Clinical trial NCT00788125
Conditions: Brain and Central Nervous System Tumors Childhood Germ Cell Tumor Extragonadal Germ Cell Tumor Kidney Cancer Liver Cancer Lymphoma Neuroblastoma Ovarian Cancer Sarcoma Testicular Germ Cell Tumor Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: previously treated childhood rhabdomyosarcoma metastatic childhood soft tissue sarcoma metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor metastatic osteosarcoma recurrent childhood rhabdomyosarcoma recurrent childhood soft tissue sarcoma recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor recurrent osteosarcoma unspecified childhood solid tumor, protocol specific recurrent Wilms tumor and other childhood kidney tumors recurrent neuroblastoma stage 4S neuroblastoma childhood extracranial germ cell tumor childhood malignant ovarian germ cell tumor childhood malignant testicular germ cell tumor childhood teratoma clear cell sarcoma of the kidney childhood renal cell carcinoma recurrent renal cell cancer congenital mesoblastic nephroma cystic nephroma peripheral primitive neuroectodermal tumor of the kidney rhabdoid tumor of the kidney disseminated neuroblastoma recurrent malignant testicular germ cell tumor recurrent ovarian germ cell tumor recurrent childhood liver cancer stage IV childhood liver cancer angioimmunoblastic T-cell lymphoma stage IV childhood Hodgkin lymphoma stage IV childhood large cell lymphoma stage IV childhood lymphoblastic lymphoma stage IV childhood small noncleaved cell lymphoma recurrent childhood grade III lymphomatoid granulomatosis recurrent childhood large cell lymphoma recurrent childhood lymphoblastic lymphoma recurrent childhood small noncleaved cell lymphoma recurrent/refractory childhood Hodgkin lymphoma childhood diffuse large cell lymphoma childhood grade III lymphomatoid granulomatosis childhood immunoblastic large cell lymphoma childhood nasal type extranodal NK/T-cell lymphoma Burkitt lymphoma recurrent childhood anaplastic large cell lymphoma stage IV childhood anaplastic large cell lymphoma childhood central nervous system choriocarcinoma childhood central nervous system embryonal tumor childhood central nervous system germ cell tumor childhood central nervous system germinoma childhood central nervous system mixed germ cell tumor childhood central nervous system teratoma childhood central nervous system yolk sac tumor recurrent childhood central nervous system embryonal tumor childhood choroid plexus tumor childhood craniopharyngioma childhood ependymoblastoma childhood medulloepithelioma childhood infratentorial ependymoma childhood supratentorial ependymoma childhood oligodendroglioma childhood pineal parenchymal tumor childhood grade I meningioma childhood grade II meningioma childhood grade III meningioma recurrent childhood cerebellar astrocytoma recurrent childhood cerebral astrocytoma recurrent childhood ependymoma recurrent childhood medulloblastoma recurrent childhood pineoblastoma recurrent childhood supratentorial primitive neuroectodermal tumor recurrent childhood visual pathway and hypothalamic glioma recurrent uterine sarcoma childhood high-grade cerebellar astrocytoma childhood high-grade cerebral astrocytoma childhood low-grade cerebellar astrocytoma childhood low-grade cerebral astrocytoma childhood atypical teratoid/rhabdoid tumor primary central nervous system non-Hodgkin lymphoma primary central nervous system Hodgkin lymphoma childhood extragonadal germ cell tumor recurrent childhood malignant germ cell tumor recurrent childhood brain stem glioma recurrent childhood subependymal giant cell astrocytoma recurrent childhood brain tumor recurrent childhood spinal cord neoplasm
Sponsor: City of Hope Medical Center
Start date: 2008-09-03; Completion date: 2022-07-30
Enrollment: 7 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs in chemotherapy, such as ifosfamide, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving dasatinib together with ifosfamide, carboplatin, and etoposide may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of dasatinib when given together with ifosfamide, carboplatin, and etoposide and to see how well they work in treating young patients with metastatic or recurrent malignant solid tumors.

Detailed description:
OBJECTIVES:

Primary

* To determine the maximum tolerated dose (MTD) of dasatinib when given immediately following ifosfamide, carboplatin, and etoposide phosphate (D-ICE) as a re-induction regimen in young patients with metastatic or recurrent malignant solid tumors. (Phase I)
* To describe and define the toxicities of D-ICE in these patients. (Phase I)
* To determine the safety and feasibility of prolonged administration of single-agent dasatinib following completion of 2-6 courses of D-ICE in these patients. (Phase I)
* To estimate the overall survival, progression-free survival, and time to progression in patients treated with D-ICE at the MTD followed by single-agent dasatinib. (Phase II)
* To estimate the response rate to two courses of D-ICE when given at the MTD in these patients. (Phase II)

Secondary

* To determine the phosphotyrosine state of SRC family kinases and related signaling pathways, including FAK, STAT3, VEGFR, AKT, EGFR, KIT, EPHA2, and PDGFR, in paraffin-embedded tumor samples as measured by immunohistochemistry prior to and during treatment with dasatinib.
* To assess gene expression profiling in fresh frozen tissue samples as measured by microarray analysis (Affymetrix GeneChips) at baseline to identify molecular signatures that may predict response to dasatinib.
* To correlate biomarkers and molecular signatures with dasatinib dosage, toxicity, and antitumor activity.
* To evaluate the effect of dasatinib on phosphorylation of SRC family kinases in peripheral blood mononuclear cell samples as a surrogate marker of response prior to treatment with dasatinib, at days 14-21 or when WBC ≥ 500/μL, during each treatment course, at the time of local control, and at the time of progression.

OUTLINE: This is a multicenter, phase I, dose-escalation study of dasatinib followed by a phase II study. Patients enrolled in phase II are stratified according to disease.

Patients receive D-ICE comprising oral dasatinib twice daily on days 5-21, ifosfamide IV over 1 hour and etoposide phosphate IV over 1 hour on days 1-5, and carboplatin IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo radiotherapy and/or surgery (consolidation therapy) after 2, 4, or 6 courses of D-ICE. After completion of consolidation therapy, patients receive oral dasatinib twice daily for up to 6 months in the absence of disease progression or unacceptable toxicity.

Tumor tissue and peripheral blood mononuclear cell (PBMC) samples are collected periodically for correlative laboratory studies. PBMCs are analyzed by western blotting for total and phospho-SRC, phospho-FAK, and other relevant biomarkers. Tumor tissue samples are analyzed by IHC for total and phospho-SRC, phospho-FAK, phospho-STAT3, phospho-KIT, and phospho-PDGFR, EPHA2, and VEGF. Tumor tissue samples are also analyzed by microarray gene expression profiling to define a potential molecular signature or gene expression pattern that may predict response to dasatinib.

After completion of study treatment, patients are followed periodically.

Arms: arm 1: None
Interventions: intervention 1: carboplatin intervention 2: dasatinib intervention 3: etoposide phosphate intervention 4: ifosfamide intervention 5: microarray analysis intervention 6: western blotting intervention 7: immunohistochemistry staining method intervention 8: laboratory biomarker analysis intervention 9: therapeutic conventional surgery intervention 10: radiation therapy
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None intervention 10: None

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB 07053 
 
12/08/09 
Packet: 09 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF   PEDIATRICS       
 
 
TITLE: 
Dasatinib with Ifosfamide, Carboplatin, Etoposide: A Pediatric Phase I/II Trial 
   
BMS Protocol Number CA 180 121 
 
 
CITY OF HOPE PROTOCOL VERSION: 
IRB # 07053  
 
Protocol Date: 12/08/09 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
  
COH Initial Submission  
 
Dated  12/31/2007 
 
 
 
 
Version: 00 
COH Amendment # 01  
 
Dated    08/29/2008 
 
 
 
 
Version: 01 
COH Amendment # 02  
 
Dated    11/12/2008 
 
 
 
 
Version: 02 
COH Amendment # 03  
 
Dated    02/27/2009 
 
 
 
 
Version: 03 
COH Amendment # 04  
 
Dated    12/08/2009 
 
 
 
 
Version: 04 
COH Amendment # 05 At Continuation Dated    10/06/2014 
 
 
 
 
Version: 05 
COH Amendment # 06 At Continuation Dated    09/22/2016 
 
 
 
 
Version: 06 
COH Amendment # 07 At Continuation Dated    09/18/2017 
 
 
 
 
Version: 07 
COH Amendment # 08 At Continuation  
Protocol dated 12/08/09 (tp) 
 
 
 
Packet: 08 
COH Amendment # 09 At Continuation  
Protocol dated 12/08/09 (tp) 
 
 
 
Packet: 09 
 
SITE:  
 
 
 
 
All Recurrent or metastatic Solid Tumors  
STAGE (If applicable): 
 
 
  
MODALITY:  
 
 
 
Chemotherapy  
TYPE:  
 
 
 
 
Phase I/II 
 
PRINCIPAL INVESTIGATOR: 
 
Judith K. Sato, M.D. 
 
 
COLLABORATING INVESTIGATORS: 
 
 
 
 
 
 
 
Paul Frankel, Ph.D.  
 
 
 
 
 
 
J. Dominic Femino, M.D. 
 
 
 
 
 
 
Lalit Vora, M.D. 
 
 
PARTICIPATING CLINICIANS: 
 
Clarke Anderson, M.D. 
Saro Armenian, D.O. 
 
 
 
 
 
 
 
Nadia Ewing, M.D. 
 
Anna Pawlowska, M.D. 
 
 
 
 
 
 
Joseph Rosenthall, M.D. 
 
 
 
 
 
 
 
 


 
1
 
Version Date: 12/08/2009 
Amendment No: 04 
 
 
 
Dasatinib with Ifosfamide, Carboplatin, Etoposide: 
A Pediatric Phase I/II Trial 
 
BMS Protocol Number: CA180 121                    
 
 
 
 
 
 
 
Principal Investigator: 
 
Judith K. Sato, MD 
 
 
 
 
 
 
 
 
City of Hope National Medical Center 
 
 
 
 
 
 
 
 
1500 E. Duarte Road 
 
 
 
 
 
 
 
 
Duarte, CA  91010 
 
 
 
 
 
 
 
 
Tel: 
626 930 5430 
 
 
 
 
 
 
 
 
Fax: 
626 930 5415 
 
 
 
 
Co-Principal Investigator: 
Richard Jove, PhD 
 
 
 
 
 
 
 
 
City of Hope National Medical Center 
 
 
 
 
 
 
 
 
1500 E. Duarte Road 
 
 
 
 
 
 
 
 
Duarte, CA  91010 
 
 
 
 
 
 
 
 
Tel: 
626 301 8179 
 
 
 
 
 
 
 
 
Fax: 
626 256 8708 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version ______:   December 08, 2009 
 


 
2 
Institutions:  
 
 
 
 
City of Hope National Medical Center 
 
 
 
 
All Children's Hospital of St. Petersburg 
 
 
 
 
H. Lee Moffitt Cancer Center and Research Institute 
 
 
 
 
Nemours Children's Clinics of Jacksonville 
 
POETIC Consortium: 
 
 
 
 
Children's Healthcare of Atlanta 
 
 
 
 
MD Anderson Cancer Center 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
 
 
 
 
Phoenix Children's Hospital 
 
 
 
 
Southern Alberta Children's Cancer Program 
Sydney Kimmel Comprehensive Cancer Center at John Hopkins 
University of Arizona, Health Sciences Center 
University of Colorado Health Sciences Center 
University of Florida, College of Medicine 
Vanderbilt Children's Hospital 
 
 
 
Study Committee: 
 
 
Principal Investigator:  
 
 
 
Judith K. Sato, MD 
 
 
Co-Principal Investigator:  
 
 
Richard Jove, PhD 
 
 
Statistician:  
 
 
 
 
 
Paul Frankel, PhD 
 
 
Orthopedic Surgeon:  
 
 
 
J. Dominic Femino, MD 
 
 
Diagnostic Radiologist: 
 
 
 
Lalit Vora, MD 
 
 
Physician Assistant: 
 
 
 
 
Margarita Munoz, MPH, PAC 
 
 
Research Nurse:  
 
 
 
 
Jayne Roses-Landau, RN 
 
 
Clinical Trials Systems Administrator: 
Sonia Corona Chico, MSM 
 
 
Clinical Research Coordinator:  
 
Gina Christiansen, MHS 
 
 
 
 
 
 
 


