Objective 
Revised to compare the 3-year event-free survival (EFS) with the external historical 
controls of the AIEOP BFM 2000 and EsPhALL trials. 
5) Synopsis, Study Population 
Clarified inclusion criteria 
6) Synopsis, Statistical Methods 
Revised to reflect the new primary endpoint.  
7) Section 1.1, Study Rationale 
Added 3-year EFS data from the AIEOP BFM 2000 trial and expected 3-year EFS 
data from the amended EsPhALL trial. 
8) Section 1.2, Research Hypothesis 
Revised to reflect the new primary endpoint. 
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9) Section 1.3.1, Primary Objective 
Revised to reflect the new primary endpoint. 
10) Section 1.3.2, Secondary Objectives 
Added the key secondary objective of complete remission rates (< 5% blasts in bone 
marrow and no peripheral blasts) at end of induction 
11) Section 1.3.3, Exploratory Objectives 
Removed overall EFS as this is included in the revised secondary endpiont. 
12) Section 3.3.1, Inclusion Criteria 
Clarified inclusion criteria. 
13) Section 4.3, Selection and Timing of Dose for Each Subject, Table 4.3 
Changed to Table 4.3.1.  Changed vincristine dosing in HR1 and HR2 block from day 
1 to day 2 and added SI units to hematology parameters.  Corrected the day of 
administration of L-asparaginase in HR2 and HR3 to day 6.  Added Table 4.3.2 to 
summarize hematological counts prior to the start of each block of therapy.  Ordered 
chemotherapy according to days of administration.  Added Table 4.3B to clarify 
hematological parameters prior to each treatment block. 
14) Section 4.3.1.2, Induction Therapy IB.   
Added that pneumocystis pneumonia (PCP) prophylaxis is recommended with 
trimethoprim/sulfamethoxazole, cotrimoxazole or other appropriate agent against 
Pneumocystis jirovecii according to the institutional standard of care.  SI units were 
added to hematology parameters.  Hydration guidelines for cyclophosphamide were 
clarified as optional and added to a new appendix 12.  Clarified that anti-emetic 
support should be according to standard institutional guidelines. 
15) Section 4.3.1.3, Consolidation Block 1 (HR1) 
SI units were added to hematology parameters.  Vincristine dose was moved from day 
1 to day 2.  Methotrexate hydration guidelines were modified to incorporate the 
standard of care in UK institutions.  Clarified nomenclature for citrovorum factor to 
include calcium folinate and leucovorin.  Clarified that MESNA guidelines were 
optional and moved to appendix 12.  Clarified that corticosteroid eye drops are 
suggested during high-dose Ara-c administration.  Included i.m. administration of the 
asparaginase preparation, PEG-ASP and removed reference to brand name 
ONCASPAR.  Clarified that G-CSF use was optional and moved to appendix 12. 
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16) Section 4.3.1.4, Consolidation Block 2 (HR2) 
SI units were added to hematology parameters.  Vincristine dose was moved from day 
1 to day 2.  Methotrexate hydration guidelines were modified to incorporate the 
standard of care in UK institutions.  Clarified nomenclature for citrovorum factor to 
include calcium folinate and leucovorin.  Clarified that MESNA guidelines were 
optional and moved to appendix 12.  Included i.m. administration of the asparaginase 
preparation, PEG-ASP (ONCOSPAR) and corrected day of administration to day 6.  
Removed reference to brand name of PEG-ASP, ONCASPAR.  Clarified that G-CSF 
use was optional and moved to appendix 12. 
17) Section 4.3.1.5, Consolidation Block 3 (HR3) 
SI units were added to hematology parameters.  Clarified that corticosteroid eye drops 
are suggested during high-dose Ara-c administration.  Included i.m. administration of 
the asparaginase preparation, PEG-ASP and corrected day of administration to day 6.  
Removed reference to brand name of PEG-ASP, ONCASPAR.  Clarified that G-CSF 
use was optional and moved to appendix 12. 
18) Section 4.3.1.6, First Reinduction (Protocol II), Phase IIa 
SI units were added to hematology parameters.  Included i.m. administration of the 
asparaginase preparation, PEG-ASP (ONCOSPAR).   
19) Section 4.3.1.6, First Reinduction (Protocol II), Phase IIb 
SI units were added to hematology parameters.  Clarified that MESNA guidelines 
were optional and moved to appendix 12.  Removed reference to brand name of PEG-
ASP, ONCASPAR.     
20) Section 4.3.1.7, Interim Maintenance 
Added the following hematological parameters to proceed with interim maintenance 
therapy: adequate ANC (≥ 750/µl; 0.75 x 109/L) and platelet counts (≥ 75,000/µl; 75 
x 109/L).  Clarified dose and age range for cranial irradiation. 
21) Section 4.3.1.8, Second Reinduction (Protocol II), Phase IIa  
SI units were added to hematology parameters.  Included i.m. administration of the 
asparaginase preparation, PEG-ASP and removed reference to brand name, 
ONCOSPAR. 
22) Section 4.3.1.8, Second Reinduction (Protocol II), Phase IIb  
SI units were added to hematology parameters.  Clarified that MESNA guidelines 
were optional and moved to appendix 12.   
23) Section 4.3.1.9, Continuation Therapy 
SI units were added to hematology parameters.  Added the following hematological 
parameters to proceed with continuation therapy: adequate ANC (≥ 750/µl; 0.75 x 
109/L) and platelet counts (≥ 75,000/µl; 75 x 109/L).  Clarified the dose modification 
guidelines for chemotherapy. 
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24) Section 4.3.1.11 Hematopoietic Stem Cell Transplant (HSCT) 
Added the use of flow cytometry results for HSCT determination in the event other 
MRD assessments are uninformative. 
25) Section 4.3.2.1, Dasatinib 
SI units were added to hematology parameters.   
26) Section 4.3.2.4, Cytarabine (Ara-C) 
SI units were added to hematology parameters.   
27) Section 4.3.2.5, Daunorubicin or Doxorubicin 
SI units were added to hematology parameters.   
28) Section 4.3.2.8, High-Dose Methotrexate (HD MTX) and Leucovorin Rescue 
SI units were added to hematology parameters.  Criteria for ANC and platelets 
removed as these were greater than criteria to start blocks with HD MTX.   
29) Section 4.3.2.10, PO Methotrexate (MTX) and 6-Mercaptopurine (MP) 
SI units were added to hematology parameters.  Modified dose interruption, reduction 
and escalation guidelines to be consistent with standard supportive care guidelines.   
30) Section 4.3.1.11, Hematopoietic Stem Cell Transplant (HSCT) 
In the rare circumstance that both Ig/TCR and BCR-ABL PCR are uninformative, 
flow cytometry results may be utilized for the HSCT decision. 
31) Section 5.1, Flow Chart/Time and Events Schedule 
Added a new column to Table 5.1A of “End of I/HD blocks” to clarify that 
extramedullary assessment of leukemia, bone marrow blasts and bone marrow MRD 
assessment may be done at the end of induction/HR blocks or beginning of the first 
reinduction block.  Removed reference to growth curve in Table 5.1B as these will be 
automatically derived from height/weight data.  Added clarification about bone 
marrow MRD assessments. 
32) Section 5.3.1, Physical Exam 
Removed reference to growth curve as these will be automatically derived from 
height/weight data. 
33) Section 8.1, Sample Size Determination 
Revised to reflect the new primary endpoint. 
Additional language was added to ensure that at least 20 evaluable subjects for the 
primary endpoint were accrued including for each of the following age ranges: 1 to < 
12 years and 12 to < 18 years. 
34) Section 8.3.1, Primary Endpoint 
Added the definition of high risk and low/standard risk Ph+ ALL for stratification in 
the sensitivity analysis of EFS.   
35) Added Section 8.3.2.2, Event Free Survival (EFS) 
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Definitions for secondary and sensitivity analyses of EFS are described. 
36) Section 8.3.2.2, Minimal Residual Disease (MRD) 
Clarified that PCR for BCR-ABL will be compared to baseline values. 
37) Add Section 8.3.2.4, Complete Remission Rate 
Added the definition for the complete remission rate at end of induction therapy. 
38) Section 8.4.2.1, Estimation of 3-yr EFS rate 
Revised to reflect the modified primary and secondary endpoints. 
39) Section 8.4.2.2, Differences in 3-Year EFS Rate With Other Studies 
Removed as this is now part of the primary endpoint.  This section now reflects time 
to event analysis for DFS and OS. 
40) Section 8.4.2.3, Complete Remission Rate 
Added the method of analysis of complete remission rate to include assessments 
between the start of dasatinib and the last day of induction IB.  Subsequent headers 
renumbered. 
41) Appendix 1, Monitoring of MTX Serum Levels and Intensification of LCV Rescue 
Added guidelines for intravenous administration of high dose Methotrexate 
commonly used at UK institutions. 
42) Appendix 2, HD-MTX Infusion and Rescue Guidelines and Flow Chart 
Removed reference to aerosolized pentamidine as this is a prohibited mediction as 
stated in section 3.4.1.1 due to the potential risk of QTc prolongation when combined 
with dasatinib. 
43) Appendix 11, Example Induction Therapies Phase IA 
SI units were added to hematology parameters.  Example Induction IA therapy 
common among UK institutions was added.  This chemotherapy would be 
administered as part of the standard of care to patients prior to participation in this 
trial. 
44) Appendix 12, Optional Supportive Treatment Guidelines 
Optional supportive treatment for use during chemotherapy administration were 
moved from the body of the protocol to this new appendix. 
 
Please maintain a copy of this amendment with your protocol. Please provide a copy 
to your Investigational Review Board / Ethics Committee, unless agreed otherwise 
with BMS. 
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AMENDMENT ACKNOWLEDGMENT 
I have read this Amendment and agree that it contains all necessary details for carrying 
out the changes described. I understand that it must be reviewed by the Institutional 
Review Board or Independent Ethics Committee overseeing the conduct of the study and 
approved or given favorable opinion by all necessary Health Authorities before 
implementation unless to eliminate an immediate hazard to subjects. 
If this Amendment substantially alters the study design or increases potential risk to 
subjects, the consent form will be revised and submitted to the Institutional Review 
Board/Independent Ethics Committee for approval/positive opinion. I will use the new 
consent form for any new subjects prior to enrollment, and for subjects currently enrolled 
in the study if they are affected by the Amendment. 
 
 
 
 
 
___________________________________  
 
_______________ 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Number: CA180372 
Site Number:  
Amendment Number: 01 
 
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Protocol Number:
CA180372
IND Number:
66,971
EUDRACT Number
2011-001123-20
Date:
07-Dec-2012
Protocol CA180372: A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib 
Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia 
Chromosome Positive Acute Lymphoblastic Leukemia
Amendment Number 02
Site Number: All
Study Director 
Medical Monitor
M. Brigid Bradley-Garelik, MD
Co-Principal Investigator
Co-Principal Investigator
 