 
3
TABLE OF CONTENTS 
 
BMS Protocol Number: CA180 121                    
LIST OF TABLES............................................................................................................................ 7 
ABSTRACT..................................................................................................................................... 8 
EXPERIMENTAL DESIGN SCHEMA*: .......................................................................................... 9 
1.0 
INTRODUCTION............................................................................................................. 10 
1.1 
DASATINIB ..................................................................................................................... 11 
1.1.1 
Preclinical Anti-tumor Activity .................................................................................. 11 
1.1.2 
Preclinical Toxicology .............................................................................................. 12 
1.1.3 
Clinical Pharmacokinetics........................................................................................ 12 
1.2 
Safety of Dasatinib in Clinical Studies in CML and Ph+ ALL.......................................... 13 
1.2.1 
Laboratory Abnormalities......................................................................................... 15 
1.2.2 
Anticipated Adverse Events..................................................................................... 16 
1.3 
Phase I Experience in Solid Tumors............................................................................... 16 
1.4 
Ifosfamide, Carboplatin, Etoposide................................................................................. 17 
2.0 
STUDY RATIONALE.......................................................................................................... 18 
3.0 
OVERVIEW OF STUDY DESIGN AND EVALUATION..................................................... 18 
3.1 
Study Design................................................................................................................... 18 
3.1.1 
Duration of Study ..................................................................................................... 20 
4.0 
STUDY OBJECTIVES........................................................................................................ 20 
4.1 
Primary Objective............................................................................................................ 20 
4.1.1 
Phase I..................................................................................................................... 20 
4.1.2 
Phase II.................................................................................................................... 20 
4.2 
Secondary Objectives..................................................................................................... 20 
5.0 
STUDY POPULATION AND PATIENT ELIGIBILITY........................................................ 21 
5.1 
Inclusion Criteria ............................................................................................................. 21 
5.1.1 
Evidence of Disease ................................................................................................ 21 
5.1.2 
Age........................................................................................................................... 21 
5.1.3 
Prior Therapy ........................................................................................................... 21 
5.1.4 
Organ Function Requirements................................................................................. 22 
5.1.5 
Life Expectancy........................................................................................................ 22 
5.1.6 
Diagnostic Categories.............................................................................................. 22 
5.1.7 
Performancy Status ................................................................................................. 23 
5.2 
Exclusion Criteria ............................................................................................................ 23 
6.0 
TREATMENT OF SUBJECTS ........................................................................................... 24 
6.1 
Treatment Overview........................................................................................................ 24 
6.1.1 
Phase I Therapy with D-ICE .................................................................................... 24 
6.1.2 
Phase II Therapy with D-ICE: Stratum A & B .......................................................... 24 
6.1.3 
Phase II Therapy with D-ICE: Stratum C ................................................................ 25 
6.2 
Study Registration........................................................................................................... 25 


 
4 
6.2.1 
Subject Registration................................................................................................. 25 
6.3 
Study Treatment.............................................................................................................. 26 
6.3.1 
Dasatinib.................................................................................................................. 28 
6.3.2 
Ifosfamide, Carboplatin, Etoposide.......................................................................... 29 
6.4 
Grading Adverse Events................................................................................................. 29 
6.5 
Definition of Dose-Limiting Toxicity (DLT) ...................................................................... 30 
6.5.1 
Non-Hematological Dose-Limiting Toxicity.............................................................. 30 
6.5.2 
Hematological Dose Limiting Toxicity...................................................................... 30 
6.6 
Criteria for Starting Subsequent Courses....................................................................... 30 
6.7 
Dose Modifications.......................................................................................................... 31 
6.7.1 
Myelosuppression.................................................................................................... 31 
6.7.2 
Non-Hematological Toxicity ..................................................................................... 31 
6.7.3 
Dose Escalation....................................................................................................... 32 
6.8 
Discontinuation of Therapy ............................................................................................. 32 
6.9 
Prohibited and Restricted Therapies During Study......................................................... 33 
6.9.1 
Prohibited Therapies................................................................................................ 33 
6.9.2 
Restricted Therapies................................................................................................ 34 
7.0 
EVALUATION AND VISIT SCHEDULE............................................................................. 35 
7.1 
Required Clinical, Laboratory and disease Evaluation ................................................... 35 
7.1.1 
Post-therapy Evaluation........................................................................................... 36 
7.2 
Correlative Laboratory Studies ....................................................................................... 36 
7.2.1 
Overview of Laboratory Studies............................................................................... 36 
7.2.2 
Peripheral Blood Mononuclear Cells ....................................................................... 36 
7.2.3 
Tumor Specimens.................................................................................................... 37 
7.2.4 
Blood Sample Labeling............................................................................................ 37 
7.2.5 
Blood Sample Shipping Instructions........................................................................ 38 
7.2.6 
Tumor Specimen Labeling....................................................................................... 38 
7.2.7 
Tumor Specimen Shipping Instructions................................................................... 38 
7.2.8 
Summary: Submission of Biological Specimens ..................................................... 39 
8.0 
EFFICACY ASSESSMENTS.............................................................................................. 39 
8.1 
Response Criteria for Patients with Solid Tumors (RECIST) ......................................... 39 
8.1.1 
Measurable Disease ................................................................................................ 39 
8.1.2 
Evaluable Disease ................................................................................................... 40 
8.2 
Best Response................................................................................................................ 40 
8.3 
Definitions of PFS, OS, and PFS rate and OS ............................................................... 41 
9.0 
STUDY DRUGS INFORMATION ....................................................................................... 41 
9.1 
Dasatinib [SPRYCEL®]................................................................................................... 41 
9.2 
Ifosfamide (IFX, IFOS) NSC #109724 ............................................................................ 47 
9.3 
Etoposide (VP-16, VePesid) NSC #141540 ................................................................... 48 
9.4 
Carboplatin (Paraplatin, CBDCA) NSC #241240............................................................ 49 
9.5 
Mesna (sodium 2-mercaptoethane sulfonate, MESNA) NSC #113891.......................... 50 
9.6 
Granulocyte Colony-Stimulating Factor (R-MetHuG-CSF, G-CSF, Filgastim, Neupogen)     
           NSC #614629 ................................................................................................................. 51 


 
5
10.0 ADVERSE EVENTS........................................................................................................... 53 
10.1 Reporting of SAEs .......................................................................................................... 53 
11.0 STATISTICAL METHODOLOGY....................................................................................... 55 
11.1 Phase I Portion of Study: ................................................................................................ 55 
11.1.1 
Sample Size and Study Duration............................................................................. 55 
11.2 Phase II Portion of Study: ............................................................................................... 56 
11.2.1 
Sample Size and Study Duration............................................................................. 56 
11.2.2 
Phase II Study Design: Progression Free Survival.................................................. 56 
11.2.3 
Methods of Analysis................................................................................................. 57 
12.0 RECORDS, REPORTING, AND DATA SAFETY MONITORING PLAN........................... 57 
12.1 Research Records ............................................................................................................. 57 
12.1.1  Eligibility Verification ................................................................................................ 57 
12.1.2 
Case Report Forms.................................................................................................. 57 
12.2 Compliance ........................................................................................................................ 58 
12.2.1 Compliance with the Protocol and Protocol Revisions................................................ 58 
12.3 Monitoring .......................................................................................................................... 58 
12.4 Records Retention ............................................................................................................. 59 
12.5 CRADA/CTA ................................................................................................................... 59 
12.6 Data and Safety Monitoring Plan....................................................................................... 60 
12.6.1 Data and Safety Monitoring Committee ...................................................................... 60 
12.6.2 Monitoring by the Study Chair and Coordinating Center ............................................ 61 
12.7 Investigational Product Records........................................................................................ 61 
12.8 Return and Destruction of Investigational Product ............................................................ 61 
12.8.1 Return of Investigational Product................................................................................ 61 
12.8.2 Destruction of Investigational Product......................................................................... 61 
REFERENCES .............................................................................................................................. 62 
APPENDIX 1:  List of Abbreviations .......................................................................................... 64 
APPENDIX 2:  Dasatinib Subject Diary for Study..................................................................... 65 
APPENDIX 3: COH Specimen Transmittal Form ...................................................................... 66 
APPENDIX 4:  Submission Of Biological Samples .................................................................. 67 
APPENDIX 5:  POETIC Consortium Responsible Investigators ............................................. 68 
APPENDIX 6:  Performance Status Scales/Scores .................................................................. 69 
APPENDIX 7:  Study Calendar.................................................................................................... 70 
APPENDIX 8:  Data and Submission Schedule ........................................................................ 71 
APPENDIX 9:  Surgical Guidelines ............................................................................................ 73 
APPENDIX 10:  Radiation Therapy Guidelines......................................................................... 74 


 
6 
APPENDIX 11:  Informed Consent Template – Phase I............................................................ 78 
APPENDIX 12:  Informed Consent Template – Phase II........................................................... 94 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
7
LIST OF TABLES 
 
 
Table 1:  Adverse Events Reported > 20% in Clinical Studies in CML and 
               Ph + A.L.L............................................................................................13 
 
Table 2:  CTC Grades 3 / 4 Laboratory Abnormalities in Clinical Studies in CML                       
 
         and Ph + A.L.L.....................................................................................14 
 
Table 3:  Inter-patient Dose Escalation Schema.................................................25 
 
Table 4:  Schedule for Chemotherapy Administration ........................................25 
 
 
 
 
 
 
 


 
8 
ABSTRACT 
Dasatinib, a kinase inhibitor that has demonstrated activity to inhibit SRC family kinases, BCR-
ABL, c-KIT, EPHA2 and the PDGF-∃, has been shown to inhibit cellular proliferation, cell 
adhesion, migration and invasion, in numerous cancer cell lines that express activated SRC or c-
KIT (13, 14). This novel molecular –targeted agent will be administered with a proven cytotoxic 
chemotherapy regimen, ifosfamide, carboplatin, and etoposide (ICE) in this study, in two phases: 
the Phase I portion to define the maximally tolerated dose of dasatinib when administered with 
ICE; the Phase II portion (stratum A & B) to define the overall response rate of the 4 drug 
combination as well as to estimate the progression free survival for relapsed pediatric 
malignancies;  and the Phase II (stratum C) study for newly diagnosed, high risk patients with 
sarcoma, to define the overall response rate of D-ICE in previously untreated patients. 
 
Patients aged 1 – 25 years with recurrent childhood solid tumors are eligible for this study.  
Patients will first be enrolled in the Phase I portion of this study, in a standard Phase I dose 
escalation manner with a starting dose of Dasatinib at 35 mg/m2/dose twice a day, given 
immediately following standard doses of ICE chemotherapy.  After two to six courses of D-ICE, 
patients with stable disease or with response, will undergo local control/consolidation by either 
surgical resection of metastases and/or radiation.  In the Phase I portion, patients will then 
continue with Dasatinib alone for six months, if tolerable.  If the patient does not develop dose 
limiting toxicity in the first two months after consolidation, he/she may escalate the dose of 
dasatinib to the next level. 
 
After completion of the Phase I portion of the study, patients with relapsed sarcomas and other 
solid tumors will be enrolled in the Phase II portion of the study, at the maximally tolerated dose 
of Dasatinib, as defined in the Phase I portion of this study.  All patients will be evaluated for 
overall response rate and time to progression. 
 
Patients with metastatic sarcoma and very poor chance of response will be allowed to enroll on 
this study in the Phase II portion of the study, at the defined MTD.  The data from these patients 
will be analyzed for 1-yr overall survival response.  
 
Correlative studies of Dasatinib are a crucial part of this study.  Characteristics to be examined by 
Richard Jove, Ph.D. at the City of Hope Cancer Center include: (1) phosphotyrosine state of the 
tumor by immunohistochemistry analysis in paraffin-embedded tumor specimens, and in 
peripheral blood mononuclear cells as a surrogate of the tumor, (2) gene expression profiling by 
microarray analysis in fresh frozen tissues to identify molecular signatures to predict 
responsiveness to dasatinib, and (3) correlate the biomarkers and molecular signatures with 
dasatinib dosage, toxicity, and antitumor activity. 
 
Our hypothesis is that pediatric patients with recurrent solid tumors including recurrent or 
refractory sarcomas, will tolerate and respond to a novel combination of dasatinib with cytotoxic 
chemotherapy, ICE (D-ICE).  Furthermore, we propose that prolonged treatment with dasatinib 
alone will be safe and feasible following completion of 2-6 courses of D-ICE. 


 
9
 
EXPERIMENTAL DESIGN SCHEMA*:   
 
 
 
 
ON STUDY 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
D-ICE x 2 
(level x of Dasatinib 
as determined by P.I.) 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
PD 
 
SD / PR# 
 
 
 
CR 
↓ 
 
↓ 
 
 
 
↓  
Off Protocol 
Therapy 
 
D-ICE x 2 
 
 
 
Consolidation 
Radiation &/or 
Surgery 
 
 
↓ 
 
 
 
  
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR# 
 
 
CR 
 
↓ 
 
↓ 
 
 
↓ 
 
Off Protocol 
Therapy 
 
D-ICE x 2 
 
  
Consolidation 
Radiation &/or 
Surgery 
 
 
 
↓ 
 
 
  
 
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR 
 
CR 
 
 
↓ 
 
↓ 
 
↓ 
 
 
Off Protocol 
Therapy 
 
Consolidation 
Radiation &/or Surgery 
 
Consolidation 
Radiation &/or 
Surgery 
  
 
 
 
↓ 
 
↓ 
 
 
 
 
Dasatinib alone start at (level x) 2 months  
 
 
 
 
↓ 
 
 
Legend: 
 
After 2 months then may increase Dasatinib to level (x + 1) 
CR – Complete Response 
 
 
↓ 
 
 
PR – Partial Response 
Continue x 4 more months (total 6 months) Dasatinib alone 
SD – Stable Disease 
 
 
↓ 
 
 
PD – Progressive Disease  
 
END OF THERAPY 
 
*  Phase I:  Dasatinib (SPRYCEL®) dose escalation per Table 3 
 Phase II: Dasatinib  (SPRYCEL®) dose will be administered at the maximally tolerated dose, as determined by the  
  
 
  Phase I portion of this study. 
# At Investigators discretion subject may proceed to consolidation, radiation and/or surgery 


 
10 
1.0 INTRODUCTION 
 
Rational incorporation of novel molecular targeted anticancer agents into cytotoxic chemotherapy 
regimens, is an exciting and new challenge sure to increase overall response rates in all forms of 
cancer.  The purpose of this study is to combine dasatinib [SPRYCEL®], a kinase inhibitor with 
demonstrated activity inhibiting tyrosine kinases including SRC family kinases, BCR-ABL, c-KIT, 
EPHA2, and PDGFb receptors (1), with cytotoxic chemotherapy, ifosfamide, carboplatin, and 
etoposide (ICE). 
 
The prognosis for children with recurrent childhood solid tumors including recurrent or refractory 
sarcomas, such as rhabdomyosarcoma, osteosarcoma, and Ewings sarcoma, is poor with 5 year 
survival rates between 4% and 31% (2-4).  Re-induction chemotherapy regimens including 
cytotoxic agents such as cyclophosphamide/ topotecan (5), ifosfamide/etoposide (6,7), 
carboplatin/etoposide (8,9), irinotecan (10, 11) and ifosfamide/carboplatin/etoposide (12) have 
been used in an attempt to re-induce remissions and thus achieve an improved overall survival.  
The most effective regimen for relapsed or refractory sarcoma reported to date, is the use of 
ifosfamide/carboplatin/ etoposide (ICE) with an overall response rate of 51% (12). This 
combination was in fact, superior to each agent given alone or to regimens given as two drug 
combinations (12).  ICE induced a complete or partial response in 65% of patients with Wilm's 
Tumor, Ewing's sarcoma, rhabdomyosarcoma, other soft tissue sarcomas and lymphomas (12).   
 
Dasatinib has been shown to inhibit cellular proliferation, cell adhesion, migration and invasion, in 
numerous cancer cell lines that express activated SRC or c-KIT (13, 14).   We have recently 
shown that dasatinib inhibits the migration and invasion of 12 different human sarcoma cell lines 
of diverse origins, including osteogenic and soft-tissue sarcomas (15).  Furthermore, dasatinib 
induces apoptosis of bone sarcomas, including osteosarcomas and Ewings sarcoma, but not soft-
tissue sarcomas.  This is based on the first report on the action of dasatinib in mesenchymally 
derived tumors.  Based on these findings, we predict that dasatinib will complement the cytotoxic 
activity of ICE by preventing invasion and metastases of sarcomas.   
 
Because of the very different mechanisms of action of dasatinib and ICE, we do not expect that 
these therapies will synergize with each other, if given simultaneously.  In addition, we 
hypothesize that dasatinib and ICE given simultaneously could mask the anti-tumor benefit of 
dasatinib or result in antagonistic effects.  For these reasons, we propose to give ICE first 
followed by dasatinib daily, during each course of D-ICE prior to consolidation, and then to 
continue with dasatinib alone after consolidation. Thus, dasatinib will be given during the re-
induction phase of treatment and should theoretically, increase the response rate of the cytotoxic 
chemotherapy.   We hypothesize that dasatinib can be given with cytotoxic therapy without a 
significant increase in toxicity.  Furthermore, we propose that prolonged treatment with dasatinib 
alone following local control/consolidation will be feasible and ultimately decrease the chance of 
disease progression/recurrence and metastases.   
 
This phase I/II study is designed to establish the feasibility and safety of  dasatinib given 
immediately following ICE cytotoxic therapy administered every 28 days (D-ICE) and to define the 
feasibility and safety of prolonged administration of dasatinib alone following completion of 2-6 
courses of D-ICE.     
 
Our hypothesis is that pediatric patients with recurrent solid tumors including recurrent or 
refractory sarcomas, will tolerate and respond to a novel combination of dasatinib with cytotoxic 
chemotherapy, ICE (D-ICE).  Prolonged treatment with dasatinib alone will be safe and feasible 
following completion of 2-6 courses of D-ICE. 


 
11
 
1.1 DASATINIB 
 
Dasatinib [SPRYCEL®] is a potent, broad spectrum ATP-competitive inhibitor of 5 critical 
oncogenic tyrosine kinase/kinase families: BCR-ABL, SRC, c-KIT, PDGF receptor β (PDGFRβ), 
and ephrin (EPH) receptor kinases, each of which has been linked to multiple forms of human 
malignancies (16). 
 
Drug discovery and nonclinical pharmacology studies showed that dasatinib (16): 
 
• 
Kills BCR-ABL dependent leukemic cell lines, including a number that are resistant to imatinib 
due to kinase domain mutations or overexpression of SRC family kinases and is effective 
against all imatinib-resistant kinase domain mutations tested to date, except T315I 
• 
Inhibited proliferation of cancer cell lines that express activated SRC or  c-KIT 
• 
Potently inhibits VEGF-stimulated proliferation and migration in HUVECs 
• 
Has potent bone anti-resorptive activity 
1.1.1 
Preclinical Anti-tumor Activity 
1.1.1.1 
In Vitro Molecular Studies 
 
Dasatinib potently inhibits: SRC kinases, BCR-ABL, c-KIT, PDGFRβ and EPHA and was less 
potent against 16 other unrelated protein tyrosine kinases (PTKs) and serine/threonine kinases. 
Imatinib is less potent against several key enzymes: for example, Dasatinib was 260-, 8-, 60-, 
and >1000-fold more potent than imatinib versus BCR-ABL, c-KIT, PDGFRβ, and SRC kinases, 
respectively (17). 
   
In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate 
sensitive and resistant disease. dasatinib inhibited the growth of chronic myeloid leukemia (CML) 
and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the 
conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-
ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family 
kinases (LYN, HCK), and multi-drug resistance gene overexpression (16). 
 
Dasatinib inhibits the BCR-ABL kinase with an in vitro IC50 of 3 nM, a potency 260-fold greater 
than that of imatinib mesylate (IC50 = 790 nM). In cellular assays, dasatinib killed or inhibited the 
proliferation of all BCR-ABL dependent leukemic cell lines tested to date. Dasatinib also 
demonstrated undiminished anti-tumor activity against several preclinically- and clinically-derived 
models of imatinib mesylate resistance. Evidence that SRC family kinase over expression may 
play a role in clinical resistance to imatinib mesylate was demonstrated in three CML cell lines 
established from patients who failed imatinib mesylate therapy. These cells remained highly 
sensitive to the cell-killing effects of dasatinib (17). 
 
These results demonstrate that dasatinib is effective in reducing the proliferation or survival of 
both imatinib mesylate-sensitive and resistant cells, and its inhibitory activity is not solely 
dependent on BCR-ABL. 
 
Recently, the Jove Laboratory has demonstrated the efficacy of dasatinib against 12 human 
sarcoma cell lines of diverse origins (15).  In these sarcoma cells, dasatinib inhibited SRC kinase 
activity at low nanomolar concentrations.  Furthermore, signaling pathways downstream of SRC, 
including Focal Adhesion Kinase (FAK), were also inhibited at similar concentrations.  These 
signaling pathways have been shown previously to have important roles in cell migration and 
invasion.  Significantly, inhibition of SRC kinase and downstream signaling through FAK was 


 
12 
accompanied by blockade of cell migration and invasion in all of the sarcoma cell lines.  
Moreover, apoptosis was induced in the osteosarcoma and Ewings subset of bone sarcomas, but 
not in the soft-tissue subset of sarcomas.  These finding provide the first evidence that dasatinib 
inhibits migration and invasion of diverse sarcoma cell types, and selectively blocks the survival 
of bone sarcoma cells.  Therefore, dasatinib may provide therapeutic benefit by preventing the 
growth and metastasis of sarcomas in pediatric patients. 
1.1.1.2 
In Vivo Studies 
 
The activity of dasatinib against CML cells in vitro was reproduced in vivo against several human 
CML xenograft models grown subcutaneously in SCID mice. Against the K562/imatinib 
mesylate/R CML model, dasatinib was curative in 100% of the treated animals. In contrast, at its 
optimal dose and schedule, imatinib mesylate was inactive. 
1.1.2 
Preclinical Toxicology 
 
Single or repeated oral administration of dasatinib principally affected the gastro-intestinal (GI) 
tract, including the liver, the hematopoietic and lymphoid systems in rats and monkeys. Other 
prominent effects after single oral administration of dasatinib included renal and cardiac toxicity in 
rats at lethal doses, and cutaneous hemorrhage in monkeys.  Dasatinib can also affect the 
immune system and bone turnover. 
 
Dasatinib in vitro activity in the HERG/IKr and Purkinje-fiber assays indicated a moderate liability 
for prolongation of cardiac ventricular repolarization (QT interval) in the clinic. However, there 
were no dasatinib -related changes observed in electrocardiograms, nervous system function, 
respirations and heart rate, blood pressure, or arterial oxygen saturation in single-dose, 10-day, 
or 1-month oral toxicity studies in monkeys. 
 
Dasatinib was found to exhibit a profile of broad-spectrum platelet inhibition best typified by anti-
platelet agents such as the GPIIb/IIIa antagonists, integrelin and abciximab. Finally, modulation of 
SRC kinase activity could also affect osteoclast morphology and function and bone remodeling. 
This effect could potentially result in an increase in bone mineral density and a phenotype 
analogous to osteopetrosis (17).  
1.1.3 
Clinical Pharmacokinetics 
 
The pharmacokinetics of dasatinib have been evaluated in 229 healthy subjects and in 137 
patients with leukemia.  
1.1.3.1 
Absorption 
 
Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) 
following oral administration. Dasatinib exhibits dose proportional increases in AUC and linear 
elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean 
terminal half-life of dasatinib is 3–5 hours (16).  
 
Data from a study of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 
minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of 
dasatinib. The observed food effects were not clinically relevant.  
1.1.3.2 
Distribution 
 
In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is 
extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to 


 
13
human plasma proteins in vitro was approximately 96% and 93%, respectively, with no 
concentration dependence over the range of 100–500 ng/mL (16).  
1.1.3.3 
Metabolism 
 
Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4.  
CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. Flavin-
containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) 
enzymes are also involved in the formation of dasatinib metabolites.  In human liver microsomes, 
dasatinib was a weak time-dependent inhibitor of CYP3A4.  
  
The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 
5% of the dasatinib AUC.  This indicates that the active metabolite of dasatinib is unlikely to play 
a major role in the observed pharmacology of the drug.  Dasatinib also had several other inactive 
oxidative metabolites.  
1.1.3.4 
Elimination 
 
Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled dasatinib, 
approximately 4% and 85% of the administered radioactivity was recovered in the urine and 
feces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the 
administered dose in urine and feces, respectively, with the remainder of the dose being 
metabolites.  
1.2 Safety of Dasatinib in Clinical Studies in CML and Ph+ ALL 
 
The data described below reflect exposure to dasatinib in 911 patients with leukemia from 1 
Phase I and 5 Phase II clinical studies. The median duration of therapy was 6 months (range 0–
19 months).  
 
The majority of dasatinib -treated patients experienced adverse drug reactions at some time. 
Drug was discontinued for adverse drug reactions in 6% of patients in chronic phase CML, 5% in 
accelerated phase CML, 11% in myeloid blast phase CML, and 6% in lymphoid blast phase CML 
or Ph+ ALL.  
 
The most frequently reported serious adverse events (SAEs) included pyrexia (9%), pleural 
effusion (8%), febrile neutropenia (7%), gastrointestinal bleeding (6%), pneumonia (6%), 
thrombocytopenia (5%), dyspnea (4%), anemia (3%), cardiac failure (3%), and diarrhea (2%).   
All treatment-emergent adverse events (excluding laboratory abnormalities), regardless of 
relationship to study drug, that were reported in at least 20% of the patients in dasatinib clinical 
studies are shown in Table 1. 
 
 
 
 
 
 
 
 
 
 


 
14 
Table 1: 
Adverse Events Reported ≥20% in Clinical Studies in CML and Ph+ ALL 
All Patients 
(n=911) 
Chronic 
Phase 
(n=488) 
Accelerate
d Phase 
(n=186) 
Myeloid 
Blast 
Phase 
(n=132) 
Lymphoid 
Blast 
Phase and
Ph+ ALL 
(n=105) 
All 
Grades 
Grades 
3/4 
Grades 3/4
Grades 
3/4 
Grades ¾ Grades ¾ 
Preferred Term 
Percent (%) of Patients 
Fluid Retention 
50 
9 
6 
6 
23 
9 
 
Superficial Edema 
36 
1 
0 
2 
3 
2 
 
Pleural Effusion 
22 
5 
3 
3 
14 
8 
Diarrhea 
49 
5 
3 
10 
8 
6 
Headache 
40 
2 
2 
2 
4 
6 
Hemorrhage 
40 
10 
3 
18 
23 
17 
Musculoskeletal Pain 
39 
4 
2 
3 
6 
13 
Pyrexia 
39 
5 
1 
5 
13 
9 
Fatigue 
39 
3 
2 
4 
4 
8 
Skin Rasha 
35 
1 
1 
1 
1 
4 
Nausea 
34 
1 
<1 
0 
5 
2 
Dyspnea 
32 
6 
5 
7 
11 
9 
Cough 
28 
<1 
<1 
1 
1 
0 
Infection (including 
bacterial, viral, fungal, 
non-specified) 
34 
7 
4 
8 
15 
13 
Infection/Inflammation 
26 
1 
1 
1 
5 
1 
Abdominal Pain 
25 
2 
1 
2 
4 
6 
Pain 
26 
2 
<1 
1 
5 
4 
Vomiting 
22 
1 
1 
2 
2 
2 
Febrile Neutropenia 
9 
8 
2 
11 
17 
20 


 
15
1.2.1 
Laboratory Abnormalities 
 
Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 
4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced CML or Ph+ 
ALL than in chronic phase CML. Myelosuppression was reported in patients with normal baseline 
laboratory values as well as in patients with pre-existing laboratory abnormalities.  (Table 2) 
 
In patients who experienced severe myelosuppression, recovery generally occurred following 
dose interruption and/or reduction; permanent discontinuation of treatment occurred in 1% of 
patients.  
 
Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia and 
hypophosphatemia were reported in patients with all phases of CML but were reported with an 
increased frequency in patients with myeloid or lymphoid blast CML and Ph+ ALL. Elevations in 
transaminases or bilirubin were usually managed with dose reduction or interruption. Patients 
developing Grade 3 or 4 hypocalcemia during the course of dasatinib therapy often had recovery 
with oral calcium supplementation.  (Table 2) 
 
Table 2: 
CTC Grades 3/4 Laboratory Abnormalities in Clinical Studies in 
CML and Ph+ ALL 
 
Chronic 
Phase 
(n=488) 
Accelerated 
Phase 
(n=186) 
Myeloid 
Blast Phase 
(n=132) 
Lymphoid 
Blast Phase 
and 
Ph+ ALL 
(n=105) 
 
Percent (%) of Patients 
Hematology Parameters 
 
 
 
 
 
Neutropenia 
49 
74 
83 
81 
 
Thrombocytopenia 
48 
83 
82 
83 
 
Anemia 
18 
70 
70 
51 
Biochemistry Parameters 
 
 
 
 
 
Hypophosphatemia 
11 
13 
23 
21 
 
Hypocalcemia 
2 
9 
20 
15 
 
Elevated SGPT (ALT) 
1 
4 
7 
11 
 
Elevated SGOT (AST) 
1 
2 
5 
8 
 
Elevated Bilirubin 
<1 
1 
5 
8 
 
Elevated Creatinine 
0 
2 
1 
1 
CTC grades: neutropenia (Grade 3 ≥0.5–1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia 
(Grade 3 ≥10–50 × 109/L, Grade 4 <10 × 109/L); anemia (hemoglobin ≥65–80 g/L, Grade 4 <65 g/L); 
elevated creatinine (Grade 3 >3–6 × upper limit normal range (ULN), Grade 4 >6 × ULN); elevated 
bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × 
ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); 
hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL).  
 
 


 
16 
1.2.2 
Anticipated Adverse Events 
Myelosuppression  
Treatment with dasatinib is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, 
neutropenia, and anemia. Their occurrence is more frequent in patients with advanced CML or 
Ph+ ALL than in chronic phase CML. Complete blood counts should be performed weekly for the 
first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was 
generally reversible and usually managed by withholding dasatinib temporarily or dose reduction 
(16).  
Bleeding Related Events 
In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction 
in vitro. Severe CNS hemorrhages, including fatalities, occurred in 1% of patients receiving 
dasatinib. Severe gastrointestinal hemorrhage occurred in 7% of patients and generally required 
treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 4% of 
patients. Most bleeding events were associated with severe thrombocytopenia. 
  
Patients were excluded from participation in dasatinib clinical studies if they took medications that 
inhibit platelet function or anticoagulants. Caution should be exercised if patients are required to 
take medications that inhibit platelet function or anticoagulants. 
Fluid Retention 
Dasatinib is associated with fluid retention, which was severe in 9% of patients, including pleural 
and pericardial effusion reported in 5% and 1% of patients, respectively. Severe ascites and 
generalized edema were each reported in 1%. Severe pulmonary edema was reported in 1% of 
patients. Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry 
cough should be evaluated by chest X-ray.  Severe pleural effusion may require thoracentesis 
and oxygen therapy.  Fluid retention events were typically managed by supportive care measures 
that include diuretics or short courses of steroids (16). 
QT Prolongation 
In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization 
(QT interval). In single-arm clinical studies in patients with leukemia treated with dasatinib, the 
mean QTc interval changes from baseline using Fridericia’s method (QTcF) were 3–6 msec; the 
upper 95% confidence intervals for all mean changes from baseline were <8 msec. Nine patients 
had QTc prolongation reported as an adverse event.  Three patients (<1%) experienced a QTcF 
>500 msec.  
 
Dasatinib should be administered with caution to patients who have or may develop prolongation 
of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital 
long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that 
lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or 
hypomagnesemia should be corrected prior to dasatinib administration (16).  
1.3 Phase I Experience in Solid Tumors 
 
In a Phase I study (CA180003) conducted by Bristol Myers Squibb (BMS), dasatinib was 
administered on a BID schedule to 42 subjects with refractory solid tumor. To date, doses up to 
160 mg BID on a 5-day on/2-day off schedule have been administered. A dose of 120 mg BID 
continuous daily schedule is currently under investigation.  
 
No severe clinical toxicity has been encountered. Gastrointestinal symptoms were reported in 
most subjects, fatigue was reported in 17 subjects (40%) and rash in 10 subjects (24%). Edema, 
lethargy and headache were uncommon, and appear to be dose-related. Grade 3 asymptomatic 


 
17
hypocalcemia was considered dose-limiting in one subject, Grade 2 rash was considered dose-
limiting in two other subjects, and Grade 2 nausea and vomiting (with dysarthria, lightheadedness 
and lethargy in a 49 kg subject taking concurrent diazepam) was considered dose-limiting in one 
subject.   
 
In another Phase I study (CA180021), dasatinib was administered on a QD schedule to 24 
subjects at doses up to 180 mg. Pleural effusions were observed in three subjects at the 180 mg 
dose level (one with pneumonia and two with malignant effusion). A dose of 250 mg QD is 
currently under consideration. Hypocalcemia, GI symptoms and skin rash have been mild and 
infrequent.   
 
To date, the safety profile in solid tumor subjects has been similar to that in CP CML subjects with 
the exception of severe myelosuppression, which has not been observed in solid tumor subjects 
and is considered related to efficacy against the leukemia as noted above, and severe bleeding 
which is secondary to thrombocytopenia in most instances (18). 
1.4 Ifosfamide, Carboplatin, Etoposide 
 
The combination of ifosfamide, carboplatin, and etoposide (ICE) has been successful in the 
treatment of relapsed/refractory pediatric malignancies (12,30).  Preclinical studies demonstrate 
that the three drug combination may have a higher efficacy as each agent has different 
mechanisms of action with minimal overlap of non-hematologic toxicities; each drug has a 
different antitumor profile in tumor cell lines as well as in preclinical models (30-33). 
 
Each agent alone has demonstrated some activity in pediatric solid tumors.   Ifosfamide (I) 
demonstrated an overall response rate (ORR) of 24-33% in children with osteosarcoma (OGS) 
and soft tissue sarcomas (STS) (19-22).  In Wilms Tumor, a response rate of 50% to Ifosfamide 
was reported (23). 
 
Carboplatin (C) has been studied as a single agent in pediatric recurrent disease with limited 
success: an ORR of 6-9% was reported in recurrent OGS, STS, Wilms tumor, and pediatric brain 
tumors (24, 25).  For relapsed Wilms tumor, an ORR of 40-53% was reported (24, 26). 
 
Etoposide (E) as a single agent produces limited responses.  In refractory Wilms tumor, an ORR 
of 42% was reported (27), with an ORR in recurrent childhood solid tumors of only 6%.  
Etoposide however, has been evaluated in combination trials (IE, CE, or ICE) for its possible 
synergistic or additive effects in pediatric recurrent solid tumors, with improved responses. 
 
The combination of Ifosfamide and Etoposide was studied in a phase II study which 
demonstrated the effectiveness of this regimen in children with recurrent Ewing’s sarcoma, 
osteosarcoma, rhabdomyosarcoma, primitive neuroectodermal tumor, lymphomas and other solid 
tumors (6,28).  In a separate study, a CR of 10% was reported in children with recurrent solid 
tumors, including hepatoblastoma, neuroblastoma, and Wilms tumor (7). 
 
The combination of Carboplatin and Etoposide has also been studied in relapsed Wilms tumor 
(29), resulting in an ORR of 73%. 
 
The Children’s Cancer Group (CCG) studied a large number of relapsed patients using ICE as 
the cytotoxic chemotherapy regimen while investigating multiple cytokines and growth factors, 
including g-CSF, IL-6, PIXY 321, thrombopoietin.  In a recently published report from the CCG, 
Van Winkle reported a 51% overall response rate in children with recurrent/refractory sarcomas, 
with overall survival at 1 and 2 years of 49% and 28%, respectively (12).   Ninety-seven patients 
with recurrent sarcomas were evaluable for response, with rhabdomyosarcoma having the 
highest response rate of 66% (12).  


 
18 
2.0 STUDY RATIONALE 
 
The prognosis for children with recurrent childhood solid tumors including recurrent or refractory 
sarcomas, such as rhabdomyosarcoma, osteosarcoma, and Ewings sarcoma, is poor with 5 year 
survival rates between 4% and 31% (2-4).  Re-induction chemotherapy regimens including 
cytotoxic agents such as cyclophosphamide/ topotecan (5), ifosfamide/etoposide (6,7), 
Carboplatin/etoposide (8,9), irinotecan (10, 11) and ifosfamide/carboplatin/etoposide (12) have 
been used in an attempt to re-induce remissions and thus achieve an improved overall survival.  
The most effective regimen for relapsed or refractory sarcoma reported to date, is the use of 
ifosfamide/carboplatin/ etoposide (ICE) with an overall response rate of 51% (12).   This 
combination was in fact, superior to each agent given alone or to regimens given as two drug 
combinations (12).   ICE induced a complete or partial response in 65% of patients with Wilm's 
Tumor, Ewing's sarcoma, rhabdomyosarcoma, other soft tissue sarcomas and lymphomas (12).  
  
Dasatinib has been shown to inhibit cellular proliferation, cell adhesion, migration and invasion, in 
numerous cancer cell lines that express activated SRC or c-KIT (13, 14).  Given that ICE is a 
cytotoxic regimen, and dasatinib is a molecular targeted agent with defined biological activities in 
terms of preventing invasion and metastases (15), we do not expect that dasatinib will enhance 
the cytotoxic activity of ICE.  Instead, our prediction, based on the molecular and biological 
mechanism of action of dasatinib, is that dasatinib will complement the cytotoxic activity of ICE by 
inhibiting invasion and metastases of tumor cells that escape ICE cytotoxic killing.  Therefore, we 
propose to administer dasatinib immediately following each ICE in order to better evaluate the 
complementary activities of dasatinib and ICE, as well as to avoid potential adverse interactions 
between these two therapeutic combinations. 
 
In this study, dasatinib will be given after each ICE administration, during the re-induction phase 
of treatment and should theoretically, increase the response rate of the cytotoxic chemotherapy.   
We hypothesize that dasatinib can be given with cytotoxic therapy without a significant increase in 
toxicity.  Furthermore, we propose that prolonged treatment with dasatinib alone following local 
control/consolidation will be feasible and ultimately decrease the chance of disease 
progression/recurrence.   
 
This phase I/II study is designed to establish the feasibility and safety of  dasatinib given 
immediately following each ICE cytotoxic therapy administered every 28 days (D-ICE) and to 
define the feasibility and safety of prolonged administration of dasatinib alone following 
completion of 2-6 courses of D-ICE.     
 
3.0 OVERVIEW OF STUDY DESIGN AND EVALUATION 
3.1 Study Design 
This novel molecular – targeted agent will be administered with a proven cytotoxic chemotherapy 
regimen, ifosfamide, carboplatin, and etoposide (ICE) in this study, in two phases: the Phase I 
portion to define the maximally tolerated dose of dasatinib when administered with ICE; the 
Phase II portion (stratum A & B) to define the overall survival and response rate of the 4 drug 
combination as well as to estimate the progression free survival for relapsed pediatric 
malignancies;  and the Phase II (stratum C) study for newly diagnosed, high risk patients with 
sarcoma, to define the overall survival, response rate and progression-free survival associated 
with D-ICE in previously untreated patients. 
 
Patients aged 1 – 25 years with recurrent childhood solid tumors are eligible for this study.  
Patients will first be enrolled in the Phase I portion of this study, in a standard Phase I dose 
escalation manner with a starting dose of Dasatinib at 35 mg/m2/dose twice a day, given 
immediately following standard doses of ICE chemotherapy.  After two to six courses of D-ICE, 


 
19
patients with stable disease or with response, will undergo local control/consolidation by either 
surgical resection of metastases and/or radiation.  In the Phase I portion, patients will then 
continue with Dasatinib alone for six months, if tolerable.  If the patient does not develop dose 
limiting toxicity in the first two months after consolidation, he/she may escalate the dose of 
dasatinib to the next level. 
 