24-hr Emergency Telephone Number:
Bristol-Myers Squibb Research and Development
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This document contains information confidential and proprietary to Bristol-Myers Squibb
This protocol amendment contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS). 
This amendment must be maintained with the referenced protocol.
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Amendment Rationale:
The key purposes of this amendment are to incorporate the following key changes:
1. Introduce a new pediatric formulation of dasatinib, a berry flavored oral suspension 
constituted from a powder (also known as the powder for oral suspension (PFOS)) as 
an alternative for administering dasatinib to children unable to swallow tablets. This 
revision should have no impact on study conduct or data analysis. This revision 
applies to all subjects not able to swallow tablets.
2. Address lack of availability of native-asparaginase in the United States and allow use of 
Peg-Asparaginase upfront in such instances as well as provide more detailed 
instruction for dose modifications of the various asparaginase formulations. This 
revision should have no impact on study conduct or data analysis. This revision 
applies to all subjects as indicated in the protocol. 
3. Indicate that the BCR-ABL mutation status will be reported for baseline and at time of 
progression as a secondary objective instead of as an exploratory objective in order to 
bring into alignment with the binding elements of the Pediatric Investigational Plan 
with the EMA. These baseline samples were being collected prior to this amendment 
as per the Time and Events table. This revision should have no impact on study 
conduct and is applicable to all subjects.
4. Since Philadelphia chromosome status determined by RT-PCR with peripheral blood is 
unlikely to result in a false positive result, Philadelphia chromosome positivity from 
peripheral blood will be acceptable for study entry as well as the conventional 
approach in this setting using a bone marrow aspirate. This revision should have no 
impact on study conduct or data analysis. This revision applies to all subjects.
5. The acceptable window for screening activities was expanded from 15 days prior to 
treatment with dasatinib to 21 days, except when noted otherwise, for two reasons; 
1) so that tests that may have been performed as part of the initial diagnostic work up 
such as chest X-ray, ECG, echocardiogram or MUGA and CSF sampling would not 
need to be repeated and 2) in the event there is a delay in initiating day 15 backbone 
chemotherapy treatment with dasatinib for recovery of adverse events or logistical 
scheduling. This expanded window is not expected to increase any potential risk for 
subjects. This revision should have no impact on study conduct or data analysis. This 
revision applies to all subjects.
6. Prior stem cell transplant and Ph+ ALL occurring as a second malignant neoplasm after 
treatment of a prior malignancy were added as exclusion criteria. Although these 
circumstances are rare the prognosis may be different, therefore, in this small study
such prior conditions will be excluded. This revision should have no impact on study 
conduct or data analysis. This revision applies to all subjects.
7. The definition of high risk group and low/standard risk group in response to Induction 1A 
treatment has been modified. In Europe, for induction treatment not adopting a steroid 
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prephase, a day 15 bone marrow is still obtained. However the AIEOP BFM 2000 
study has been reported using the day 29 BM for risk group assignment. Bone 
marrow aspirates are no longer performed in COG centers before day 29. So as not to 
require the study subjects to undergo a BM aspiration at a time point in the therapy 
that is no longer a consistent standard of practice and is not needed for clinical 
management decisions, the protocol will use the end of Induction 1A BM result for 
defining risk groups. The high risk group would be defined by a MRD 0.01%; 
low/standard risk would be defined as day 29 MRD < 0.01%. This approach is 
consistent with the criteria used in other COG trials, and/or NCI risk group and being 
adopted by EsPhALL trials. This revision will impact study conduct by improving 
compliance with obtaining this data point with no added risk for subjects. The data 
analysis will be used to conduct a sensitivity analysis around the EFS endpoint. This 
revision applies to all subjects.
This amendment also provides for clarifications, fixes inconsistencies across sections of the 
protocol and repairs typographical errors as described below. These revisions should improve 
consistency in study conduct but is not expected to have an impact on data analysis. These 
revisions apply to all subjects as they proceed through the treatment blocks.
Changes to the Protocol:
1. Synopsis: Study Design Section, Design paragraph
a) 1st Paragraph, 2nd to last sentence “recovery period (14 days, 2 weeks),” deleted as this 
period is already included as the last 2 weeks of HR3 when only dasatinib is 
administered.
b) 1st Paragraph, last sentence “L” deleted from asparaginase as various forms are allowed.
c) 2nd Paragraph, added a new second sentence and revised subsequent sentence to more 
clearly indicate that the use of dasatinib is optional in HSCT subjects. This change was 
made to be consistent with the in-body text of the existing protocol.
2. Synopsis: Statistical Methods
a) 1st sentence added less than symbol for clarity.
b) Last Paragraph, objective regarding BCR-ABL mutation status moved from exploratory 
objectives to secondary objectives and added “at baseline” to text to bring into alignment 
with the binding elements of the Pediatric Investigational Plan with the EMA. These 
baseline samples were being collected prior to this amendment as per the Time and 
Events table.
3. Section 1.3.2 Secondary Objectives and Section 1.3.3 Exploratory Objectives
a) Objective regarding BCR-ABL mutation status moved from exploratory objectives to 
secondary objectives and added “at baseline” to bring into alignment with the binding 
elements of the Pediatric Investigational Plan with the EMA. These baseline samples 
were being collected prior to this amendment as per the Time and Events table.
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4. Section 1.4.4.1 Formulation
a) Section has been updated to include information on the age appropriate dasatinib Powder 
for Oral Suspension formulation provided for use in this study.
5. Section 3.1 Study Design and Duration - Design Paragraph
a)
2nd Paragraph, first sentence reworded for clarity.
b) 2nd Paragraph, 5th bullet deleted as this period is actually already included as the last 
2 weeks of HR3 when only dasatinib is administered.
c) 2nd Paragraph, 7th bullet deleted “overlaps 2 weeks with end of reinduction block 1)” to 
make consistent with Table 4.3A and section 4.3.1.7 which indicate Interim maintenance 
will start 2 weeks after completion of the last backbone chemotherapy administered in the 
previous phase (which is day 49 of a 63 day block). Dasatinib should continue through 
day 63 of the Reinduction block, until Interim Maintenance begins.
d) 3rd Paragraph, third sentence added to clarify that patients receiving chemotherapy other 
than that prescribed in the protocol should be discontinued from the study and to 
specifically state that dasatinib will not be provided if the patient receives non-protocol 
chemotherapy and 4th, 5th and 6th sentences reworded.
e) 4th Paragraph, added OR between the 1rst and 2nd bullet for clarity and added an 
additional bullet to clarify the quantifiable range.
6. Section 3.2 Post Study Access to Therapy
a) 2nd Paragraph, 2nd and 3rd sentences reworded to emphasize that treatment with 
dasatinib for an additional 12 months post-HSCT is optional.
b) 2nd Paragraph, deleted last sentence which stated there was “no evidence that subjects 
who relapse after multi-agent chemotherapy or HSCT with the addition of dasatinib 
would benefit from further dasatinib treatment” since there is also no evidence that that 
these subjects would not benefit from continued dasatinib treatment. Since this is not a 
question addressed in this study, this sentence was deleted.
7. Section 3.3.1 Inclusion Criteria, Target Population 
a) Item 2 a i, “deleted conventional bone marrow” to allow use of PH positivity determined 
from peripheral blood as well.
b) Item 2 c iv, reorganized acceptable tests for assessment of renal function and added 
gender as an additional qualifier for the upper limit of normal for serum creatinine as 
normal serum creatinine levels in children can differ by gender as well as by age.
c) Item 2 d i, expanded screening window to 21 days prior to starting dasatinib to avoid 
unnecessary repeat of assessments preformed during diagnostic work-up and to 
accommodate delays in initiating day 15 of the backbone chemotherapy.
d) Added new criteria letter e to remind COG sites (excluding DFCI Consortium sites) that 
subjects must be enrolled in the COG Classification Trial (AALL08B1 or successor).
8. Section 3.3.1 Inclusion Criteria, Age and Reproductive Status
a) Item b changed acceptable method to highly effective method of contraception and 72 to 
24 hours prior as per updates to BMS SOP.
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9. Section 3.3.2 Exclusion Criteria, Medical History and Concurrent Diseases
a) Item a, reworded for clarity. The intent of the exclusion criteria regarding active systemic 
bacterial, fungal or viral infections was to prevent the enrollment of patients with ongoing 
serious infections. Infection alone is not a concern for enrolling in the trial. Serious 
infections, with the noted complications of septic shock syndrome that require either 
vasopressor support or mechanical ventilation would be severe enough so that study 
enrollment may not be in the best interest of the patient.
b) Added new criteria letters e and f.
10. Section 3.4.1.1 Prohibited Treatments 
a) 3rd bullet, added azithromycin to complete the list of macrolide antibiotics in this 
category of prohibited drugs.
11. Section 4.1 Study Treatments, Table 4.1
a) Added last row to the table to describe the dasatinib Powder for Oral Suspension.
12. Section 4.1.1 Investigational Product
a) Last Paragraph added to provide information about the dasatinib Powder for Oral 
Suspension.
13. Section 4.1.2 Noninvestigational Product, Table 4.1.2 
a) Methotrexate added under 2nd Reinduction Block as it was accidentally omitted in the 
original table.
14. Section 4.3 Selection and Timing of Dose for Each Subject
a) 2nd Paragraph, ”or no later than when the day 15 induction chemotherapy is 
administered” added in the 2nd sentence to allow for a window for treatment.
15. Section 4.3 Selection and Timing of Dose for Each Subject and Table 4.3A
a) 2nd Paragraph, or no later than when the day 15 induction chemotherapy is administered” 
added in the 2nd sentence. This will allow for minor delays due to scheduling 
adjustments or toxicity of Induction 1A backbone chemotherapy.
b) L-ASP/iv (2h) or im clarified to ASP/iv (1-2h) or im for all Phases to accomodate 
different asparaginase forms and their associated infusion times.
c) L-ASP clarified to asparaginase in the abbreviations at the end of the table.
d) “ Starts no sooner than day 33” added to the Induction Therapy Phase 1B column to 
provide clarity.
e) Sentence regarding recovery period under Consolidation Block 3 was deleted to eliminate 
confusion. This recovery period refers to the 2 weeks in Consolidation Block 3 when no 
backbone chemotherapy is given however dasatinib continues, therefore the 2 weeks are 
already included in the 21 days of Block 3 and this additional recovery period is not 
necessary.
16. Section 4.3.1.1 Induction Therapy Phase 1A
a) 2nd Paragraph, 1st and 2nd sentences modified for clarity and to allow for a window for 
treatment. This will allow for minor delays due to scheduling adjustments or toxicity of 
Induction 1A backbone chemotherapy.
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17. Section 4.3.1.2 Induction Therapy Phase 1B
a) New sentence added after 1st paragraph for clarity and consistency with other sections of 
the protocol.
b) New sentence added at the end of the 6-MERCAPTOPURINE paragraph for clearer 
guidance. 
c) CYTOSINE ARABINOSIDE paragraph, 2nd sentence modified and a new sentence 
added at the end of the paragraph for clarity.
18. Section 4.3.1.3 Consolidation Block 1 (HR1)
a) 2nd Paragraph, 1st sentence modified for clarity.
b) DEXAMETHASONE (DXM) paragraph, fixed typographical error so that 2nd sentence 
refers to appropriate section.
c) HIGH-DOSE METHOTREXATE (HD-MTX) paragraph, Gluc. 5%+ modified to Gluc. 
5%(D5W)+ for clarity and reference to relevant appendices added.
d) CITROVORUM FACTOR paragraph, added reference to relevant appendices.
e) HIGH-DOSE ARA-C (HD-ARA-C) paragraph modified for clarity.
f)
HIGH-DOSE L-ASPARAGINASE (HD-L-ASP) paragraph modified for clarity and new 
wording added to provide additional guidance regarding choice of asparaginase to be 
used.
19. Section 4.3.1.4 Consolidation Block 2 (HR2)
a) DEXAMETHASONE (DEXA) paragraph, fixed typographical error so that 2nd sentence
refers to the appropriate section.
b) HIGH-DOSE METHOTREXATE (HD-MTX) paragraph, Gluc. 5%+ modified to Gluc. 
5%(D5W)+ for clarity.
c) IFOSFAMIDE paragraph, new wording added at end of paragraph to eliminate any 
potential confusion about hydration administrated with and following ifosfamide.
d) HIGH-DOSE L-ASPARAGINASE (HD-L-ASP) paragraph modified for clarity and new 
wording added to provide additional guidance regarding choice of asparaginase to be 
used.
20. Section 4.3.1.5 Consolidation Block 3 (HR3)
a) DEXAMETHASONE (DEXA) paragraph, 2nd sentence modified to refer to Section 
3.4.1.2.
b) HIGH-DOSE L-ASPARAGINASE (HD-L-ASP) paragraph modified for clarity and new 
wording added to provide additional guidance regarding choice of asparaginase to be 
used.
21. Section 4.3.1.6 First Reinduction (Protocol II)
a) 1st Paragraph, 1st sentence modified to provide additional interpretation of the MRD rule 
existing.
b) 2nd Paragraph, 1st sentence modified for clarity.
c) DEXAMETHASONE (DXM) paragraph, fixed typographical error so that the 2nd 
sentence refers to the appropriate section.
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d) DOXORUBICIN (DOX)/ADRIAMYCIN (ADR) paragraph modified to accomodate 
institutional standards.
e) L-ASPARAGINASE (L-ASP) paragraph modified for clarity and new wording added to 
provide additional guidance regarding choice of asparaginase to be used.
f)
New INTRATHECAL METHOTREXATE paragraph added. This Day 1 administration 
originally appeared with the Phase IIb doses. This change makes the text consistent with 
Table 4.3A
g) CYTOSINE ARABINOSIDE paragraph, 2nd sentence modified to be consistent with 
Section 4.3.1.8 and a new sentence added at the end of the paragraph for clarity.
h) INTRATHECAL METHOTREXATE paragraph in Phase IIb modified for clarity.
22. Section 4.3.1.7 Interim Maintenance
a) 1st Paragraph, 2nd sentence modified for clarity.
b) Days adjusted in the METHOTREXATE paragraph to be consistent with AIEOP-BFM 
2009. Dosing logistics are improved but total dose remains the same. 
23. Section 4.3.1.8 Second Reinduction (Protocol II)
a) DEXAMETHASONE (DEXA) paragraph, fixed typographical error so that the 2nd 
sentence refers to the appropriate section.
b) L-ASPARAGINASE (L-ASP) paragraph modified for clarity and new wording added to 
provide additional guidance regarding choice of asparaginase to be used.
c) New INTRATHECAL METHOTREXATE paragraph added. This Day 1 administration 
originally appeared with the Phase IIb doses. This change makes the text consistent with 
Table 4.3A.
d) CYTOSINE ARABINOSIDE paragraph, 2nd sentence modified to be consistent with 
Section 4.3.1.8 and a new sentence added at the end of the paragraph for clarity.
e) Last sentence in the INTRATHECAL METHOTREXATE paragraph modified and 
moved up to the CYTOSINE ARABINOSIDE paragraph where it should be.
f)
INTRATHECAL METHOTREXATE paragraph in Phase IIb modified for clarity.
24. Section 4.3.1.9 Continuation Therapy
a) Corrected typographical errors in the METHOTREXATE paragraph under Dose 
Reduction for Falling Neutrophil Counts and Dose Reduction for Falling Platelet Counts.
25. Section 4.3.1.11 Hematopoietic Stem Cell Transplant (HSCT)
a) Added OR between the 1st and 2nd criteria bullet for clarity and added an additional 
bullet to provide an additional interpretation of the MRD rule.
b) 2nd, 3rd and 4th Paragraphs modified to clarify that patients receiving chemotherapy 
other than that prescribed in the protocol should be discontinued from the study, to state 
that dasatinib will not be provided if the patient receives non-protocol chemotherapy, to 
clarify reporting of concomitant medications and adverse events during the HSCT period 
and to clarify use of dasatinib after HSCT.
26. Section 4.3.2.1 Dasatinib, Table 4.3.2.1 Dose Modifications for Dasatinib
a) First row of Table modified to include Grade 4 events. Grade 4 events are expected to 
occur frequently, especially early in the treatment plan as a result of the backbone 
chemotherapy. Dasatinib can continue despite a grade 4 hematologic event unless the 
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event results in a delay in the next treatment block of > 14 days, in which case dasatinib 
should be interrupted as per instructions in the subsequent row of this table. A 
typographical error was also corrected in the fifth row.
27. Section 4.3.2.2 Asparaginase [PEG, E. coli, or Erwinia]
a) Modified Table 4.3.2.2 and added new Tables 4.3.2.2a and 4.3.2.2b to provide more 
specific guidance regarding substitution of asparaginases during different blocks of 
treatment.
28. Section 4.3.2.4 Cytarabine (Ara-C)
a)
Table 4.3.2.4 modified to include additional dose modification for neurotoxicity.
29. Section 4.3.2.5 Daunorubicin or Doxorubicin
a) Table 4.3.2.5, 1st row modified to allow subsequent doses with improvement of cardiac 
function. 
30. Section 4.3.2.8 High-Dose Methotrexate (HD MTX) and Leucovorin Rescue
a) 2nd Paragraph, 1st sentence modified to allow for window to obtain results.
b) Table 4.3.2.8, 2nd row modified for clarity and 4th row modified to be consistent with 
other recommendations regarding increased ALT related to HDMTX.
31. Section 4.3.2.10 PO Methotrexate (MTX) and 6-Mercaptopurine (MP)
a) 1st Paragraph and 2nd paragraph, 1st sentence modified for additional guidance.
b) Corrected typographical errors in the paragraph under Dose Reduction for Falling 
Neutrophil Counts and Dose Reduction for Falling Platelet Counts.
32. Section 4.3.2.11 Steroids (Dexamethasone and Prednisone)
a) Table 4.3.2.11 last row of table modified for additional guidance.
33. Section 5.1 Flow Chart/Time and Events Schedule, Table 5.1A and 5.1B
a) ECG, Echocardiogram, Mutation analysis, and Cytogenetic analysis rows modified for 
clarity to provide additional guidance or to be consistent with changes made in the 
protocol text. A note was added to the pregnancy test row that the pregnancy test needs to 
be performed within 24 hours prior to the start of dasatinib.
b) Bone marrow MRD assessment note after transplant changed from 6 months to 3 months 
in order to allow for an earlier assessment of maintained disease control. This change is 
in line with current practice. Also added to the note was guidance to have bone marrow 
sample obtained once peripheral blood counts have recovered.
c) Table Note a modified to expand screening window to 21 days prior to first dose of 
dasatinib. Also added was that the pregnancy test needs to be performed within 24 hours 
prior to start of dasatinib and a clarification that screening bone marrow MRD and 
mutation detection assessments will be performed on samples that have been previously 
banked prior to this study. No additional bone marrow sample needs to be collected at 
screening.
d) Requirement for DXA scan changed from 5 years of age to simply < 5 years of age to be 
consistent with the International Society for Clinical Densitometry Pediatric Official 
Positions of 2007.
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34. Section 5.3 Safety Assessments
a) 3rd bullet modified to include “at least” since subjects undergoing HSCT may continue 
on protocol treatment beyond HR3 until logistic around the transplant procedures are set.
35. Section 5.3.3 Long-term Growth and Development and Bone Mineral Content
a) DXA Scanning paragraph modified to include “if feasible” and to increase age limit to 
20 years. The age limit was increased to be consistent with the International Society for 
Clinical Densitometry Pediatric Official Positions of 2007.
36. Section 6.2.1 Nonserious Adverse Event Collection and Reporting
a) Added information about reporting requirements while a subject is preparing for, 
undergoing or recovering from HSCT and it is expected there will be a long interruption 
in protocol treatment during this period. This is consistent with Section 4.3.1.11.
37. Section 
7 
DATA 
MONITORING 
COMMITTEE 
AND 
OTHER 
EXTERNAL 
COMMITTEES
a) 1st Paragraph, 1st and 2nd sentences updated to reflect that the DMC has been 
established.
b) 1st sentence in Interim Monitoring for Inferior Event-Free survival paragraph added to 
provide reference to assumptions.
38. Section 8.1 Sample Size Determination
a) 2nd Paragraph, last sentence modified to correct typographical error.
39. Section 8.3.1 Primary Endpoint
a) 1st bullet added “complete” to be consistent with section 8.3.2.4.
b) 2nd Paragraph, 1st sentence in the Response Criteria for EFS modified to correct 
typographical error.
c) In the Relapse Criteria for EFS, definitions of high risk group and low/standard risk 
group revised so as not to require the study subjects to undergo a BM aspiration at a time 
point in the therapy that is no longer a consistent standard of practice and is not needed for 
clinical management decisions. The end of Induction 1A BM result will be used for defining 
risk groups to be used in the sensitivity analysis around the EFS endpoint.
40. Section 8.3.2.2 Event Free Survival (EFS)
a) Typographical error corrected in item 4 and 5.
41. Section 8.3.2.4 Complete Remission Rate
a) Further defined to require no evidence of extramedullary disease.
42. BCR-ABL Mutation definition moved from Exploratory Endpoint Section 8.3.3.4 to 
Secondary Endpoint Section 8.3.2.5. 
43. Section 11 LIST OF ABBREVIATIONS
a) DFCI added to list.
44. Section 12 References 
a) New reference numbers 52, 55 and 56 added.
45. Appendix 1 Title modified for clarity.
46. Appendix 2 Title modified for clarity and revisions made to be consistent with COG 
guidelines updated in May 2012. 
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47. Appendix 3 modified to indicate listed website to be used as source for category 1 and 2 
medications.
48. Appendix 9 Title modified for clarity and effective added preceding date of appendix for 
clarity.
49. Appendix 12 modified to eliminate any potential confusion about hydration administration
with and following ifosfamide.
50. New Appendix 13 inserted to describe PFOS reconstitution procedure.
51. New Appendix 14 inserted to describe oral suspension dosing administration.
Please maintain a copy of this amendment with your protocol. Please provide a copy to 
your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.
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This document contains information confidential and proprietary to Bristol-Myers Squibb
AMENDMENT ACKNOWLEDGMENT
I have read this Amendment and agree that it contains all necessary details for carrying out the 
changes described. I understand that it must be reviewed by the Institutional Review Board or 
Independent Ethics Committee overseeing the conduct of the study and approved or given 
favorable opinion by all necessary Health Authorities before implementation unless to eliminate 
an immediate hazard to subjects.
If this Amendment substantially alters the study design or increases potential risk to subjects, the 
consent form will be revised and submitted to the Institutional Review Board/Independent Ethics 
Committee for approval/positive opinion. I will use the new consent form for any new subjects 
prior to enrollment, and for subjects currently enrolled in the study if they are affected by the 
Amendment.
___________________________________
_______________
Protocol Number: CA180372
Site Number: 
Amendment Number: 02
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Protocol Number:
CA180372
IND Number:
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EUDRACT Number
2011-001123-20
Date:
31-Jul-2013
Protocol CA180372: A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib 
Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia 
Chromosome Positive Acute Lymphoblastic Leukemia 
Amendment Number 03
Site Number: All
Study Director 
Medical Monitor
M. Brigid Bradley-Garelik, MD
Co-Principal Investigator
Co-Principal Investigator
 