After completion of the Phase I portion of the study, patients with relapsed sarcomas and other 
solid tumors will be enrolled in the Phase II portion of the study, at the maximally tolerated dose 
of Dasatinib, as defined in the Phase I portion of this study.  All patients will be evaluated for 
overall survival, response rate and time to progression. 
 
Patients with metastatic sarcoma and very poor chance of response will be allowed to enroll on 
this study in the Phase II portion of the study, at the defined MTD.  The data from these patients 
will be analyzed for 1-year overall survival response. Data analysis at 6 months, an additional 6 
months, if beneficial. 
 
Correlative studies of Dasatinib are a crucial part of this study.  Characteristics to be examined by 
Richard Jove, Ph.D. at the City of Hope Cancer Center include: (1) phosphotyrosine state of the 
tumor by immunohistochemistry analysis in paraffin-embedded tumor specimens, and in 
peripheral blood mononuclear cells as a surrogate of the tumor, (2) gene expression profiling by 
microarray analysis in fresh frozen tissues to identify molecular signiatures to predict 
responsiveness to dasatinib, and (3) correlate the biomarkers and molecular signatures with 
dasatinib dosage, toxicity, and antitumor activity, (see Experimental Design Schema, page 8). 
 
DASTINIB TREATMENT DURING THE D-ICE PHASE I PORTION OF STUDY: 
The dose of dasatinib will be escalated as per Section 6.3.1; Cohorts of 3 subjects will be studied 
at each dose level, up to 18 patients will be accrued during Phase I and given during the re-
induction phase of treatment prior to local control measures.  Following completion of 2-6 courses 
of D-ICE and appropriate local control measures, responding patients and those with stable 
disease will receive 28 day courses of dasatinb alone.  Courses 1 and 2 will be administered at 
the dose of dasatinib received in the initial phase of D-ICE.  If tolerated without significant 
adverse events, intra-patient dose escalation of dasatinib may occur after the first 2 months of 
dasatinib alone, using the dose levels outlined in Section 6.3.1, by only 1 dose level to a 
maximum of the Level 5 dose.   In addition, data from other dasatinib trials will be reviewed and 
the maximum dose and dose levels may be modified based on clinical data available at that time 
from other trials, as well as target modulation data available from this and other trials. 
 
PHASE II PORTION OF STUDY 
Thus, during the Phase II portion of the study, there are three strata: 
• 
Stratum A (75 patients): patients with relapsed Osteosarcoma, Ewings Sarcoma, 
Rhabdomyosarcoma; 
• 
Stratum B (max of 25 patients): Patients with relapsed solid tumors not listed above; 
• 
Stratum C (max of 25 patients): Patients with newly diagnosed metastatic sarcomas of 
poor risk 
 
Stratum A & B: 
Once the MTD of D-ICE and dasatinib alone are defined, a phase II portion of the study will occur 
at the MTD.  Up to 100 patients (Stratum A: 75 from the sarcoma tumor group and Stratum B: 25 
patients from other tumor types) will be accrued during the Phase II portion. 
During the phase II study, patients will receive a minimum of 2 and a maximum of 6 courses of D-
ICE followed by appropriate local control/consolidation measures (e.g., surgical resection of 


 
20 
metastases or radiation to metastatic sites).  Responding patients and those with stable disease 
will then receive 28-day courses of dasatinib alone.  A primary objective of the phase II portion of 
the study will be to determine the 1-yr overall survival of Stratum A.  Secondary endpoints include 
response rate as defined by RECIST criteria prior to consolidation; progression-free survival; 
further assessment of toxicity; and evaluation of exploratory correlative studies.  
 
Stratum C: 
After completion of the Phase I portion of this study which will have determined the MTD of 
dasatinib when given with ICE, 25 patients with metastatic disease at initial diagnosis and who 
have a poor risk for response and survival (e.g., unresectable metastases, pulmonary metastases 
greater than 6 in number), will be treated at the MTD of D-ICE.  These patients will receive D-ICE 
at the MTD, be evaluated for response after every two courses of D-ICE, undergo local 
control/consolidation with either surgery and/or radiation, and then will continue with dasatinib 
alone for a minimum of 6 months of dasatinib. 
3.1.1 
Duration of Study 
Subjects with stable disease or objective tumor response will be allowed to continue treatment as 
long as clinical benefit is observed.  Treatment will be discontinued for disease progression, 
unacceptable toxicity and/or reasons outlined in Section 6.4. 
4.0 STUDY OBJECTIVES 
4.1 Primary Objective 
4.1.1 
Phase I 
 
1) 
To determine the maximally tolerated dose (MTD) of dasatinib given immediately 
following ifosfamide, carboplatin and etoposide (D-ICE) as a re-induction regimen to 
pediatric patients with recurrent solid tumors 
2) 
To describe and define the toxicities of D-ICE 
3) 
To determine the safety and feasibility of prolonged administration of single agent 
dasatinib following completion of 2-6 courses of D-ICE therapy 
 
4.1.2 
Phase II 
 
1) 
In the phase II portion of the study, to estimate the overall survival, progression free 
survival and time to progression in patients with recurrent sarcoma and other solid tumors 
(including primary CNS tumors), to D-ICE given at the MTD, plus dasatinib alone given 
after consolidative therapy. 
2) 
In the phase II portion of the study, to estimate the response rate to 2 courses of D-ICE, 
given at the MTD. 
 
4.2 Secondary Objectives 
 
1) 
To determine the phosphotyrosine state by immunohistochemistry of SRC family kinases 
and related signaling pathways including FAK, STAT3, VEGFR, AKT, EGFR, KIT, 
EPHA2 and PDGFR in paraffin-embedded tumor specimens prior to and during treatment 
with dasatinib. 


 
21
2) 
Gene expression profiling by microarray analysis (Affymetrix GeneChips) of fresh frozen 
tissues prior to treatment to identify molecular signatures that may predict response to 
dasatinib. 
3) 
To correlate the biomarkers and molecular signatures with dasatinib dosage, toxicity, and 
anti-tumor activity. 
4) 
To evaluate the effect of dasatinib on phosphorylation of SRC family kinases in peripheral 
blood mononuclear cells (PBMCs) as a surrogate marker of response prior to treatment 
with dasatinib, at day 14 - 21 or when WBC > 500, during each treatment course, at the 
time of local control, and at time of progression, if any. 
5.0 STUDY POPULATION AND PATIENT ELIGIBILITY 
5.1 Inclusion Criteria 
5.1.1 
Evidence of Disease 
 
Subjects must have histologic proof of malignancy at initial diagnosis.  Each subject must have 
radiographic, nuclear image, or biopsy proof of recurrent disease within 4 weeks prior to study 
entry.  Patients must have failed or relapsed from standard first-line chemotherapy (or other 
antineoplastic therapy) for their tumor, if a standard treatment for their tumor is generally 
recognized to be beneficial.   
5.1.1.1 
Phase I  
 
Patients who have recurrent or metastatic disease completely resected just prior to study entry 
are eligible for the phase I portion of the study. 
 
Subjects with bone marrow involvement are NOT eligible for the phase I portion of the study.   
 
Relapsed patients on the Phase I study do not have to have measurable disease. 
 
5.1.1.2 
Phase II 
 
Enrollment of patients with bone marrow involvement will be allowed on the phase II portion of the 
study; they will not be evaluable for hematologic toxicity.  These patients must not be known to be 
refractory to red cell or platelet transfusions.   
 
The patient must have measurable disease defined radiographically, to be eligible for this portion 
of study.  
 
5.1.2 
Age 
All subjects must be > 1 year old at study entry, and must have initially been diagnosed with their 
malignancy prior to the age of 25 years old. 
 
5.1.3 
Prior Therapy 
Subjects must have fully recovered from the toxic effects of any prior therapy.  At least 3 weeks 
should have elapsed since the last dose of chemotherapy (6 weeks in the case of nitrosourea-
containing therapy).  
Subjects who have received the exact combination and dosage of ifosfamide, carboplatin and 
etoposide as administered in this study, within the last 3 months are ineligible.  Patients may have 


 
22 
received ifosfamide, carboplatin, and/or etoposide singly, in pairs, or in the same combination and 
doses, prior to study entry, and still be eligible. 
Patients who have received cranial-spinal irradiation (>2400 cGy) are ineligible.  Patients are also 
ineligible if they have received radiation therapy (including TBI) to greater than 50% of the bone 
marrow space. 
Patients must have recovered from previous colony-stimulating factor therapy and have been off 
colony-stimulating factors (G-CSF, GM-CSF, IL-11) for more than 7 days (G-CSF) or 14 days 
(Neulasta) and off EPO for 30 days. 
5.1.4 
Organ Function Requirements 
 
ANC and Platelet Count 
Subjects must have an ANC > 1000/uL and a platelet count > 75,000/uL to be eligible for therapy. 
 
Renal Function 
All subjects must have a creatinine clearance or GFR which is greater than or equal to 70 
ml/min/1.73 m2, or Cr < 1.5 X ULN. 
 
Hepatic function 
All subjects must have bilirubin less than 1.5 x NL and an SGOT or SGPT less than 2.5 x NL for 
age.  If there is liver involvement by tumor, the ALT/AST must be less than 5x ULN. 
 
Cardiac function 
Patients should have a normal ejection fraction and a fractional shortening of >28% (per 
institutional limits) or normal MUGA, no evidence of cardiac arrhythmias requiring therapy, and 
corrected QT (QTc) interval < 450 msecs 
5.1.5 
Life Expectancy 
 
All patients must have a life expectancy of 8 weeks or more 
5.1.6 
Diagnostic Categories 
5.1.6.1 
Phase I   
All patients with relapsed/refractory solid tumor malignancies (excluding CNS tumors) will be 
eligible for enrollment and data will be analyzed in cohorts of 3 patients. 
5.1.6.2 
Phase II (Stratum A & B)   
For the Phase II portion of the study, patients will be stratified by their diagnosis.   
Stratum A:  
 
Sarcoma (Rhabdomyosarcoma, Osteosarcoma, Ewings sarcoma)  
Stratum B: 
   a) 
Other Soft Tissue sarcomas 
   b)    Kidney Tumors 
   c)    
Lymphoma 
   d)    CNS Tumors (pending toxicities analysis in any Phase I study, including dasatinib) 
   e)   
Other solid tumors (neuroblastoma, gonadal and germ cell tumors, liver tumors, and  
 
 
miscellaneous tumors) 


 
23
5.1.6.3 
Phase II (Stratum C)   
 
Newly diagnosed, poor risk patients with metastatic sarcoma consisting of unresectable 
pulmonary metastases (six or more nodules) and/or disease involving multiple bones or other 
organs, will be eligible.  Sarcoma  includes Rhabdomyosarcoma, Osteosarcoma, Ewings 
sarcoma and other Soft Tissue Sarcomas. 
5.1.7 
Performancy Status 
 
Must be > or = 50 from Lansky (age 1 to 16) or Karnofsky (age >16) 
5.2 Exclusion Criteria 
 
Patients with any of the following will not be eligible for study: 
1)   Pregnancy or Breast-Feeding 
 
Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and 
 
teratogenic adverse events seen in animal studies.  Pregnancy tests must be obtained in 
 
girls who are post-menarchal.  Males or females of reproductive potential may not participate 
 
unless they have agreed to use an effective contraceptive method. 
2)   Patients with central nervous system tumors are excluded from the Phase I portion of the 
 
study. Patients with recurrent primary CNS tumors will be added to the Phase II portion of 
 
the study if there is no significant intratumor bleeding toxicities seen on either the COG 
 
Pediatric Phase I studies of Dasatinib or the Phase I portion of this study. 
3)   Concomitant Medications 
a)   Growth factors:  Growth factors that support the number or function of platelets or white 
 
cells must not have been administered within the past 7 days.  Pegfilgrastin (Neulasta) 
 
must not have been administered within the past 14 days. 
   b)   Investigational Agents:  Patients who are currently receiving another investigational drug. 
   c)   Anti-cancer Agents:  Patients who are currently receiving other anti-cancer agents. 
d) Enzyme inducing anticonvulsants: phenytoin, phenobarbital, felbamate, primdone, 
 
oxcarbazepine and/or carbamazepine. 
e)  Anti-thrombotic and anti-platelet agents: warfarin (coumadin), heparin, low molecular 
 
weight heparin, aspirin, and/or ibuprofen, or other NSAIDs. 
   f)   CYP3A4 inhibitors including itraconazole, ketoconazole, and voriconazole.  
   g)   Infection:  Patients who have an uncontrolled infection. 
   h)  Patients who have swallowing dysfunction that would prevent taking an oral medication 
 and who do not have a functioning gastric or jejunal tube (if a patient is unable to 
 swallow a pill, dasatinib may be administered via a nasogastric tube (NGT) or 
 gastrostomy, see section 9.1.8) 
   i) 
HIV+ patients whose HAART regimen may interact with dasatinib. 
   j)   Drugs that are generally accepted to have a risk of causing Torsades de Pointes 
including: (Patients must discontinue drug 7 days prior to starting dasatinib) 
i) 
procainamide, disopyramide 
ii) amiodarone, sotalol, ibutilide, dofetilide 
iii) erythromycin, clarithromycin 


 
24 
iv) chlorpromazine, haloperidol, mesoridazine, thioridazine 
v) bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, 
levomethadyl, pentamidine, sparfloxacin, lidoflazine. 
   k)  The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not 
recommended. The use of antacids should be considered in place of H2 blockers or 
proton pump inhibitors in patients receiving dasatinib therapy. 
l) 
Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy  
m) Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib 
therapy due to risk of hypocalcemia. 
4) History of significant bleeding disorder unrelated to cancer, including: 
a) 
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) 
b) 
Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII 
  
 
antibodies) 
c) 
Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding 
5) Patients who in the opinion of the investigator may not be able to comply with the safety 
monitoring requirements of the study. 
 
6.0 TREATMENT OF SUBJECTS 
6.1 Treatment Overview 
6.1.1 
Phase I Therapy with D-ICE 
 
During the initial phase I portion of the study, dose limiting toxicities (DLT) will be defined based 
on the agent-specific toxicities of dasatinib including prolongation of blood count recovery 
significantly beyond that expected with ICE alone (see Section 6.5).  Disease re-evaluation will be 
performed following 2, 4 and 6 courses of D-ICE.   
 
Patients who achieve a complete response to therapy may undergo local control/consolidative 
therapy as clinically indicated (including surgical resection of metastatic sites of disease, if 
possible, or radiation to bony metastases) after 2-6 courses of D-ICE.  Patients achieving a partial 
response or stable disease after 2 or 4 courses of D-ICE, may receive an additional 2 courses of 
D-ICE, up to a maximum of 6 courses of D-ICE.   
 
Following completion of a maximum of 6 courses of D-ICE, patients will receive therapy with 
dasatinib alone for up to 6 months or until disease progression occurs.  Single agent therapy will 
initially be at the same dose of dasatinib used in D-ICE, but may be escalated by one dose level, 
after two months of dasatinib alone.  Patients treated at Level 4 of D-ICE, who have no dose 
limiting toxicities, may be escalated to the maximum dasatinib dose level 5.   
 
No patients will be treated at dose level 5 in combination with ICE. 
 
 
6.1.2 
Phase II Therapy with D-ICE: Stratum A & B 
 
In the phase II portion of the study, patients will receive D-ICE at the MTD, be evaluated for 
response after every two courses of D-ICE, undergo local control/consolidation with either 
surgery and/or radiation, and then will continue with dasatinib alone for a minimum of 6 months of 
dasatinib. 


 
25
6.1.3 
Phase II Therapy with D-ICE: Stratum C (Newly Diagnosed, Poor Risk Patients with 
Metastatic Disease at Diagnosis) 
 
After completion of the Phase I portion of this study which will have determined the MTD of 
dasatinib when given with ICE, selected patients with metastatic disease at initial diagnosis and 
who have a poor risk (consisting of unresectable pulmonary metastases (six or more nodules) 
and/or disease involving multiple bones or other organs).for response and survival, will be treated 
at the MTD of D-ICE.  These patients will receive D-ICE at the MTD, be evaluated for response 
after every two courses of D-ICE, undergo local control/consolidation with either surgery and/or 
radiation, and then will continue with dasatinib alone for a minimum of 6 months of dasatinib. 
 
6.2 Study Registration 
6.2.1 
Subject Registration 
6.2.1.1 
Contact Requirements 
 
Written consent must be documented on the appropriate consent form designated and approved 
by the Institutional Review Board at the institution at which the patient is enrolled.   
 
For Phase I portion only:  Before enrolling the patient, the Principal Investigator, Judith K. 
Sato, M.D. at (626) 930-5430 (office) or (626)257-1315 (cell phone) and/or her designee, 
must be contacted to discuss patient eligibility, assign dose level and review correlative 
studies.   
 
Then, all patients must be centrally registered by fax to City of Hope National Medical Center 
at (626) 256-8787 
 
6.2.1.2 
Informed Consent/Assent 
 
The investigational nature and objectives of the trial, the procedures and treatments involved and 
their attendant risks and discomforts, and potential alternative therapies will be carefully 
explained to the patient or the patient’s parents or guardian if the patient is a child, and a signed 
informed consent and assent will be obtained according to the institutional guidelines. 
6.2.1.3 
Eligibility Checklist 
 
Before the patient can be enrolled, the responsible institutional investigator must sign and date 
the completed eligibility checklist.  A signed copy of the checklist will be FAXed to the Principal 
Investigator, Judith K. Sato, M.D. at (626) 930-5415 and/or her designee (to facilitate enrollment 
verification as noted in 6.2.1.1) and City of Hope National Medical Center at (626) 256-8787. 
 
 
6.2.1.4 
Study Enrollment 
 
Patients may be enrolled on the study once all eligibility requirements for the study have been 
met.  Patients must be enrolled before treatment begins.  Patients must not receive any protocol 
therapy prior to enrollment. 
 


 
26 
6.3 Study Treatment 
 
Overall Study Plan: 
 
 
 
 
 
Induction:  
 
 
 
For the Phase I portion of study, dasatinib will be escalated as per table 3. 
 
Consolidation:   
 
 
 
After 2-6 courses of D-ICE, patients will have surgery and/or radiation for residual 
disease (see Appendix 10 [Surgical Guidelines] and Appendix 11 [Radiation Therapy 
Guidelines]) 
 
Post-Consolidation: Dasatinib administered alone without ICE. 
 
 
 
In the Phase I portion of study, dose of dasatinib starts at same level as study entrance. 
 
In the Phase II portion of study, dose of dasatinib is at the M.T.D. as determined by the 
Phase I portion of study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INDUCTION 
D-ICE X 2 – 6 COURSES 
 
CONSOLIDATION 
SURGERY &/OR RADIATION 
 
POST-CONSOLIDATION 
DASATINIB ALONE 


 
27
EXPERIMENTAL DESIGN SCHEMA*:   
 
 
 
 
 
 
 
 
 
 
 
ON STUDY 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
D-ICE x 2 
(level x of Dasatinib 
as determined by P.I.) 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR# 
 
 
 
CR 
↓ 
 
↓ 
 
 
 
↓  
Off Protocol 
Therapy 
 
D-ICE x 2 
 
 
 
Consolidation 
Radiation &/or 
Surgery 
 
 
↓ 
 
 
 
  
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR# 
 
 
CR 
 
↓ 
 
↓ 
 
 
↓ 
 
Off Protocol 
Therapy 
 
D-ICE x 2 
 
  
Consolidation 
Radiation &/or 
Surgery 
 
 
 
↓ 
 
 
  
 
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR 
 
CR 
 
 
↓ 
 
↓ 
 
↓ 
 
 
Off Protocol 
Therapy 
 
Consolidation 
Radiation &/or Surgery 
 
Consolidation 
Radiation &/or 
Surgery 
  
 
 
 
↓ 
 
↓ 
 
 
 
 
Dasatinib alone start at (level x) 2 months  
 
 
 
 
↓ 
 
 
Legend: 
 
After 2 months then may increase Dasatinib to level (x + 1) 
CR – Complete Response 
 
 
↓ 
 
 
PR – Partial Response 
Continue x 4 more months (total 6 months) Dasatinib alone 
SD – Stable Disease 
 
 
↓ 
 
 
PD – Progressive Disease 
 
END OF THERAPY 
 
* Phase I:   Dasatinib (SPRYCEL®) dose escalation per Table 3 
 Phase II:  Dasatinib (SPRYCEL®)  dose will be administered at the maximally tolerated dose, as determined by the  
  
 
Phase I portion of this study. 
# At Investigators discretion subject may proceed to consolidation, radiation and/or surgery 
 


 
28 
6.3.1 
Dasatinib 
 
1) 
Patients will receive dasatinib twice daily for 17 days, starting on Day 5 of each 
course until Day 21, of each course.  One course of therapy will be 28 days.  Use of a 
medication calendar to monitor patient compliance is recommended (See Appendix 
2). 
 
2) 
Drug doses should be adjusted based on the BSA determined at the beginning of 
each course and rounded to the nearest 5 mg. 
 
3) 
If necessary to permit administration in young children, tablets may be allowed to 
dissolve into 1 oz of lemonade; double-strength juice is recommended to obscure the 
bitter taste (see section 9.1.8.1), 
 
4) 
If the patient is unable to swallow a pill, dasatinib may be administered via a 
nasogastric tube or gastrostomy. 
 
Table 3  Inter-patient Dose Escalation Schema (Phase I portion only): 
Dasatinib Level 
Dose, BID PO Daily x 17 days 
Level -1 
25 mg/m2/dose 
Level 1 
35 mg/m2/dose 
Level 2 
50 mg/m2/dose 
Level 3 
65 mg/m2/dose 
Level 4 
85 mg/m2/dose 
Level 5 (Dasatinib alone phase only) 
110 mg/m2/dose 
 
 
5) 
In the Post-Consolidation phase of treatment, each patient will receive dasatinib only, 
and take the same dose as assigned for the Re-Induction phase of treatment.  The 
patient will take the same dose twice a day, every day of each 28 day course of 
treatment.  If there is no DLT from dasatinib alone after the first 2 months of dasatinib 
alone, the dose will be escalated by one dose level. 
Chemotherapy 
should 
be 
resumed two weeks after surgery is performed or thereafter when ANC > 750 /uL or 
platelets > 75,000 /uL. 
 
 
 
 
 


 
29
6.3.2 
Ifosfamide, Carboplatin, Etoposide 
Ifosfamide, Carboplatin, Etoposide, MESNA doses will not be escalated. 
Table 4:  Schedule for Chemotherapy Administration 
Drug 
Route 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 - 21 
Day 22 - 28 
Ifosfamide 
Intravenous 
(IV) 
X 
X 
X 
X 
X 
 
 
Carboplatin Intravenous 
(IV) 
X 
X 
 
 
 
 
 
Etoposide 
Intravenous 
(IV) 
X 
X 
X 
X 
X 
 
 
Mesna 
Intravenous 
(IV) 
X 
X 
X 
X 
X 
 
 
Dasatinib 
By mouth 
(oral) 
 
 
 
 
 
X 
 
Rest 
 
 
 
 
 
 
 
X 
Ifosfamide 
1800 mg/m2/day IV over 1 hour per day x 5 days Q 28 days 
Carboplatin 400 mg/m2/day IV over 1 hour per day x 2 days Q 28 days 
Etoposide 
100 mg/m2/day IV over 1 hour per day x 5 days Q 28 days 
Dasatinib 
During Phase I (refer to table 3) 
During Phase II (as determined in Phase I) 
MESNA 
360 mg/m2/dose IV with ifosfamide, then 360mg/m2 IV over 3 hours after completion 
of ifosfamide/mesna, then 360mg/m2 IV over 15min Q3H x 3 more doses/day after 
completion of 3hr mesna infusion daily x 5 days on days 0-4 Q 28 days 
Neupogen 
5-10 microgms/kg/day subcutaneously, daily starting on Day 5, until ANC > 10,000, 
every course; Neupogen required first course only.  Neulasta may be given for 
subsequent courses to patient > 50 kg. 
See DRUG INFORMATION, section 9, for guidelines for administration, formulation, source and 
pharmacology. 
6.4 Grading Adverse Events 
 
Adverse events (toxicities will be graded according to the NCI Common Terminology Criteria for 
Adverse Events v3.0 (CTCAE) http://ctep.cancer.gov/reporting/ctc.html, CTEP Simplified Disease 
Classification v1.0 (MedDRA v10.0)  (Effective July 1, 2007) = CTCAE v3.0 (MedDRAv10.0) 
(Effective July 1, 2007). Any suspected or confirmed dose-limiting toxicity should be reported 
immediately (i.e. within 24 hours) to the Study Chair, Judith K. Sato, M.D. at (626) 930-5430 


 
30 
(office) or (626) 257-1315 (cell) and/or her designee. Case report forms outlining the DLT must be 
submitted to City of Hope National Medical Center at (626) 301-8787 by 7 days after the event.  
6.5 Definition of Dose-Limiting Toxicity (DLT) 
 
Definition of Dose Limiting Toxicity (DLT): DLT will be determined in the Phase I portion of this 
study. DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to dasatinib.  Dose limiting toxicities likely due to ICE will be excluded from the 
definition of DLT for dasatinib.  DLT will be determined in the Phase I portion of the study, as 
specified below. 
6.5.1 
Non-Hematological Dose-Limiting Toxicity 
• 
Any Grade 4 non-hematological toxicity 
• 
Any Grade 3 non-hematological toxicity, with the specific exception of: 
- 
Grade 3 nausea and vomiting of less than 3 days duration with appropriate 
anti-emetic therapy, and/or 
- 
Grade 3 transaminase elevation that return to levels that meet initial eligibility 
criteria within 13 days of study drug interruption and that do not recur upon 
study re-challenge with study drug 
- 
Grade 3 fever or infection < 7 days duration, and/or, 
- 
Grade 3 hypocalcemia responsive to oral calcium supplementation; note that 
an adequate response to oral calcium supplementation is a return to a < 
grade 1 hypocalcemia. 
 