24-hr Emergency Telephone Number:
Bristol-Myers Squibb Research and Development
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Bristol-Myers Squibb (BMS). 
This amendment must be maintained with the referenced protocol.
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Amendment Rationale:
The key purposes of this amendment are to incorporate the following key changes:
1. Increase the number of treated subjects from 75 to at least 75 and up to 90. The rate of 
subjects discontinuing study participation prior to reaching 3 years of follow-up from the 
start of dasatinib without having an event may potentially reach 20%. In order to assure
robustness of the long-term efficacy and safety analysis results, up to 15 additional subjects 
may be treated in the trial.
2. Modify language regarding pregnancy prevention. Dasatinib has not been formally studied in 
pregnant women. However, the dasatinib team has recently completed a comprehensive 
review of the BMS Dasatinib safety database (CARES) for all pregnancies in female patients 
or female partners of male patients in order to reassess  the risk of use of dasatinib during 
pregnancy.  Pregnancies in female patients on dasatinib sometimes resulted in spontaneous 
abortions or infant and fetal anomalies.   Based on this analysis and a revision to an internal 
BMS directive related to “Women of Childbearing Potential (WOCBP) in clinical trials”, 
BMS protocols in the dasatinib program are being amended to: 

update language related to WOCBP to harmonize with the new BMS directive including 
the requirement of 2 forms of birth control one of which is regarded as a highly effective 
form.

define highly effective forms of birth control

adjust language related to sexually active fertile male study participants with WOCBP 
partners and define the duration of birth control use after the last dose of investigational 
product as 90 days (duration of spermatogenesis).
3. Incorporate recommendations for subject management and supportive care during High Risk 
(HR) Blocks 1-3.  The three HR blocks are profoundly myelosuppressive and also include 
5 days of high dose dexamethasone.  Because clinical signs of infection can be blunted 
following high dose dexamethasone therapy, a very low threshold should be considered for 
admission to the hospital and/or institution of empiric antimicrobial therapy, growth factor 
support should be considered starting anytime 24 hours or more after completion of 
chemotherapy (as noted in protocol appendix) and blood counts should be monitored 2-3x 
week until recovery. This guidance has been further highlighted within each of the HR 
blocks.
This amendment also provides for clarifications, fixes inconsistencies across sections of the 
protocol and repairs typographical errors as described below. 
These revisions should improve consistency in study conduct but are not expected to have an 
impact on data analysis. These revisions apply to all subjects as they proceed through the 
treatment blocks.
Changes to the Protocol:
1. Synopsis: Select Exclusion Criteria
a) Last bullet updated WOCBP wording.
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2. Synopsis: Statistical Methods
a) 1st sentence updated to reflect change in sample size.
b) 1st sentence of last paragraph updated for clarity.
3. Section 1.3.2 Secondary Objectives Synopsis:
a) Item number 3 updated to be consistent with the Pediatric Investigational Plan.
4. Section 1.4.4.1 Formulation
a) 4th paragraph added clarity to define the single agent study as CA180226.
5. Section 3.1 Study Design and Duration
a) Last sentence of first paragraph updated to reflect change in sample size.
6. Section 3.1 Study Design and Duration, Design
a) Last sentence of fourth paragraph updated for clarity.
7. Section 3.3.1 Inclusion Criteria, Age and Reproductive Status
a) Items 3b, 3c and 3d provide updated WOCBP wording.
8. Section 3.3.2 Exclusion Criteria, Sex and Reproductive Status
a) Items a and b provide updated WOCBP wording.
9. Section 3.3 3 Women of Childbearing Potential
a) 1st and 2nd paragraphs provide updated WOCBP wording.
10. Section 4.1 Study Treatments, Table 4.1
a) 2nd column of the fourth row corrected typographical error and provide additional 
clarification regarding primary packaging of dasatinib powder for oral suspension.
11. Section 4.1.1 Investigational Product
a) 5th paragraph added sentence to provide clarity regarding the constitution of the dasatinib 
PFOS.
12. Section 4.3 Selection and Timing of Dose for Each Subject
a) 2nd paragraph added 2nd to last sentence to provide guidance in situations of drug 
shortages pertaining to the standard chemotherapy agents.
13. Section 4.3 Selection and Timing of Dose for Each Subject, Table 4.3A
a) 3rd column under Interim Maintenance revised methotrexate p.o. dosing days to be 
consistent with Section 4.3.1.7.
14. Section 4.3.1.2 Induction Therapy 1B, 6-Mercaptopurine (6-MP)
a) Last sentence updated to provide clarity.
15. Sections 4.3.1.3, 4.3.1.4 and 4.3.1.5 Consolidation Blocks 1, 2 and 3 (HR1, HR2 and HR3)
a) Wording added to enhance subject managment and supportive care guidelines during the 
High Risk Blocks.
16. Section 4.3.1.6 First Reinduction (Protocol II), Phase IIa
a) Dexamathasone (DXM) paragraph updated to allow i.v. administration.
17. Section 4.3.1.6 First Reinduction (Protocol II), Phase IIb, 6-Thioguanine (6-TG)
a) Last sentence updated to provide clarity.
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18. Section 4.3.1.8 Second Reinduction (Protocol II), Phase IIa
a) Dexamathasone (DEXA) paragraph updated to allow i.v. administration.
b) Doxorubicin (DOX)/Adriamycin (ADR) paragraph updated to be consistent with 
Section 4.3.1.6.
19. Section 4.3.1.8 Second Reinduction (Protocol II), Phase IIb
a) 6-Thioguanine paragraph updated to provide clarity.
b) Cytosine Arabinoside (ARA-C) last paragraph corrected typographical error.
20. Section 4.3.1.9 Continuation Therapy
a) 1st paragraph updated for clarity.
b) Intrathecal Methotrexate paragraph updated for clarity.
c) Methotrexate paragraph updated second bullet under Dose Reduction for Falling 
Neutrophil Count and subsequent paragraph to indicate that the dosage upon restart 
should be the last dose administered rather than the original prescribed dose and to 
correct a typographical error.
21. Section 4.3.1.11 Hematopoetic Stem Cell Transplant (HSCT) Use of dasatinib after stem cell 
transplant
a)
Updated paragraph to provide clarity around re-starting dasatinib treatment.
22. Section 4.3.2.4 Cytarabine (Ara-C), Table 4.3.2.4
a) 4th row refined event term for clarity.
23. Section 4.3.2.10 PO Methotrexate (MTX) and 6-Mercaptopurine (MP)
a) Revised 1st sentence and added bulleted text for clarity.
b) Updated second bullet under Dose Reduction for Falling Neutrophil Count and 
subsequent paragraph to indicate that the dosage upon restart should be the last dose 
administered rather than the original prescribed dose and to correct a typographical error.
24. Section 4.3.2.12 Thioguanine, Table 4.3.2.12
a) Replaced Table 4.3.2.12 with indicated text for clarity.
25. Section 5.1 Flow Chart/Time and Events Schedule, Table 5.1A
a) X in Physical Exam line removed from EndI/HR blocks since this would be redundant 
with the Physical Exam required at R!.  
b) Echocardiogram / MUGA row now indicates MUGA in all capital letters.
c) Serum Chemistry row added text to indicate direct bilirubin is required at screening 
which is consistent with the inclusion criteria.
d) Mutation analysis row updated note column for clarity.
e) Bone Marrow MRD Asssessment row updated note column for clarity.
f)
Assessment of survival and secondary malignancies row updated note column to assure 
assessment specifically at the 3 year and 5 year timepoint following first dose of 
dasatinib.
26. Section 5.1 Flow Chart/Time and Events Schedule, Table 5.1B
a) Table note item a is updated to provide consistency with 3 week screening period.
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27. Section 5.3 Safety Assessments
a) 1st paragraph updated to reflect pregnancy testing to be performed 24 hours prior to start 
of dasatinib therapy and to provide consistency of screening assessment timepoints noted 
in Tables 5.1A and 5.1B.
28. Section 5.3.1 Physical Examination
a) Added last sentence to assure assessment specifically at the 3 year and 5 year timepoint 
following first dose of dasatinib.
29. Section 5.3.2.2 Serum Chemistry Tests
a) Added text to indicate that direct bilirubin is required at screening which is consistent 
with the inclusion criteria.
30. Section 5.4.2.1 Overall Survival and Secondary Malignancy
a) Added 2nd paragraph to assure assessment at the 3 year and 5 year timepoint following 
first dose of dasatinib.
31. Section 6.5 Overdose
a) Corrected the section referenced in the last sentence.
32. Section 7 Data Monitoring Committee and Other External Committees
a) Updated Tables 7A and 7B to accomodate the increase in sample size.
b) Updated 2nd to last paragraph to reflect increase in sample size and correct errors.
33. Section 8.1 Sample Size Determination
a) Added the last paragraph to address the change in sample size.
34. Section 8.3.1 Primary Endpoint, Response Criteria for EFS
a) Added last sentence to the third paragraph to provide clarity.  
Please maintain a copy of this amendment with your protocol. Please provide a copy to 
your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.
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AMENDMENT ACKNOWLEDGMENT
I have read this Amendment and agree that it contains all necessary details for carrying out the 
changes described. I understand that it must be reviewed by the Institutional Review Board or 
Independent Ethics Committee overseeing the conduct of the study and approved or given 
favorable opinion by all necessary Health Authorities before implementation unless to eliminate 
an immediate hazard to subjects.
If this Amendment substantially alters the study design or increases potential risk to subjects, the 
consent form will be revised and submitted to the Institutional Review Board/Independent Ethics 
Committee for approval/positive opinion. I will use the new consent form for any new subjects 
prior to enrollment, and for subjects currently enrolled in the study if they are affected by the 
Amendment.
___________________________________
_______________
Protocol Number: CA180372
Site Number:
Amendment Number: 03
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Page:
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Protocol Number:
CA180372
IND Number:
66,971
EUDRACT Number
2011-001123-20
Date:
28-Oct-2013
Protocol CA180372: A Phase 2 Multi-Center, Historically-Controlled Study of Dasatinib 
Added to Standard Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia 
Chromosome Positive Acute Lymphoblastic Leukemia
Amendment Number 04
Site Number: All
Study Director 
Medical Monitor
M. Brigid Bradley-Garelik, MD
Co-Principal Investigator
Co-Principal Investigator
24-hr Emergency Telephone Number:
Bristol-Myers Squibb Research and Development
Oncology Clinical Research and Development
This protocol amendment contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS). 
This amendment must be maintained with the referenced protocol.
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Protocol Amendment 04
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Amendment Rationale:
The key purposes of this amendment are to incorporate the following changes:
1. Add mandatory supportive care measures during the 3 High Risk Blocks
As of October 16, 2013, 73 subjects have initiated treatment in the CA180372 trial. Three 
subjects died due of complications after the HR3 block among the 54 patients who had initiated 
this block of treatment. The first two deaths were both associated with overwhelming infection. 
The cause of death for the 3rd event is unknown. The subject died at home while sleeping after 
having missed a scheduled visit for interim lab work. None of the deaths were attributed to 
dasatinib, the investigational medicinal product. The Data Monitoring Committee (DMC) has 
been informed and has confirmed that the number of deaths does not meet the protocol defined 
stopping rules.
From the published experience in EsPhALL as well as the unpublished experience in the 
amended EsPhALL setting, up to 10% of high-risk patients treated with the AIEOP-BFM-2000 
chemotherapy backbone plus imatinib suffer from fatal complications which are typically septic/ 
infectious in etiology after the intensive High Risk chemotherapy blocks1,2.
Based on the events observed in this study a number of changes are being instituted to the 
supportive care measures during the High Risk treatment blocks.

Mandatory blood counts with differential every 2 days after completion of 
chemotherapy until there is evidence of marrow recovery. These blocks are highly 
myelosuppressive. Recovery is defined as ANC > 0.2 x109/L (200/l) and platelet 
transfusion independence.

Mandatory myeloid growth factor support: G-CSF 5µg/kg/day s.c. or i.v. starting anytime 
from 7 to 11 days from the start of the block, until the WBC count is > 3.0 x109/L 
(> 3000/mm3). The option of pegfilgrastim 100µg/kg s.c. given once during the 7-11th day 
from the start of the block may be considered as an alternative.

Although not required, the investigators should STRONGLY consider hospitalizing patients 
for close observation after each intensive block of chemotherapy, particularly during the 
period of profound myelosuppression, until blood count recovery because this is the 
intervention most likely to reduce the death rate.

A low threshold should be used for institution of empiric antimicrobial therapy as clinical 
signs for infection can be blunted following high dose dexamethasone therapy. This 
particular guidance remains consistent with the revised protocol of July 31, 2013.
These supportive measures should be implemented immediately in all patients during the High 
Risk treatment blocks. The impact of these supportive measures on the conduct of the study will 
be more frequent subject monitoring with the potential for prompt intervention, thereby 
improving patient safety. No impact on data analysis is expected.
2. Provide updates to the women of childbearing potential (WOCBP) language to harmonize this 
language with the current BMS directives for WOCBP.
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Changes to the Protocol:
1. Section 1 Introduction and Study Rationale, Imatinib & Chemotherapy in Newly Diagnosed 
Pediatric Ph+ ALL (EsPhALL Trial)
a) Updated information and references in the first and second paragraphs
2. Section 1.1 Study Rationale
a) Updated information in the second paragraph and updated the reference
b) Updated reference in the third paragraph.
c) Added last paragraph to provide rationale for changes being made in the protocol.
3. Section 3.3.1 Inclusion Criteria, Age and Reproductive Status
a) Updated WOCBP wording to harmonize with the current BMS directives on WOCBP.
4. Section 3.3 3 Women of Childbearing Potential
a) Updated WOCBP wording to harmonize with the current BMS directives on WOCBP.
5. Section 4.3. Selection Timing of Dose for Each Subject, Table 4.3A Treatment Plan 
Summary
a) Updated wording for mandatory myeloid growth factor support.
6. Sections 4.3.1.3, 4.3.1.4 and 4.3.1.5 Consolidation Blocks 1, 2 and 3 (HR1, HR2 and HR3)
a) Updated wording and Add mandatory supportive care measures during the 3 High Risk 
Blocks
7. Section 5.1 Flow Chart/Time and Events Schedule, Table 5.1A
a) Added note for mandatory CBC & Differential counts every 2 days after completion of 
chemotherapy in HR1, HR2 and HR3 until recovery.  
8. Section 6.4 Pregnancy
a) Updated WOCBP wording to harmonize with the current BMS directives on WOCBP.
9. Appendix 12, Optional Supportive Treatment Guidelines
a) Updated wording for mandatory myeloid growth factor support.
References
1. Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for the treatment of 
children and adolescents with Philadelphia-chromosome positive acute lymphoblastic 
leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet-Oncology 2012 
http://dx.doi.org/10.1016/S1470-2045(12)70377-7.
2. Andrea Biondi, MD, unpublished data 2013.
Please maintain a copy of this amendment with your protocol. Please provide a copy to 
your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS.
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AMENDMENT ACKNOWLEDGMENT
I have read this Amendment and agree that it contains all necessary details for carrying out the 
changes described. I understand that it must be reviewed by the Institutional Review Board or 
Independent Ethics Committee overseeing the conduct of the study and approved or given 
favorable opinion by all necessary Health Authorities before implementation unless to eliminate 
an immediate hazard to subjects.
If this Amendment substantially alters the study design or increases potential risk to subjects, the 
consent form will be revised and submitted to the Institutional Review Board/Independent Ethics 
Committee for approval/positive opinion. I will use the new consent form for any new subjects 
prior to enrollment, and for subjects currently enrolled in the study if they are affected by the 
Amendment.
___________________________________
_______________
Protocol Number: CA180372
Site Number:
Amendment Number: 04
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 2 MULTI-CENTER, HISTORICALLY-CONTROLLED STUDY OF 
DASATINIB ADDED TO STANDARD CHEMOTHERAPY IN PEDIATRIC PATIENTS 
WITH NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME ACUTE 
LYMPHOBLASTIC LEUKEMIA
PROTOCOL CA180-372
VERSION 1.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................6
LIST OF FIGURES ....................................................................................................................6
1
BACKGROUND AND RATIONALE......................................................................7
2
STUDY DESCRIPTION ..........................................................................................9
2.1
Study Design ............................................................................................................9
2.2
Treatment Assignment............................................................................................11
2.3
Blinding and Unblinding.........................................................................................11
2.4
Protocol Amendments.............................................................................................11
2.5
Data Monitoring Committee ...................................................................................12
2.5.1
Monitoring for Effectiveness...................................................................................12
2.5.2
Monitoring for Safety..............................................................................................13
3
OBJECTIVES ........................................................................................................14
3.1
Primary...................................................................................................................14
3.2
Secondary...............................................................................................................15
3.3
Exploratory.............................................................................................................15
4
ENDPOINTS..........................................................................................................15
4.1
Primary Endpoint....................................................................................................15
4.2
Secondary Endpoints ..............................................................................................17
4.2.1
Safety and Feasibility .............................................................................................17
4.2.2
Event Free Survival (EFS) ......................................................................................17
4.2.3
Complete Remission ...............................................................................................17
4.2.4
Minimal Residual Disease (MRD)...........................................................................18
4.2.5
BCR-ABL Mutations...............................................................................................18
4.3
Exploratory Endpoints............................................................................................18
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................20
6.1
Study Periods..........................................................................................................20
6.1.1
Screening................................................................................................................20
6.1.2
On-Treatment .........................................................................................................20
6.1.3
Stem Cell Transplant ..............................................................................................20
6.1.4
Follow-Up Phase....................................................................................................21
6.1.5
Overall Follow-Up .................................................................................................21
6.2
Treatment Regimens...............................................................................................21
6.3
Populations for Analyses ........................................................................................21
7
STATISTICAL ANALYSES..................................................................................22
7.1
General Methods ....................................................................................................22
7.2
Study Conduct........................................................................................................22
7.2.1
Protocol deviations.................................................................................................22
7.2.2
Enrollment..............................................................................................................23
7.3
Study Population ....................................................................................................23
7.3.1
Subject Disposition.................................................................................................23
7.3.2
Demographics at baseline.......................................................................................24
7.3.3
Medical history.......................................................................................................24
7.3.3.1
General medical history..........................................................................................24
7.3.3.2
Disease history .......................................................................................................24
7.3.4
Pre-treatment Clinical complaints and findings......................................................24
7.3.5
Baseline evaluations...............................................................................................24
7.3.5.1
Subject Characteristics at baseline .........................................................................25
7.3.5.2
Physical Examination at baseline ...........................................................................25
7.3.5.3
Laboratory parameters at baseline .........................................................................25
7.3.5.4
Risk Groups............................................................................................................25
7.4
Extent of Exposure .................................................................................................25
7.4.1
Administration of Dasatinib....................................................................................25
7.4.2
Dose modifications for Dasatinib............................................................................26
7.4.3
Previous and Concomitant Medications..................................................................27
7.4.4
Duration of Treatment Blocks.................................................................................27
7.5
Efficacy..................................................................................................................27
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7.5.1
Event -Free Survival (EFS) Analyses ......................................................................28
7.5.1.1
Regulatory Background ..........................................................................................28
7.5.1.2
Primary analysis.....................................................................................................29
7.5.1.3
Secondary analyses.................................................................................................30
7.5.1.4
Sensitivity and Subgroup analyses ..........................................................................31
7.5.2
Complete remission rate .........................................................................................32
7.5.3
Disease-Free Survival Analysis...............................................................................32
7.5.4
Overall Survival Analysis .......................................................................................32
7.5.5
Minimal Residual Disease (MRD)...........................................................................32
7.5.5.1
MRD Negative Rates...............................................................................................32
7.5.5.2
Correlation between the 3 methods of assessing MRD ............................................33
7.5.5.3
Prognostic value of MRD on EFS ...........................................................................33
7.5.6
HSCT......................................................................................................................33
7.5.6.1
Cerebrospinal Fluid (CSF) .....................................................................................34
7.6
Safety.....................................................................................................................34
7.6.1
Deaths ....................................................................................................................34
7.6.2
Other Serious Adverse Events.................................................................................34
7.6.3
AEs leading to discontinuation ...............................................................................34
7.6.4
AEs of special interest.............................................................................................35
7.6.5
Overall AES............................................................................................................35
7.6.6
Neoplasms ..............................................................................................................36
7.6.7
Treatment Block Delays..........................................................................................36
7.6.8
Clinical laboratory evaluation................................................................................36
7.6.8.1
Hematology ............................................................................................................36
7.6.8.2
Serum chemistry .....................................................................................................36
7.6.9
Other Safety considerations....................................................................................36
7.6.9.1
Electrocardiogram (ECG) ......................................................................................36
7.6.9.2
Echocardiogram / MUGA.......................................................................................37
7.6.9.3
Chest X-Ray............................................................................................................37
7.6.9.4
Physical measurements and vital signs ...................................................................37
7.6.9.5
Long-term Growth and Development and Bone Metabolism ...................................37
7.7
Mutation Analysis ..................................................................................................38
8
CONVENTIONS....................................................................................................38
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9
CONTENT OF REPORTS .....................................................................................39
10
REFERENCES.......................................................................................................40
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LIST OF TABLES
Table 2.4-1:
Protocol Amendments ............................................................................11
Table 2.5.2-1:
Guidelines for early stopping due to treatment related mortality in 
Induction................................................................................................14
Table 2.5.2-2:
Guidelines for early stopping due to treatment related mortality in 
CCR .......................................................................................................14
Table 7.2.1-1:
Relevant Protocol Deviations..................................................................23
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic.........................................................................10
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Research Hypothesis:  
Dasatinib added to chemotherapy will demonstrate a superior 3-year event free survival (EFS) 
rate compared to chemotherapy alone in the external historical control trial Associazione Italiana 
di Ematologia Pediatrica - Berlin-Frankfurt-Muenster ALL 2000 (AIEOP-BFM 2000) and non-
inferior 3-year EFS compared to continuous imatinib added to chemotherapy in the external 
historical control trial of the amended European intergroup Study on post induction treatment of 
Philadelphia positive Acute Lymphoblastic Leukemia (EsPhALL).
Schedule of Analyses:
Interim monitoring of safety and efficacy will be done by an independent Data Monitoring 
Committee (DMC) for all subjects starting from the date each subject signs informed consent. 
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The DMC can recommend discontinuing the study due to excessive and unacceptable toxicities 
or to poor efficacy.
The analyses to be performed for the DMC and the schedules of reports and meetings are 
described in the DMC Charter.  They don’t include any comparison with historical controls.
This SAP will focus on all planned analyses for the final CSR.
2
STUDY DESCRIPTION
2.1
Study Design
CA180-372 is an open-label, multi-Center single-arm but Historically-Controlled study. Children 
and adolescents with newly diagnosed Ph+ ALL will be eligible and will receive dasatinib at a 
dose of 60 mg/m2 once daily in addition to the standard Associazione Italiana di Ematologia 
Pediatrica - Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 chemotherapeutic standard 
multiagent chemotherapy protocol8 for a maximum duration of 2 years.
Subjects who meet pre-defined criteria at specific time points in treatment (see section 4.3.3) 
may receive a hematopoietic stem cell transplant (HSCT) and will have the option to receive 12 
additional months of post-HSCT dasatinib (not mandatory).
The components of treatment are divided into successive blocks as follows (see protocol section 
4.1 for the complete list of individual agents).  All block durations are approximate:
Phase I - For all subjects  
1. Induction IA (4 - 5 weeks):  During the first 2 weeks, the subjects will receive frontline acute 
lymphoblastic leukemia (ALL) induction chemotherapy (standard at the investigative center) 
outside the protocol. They will be enrolled in the study and start to receive Dasatinib at Day 
15 when positive Philadelphia chromosome status is confirmed via cytogenetics, FISH or 
PCR prior to Day15).
2. Induction IB (28 days, 4 weeks)
3. Recovery period (Dasatinib continues, No chemotherapy given) (2 - 4 weeks)
4. Three successive Consolidation blocks (HR1, HR2, and HR3) of 21 days each
5. Recovery period (Dasatinib continues, No chemotherapy given) (14 days, 2 weeks)
Phase IIa - For the subjects who don’t meet the criteria for HSCT: 
6. Reinduction Block 1, including phase IIa and IIb (63 days, 9 weeks)
7. Interim maintenance (29 days, 4 weeks). Subjects with CNS3 disease at diagnosis will 
receive cranial irradiation during the Interim Maintenance period.
8. Reinduction Block 2 (63 days, 9 weeks)
9. Continuation therapy (62 weeks)
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Phase IIb - For the subjects who meet the criteria for HSCT
The subjects who meet predefined criteria for HSCT mainly based on MRD response at key 
early time points in therapy (see section 4.3.3) may receive a HSCT following the Consolidation 
Block (HR3) instead of continuing the AIEOP-BFM ALL.
During the HSCT, subjects will not receive dasatinib. Following adequate engraftment of the 
HSCT, subjects have the option to receive 12 additional months of post-HSCT dasatinib 60 
mg/m2 orally once daily (recommended but not mandatory). 
A schematic of the study design is shown in Figure 2.1-1.
Figure 2.1-1:
Study Design Schematic
The total intended duration of treatment (including chemotherapy and dasatinib) will be 
approximately 104 weeks (2 years). Subjects will be followed (including time on treatment) for 
at least 3 years for event-free survival and other secondary endpoints.
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2.2
Treatment Assignment
After informed consent and subject assent has been obtained as per local guidelines, the subject
must be enrolled into the study by calling an interactive voice response system (IVRS) to obtain 
the subject number. Instructions on the use of the IVRS will be provided to the study site.
This is a single-arm open-label study where subjects will receive up to 24 months of study 
treatment during the trial. Since subjects with Ph+ ALL often experience delays in treatment due 
to toxicities associated with therapy, delays in starting treatment blocks are expected. Therefore, 
all start dates for the initiation of all treatment blocks are estimates, and should not be considered 
as strict requirements.
As subjects newly diagnosed with Ph+ ALL require urgent treatment, initial therapy for their 
disease will start outside the protocol with a chemotherapy regimen that is standard at the 
investigative center (referred to as induction therapy IA). Dasatinib at a dose of 60 mg/m2 once 
daily will be introduced on day 15 from initiation of treatment in all subjects in addition to 
ongoing chemotherapy (approximately until day 29 - 33). From the start of induction therapy IB, 
all subjects will follow the same treatment plan shown in the protocol Table 4.3A till end of HR3 
where they either pursue the chemotherapy + Dasatinib or have a HSCT.
2.3
Blinding and Unblinding
Not applicable; this is an open label study.
2.4
Protocol Amendments
Table 2.4-1:
Protocol Amendments
Amendment
Date of Issue
Summary of Major Changes
4
28-Oct-2013
Addition of mandatory supportive care measures during the 3 High Risk 
Blocks
3
31-Jul-2013