• 
Any Grade 2 non-hematologic toxicity that persists for > 7 days and is considered either 
sufficiently medically significant or sufficiently intolerable by patient that it requires 
treatment interruption; 
 
• 
Any adverse event requiring interruption of study drug for 7 days or which recurs upon 
drug rechallenge. 
6.5.2 
Hematological Dose Limiting Toxicity 
 
Hematologic suppression is an expected toxicity from ICE chemotherapy.  Therefore, the 
definition of hematologic dose limiting toxicity will be modified to include the addition of Dasatinib 
to ICE.  Prolongation of recovery to ANC > 750 /uL or platelets > 50,000 significantly beyond that 
expected with ICE alone.  If these parameters are not attained by day 42 (14 days after the 28 
day length of each course), then a DLT has occurred, see Section 6.7.1.1) 
 
6.6 Criteria for Starting Subsequent Courses 
 
A course may be repeated every 28 days if the patient has at least stable disease and has met 
the following laboratory parameters as defined in the eligibility section, except for hematologic 
parameters as follows: 
- 
Peripheral absolute neutrophil count (ANC) > 750/uL 
- 
Platelet count > 50,000 (transfusion independent) 
- 
Hemoglobin > 8.0 gm/dL (may receive RBC transfusions) 


 
31
 
6.7 Dose Modifications 
 
During the Phase I portion of this study, there will be no dose modification of dasatinib for 
mylosuppresion. 
 
The Principal Investigator must be notified within 24 hours of any dose limiting toxicity as 
defined in section 6.5.      
6.7.1 
Myelosuppression 
6.7.1.1 
Neutropenia and Thrombocytopenia 
 
Neutropenia and thrombocytopenia are expected toxicities of ICE chemotherapy.  Dasatinib will 
be administered after ICE chemotherapy between days 5 and 21, for 17 days.  There is a 7 day 
“rest” period between day 21 and 28.  DLT for this study is defined as inability to start the next 
course of therapy by day 42.  Thus, there is no dose modification for neutropenia or 
thrombocytopenia in the Phase I portion of the study.  Dasatinib should be stopped for sepsis, 
overwhelming infection with neutropenia, or bleeding not responsive to best therapeutic 
measures.  The Principal Investigator must be notified of any dose modification. 
6.7.1.2 
Hematological Dose Modifications in the Phase II study 
 
If a patient experiences hematological dose-limiting toxicity, the treatment will be withheld.  When 
the toxicity resolves to meet on study paramenters within 7 days of drug discontinuation, the 
patient may resume treatment at the next lower dose level in the subsequent course.  For 
patients enrolled at dose Level 1, the dose should be reduced to 25 mg/m2/dose. 
 
If toxicity does not resolve to meet study parameters for re-treatment by day 42 of the course, the 
patient must be removed from study 
If dose-limiting toxicity recurs in a patient who has resumed treatment at the reduced dose, the 
patient must be removed from study. 
It is up to the discretion of the investigator/participating clinician for a patient to go off study.  
6.7.2 
Non-Hematological Toxicity 
 
If a patient experiences non-hematological dose-limiting toxicity as defined in Section 6.5, the 
treatment will be withheld.  When the toxicity resolves to meet on study paramenters within 7 
days of drug discontinuation, the patient may resume treatment at the next lower dose level.  For 
patients enrolled at dose Level 1, the dose should be reduced to 25 mg/m2/dose. 
If a patient misses a dose due to vomiting that does NOT qualify as a dose limiting toxicity as 
defined in Section 6.5.1, then the dose will be re-administered if the vomiting occurs within 15 
minutes of drug ingestion.  Doses will not be re-administered if the vomiting occurs more than 15 
minutes after drug ingestion. 
If toxicity does not resolve to meet on study parameters within 14 days of drug discontinuation, 
the patient must be removed from study. 


 
32 
If dose-limiting toxicity recurs in a patient who has resumed treatment at the reduced dose level, 
the patient must be removed from study. 
6.7.3 
Dose Escalation 
6.7.3.1 
Inter-patient Escalation Schema 
 
The starting dose will be 35 mg/m2/dose BID with dose level for subsequent groups of patients as 
follows: 
Table 3 Inter-patient Dose Escalation Schema: 
Dasatinib Level 
Dose, BID PO Daily x 17 days 
Level -1 
25 mg/m2/dose 
Level 1 
35 mg/m2/dose 
Level 2 
50 mg/m2/dose 
Level 3 
65 mg/m2/dose 
Level 4 
85 mg/m2/dose 
Level 5 (Dasatinib alone phase only) 
110 mg/m2/dose 
 
There will be no dose escalations for dasatinib beyond Level 5 (110 mg/m2/dose). 
If the MTD has been exceeded at the first dose level, then the subsequent cohort of patients will 
be treated at a dose of 25 mg/m2/dose. 
After the initial re-induction phase of therapy and the local control/consolidative phase of 
treatment, patient will continue with dasatinib alone at the same assigned dose level at study 
entry.  If after two post-consolidative courses of therapy, there is no dose limiting toxicities, the 
dose of dasatinib will be escalated by one level (intra-patient dose escalation). 
 
6.8 Discontinuation of Therapy 
 
Study therapy must be discontinued for the following reasons: 
1) 
Progressive disease at any time 
2) 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the 
opinion of the Investigator, indicates that continued treatment with the study therapy 
is not in the best interest of the subject 
3) 
Excessive toxicity despite dose reduction 
4) 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
5) 
Pregnancy 


 
33
- 
All WOCBP should be instructed to contact the Investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period at any time 
during study participation.  Institutional policy and local regulations should 
determine the frequency of on-study pregnancy tests for WOCBP enrolled in the 
study 
- 
The Investigator must immediately notify the Principal Investigator and BMS in 
the event of a confirmed pregnancy in a patient participating in the study 
All patients will be assessed for adverse events according to the NCI Common Terminology 
Criteria for Adverse Events v3.0 (CTCAE). 
  
6.9 Prohibited and Restricted Therapies During Study 
6.9.1 
Prohibited Therapies 
 
Subjects requiring any of the following prohibited therapies should not be enrolled.   
Bisphosphonates  
Intravenous bisphosphonates will be withheld for the first 8 weeks of treatment due to the risk of 
hypocalcemia. After the need for Ca2+ supplementation has been assessed and levels 
documented to be >LLN, subjects on prior bisphosphonate may be restarted with caution at the 
investigator’s discretion.  
CYP3A4 
Drugs that may increase dasatinib plasma concentrations 
Strong CYP3A4 Inhibitors: Dasatinib is primarily metabolized by the CYP3A4 enzyme. 
Therefore, potent inhibitors of CYP3A4 are prohibited during study; for such medications (e.g., 
ketoconazole, itraconazole,  clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin and voriconazole), a wash-out period of ≥7 days is required prior to 
starting dasatinib. Subjects should be advised not to consume substantial quantities of grapefruit 
juice.  
Drugs that may decrease dasatinib plasma concentrations 
Strong CYP3A4 Inducers:  Drugs that induce CYP3A4 activity may decrease dasatinib plasma 
concentrations. In patients in whom CYP3A4 inducers (e.g., dexamethasone, phenytoin, 
carbamazepine, rifampicin, rifabutin, phenobarbital) are indicated, alternative agents with less 
enzyme induction potential should be used.    
 
St. John's wort (Hypericum perforatum): May decrease dasatinib plasma concentrations 
unpredictably.  Patients receiving dasatinib should not take St. John's wort.  
 
H2 Blockers/Proton Pump Inhibitors:  Long-term suppression of gastric acid secretion by H2 
blockers or proton pump inhibitors (e.g., famotidine and omeprazole) is likely to reduce dasatinib 
exposure. The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not 
recommended. The use of antacids should be considered in place of H2 blockers or proton pump 
inhibitors in patients receiving dasatinib therapy.  
 
 
In patients receiving treatment with dasatinib, close monitoring for toxicity and a dasatinib dose 
reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be 
avoided.  


 
34 
Medications that prolong QT Interval 
Subjects enrolled in this study should not take or begin to take concomitant medications known to 
prolong the QT interval. For such medications, a wash-out period of ≥7days is required prior to 
starting dasatinib. (Agents which may possibly prolong the QT interval are restricted). 
Medications known to prolong the QT interval (Class I; see http://www.qtdrugs.org/medical-
pros/drug-lists/drug-lists.htm) are:  
 
Drugs that are generally accepted to have a risk of causing Torsades de Pointes include: 
• 
procainamide, disopyramide 
• 
amiodarone, sotalol, ibutilide, dofetilide 
• 
erythromycin, clarithromycin 
• 
chlorpromazine, haloperidol, mesoridazine, thioridazine 
• 
bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, 
levomethadyl, pentamidine, sparfloxacin, lidoflazine 
 
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, the 
Investigator must check that the subject’s prior on-therapy EKG has not shown a QTcF ≥ 450 
msec or an increase in QTc ≥ 60 msec over the baseline value.  
6.9.2 
Restricted Therapies 
Drugs that may have their plasma concentration altered by dasatinib 
CYP3A4 Substrates:  CYP3A4 substrates known to have a narrow therapeutic index such as 
alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered 
with caution in patients receiving dasatinib.    
Less-potent inhibitors, inducers, and substrates of CYP3A4 are restricted.   
 
Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. 
Simultaneous administration of dasatinib with antacids should be avoided.  If antacid therapy is 
needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the 
dose of dasatinib.  
 
Medications that inhibit Platelet Function and Anticoagulants 
Caution should be exercised if patients are required to take medications that inhibit platelet 
function or anticoagulants. 
Subjects enrolled in this study should not take concomitant medications which durably inhibit 
platelet function. For such medications, a wash-out period of ≥7days is required prior to starting 
dasatinib. (Agents which inhibit platelet function transiently or inhibit coagulation by other 
mechanisms are restricted.)  
Medications which directly and durably inhibit platelet function include: 
• 
dipyridamole 
• 
tirofiban, dipyridamole, epoprostenol, eptifibatide, cilostazol, abciximab, ticlopidine, cilostazol 
Medications which directly and durably inhibit anticoagulation include: 
• 
Exceptions: low-dose warfarin for prophylaxis to prevent catheter thrombosis, and heparin for 
flushes of IV lines.  


 
35
7.0 EVALUATION AND VISIT SCHEDULE 
7.1 Required Clinical, Laboratory and disease Evaluation 
All entry and eligibility studies must be performed within 2 week prior to treatment, unless 
otherwise specified.  If more than 14 calendar days elapse between the date eligibility studies 
outlined in Section 5.1 were obtained and the start date of treatment, then the following studies 
must be repeated prior to treatment: CBC with differential, bilirubin, ALT (SGPT) and serum 
creatinine.  If any of these repeat laboratory studies are outside the parameters required for 
eligibility, then the patient is off study.  Imaging studies are required within 2 weeks prior to study 
entry. 
STUDIES 
Pre-
Study 
During Phase I 
Course 1  
Subsequent Courses 
End of therapy 
/ relapse 
History 
X 
X 
Start of each course 
X 
Physical Exam with vital 
signs 
X 
Weekly 
Days 1 and 14 of each 
course 
X 
Height, weight, BSA 
X 
X 
Start of each course 
X 
Performance Status 
X 
 
 
X 
CBC, differential, 
platelets 
X 
Twice Weekly 
(every 3 to 4 
days)3 
Weekly4 
X 
Peripheral blood for 
biology studies1 
X 
Day 14 - 21 or 
when WBC > 
500 
Day 14 - 21 or when 
WBC > 500 of each 
course 
X 
Electrolytes including Ca, 
PO4, Mg 
X 
Weekly 
Days 1 and 14 of each 
course5 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
Days 1 and 14 of each 
course5 
X 
Total protein/albumin 
X 
Days 1 and 14 of 
each course 
Days 1 and 14 of each 
course5 
X 
Disease Evaluation 
X 
 
Start of every other 
course6 
X 
Pregnancy Test2 
(must be done wihtin 72 
hours prior to 1st dose of 
treatment) 
X 
 
 
 
EKG 
X 
 
Start of each course prior 
to Consolidation; Start of 
first post-consolidation 
course & any time 
dasatinib dose escalated 
 
Echocardiogram/MUGA 
X 
 
As clinically indicated 
 
Tumor tissue for 
Correlative Studies1 
X 
 
From any surgical 
specimen; At time of 
progression, if possible 
X 
1 
See Section 7.2  for details and  timing of biology studies 
2 
Patients of child bearing potential require a negative pregnancy test prior to starting treatment and must use an 
acceptable method of birth control.  Abstinence is an acceptable method of birth control. 