Increase of the number of treated subjects from 75 to at least 75 and up to 
90.

Incorporate recommendations for subject management and supportive 
care during High Risk (HR) Blocks 1-3
2
07-Dec-2012

Introduce a new pediatric formulation of dasatinib (Powder of Oral 
Solution - PFOS)

BCR-ABL mutation status at baseline and at time of progression moved 
from being an exploratory objective to a secondary objective

Allow Philadelphia chromosome positivity from peripheral blood to be 
acceptable for study entry.

Expand the window for screening activities to 21 days.

Modify the definition of high risk group and low/standard risk group in 
response to Induction 1A treatment. The high risk group will be defined 
by a MRD 0.01%; low/standard risk will be defined as day 29 MRD < 
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Table 2.4-1:
Protocol Amendments
Amendment
Date of Issue
Summary of Major Changes
0.01%. This approach is consistent with the criteria used in other COG 
trials, and/or NCI risk group and being adopted by EsPhALL trials.
1
20-Sep-2011
Changing the statistical design of the trial to allow comparison to historical 
external controls. Specifically, the 3-year event free survival (EFS) of 
dasatinib plus chemotherapy will be compared to the 3-year EFS of 
chemotherapy alone from the Associazione Italiana di Ematologia Pediatrica-
Berlin-Frankfurt-Muenster ALL 2000 (AIEOP-BFM 2000) trial and the 3-
year EFS of imatinib plus chemotherapy from the European intergroup Study 
on post induction treatment of Philadelphia positive Acute Lymphoblastic 
Leukemia (EsPhALL). This analysis will improve the ability to interpret the 
safety and efficacy of dasatinib added to chemotherapy among other treatment 
options for pediatric leukemia.
2.5
Data Monitoring Committee

An independent DMC will review safety and efficacy data for all subjects starting from 
the date each subject signs informed consent. These data will consist of tables and listings related
to protocol deviations, subject disposition, demographics, deaths, extent of exposure and dose 
modifications for dasatinib, AEs, neoplasms, Complete Remission Rate and Event Rate for 
Event Free Survival. 

The DMC will monitor the study for effectiveness and safety as described below and can 
recommend discontinuing the study due to excessive and unacceptable toxicities or due to poor 
efficacy. 
2.5.1
Monitoring for Effectiveness
Interim analyses will be conducted to protect against poor EFS. Under the exponential 
assumption, a three-year EFS rate of 78% (lower limit of the 95% confidence interval for an 
observed 88% EFS rate) translates to a hazard rate of 0.083. Interim analyses will be based on 
the estimated hazard rate, testing the null-hypothesis H0 that the hazard rate <= 0.083 versus the 
alternative hypothesis H1 that the hazard rate is > 0.083 (at an alternative of 0.119 which 
corresponds to a 3-year EFS of 70%).
Testing H0:  S(3) ≥ 0.78  vs. H1: S(3) < 0.78 where S(3) is the 3-year EFS rate.
Test statistic:  Zi = (lambda_hat) - lambda_0) / sqrt (lambda0/Ti)
Where:
Zi = value of the test statistic at the time of the i-th interim analysis
lambda_hat = estimate of hazard rate at the time of i-th interim analysis 
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lambda_0 = hazard rate under the null hypothesis 
Ti = Total time at risk for subjects at the time of i-th interim analysis
The αt2 spending function will be used to maintain an overall one-sided Type I error rate of 10%. 
Based on 106 treated subjects, the total number of expected events is 30. Interim analyses will be 
performed when 33%, 66%, 100% (if prior to 3 year EFS landmark) of the expected information 
(events), respectively have been observed. The corresponding critical values (boundaries) are Zc:  
2.29, 1.76, and 1.37, assuming the three interim analyses will occur after reaching 10, 20, and 30
events, respectively.  If Zi at one of these interim looks is > Zc, then the monitoring boundary 
would be crossed and the DMC can recommend the study be stopped for inferior EFS.  
The DMC will monitor for effectiveness until all subjects are off-treatment.
2.5.2
Monitoring for Safety
The DMC may recommend termination of the entire study for any safety concern that is felt to 
outweigh potential benefits. 
Safety review will occur after each new treatment related death. The DMC will be provided
information on each new treatment related death and after review will decide if additional 
information is needed from the sponsor. The DMC will also meet at least once per year to review 
all available safety tables and listings and per the charter.
The DMC may recommend stopping the trial if the observed death rate is above the acceptable 
limit. 
The tables below show the minimum number of treatment related deaths in induction (after day 
15) and in continuous complete remission (CCR), excluding deaths after HSCT, at which the 
DSMB should evaluate stopping the study. The method applied for developing these guidelines 
follows a Bayesian approach, extending that of Metha and Caine10, 11. In these guidelines, the 
maximum acceptable level of probability of treatment related deaths in induction (IND) and in 
CCR were pIND = 3% and pCCR = 7% respectively. The number of failures is assumed to be 
taken from a binomial distribution. The prior distribution for the probability of the endpoint of 
interest was taken as a beta (1,1), corresponding to an uninformative uniform distribution. The 
stopping bounds reported in tables 2.5.2-1 and 2.5.2-2 below are the experimental results that 
give a posterior probability of 90% or more, of observing pIND 3% and pCCR 7%, 
respectively. 
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Table 2.5.2-1:
Guidelines for early stopping due to treatment related mortality in 
Induction
No. of subjects on treatment pIND = 3%
No. of Death Events
11 - 36
2
37 - 58
3
59 - 82
4
83 - 106
5
Table 2.5.2-2:
Guidelines for early stopping due to treatment related mortality in 
CCR
No. of Subjects on Study pCCR = 7%
No. of Death Events
11 - 15
2
16 - 25
3
26 - 35
4
36 - 45
5
46 - 56
6
57 - 67
7
68 - 78
8
79 - 90
9
91 - 101
10
102 - 106
11
3
OBJECTIVES
3.1
Primary
The primary objective is to compare the 3-year EFS of dasatinib plus chemotherapy with 
external historical controls, in hierarchical order, as follows: 
1)
Superiority over chemotherapy alone of AIEOP-BFM 2000 
2)
Non-inferiority to continuous imatinib plus chemotherapy of the amended EsPhALL
     
trial
3)
Superiority over continuous imatinib plus chemotherapy of the amended EsPhALL 
      
trial
The trial will be considered positive if at least the first two comparisons are statistically 
significant.  
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3.2
Secondary
The key secondary objectives are to determine:
1. The safety and feasibility of dasatinib added to standard chemotherapy
2. Estimate the EFS of dasatinib plus chemotherapy (including 3 and 5-year rates)
3. Complete remission rates (< 5% blasts in bone marrow and no peripheral blasts) at 
     end of induction
Other secondary objectives are to estimate:
1. The difference in 3-year EFS rate with the 3-year EFS rate of available historical  controls 
such as the COG AALL0031 study
2. MRD levels (defined by PCR detection of clone-specific immunoglobulin and T-cell      
receptor gene rearrangements)
3. BCR-ABL mutation status at baseline and time of disease progression or relapse
3.3
Exploratory
4
ENDPOINTS
4.1
Primary Endpoint
The 3-year event-free survival (EFS) rate is the primary endpoint where EFS is defined as the 
time from the starting date of dasatinib until an event and will be computed using binomial 
proportions.
Events for EFS are defined as ANY first one of the following:

Lack of complete response in bone marrow (see below definition)

Relapse at any site
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
Development of second malignant neoplasm

Death from any cause
Response Criteria for EFS
Criteria for Response in Bone marrow (BM) are:

M1: < 5% lymphoblasts (Complete Response in BM)

M2: 5 - 25% lymphoblasts

M3: > 25% lymphoblasts
For the primary analysis as described in protocol section 7.5.1, complete response (CR) in the 
bone marrow will be assessed between the start of dasatinib and completion of Consolidation 
Block 3 (HR3) / start of Reinduction 1. Three assessments are planned during that period:
-
MRD2 at end of induction IA, 
-
MRD3 at end of IB / start of HR1, and 
-
MRD4 at end of HR3 /start of Reinduction 1. 
(MRD1 is the screening assessment.)

Subjects who reach CR within this window will be considered at risk for relapse or death 
without relapse.

Those who do not reach CR (i.e. M1 bone marrow) between the start of dasatinib and the last 
day of Consolidation Block HR3/start of Reinduction 1 (Protocol II) will be considered as an 
event (resistant). 

For subjects who undergo HSCT, the date of the HSCT will not be considered as an event in 
the primary efficacy analysis. These subjects will continue to be followed for an event during 
and after HSCT.

Subjects without valid BM results during this window (no BM done or no evaluable aspirate) 
will be considered having lack of complete response.
Relapse Criteria for EFS
Relapse is defined as any recurrence of disease, whether in the marrow or extramedullary site:

CNS relapse: Positive cytomorphology and 5 or more WBC/μL in CSF, or any signs of CNS 
leukemia such as facial nerve palsy, brain/eye involvement, or hypothalamic syndrome.

Testicular relapse: Must be documented by testicular biopsy, in the absence of concomitant 
bone marrow or CNS relapse.

Bone marrow relapse: An M3 marrow (>25% blasts), or peripheral blood with >25% blasts if 
bone marrow not available, after first CR has been achieved.
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
Combined bone marrow + other site: >=5% blasts (or >25 % peripheral blood blasts if bone 
marrow not available) with other site of relapse.
Relapse should be histopathologically determined.  All BM samplings, CSF evaluations, physical 
examinations and death information subsequent to achievement of a CR will be utilized to 
determine relapse, second malignancy and death for EFS analysis.
4.2
Secondary Endpoints
4.2.1
Safety and Feasibility
The safety and feasibility endpoint will include computation of frequencies of 
(a) Treatment related deaths during induction as well as in subjects in complete remission
(b) All adverse events  
(c) Laboratory abnormalities 
(d) Dose interruptions, dose reductions and treatment discontinuations for dasatinib related 
toxicity 
(e) Treatment block delays expressed in lapsed time (≤ 7 days, 8-14 days, etc.) will be 
summarized for start of dasatinib until start of HR1, and for start of HR1 until start of 
Reinduction (for subjects starting Reinduction):

For start date of dasatinib (target day 15) to start date of HR1 (target day 78) a lapsed time of 
63 days is exactly on target. If the lapsed time is <= 70 days, the delay is ≤ 7 days; if the 
lapsed time is 71-77 days, the delay is 8-14 days, etc.

For start date of HR1 (target day 78) until start of Reinduction (target day 154) a lapsed time 
of 76 days is exactly on target). If the lapsed time is <= 83 days, the delay is ≤ 7 days; if the 
lapsed time is 84-90 days, the delay is 8-14 days, etc.
4.2.2
Event Free Survival (EFS)
The EFS endpoint is also considered for secondary/sensitivity analyses:

Overall EFS analysis using Kaplan-Meier estimates of EFS probabilities (for overall EFS 
estimation and the 3-year and 5-year Kaplan-Meier estimates).

Comparison of the 3-year EFS rate with that in study COG AALL0031.

Sensitivity analyses of overall EFS (as described in section 7.5.1): EFS analysis by subgroup 
or with alternative event definition.
4.2.3
Complete Remission
Complete remission assessed by morphological examination is defined as <5% lymphoblasts in 
the bone marrow (i.e. M1 bone marrow) and CSF with no evidence of other extramedullary 
disease. Complete remission will be assessed at the end of Induction IA, end of induction IB and 
end of HR3.
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4.2.4
Minimal Residual Disease (MRD)
At the time of morphologic complete remission, the extent of minimal residual disease (MRD) 
can vary considerably. In this study, 3 different techniques are used: 

Real-time quantitative PCR detection of clone-specific immunoglobulin and T-cell receptor 
gene rearrangements (Ig/TCR). 

Real-time quantitative PCR for BCR-ABL transcript levels.

Multiparameter flow cytometry.  
Each of the 3 methods will be applied for every bone marrow assessment for every subject. The 
Ig/TCR will be considered as the method of reference. For the first two methods the limit of 
detection of these assays will be approximately 10-4 (0.01%) - 10-5 (0.001%). The sample will be 
declared as MRD negative if the MRD level is undetectable providing the assay lower limit of 
quantification is at least 0.1%.
4.2.5
BCR-ABL Mutations
A BCR-ABL mutation is defined as the presence of a detectable amino acid substitution in the 
ABL kinase domain.
4.3
Exploratory Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Screening
After diagnosis of acute lymphoblastic leukemia (ALL), subjects will begin standard induction 
chemotherapy (Block IA). Since the diagnosis of ALL typically requires urgent treatment and it 
takes up to 10-14 days to determine which patients have Philadelphia chromosome positive 
(Ph+) ALL, frontline induction chemotherapy (Block IA) will start prior to enrollment in this 
trial (approximately 2 weeks) and will be based upon the investigator’s institutional standard of 
care. Enrollment on this study will occur prior to day 15 of Induction Block IA. On day 15, 
dasatinib treatment shall begin and continue without planned interruption until the completion of 
therapy (102 weeks).
For adverse events, including deaths, and for medications other than study medication, the 
baseline period ends the day prior to the first day of dasatinib treatment. Otherwise, the latest 
assessment prior to, or on, the first day of dasatinib will be considered the baseline assessment.
6.1.2
On-Treatment
On-treatment period: 

For evaluations: period after the first day (i.e. as from the 2nd day) of dasatinib, until and 
including 30 days after the last dose of dasatinib.

For adverse events, including deaths, and medications other than study medication 
(concomitant medications): period as from the first dasatinib dosing day until and including 
30 days after last dose of dasatinib.
6.1.3
Stem Cell Transplant
Subjects who meet pre-defined MRD criteria prior to the start of the first consolidation block 
(HR1) or after the completion of the third consolidation block (HR3) of chemotherapy and have 
a genotype-matched donor (9/10 or 10/10) will receive a hematopoietic stem cell transplant
(HSCT) instead of continuing the AIEOP-BFM ALL 2000 regimen. The timing of HSCT would
be following the consolidation block 3 (HR3). In practice the HSCT may not follow HR3 
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directly. For example, if a suitable donor becomes available later. In that case, subjects may 
continue in Reinduction for a certain time before receiving stem cell transplant. During the 
HSCT, subjects will not receive dasatinib. Following HSCT, the use of dasatinib is optional at 
the discretion of the treating investigator. Subjects may receive 12 additional months of post-
HSCT dasatinib. 
6.1.4
Follow-Up Phase
Subjects who complete or discontinue study treatment will enter the Follow-Up phase. This 
includes subjects not receiving HSCT, as well as subjects receiving HSCT with or without post-
HSCT dasatinib treatment. 
6.1.5
Overall Follow-Up
Overall follow-up refers to subject being followed up both on study treatment and off study 
treatment. For subjects not receiving HSCT and who complete study treatment, the duration of 
treatment (including chemotherapy and dasatinib) will be approximately 104 weeks (2 years). 
Subjects will be followed (including time on treatment) for at least 3 years for event-free survival 
and other secondary endpoints, 5 years for overall survival and 7 years (2 years of treatment + 5 
years after completion of treatment) for 
 and other exploratory endpoints.
6.2
Treatment Regimens
From the start of induction therapy IB, all subjects will follow the same treatment plan shown in 
Table 4.3A of the protocol until the end of HR3 where 

Subjects who proceed to HSCT will receive preparatory regimen prior to HSCT and the 
treatment for the HSCT. After stem cell transplantation dasatinib is allowed in all HSCT 
recipients, however, is considered optional at the discretion of the treating physician. If 
dasatinib treatment is given post-HSCT, an initial dose of 48 mg/m2 daily will be
administered provided PTL and WBC counts are satisfactory, with stable neutrophils 
engraftment (PTL > 50 x 109/L; WBC > 1.5 x 109/L; neutrophils > 0.5 x 109/L for at least 15 
days). If the initial dose is deemed tolerable by the treating physician, the dose of dasatinib 
should be escalated to 60 mg/m2 within the first month of starting post-HSCT dasatinib. For 
those subjects that opt for post-HSCT dasatinib, administration is suggested throughout the 
first year post-transplantation until day +365 from HSCT. The preparative regimen prior to 
HSCT and the treatment for the HSCT will be according to the institutional standard of care.
Subjects not receiving HSCT will, after the recovery period following HR3, continue with 
Reinduction Block 1 (followed by Interim Maintenance, Reinduction Block 2 and 
Continuation).
6.3
Populations for Analyses

All Enrolled Subjects Data Set: All subjects with signed informed consent form.
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
All Treated Subjects Data Set: All subjects who received at least one dose of dasatinib. 
Demographic, baseline characteristics, exposure to dasatinib, efficacy, and safety analyses 
will be performed on all treated subjects.

Mutation Data Set: All treated subjects who have mutation data available will be included in 
the mutation data set.
7
STATISTICAL ANALYSES
7.1
General Methods
A complete description of the tables is given in the data presentation plan. By-subject listings 
will be prepared to support summaries and analyses. Basic principles for table presentation are 
the following:

Analyses and summaries will be, except where indicated otherwise, based on the whole
target study population, as well as on the following sub-populations: 
o
Subjects treated with dasatinib tablets only, and 
o
Subjects who at any time received dasatinib in the PFOS (Powder For Oral Solution) 
formulation.

Descriptive statistics will be used to summarize demographic characteristics, extent of 
exposure, safety and laboratory observations (hematology, serum chemistry). Categorical 
variables will be summarized in frequency tables. In general, continuous and other numeric 
variables will be summarized by presenting the number of observations, mean, standard 
deviation, median, interquartile range, minimum and maximum.

Laboratory results will be classified according to the National Cancer Institute - Common 
Terminology Criteria (NCI-CTCAE) Version 4.0. Additional laboratory results that are not 
part of NCI-CTCAE will be presented according to the following categories: below normal 
limits, within normal limits, and above normal limits. Toxicities will be coded using the most 
current version at the time of analysis of Medical Dictionary for Regulatory Activities 
(MedDRA) system organ classes and preferred terms and will be graded using the NCI-
CTCAE Version 4.0 criteria. 

Concomitant medications will be coded using the World health Organization (WHO) Drug 
Dictionary (modified by BMS).
7.2
Study Conduct
7.2.1
Protocol deviations
Relevant protocol deviations as listed in the table below will be tabulated for all treated subjects. 
In addition, a by-subject listing will be provided.
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Table 7.2.1-1:
Relevant Protocol Deviations
A. Baseline deviations
I. Inclusion Criteria:
1. Diagnosis
Correct identification of the disease, i.e. ALL. This refers to inclusion criterion 2)a).
Documented presence of reciprocal translocation between chromosomes 9 and 22. This refers 
to inclusion criterion 2)a)i).
Cytogenetic testing or FISH analysis must have been performed or both.
2.  Target population
Age at diagnosis must be >1 and <18 years
3.  Induction chemotherapy
Subject must have received induction therapy as per institutional standard (At least one record of study 
medication should be entered for visit B01: Did the subject receive study medication=Yes, and at least one drug 
name should be provided).
II. Exclusion criteria: 
1.  Prior treatment with a BCR-ABL inhibitor
BCR-ABL inhibitors include, but may not be limited to, Imatinib, Nilotinib, and Ponatinib. A list of BCR-ABL 
inhibitors will be provided, and when necessary updated based on clinical input.
2.  Biopsy proven Ph+ ALL extramedullary involvement of the testicles
(From Extramedullary Involvement CRF page - extramedullary involvement of the testicles has code #73)
B. On study deviations
1. Concomitant medications known to prolong the QT interval
See section 3.4.1.1 of the protocol for a list of medications associated with QT interval prolongation. 
“Concomitant” should be interpreted in the strict sense in that these medications are only prohibited on days when 
also dasatinib is administered.
7.2.2
Enrollment

Accrual by country will be tabulated for all enrolled subjects. Accrual by site will be 
tabulated for all treated subjects. Subjects enrolled but not treated will be included in a subject 
disposition listing.
7.3
Study Population  
7.3.1
Subject Disposition
The subject disposition table will include the percentage of treated subjects in the enrolled 
population and the percentages of subjects off treatment and off study among treated subjects. 
Subject status will be summarized separately for the following phases: Induction through HR3, 
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Reinduction through Continuation, HSCT, and Follow-up. Off-treatment and off-study reasons 
will also be tabulated and listed.
7.3.2
Demographics at baseline
Demographic data, i.e. gender, race, ethnicity, age at disease diagnosis, age at consent, country 
and site will be summarized and listed. For age at disease diagnosis, in addition to the 
presentation of sample statistics, frequencies of the following age categories will be presented: 
>1 to <2; ≥2 to <7; ≥7 to <12; ≥12 to <18.
7.3.3
Medical history
7.3.3.1
General medical history 
General Medical History will be summarized by system and listed.
7.3.3.2
Disease history
Disease history will be summarized as follows:
- Time (in days) from initial ALL disease diagnosis to first dasatinib dosing date (Median, Min-
Max) 
- Immunophenotype disease diagnosis and baseline CNS leukemia disease status
-Philadephia positivity (t(9:22)(q34;q11)) method: Fluorescence in-site hybridisation only, real-
time PCR only, both. 
-Transcript detected: p190 0r p210 or data not available
- Specific disease history: WBC counts at disease diagnosis will be summarized as continuous 
data using descriptive statistics and as categorical data after slotting the counts in the following 
categories: 

< 50,000/μL 

50,000-100,000/μL

> 100,000/μL.
7.3.4
Pre-treatment Clinical complaints and findings
Pre-treatment events are those adverse events with an onset date in the baseline period.
Worst CTC grade of any pretreatment events will be summarized by MedDRA system organ 
classes and preferred terms and also listed. Pre-treatment events will not be included in the on-
treatment AE tables. 
7.3.5
Baseline evaluations
Baseline evaluations are those collected for treated subjects in the baseline period. For any 
treated subject, the result included in a baseline summary is the last available measurement or 
assessment prior to, or on, the first day of dasatinib dosing.
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7.3.5.1
Subject Characteristics at baseline
Subject characteristics at baseline (Physical measurements, ECG, Echocardiogram, and site of 
extramedullary involvement) will be summarized.
7.3.5.2
Physical Examination at baseline
Abnormal physical examination at baseline will be tabulated. A listing for physical examination 
at baseline will be also provided.
7.3.5.3
Laboratory parameters at baseline
CTC grade of baseline hematology laboratory values (CBC and differential) and serum 
chemistry baseline results BUN (or urea), serum creatinine, HCO3, ALT, AST, total bilirubin, 
LDH (high), Na, K, Cl, Mg (low), phosphorus, calcium (low), and uric acid will be tabulated.
7.3.5.4
Risk Groups
High risk and low/standard risk treated subjects will be tabulated and listed. 
High risk subjects are those with MRD at end of Induction 1A 0.01%. Low/standard risk 
subjects are those with MRD at end of Induction 1A of < 0.01%. 
The MRD method used to define the risk group for a subject is Ig/TCR. For subjects that do not 
have informative results of Ig/TCR at Induction 1A, MRD as measured by RQ-PCR for 
BCR-ABL will be used. If both Ig/TCR and BCR-ABL are uninformative, flow cytometry 
results will be utilized.
7.4
Extent of Exposure
Extent of exposure will be summarized for dasatinib only (not for chemotherapy). Study therapy, 
dasatinib and chemotherapy, will be presented in by-subject listings.
7.4.1
Administration of Dasatinib 
Duration of therapy (months), the average daily dose (mg/m2/day), and the relative dose 
intensity (%) will be summarized for:

All treated subjects, extent of exposure across the study

All treated subjects, extent of exposure until end of Consolidation

Treated subjects without HSCT, extent of exposure across the study

Treated subjects with HSCT, extent of exposure until HSCT

Treated subjects with HSCT, extent of exposure post-HSCT
In each of these summaries, results will be derived for:
-
All treated subjects, 
-
The subgroup of subjects who received dasatinib exclusively in tablet form, and
-
For the subgroup of subjects who received at least 1 dose of dasatinib in PFOS formulation. 
Duration of treatment will be reported for the whole subgroup and by formulation 
(PFOS/tablet).
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For subjects not receiving HSCT, duration of therapy (in days) will be defined as: 
Last dasatinib dose date - first dasatinib dose date + 1 
For subjects who did receive HSCT and received dasatinib post-HSCT, the dosing gap around 
HSCT will be subtracted. 
Duration of therapy will be expressed in months by dividing duration of therapy in days by 
30.4375.
The average daily dose (in mg/m2/day) will be defined as the cumulative dose (i.e., the sum of 
daily doses, in mg/m2, administered during the study) divided by the duration of therapy in days.
The daily doses in mg/m2 are obtained by dividing the dose received in mg by the most recent 
value of body surface area (BSA). BSA is computed using the following formula12: Square root 
of [Height (cm) x Weight (kg) /3600].
The relative dose intensity will be defined as:  average daily dose / 60, and will be expressed as a 
percentage.
7.4.2
Dose modifications for Dasatinib
Dose modifications (interruption, or reduction to 48 mg/m2) should be made for adverse events 
considered related to dasatinib (see protocol section 4.3.2.1 for a complete description of 
Dasatinib related AEs).
Dasatinib dose modifications (reductions, interruptions and escalations) will be tabulated for the 
All Treated Subjects dataset for the period through HR3. For the period from start of Reinduction 
Block 1 through end of Continuation the tabulation will comprise:

All treated subjects, extent of exposure across the study

All treated subjects, extent of exposure until end of Consolidation

Treated subjects without HSCT, extent of exposure across the study

Treated subjects with HSCT, extent of exposure until HSCT

Treated subjects with HSCT, extent of exposure post-HSCT
In each of these summaries, results will be derived for:
-
All treated subjects, 
-
The subgroup of subjects who received dasatinib exclusively in tablet form, and
-
For the subgroup of subjects who received at least 1 dose of dasatinib in PFOS formulation.
A dose reduction  will be defined as an administration at least by 2 consecutive days of a planned 
dose (in mg/m2) which is lower than both the previous dose and the subject’s starting dose (=60 
mg/m2/day).
A dose interruption will be defined as a complete omission of actual dosing on 2 consecutive 
days, provided that the subject resumes his dosing afterwards.
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The reason for dose modification will be the first reason reported by the Investigator for the 
period during which the dose modification was reported.
Time to first reduction/interruption due to hematologic/non-hematologic toxicity will be defined 
as the time (in days) from the first dasatinib dosing date to the date of first reduction or 
interruption due to hematologic/non-hematologic toxicity. 
The length of first interruption due to hematologic/non-hematologic toxicity will be defined as 
the time (in days) from the first interruption (i.e. the first date the dosing was omitted) due to 
hematologic/non-hematologic toxicity to, but not including, the first following date the dosing 
was resumed (i.e. the first following date dasatinib was administered). 
7.4.3
Previous and Concomitant Medications
A previous and concomitant medications listing will be provided.
7.4.4
Duration of Treatment Blocks
The treatment blocks are the following (between brackets are included the target durations): 

Induction IA (4 - 5 weeks)

Induction IB (4 weeks)
Then follows a recovery period during which dasatinib treatment continues but no chemotherapy 
is given (2 - 4 weeks)

3 successive Consolidation blocks (HR1, HR2, and HR3) (3 x 3 weeks)

Reinduction Block 1 (9 weeks)

Interim maintenance (4 weeks)

Reinduction Block 2 (9 weeks)

Continuation therapy (62 weeks)
The start of a treatment block is captured as the earliest date of any non-dasatinib medication 
given during that block. The stop date of a treatment block is captured as the day before the start 
date of the subsequent block if there is a subsequent block, and the last date of any study 
treatment if there is no subsequent block.
Treatment block duration will be summarized with descriptive statistics. Subjects who receive 
HSCT after HR3 (although in individual cases subjects may have already started Consolidation)
may restart dasatinib post-HSCT. The duration of that period will be summarized similarly.
7.5
Efficacy

Efficacy analyses will be based on all treated subjects and will mainly consist of :
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
Response rates (3-year EFS rates in primary analysis, complete remission rates, HSCT rates, 
MRD rates), along with their two-sided, 95% exact (Clopper and Pearson2) confidence 
intervals.

Kaplan-Meier plots for time to event variables (i.e. EFS in secondary/sensitivity analyses,
DFS, OS and time from the MRD assessment until the event) will be provided with number 
of subjects at risk. A two-sided, 95% confidence interval for the median will be computed 
using the method of Brookmeyer and Crowley3.The 3-year and 5-year EFS and DFS rates 
will be presented with their corresponding 95% CI's using Greenwood's formula for the 
standard error and based on the log-log transformation. Listings with duration (event free, 
survival, disease free) will be provided.

7.5.1
Event -Free Survival (EFS) Analyses
7.5.1.1
Regulatory Background
Initially the intention for study CA180372 was to be a single-arm study without formal treatment 
comparisons. The European regulatory authorities (PDCO) during discussions on the PIP 
required BMS to include formal statistical comparisons with results from external historical 
control trials. These comparisons would be performed using Kaplan-Meier based analyses 
utilizing patient level data from all three trials.
A request from BMS for patient level efficacy data from the two external historical control trials 
(AIEOP-BFM 2000 and Amended EsPhALL) was refused (in May 2013) by the respective study 
steering committees due to lack of subject consent for data sharing with BMS. However BMS 
received a confirmation in writing on behalf of the study steering committees that a set of results 
from each historical control study would be made available to BMS, most importantly the 3-year 
EFS binomial rates, in which: 

Subjects lost to follow-up prior to the 3-year time point and event-free up until last contact 
will be considered event-free at the 3-year time point, 

Subjects discontinuing study treatment early but still being followed up will be assessed for 
3-year EFS, regardless of the treatment following discontinuation, and

HSCT is not regarded as an event.
According to the agreement, EFS data will be handled in the same way for study CA180372 and 
the historical control trials for the primary analyses that are based on differences in the 3-year 
EFS rates, and also with regard to the calculation of Kaplan-Meier estimates. The binomial rates 
allow for the formal statistical comparison of the data as required by the PDCO.
As part of the agreement with the steering committees of the historical control trials, the 
following sensitivity analyses to evaluate the robustness of the primary analysis are also planned:

The same approach as above, except that subjects lost to follow-up prior to the 3-year time 
point and event-free up until last contact will be considered as having had an event at the date 
of last contact.
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
The same analysis as above, but in which a subject with HSCT will be considered as having 
had an event in case the subject discontinued study treatment.

Finally, the agreement also includes that the following results from the historical control 
trials will be provided:

Kaplan-Meier estimates of EFS at 3 and 5 years.

Complete remission rates at end of Induction (defined as < 5% blasts in bone marrow and no 
peripheral blasts).
7.5.1.2
Primary analysis

In the primary analysis the 3-year EFS rate from study CA180372 will be compared with 
the 3-year EFS rates from two external historical controls  (AIEOP-BFM 2000 and Amended 
EsPhALL) in hierarchical order , so that the overall experiment-wise one-sided type I error rate 
will be preserved at 0.05. 

The comparisons will be as follows:

1.
Superiority over chemotherapy alone of AIEOP-BFM 2000: 3 year EFS rate = 
52%.

2.
Non-inferiority to continuous imatinib plus chemotherapy of the amended 
EsPhALL trial: expected 3 year EFS rate = 78%. Non-inferiority margin size of 5%.

3.
Superiority over continuous imatinib plus chemotherapy of the amended 
EsPhALL trial: expected 3 year EFS rate = 78%.

The trial will be considered positive if at least the first two comparisons are statistically 
significant.

The difference with the 3-year EFS rate from the chemotherapy alone control arm will be
tested first. If that test is significant in favor of dasatinib, then non-inferiority relative to imatinib 
plus chemotherapy in the amended EsPhALL trial will be tested. If that test is significant and 
non-inferiority of dasatinib is declared, then superiority testing of the difference with the 3-year 
EFS rate in the continuous imatinib added to chemotherapy arm from the amended EsPhALL 
trial will be tested in third place.

The comparison will be done after the last subject treated has passed the 3-year follow-up 
period to ensure all subjects have the opportunity for 3-year EFS assessments (no interim 
analysis for primary endpoint). 

The differences in 3-year EFS rates will be computed using binomial proportions of
subjects who are free of events at 3 years over all treated subjects. Subjects lost to follow-up at 
any time without an event will be considered event free in the primary analysis. All subjects
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will have the opportunity to be followed for 3 years prior to the analysis and the denominator 
will include all treated subjects.

Event rates will be provided with exact 2-sided 90% Clopper-Pearson CI’s. Differences
in event rates will be tested at the 0.05 1-sided significance level using a Pearson χ2 test.

Non-inferiority testing against the study treatment in the amended EsPhALL trial will be
carried out using the corresponding 2-sided 90% CI for the treatment difference (3-year EFS rate 
in dasatinib+chemo minus 3-year EFS rate in imatinib+chemo) and comparing the lower 
confidence limit to the non-inferiority margin of -5%. This margin corresponds to 1/4 of the 
effect size of 18% anticipated in the amended EsPhALL trial over the chemotherapy-only control 
of the original EsPhALL trial.

Analyses will be conducted in the treated population. Interim analyses for DMC reports 
don’t include evaluation of EFS rates versus those in the historical external controls. Stopping 
rules may come into effect only when poor interim EFS results are observed and the Type I error 
related to the primary analyses is not affected.

Next to performing the above analyses on all treated subjects, the same analyses will be 
performed on subjects with uncontested Ph+ ALL diagnosis, meaning that any subject that was 
considered during treatment not to have Ph+ ALL, but say CML in blast crisis, will be excluded.
7.5.1.3
Secondary analyses

Secondary analyses related to EFS are:
1. Estimation of EFS at yearly time points (including 3 year and 5 year rates) will be performed 
utilizing the Kaplan-Meier (KM) Product Limit method.
In this key secondary analysis of estimated EFS, subjects who neither relapse nor die or who are 
lost to follow-up without an event will be censored on the date of their last bone marrow (BM) 
assessment, cerebrospinal fluid (CSF) assessment or physical exam, whichever occurs last. For 
subjects not reaching complete response by end of Consolidation Block 3/start of first 
Reinduction, the event date will be the date of BM assessment at end of Consolidation Block 3 or 
the date of the last available valid on-treatment BM assessment after start of dasatinib prior to the 
end of Consolidation Block 3. Subjects without valid BM results between the start of dasatinib 
and the last day of Consolidation Block 3 (HR3)/start of Reinduction 1 (no BM  done or no 
evaluable aspirate) will be considered having lack of complete response, and in that case the 
event date will be set equal to the start date of dasatinib.
2. The difference in 3-year EFS rate with the 3-year EFS rate in study COG AALL0031 will be 
computed using binomial proportions as a secondary objective. 
When comparing with these controls, the definition of event in EFS will be modified in order to 
align the endpoints for a relevant comparison: for comparison with COG AALL0031, lack of 
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complete response will be aligned and defined as > 5% bone marrow blasts at the end of 
induction IB.
Disease relapse/progression will be summarized. Number and percentage of treated subjects with 
disease relapse/progression will be presented by site (CNS, testicular, bone marrow, other). A 
by-subject listing will also be provided.

Next to performing the above analyses on all treated subjects, the same analyses will be 
performed on subjects with uncontested Ph+ ALL diagnosis, meaning that any subject that was 
considered during treatment not to have Ph+ ALL, but say CML in blast crisis, will be excluded.
7.5.1.4
Sensitivity and Subgroup analyses

Additionally, sensitivity analyses will be performed on EFS including :

1. HSCT considered as an event if the subject discontinues; i.e. the subject does not 
continue dasatinib use after HSCT.

2. Lost to follow-up considered as an event (at the date of last contact).

3. Induction failures considered as an event at time 0. Induction failures are defined as 
patients who don’t achieve a bone marrow Complete Remission (<5% lymphoblasts) by the last 
day of consolidation block HR3/start of first Reinduction (Protocol II).
4. Resurgence of MRD considered an additional event type, defined by the reason provided to 
start subsequent systemic cancer therapy being “non protocol-defined relapse”.

5. Subgroup analyses around HSCT, presenting 3-year EFS rates with 95% CIs:

Subjects who had HSCT

Subjects who were eligible to have HSCT but did not undergo this intervention

Subjects who were ineligible for HSCT

Subjects who were eligible for HSCT
6. Subgroup analyses of high versus low/standard risk. These risk groups are defined as follows:

High risk group: subjects with MRD at end of Induction 1A ≥0.01%.

Low/standard risk group: subjects with MRD at end of Induction 1A of < 0.01%.
7. Subgroup analyses based on age group:

Age below 12 years

Age at least 12 years
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7.5.2
Complete remission rate
Complete remission (CR) rate is defined as the proportion of subjects achieving a complete 
remission, i.e. < 5% lymphoblasts in bone marrow and in CSF, with no evidence of other 
extramedullary disease. Complete remission rates at end of Induction 1A, end of Induction 1B, 
and end of Consolidation will be tabulated. A subject is in Continued Complete Remission 
(CCR) as long as no relapse occurred since Complete Remission (CR) was achieved. CCR rates 
will be tabulated for end of Induction IB and end of Consolidation. Achievement of complete 
remission will be included in a subject listing.
7.5.3
Disease-Free Survival Analysis

Kaplan-Meier plots and 3-year and 5-year DFS rates will be provided on responders 
only, i.e. subjects who achieved complete response (M1 bone marrow) by end of HR3 / start of 
first reinduction block..
7.5.4
Overall Survival Analysis

Kaplan-Meier plots will be provided on all treated subjects. Subjects will be followed for 
survival for 5 years after end of treatment.
7.5.5
Minimal Residual Disease (MRD)
The method of reference to estimate MRD levels is the quantitative PCR detection of clone-
specific immunoglobulin and T-cell receptor gene rearrangements (Ig/TCR). The limit of 
detection of this assay will be approximately 10-4 - 10-5 or 0.01% - 0.001%.
Quantitative PCR for BCR-ABL will be expressed as a ratio of BCR-ABL transcripts compared 
to a control gene (eg ABL) with log reduction compared to baseline.
MRD levels from Flow are based on the percent mononuclear cells.
7.5.5.1
MRD Negative Rates

The rates of MRD negative subjects will be computed for end of Induction 1A (MRD2), 
end of Induction 1B (MRD3), and end of Consolidation (MRD4). PCR for clone-specific 
immunoglobulin and T-cell receptor gene rearrangements(Ig/TCR) wil be the method used for 
deciding a subject MRD-negative or not.

MRD negative rates will be summarized as:

The number of MRD negative subjects among all treated subjects. In order to include all 
treated subjects, those without evaluable Ig/TCR assessment will be considered as MRD 
positive.

The number of MRD negative subjects among subjects with an evaluable Ig/TCR 
assessment.
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
Rates will be presented together with exact 2-sided 95% Clopper-Pearson confidence 
intervals.
7.5.5.2
Correlation between the 3 methods of assessing MRD
To investigate how the 3 MRD methods correlate, concordance between MRD results and 
concordance between HSCT recommendation will be assessed. These exploratory analyses will 
be performed based on all MRD data from all treated subjects, ignoring dasatinib formulation.
The three methods are:

Real-time qPCR for clone specific immunoglobulin and T-cell receptor gene 
rearrangements (Ig/TCR),

real-time qPCR for BCR-ABL transcripts (BCR-ABL), and 

multiparameter flow cytometry (Flow)
An MRD result may be positive (a numeric level of positivity is reported), negative, or ‘positive 
but not quantifiable’ (in which case no robust level of positivity could be established). Pairwise 
MRD concordance will be investigated between each 2 out of the 3 methods.
MRD concordance will be summarized and graphically presented for each on-treatment time 
point (MRD2, MRD3, and MRD4) and for pooled results across time points.
In addition to MRD concordance, also pairwise HSCT recommendation concordance will be 
tabulated.
7.5.5.3
Prognostic value of MRD on EFS
For the 3 methods of MRD evaluation, Kaplan-Meier plots will be used to estimate the time from 
the MRD assessment until the event for each category of MRD level. Landmark analyses based 
on landmark time points MRD2, MRD3, and MRD4 will be performed for the following MRD 
categories: negative, positive but not quantifiable, and positive.
The medians will be provided with their 2-sided 95% CIs computed using the method of 
Brookmeyer and Crowley.
7.5.6
HSCT
The rate of subjects who were eligible for HSCT is defined as the number of subjects who were 
eligible for HSCT divided by the number of treated subjects. The rate of subjects who received 
hematopoietic stem cell transplant is defined as the number of subjects with HSCT divided by 
the number of treated subjects.
The numbers of subjects who 1) received HSCT, 2) who were eligible for HSCT but did not 
receive it, and 3) who were ineligible for HSCT will be tabulated.
Data summarizing HSCT events (such as donor type, transplant source, degree of match and 
phase of transplant) will be tabulated and listed. Bone marrow blasts and cytogenetic
A bone marrow analysis listing will be provided.
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7.5.6.1
Cerebrospinal Fluid (CSF)
A listing with CSF results (cell counts and cytopathology) will be provided.
7.6
Safety
Analyses of safety will be based on the data set of all treated subjects. The latest available 
MedDRA Dictionary version will be used for the classification of the adverse events. The 
frequencies of adverse events and other symptoms will be calculated for the on-treatment, i.e. 
from day 1 of dasatinib treatment through last day of dasatinib treatment + 30 days, and post-
treatment period (late toxicities), i.e. IMP-related adverse events with an onset date after the last 
day of dasatinib treatment + 30 days. 
Note: The abbreviation IMP (Investigational Medicinal Product) in this study denotes dasatinib. 
The AE/SAE forms for this study collect “action taken” and “drug relatedness” for dasatinib 
specifically, not for study medication generally.
7.6.1
Deaths
The number of deaths will be tabulated by primary reason during induction, during consolidation 
therapy, and on-treatment post-consolidation. The number of treatment-related deaths will be 
identified. Death is considered treatment-related if the primary cause of death captured on the 
death data crf page is ‘study drug toxicity’. The number of deaths overall (at any time after start 
of dasatinib), the number of deaths within 30 days of last dose of dasatinib, as well as the number 
of deaths in continuous complete remission (CCR) will be tabulated along with the 
corresponding reason. Subjects are in CCR after a first assessment of Complete Remission (CR), 
provided that this first CR has been confirmed at the next assessment. A subject is only no longer 
in CCR if relapse is established. All deaths will be presented in a listing.
7.6.2
Other Serious Adverse Events
On-treatment serious adverse events (SAEs) are defined in section 6.1 of the protocol and consist 
of adverse events deemed serious by the Investigator.
On-treatment SAEs will be classified by system organ class and by preferred term, and the worst 
grade per subject will be included in the tabulation. On-treatment SAEs leading to hospitalization 
and IMP-related on-treatment SAEs will be summarized similarly.
7.6.3
AEs leading to discontinuation
On-treatment AEs leading to discontinuation (AEs with action taken = “Drug was discontinued”) 
will be classified by system organ class and preferred term, and the worst grade per subject will 
be included in the tabulation. IMP-related adverse events leading to discontinuation will be 
summarized similarly.
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7.6.4
AEs of special interest
Adverse events of special interest are defined within the project (for example pleural 
effusion/fluid retention, bleeding); the complete list of adverse event of special interest, 
including any new emerging event, will be detailed in the Data Presentation Plan. On-study 
adverse events of special interest will be tabulated by any grade versus severe (grade 3-4) and 
grade 5. IMP-related adverse events of special interest will be summarized similarly.
7.6.5
Overall AES
On- treatment adverse events will be classified by system organ class and by preferred term, and 
the worst grade per subject will be included in the tabulation. IMP-related on-treatment adverse 
events will be summarized similarly.
Non-serious adverse events
A table of on-study non-serious adverse events will be provided on the total treated population 
using a cut-off of 5%.
Adverse events post HSCT
A frequency table of post-HSCT adverse events will be prepared in subjects opting to continue 
dasatinib after receiving HSCT.
Late toxicities
Late toxicities (IMP-related adverse events reported more than 30 days after last dose of study 
medication) will be classified by system organ class and preferred term, and the worst grade per 
subject will be included in the tabulation. A by-subject listing of late toxicities will be prepared.
Analysis of Adverse Event Multiple Occurrences
Several descriptive summaries of adverse events that take into account the number of 
occurrences that an AE was reported by individual patients will be provided.  In order to prepare 
these summaries, the CRF data will be processed according to standard BMS algorithms to 
categorize each line of patient data as a new occurrence or a continuation of an existing event. 
This determination will be based upon onset and resolution dates. Each line of patient data will 
represent the maximum severity observed as well as the last known assessed relationship to study 
medication by the investigator.  
This data will be presented as the rate per 100 years of patient exposure.  Exposure to study 
medication will be calculated according to approved standard BMS algorithms as well.  
As an example, if 5 patients report 7 unique episodes of headache and had a combined 
cumulative exposure of 20 years to study medication, the incidence rate is reported as 7/20 
*(100) or 35 cases per 100 patient years of exposure.  
The following summary tables will be provided:
A table showing the total number and rate (exposure adjusted) of occurrences for all AEs 
occurring in at least 5% of the subjects treated 
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For events of clinical interest and SAEs that warrant further analysis:
A table showing total number of events and rate (exposure adjusted) by time intervals: 0-6 
months, 6-12 months, and annually thereafter 
A table showing the number of subjects experiencing an AE once or multiple times 
A listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated 
and overlapping and contiguous occurrences of the same event have been collapses.
No formal statistical testing will be performed, only summary statistics are provided.
7.6.6
Neoplasms
On-treatment neoplasms, identified from the SAE CRF page (event='cancer'), and neoplasms in 
follow-up, identified from the follow-up page for new cancer, will be presented in by-subject 
listings.
7.6.7
Treatment Block Delays
Frequencies of treatment block delay categories (≤ 7 days, 8-14 days, etc.) will be presented for 
delays in start of HR1 relative to start of dasatinib (for subjects starting HR1), and delays in start 
of R1 relative to start of HR1 (for subjects starting R1). 
7.6.8
Clinical laboratory evaluation
7.6.8.1
Hematology
Worst on-treatment grade for WBC, ANC, platelets and haemoglobin will be tabulated, as well 
as worst on-treatment grade beyond the end of Induction, and worst on-treatment grade beyond
the end of high risk block 3. Analysis will be restricted to treated subjects with at least one on-
treatment measurement. Baseline vs. worst on-treatment grade will also be tabulated (grade 0, 1-
2 vs. 3-4). Similarly, end of Induction vs. worst post-induction on-treatment grade, and end of 
consolidation therapy vs. worst post-consolidation therapy on-treatment grade will be tabulated 
(grade 0, 1-2 vs. 3-4).
7.6.8.2
Serum chemistry
Worst on-treatment grade for BUN (or urea), serum creatinine, HCO3, ALT, AST, total 
bilirubin, LDH (high), Na, K, Cl, Mg (low), phosphorus, calcium (low), and uric acid will be 
tabulated. Analysis will be restricted to treated subjects with at least one on-treatment 
measurement. Baseline vs. worst on-treatment grade will also be tabulated (grade 0, 1-2 vs. 3-4).
7.6.9
Other Safety considerations
7.6.9.1
Electrocardiogram (ECG)
Frequency distribution of maximal QTc(F) intervals on treatment and QTc(F) changes from 
baseline (<-60, -60-<-30 , -30-<0, 0-30, >30-60, >60) will be tabulated. A listing for ECG 
parameters will be provided.
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7.6.9.2
Echocardiogram / MUGA
Frequencies of abnormal echocardiograms / MUGA findings on treatment will be tabulated. A 
listing of echocardiogram/MUGA results will be displayed in a by-subject listing.
7.6.9.3
Chest X-Ray  
Abnormal chest X-ray findings will be displayed in a listing.
7.6.9.4
Physical measurements and vital signs
By-subject listings will be produced for physical measurements and vital signs.
7.6.9.5
Long-term Growth and Development and Bone Metabolism
Changes from baseline and changes from baseline in z-score, as well as percentile shifts from 
baseline, will be tabulated for height, weight and BMI. Height, weight, and BMI will be 
presented in by-subject listings, together with z-scores and percentiles. 
The z-scores will be derived using WHO growth standards13, which are based on a large study 
(1997 to 2003) on 8500 children from widely different ethnic backgrounds and cultural settings 
(Brazil, Ghana, India, Norway, Oman, and US). Selection criteria for that study included specific 
behaviors consistent with current health promotion recommendations (breastfeeding norms, 
standard pediatric care, non-smoking requirements). The z-scores are dependent on age and 
gender and correspond to a normal distribution with mean 0 and a standard deviation of 1. 
Height, weight, BMI, bone age, free T4, TSH, FSH, LH, IGF-1, IGFbeta-3, urinary 
N-telopeptide, bone alkaline phosphatase and bone densitometry scan results will be summarized 
over time using descriptive statistics. Tanner stages will be summarized in shift from baseline 
tables.
Long-term growth and development assessments and bone mineral content are collected at 
baseline, annually during treatment, and annually for 5 years after completing dasatinib. In the 
summary tables, the following periods, relative to start of dasatinib, will be defined: 1 year, >1 
and 2 years, > 2 and 3 years, > 3 and 4 years, > 4 and 5 years, etc. If a subject has more 
than 1 assessment in a time interval, the last assessment will be used.
By-subject listings will be prepared for: bone age, Tanner stage, hormone levels (T4, TSH, FSH 
(for children > 8 years old), LH (for children > 8 years old)) and growth factors (IGF-1/IGFB-3), 
long-term bone metabolism assessments (Urinary N-Telopeptide, Bone Alkaline Phosphatase), 
DXA scanning results. DXA scanning will include bone mineral content and density measures in 
lumbar spine, total body (less head), total hips and femoral neck.
Adverse event (AE) and serious adverse event (SAE) (Grade 2 and above) associated with 
growth and development disorders and bone mineralization will be listed by subject (the list of 
events will be specified in the DPP).
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7.7
Mutation Analysis
BCR-ABL mutation status will be analyzed at baseline and at disease progression or relapse. The 
specific type and frequency of mutations in the BCR-ABL kinase domain will be summarized 
using descriptive statistics. 

8
CONVENTIONS

In the instance of a missing day in a date that has the month and year, the day will be 
imputed as the 15th of the month. In the instance of a missing day and month in a date that 
has only the year, the day and month will be imputed as July 1.

For adverse events, missing onset date will be imputed according to the conventions 
described in the document “Analysis of safety data”, supplement to GD SOP 12:0  5.

The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days.

Duration (e.g. time from initial ALL disease diagnosis to first dosing date) will be calculated 
as follows:
Duration = (Last date - first date + 1)
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9
CONTENT OF REPORTS
See DMC charter for tables and listings that have to be produced for DMC review. All the tables 
and listings described in this SAP will be used for the final CSR.
The list of tables (and figures/listings where indicated) below comprises the set of topline results.

Subject Accrual

Relevant Protocol Deviations

Subject Disposition

Demographics

Deaths (summary tables and listing)

Extent of Exposure to Dasatinib

Dose Modifications for Dasatinib

Complete Remission rates

Primary efficacy analyses

Kaplan-Meier curve and estimates of EFS

All On-treatment Adverse Events, Worst CTC Grade

All On-treatment Drug-Related Adverse Events, Worst CTC Grade

All On-treatment Serious Adverse Events

All On-treatment Drug-Related Serious Adverse Events, Worst CTC Grade

Adverse Events Leading To Discontinuation

Drug-Related Adverse Events Leading To Discontinuation

On-treatment Neoplasms

Height, weight, and BMI z-scores (change from baseline tables and box-plots)
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10
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13 http://www.who.int/childgrowth/en/
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