 
36 
3 
If patients develop Grade 4 neutropenia, then CBCs should be checked every other day until recovery to Grade 3. 
4 
If patient develop Grade 4 neutropenia, then CBCs should be checked every 3 to 4 days until recovery to Grade 3 
5 
Day 14 Chemistry tests required for the Phase I portion of study only 
6 
Disease Evaluation should be obtained every other course after initial documentation of either a PR, CR, or SD, or 
at time of suspected disease relapse or progression. 
7.1.1 
Post-therapy Evaluation  
7.1.1.1 
First year off-therapy (reporting every 6 months) 
• 
 Physical and history with pertinent laboratory test examinations every months x 6 
months then every 2 months x 6 months 
• 
 Imaging studies that were positive at study entry every 3 months 
 
7.1.1.2 
Second and subsequent years off-therapy (reporting every year) 
• 
 Physical and history with pertinent laboratory test examination every 3 months 
• 
 Imaging studies that were positive at study entry every 6 months 
 
7.2 Correlative Laboratory Studies 
7.2.1 
Overview of Laboratory Studies 
Our primary emphasis for correlative laboratory studies will be peripheral blood mononuclear cells 
from the majority of patients for pre-treatment and on-treatment surrogate molecular marker 
analysis.  In all cases, we will use standard protocols that we have optimized for the biomarkers 
indicated below.  Whenever possible, tissue biopsies will also be collected for biomarker 
immunohistochemistry, with any remaining tissue specimens to be used for future microarray 
gene-expression profiling.  Funding for the collection and processing of clinical specimens at all 
study sites is being requested from BMS and from the Pediatric Cancer Foundation.  The Jove 
Laboratories will provide their own funding for the correlative laboratory biomarker and microarray 
analyses performed at the City of Hope. 
7.2.2 
Peripheral Blood Mononuclear Cells 
Based upon prior experience, we expect that only a minority of patients will consent to have pre-
treatment and on-treatment tissue biopsies performed.  Peripheral blood mononuclear cells are 
easily isolated and express many relevant tyrosine kinases, including SRC and FAK.  
Consequently, we will assess phosphorylation levels of these proteins in circulating mononuclear 
cells as a surrogate marker for dasatinib drug activity in all patients who consent to have blood 
drawn.  Ten ml of peripheral blood will be collected from study participants at the time of study 
initiation (baseline), and on day 14- 21 or when WBC > 500 of dasatinib treatment during all 
subsequent courses (total of 13 specimens).  Blood specimens should be collected in an 
EDTA (purple top) tube, labeled properly and kept in an ice-bath at 0ºC until delivered to the local 
institutional laboratory for centrifugation.  The blood must promptly undergo Ficoll-Hypaque 
gradient separation by gradient centrifugation at 1200 rpm and at 4ºC in a clinical centrifuge; the 
mononuclear cells will be collected from the interface.  Mononuclear cells will be immediately 
frozen and stored frozen at -70 º C until shipped on dry ice to Translational Research Laboratory 
(see Sections 7.2.4 and 7.2.5).   
For biomarkers analysis, the frozen cell pellets of mononuclear cells will be thawed in cell lysis 
buffer, which preserves the phosphorylation state of cellular proteins.  After brief centrifugation, 
the insoluble components will be removed, and protein lysates will be analyzed by Western 
blotting for total and phospho-SRC, phospho-FAK and other relevant biomarkers described 
below. 


 
37
7.2.3 
Tumor Specimens 
Due to the labile nature of protein phosphorylation, only freshly acquired tissue will be used for 
these studies.  Tissue specimens will be collected from patients in accordance with the standard 
of care required for each individual case, primarily either core biopsies and in some cases 
surgical biopsies.  The most important issues are the tissue processing time and methods.  It is 
extremely critical to either fix or snap freeze the specimens within 15 min of procurement, in order 
to preserve the phosphorylation state of SRC and other signaling proteins (34).  Formalin fixation 
and paraffin embedding will be done according to standard protocols, and snap freezing will be in 
liquid nitrogen.  Since only a minority of patients are expected to provide tissue specimens, we 
will also perform surrogate marker analysis using mononuclear white blood cells for the majority 
of patients (see section 7.2.2) 
If core biopsies are indicated, multiple passages will be performed to obtain several cores of the 
tumor tissues prior, during, and/or relapse/progression to dasatinib treatment.  Cores will be 
processed as follows: 1) one core for formalin fixation to be used for immunohistochemistry (e.g., 
phospho-SRC; see below for additional biomarkers) of paraffin-embedded specimens; 2) another 
core will be used for snap frozen sections to determine quality (e.g., absence of necrosis or 
fibrosis, and % tumor cells); 3) extra core to be placed in RNAlater 4) any remaining cores will be 
snap frozen for future studies (e.g., microarray gene-expression profiling, see below). 
In cases where tumor is resected prior to initiating dasatinib therapy and/or during 
relapse/progression, both tumor and adjacent non-tumor tissues will be collected whenever 
possible.  The non-tumor tissues will be collected as far away from the tumor tissue as possible.  
A piece of tissue at least 1.5 cm x 1 cm x 1 cm will be excised from each of the selected areas.  
This piece will be divided into three fragments and processed for formalin fixation, snap freezing 
and RNAlater, as described above for the core biopsies. 
We have extensive experience with all of the correlative laboratory methods described below (34, 
35)  Pre-treatment and on-treatment (if possible on day 14 - 21 or when WBC > 500 of dasatinib 
treatment), formalin-fixed, paraffin-embedded sections will be subjected to immunohistochemistry 
analysis for total SRC and phospho-SRC, phospho-FAK, phospho-STAT3, as previously 
described by us in primary breast tumors from high-risk breast cancer patients treated with 
neoadjuvant chemotherapy with docetaxel and doxorubicin (34, 35).  In these prior studies, we 
performed computer-assisted quantitative image analysis on digitized microscopy images, and 
similar analyses will be carried out in the present study to quantify biomarkers.  Other relevant 
biomarkers associated with SRC signal transduction and/or dasatinib response that will be 
examined in a similar fashion include phospho-KIT, phospho-PDGFR, EPHA2, and VEGF.  All 
paraffin-embedded, formalin-fixed specimens may be kept at room temperature. 
A second priority will be to perform microarray gene-expression profiling, preferably using frozen 
tissue specimens obtained from pre-treatment biopsies, based on the Affymetrix GeneChip 
platform.  Laboratory data will be analyzed by appropriate biostatistics and bioinformatics 
methods in order to reveal correlations of biomarkers and gene expression profiles with response 
to dasatininb treatment.  We have extensive experience with all of the above microarray 
procedures and data analysis methods (35).  The goal of these microarrays studies will be to 
define a potential molecular signature or gene expression pattern that may predict response to 
dasatinib. 
7.2.4 
Blood Sample Labeling 
Each specimen must be labeled with the patient’s identifying number.  Labels are patient and 
sampling time point specific and are not to be interchanged between patients.  Each tube must be 
labeled with the patient’s study registration number, the study I.D., the date and time the sample 
was drawn, specimen type and timepoint.  Once affixed on tubes, the labels should be wrapped 
completely by applying protective transparent tape for protection during handling, storage and 
shipment.  Data are to be recorded on the COH Specimen Transmittal Form (Appendix 3), which 
must accompany each specimen. 


 
38 
Label 
Sample: 
Study Registration number: 
Study ID number: 
RPN number:   
Date:                               Time: 
Specimen type:  
Timepoint: 
 
7.2.5 
Blood Sample Shipping Instructions 
Please send frozen peripheral blood mononuclear cells on dry ice by Federal Express to: 
Translational Research Laboratory 
City of Hope Cancer Center 
1500 E. Duarte Road 
KCRB 1026 
Duarte, CA 91010 
Fax: 626 471 7204 
 
Attention: 
Yafan Wang, M.S., M.P.H., Lab Coordinator 
Tel: 626 256 4673 x65544 
 
 
 
Email:  yawang@coh.org 
 
Linling Chen, M.S. 
Tel: 626 256 4673 x64784 
Email:  lchen2@coh.org 
 
Ship specimens by Federal Express Priority Overnight using the COH Federal Express account 
number ______________ (TBD).  Arrange for Federal Express pickup per your usual institutional 
procedure or by calling 1-800-238-5355.  Please include email notification to the COH at 
jsato@coh.org and yawang@coh.org on the billing slip.  When requesting pick-up, be sure to 
give the account number on the preprinted air-bill, but stress that pick-up is at your institutional 
address.  Specimens should only be sent to the COH Monday-Thursday for Tuesday-Friday 
delivery.  If a specimen is obtained on a Friday, please hold it under appropriate conditions until 
the following Monday. 
7.2.6 
Tumor Specimen Labeling 
Labels are patient and sampling time point specific and are not to be interchanged between 
patients.  Each specimen container must be labeled with the patient’s study registration number, 
the study I.D., and the date and time the sample was procured.  Once affixed on the specimen 
container, the labels should be wrapped completely by applying protective transparent tape for 
protection during handling, storage and shipment.  Data are to be recorded on the COH 
Specimen Transmittal Form (Appendix 3), which must accompany the sample(s). 
 
7.2.7 
Tumor Specimen Shipping Instructions 
The COH provides specimen procurement kits upon request.  To obtain a specimen procurement 
kit, call the COH at (626) 930-5430 during regular business hours, between 8 AM and 4 PM 
(Pacific time) Monday through Friday.  The specimen procurement kit is constructed to allow 
shipment of frozen (on dry ice) and ambient temperature tissues in the same container.  Dry ice 
may be placed in either compartment of the kit, but should not be put in both. 


 
39
Ship specimens by Federal Express Priority Overnight using the COH Federal Express account 
number ______________ (TBD).  Arrange for Federal Express pickup per your usual institutional 
procedure or by calling 1-800-238-5355.  Please include email notification to the COH at 
jsato@coh.org and yawang@coh.org on the billing slip.  When requesting pick-up, be sure to 
give the account number on the preprinted air-bill, but stress that pick-up is at your institutional 
address.  Specimens should only be sent to the COH Monday-Thursday for Tuesday-Friday 
delivery.  If a specimen is obtained on a Friday, please hold it under appropriate conditions until 
the following Monday. 
Using a waterproof marker, clearly label specimens with the COH number, patient I.D. number, 
Study number, and date and time specimen was obtained.  Before placing the specimens in the 
appropriate compartments of the Specimen procurement Kit, please place the individual 
specimen bags (keeping ambient and frozen specimens separated) first into the watertight 
biohazard diagnostic envelope with absorbent material.  Next place the biohazard diagnostic 
envelope into the pressure-proof Tyvek diagnostic envelope and seal the envelope securely. 
Frozen tissue must be sent on dry ice in one compartment of the Specimen Procurement Kit.  
The blocks, slides or formalin fixed tissue should be shipped in the other compartment of the kit.  
Be sure to include the specimen transmittal form with the shipment.  If available, also include the 
institutional pathology report. 
Ship all specimens to: 
Translational Research Laboratory 
City of Hope Cancer Center 
1500 E. Duarte Road 
KCRB 1026 
Duarte, CA 91010 
Fax: 626 471 7204 
 
Attention: 
Yafan Wang, M.S., M.P.H., Lab Coordinator 
Tel: 626 256 4673 x65544 
 
 
 
Email:  yawang@coh.org 
 
Linling Chen, M.S. 
Tel: 626 256 4673 x64784 
Email:  lchen2@coh.org 
 
7.2.8 
Summary: Submission of Biological Specimens 
Please see Appendix 4 for an Overview summarizing specimen types and procurement, for all 
correlative biological specimens requested for this study. 
 
8.0 EFFICACY ASSESSMENTS 
8.1 Response Criteria for Patients with Solid Tumors (RECIST) 
Although patients will be enrolled on the portion of the Phase I study, response data will be 
collected and analyzed.  All Phase II patients response will be required for study.   
This study will use the Response Evaluation Criteria in Solid Tumors (RECIST) from the NCI for 
assessment of radiographic response. 
8.1.1 
Measurable Disease  
The presence of at least one lesion that can be accurately measured in at least one dimension, 
with the longest diameter (LD) at least 20 mm.  With spiral CT scan, lesions must be at least 10 
mm.  The investigator will identify up to 10 measurable lesions to be followed for response. 


 
40 
Serial measurements of lesions are to be done with appropriate imaging modalities (bone scans 
cannot be used to measure lesions).  The same method of assessment will be used to 
characterize each identified and reported lesion at baseline and during followup. 
8.1.1.1 
Quantification of Disease Burden 
The sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
disease measurement. 
8.1.1.2 
End of Course Response 
a) Complete Response (CR) 
Disappearance of all target and non-target lesions. 
b) Partial Response (PR) 
At least a 30% decrease in the disease measurement, taking as reference the disease 
measurement done to confirm measurable disease at study entry 
c) Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest disease measurement since the treatment started. 
d) Progressive Disease (PD) 
At least a 20% increase in the disease measurement, taking as reference the smallest 
disease measurement recorded since the start of treatment, or the appearance of one or 
more new lesions, or evidence of laboratory or clinical progression. 
8.1.2 
Evaluable Disease 
The presence of at least one lesion that cannot be accurately measured in at least one 
dimension. 
 
Such 
lesions 
may 
be 
evaluable 
by 
nuclear 
medicine 
techniques, 
immunocytochemistry techniques, tumor markers or other reliable measures. 
8.1.2.1 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
a) Complete Response (CR) 
Disappearance of all evaluable disease 
b) Partial Response (PR) 
Partial responses cannot be determined in patients with evaluable disease 
c) Stable Disease (SD) 
That which does not qualify as Comprete Response (CR), Partial Response (PR), or 
Progressive Disease (PD). 
d) Progressive Disease (PD) 
The appearance of one or more new lesions, or evidence of laboratory, clinical or 
radiographic progression. 
8.1.2.2 
Overall Response Assessment 
Each patient will be classified according to their “best response” for the purposes of analysis of 
treatment effect.  Best response is determined from the sequence of the objective criteria 
described below (see Section 8.2). 
8.2 Best Response 
Two objective status determinations of disease status, by CT or MRI, obtained on two 
consecutive determinations, separated by at least four weeks, are required to determine the 


 
41
patient’s overall best response.  Two objective status determinations of CR before progression 
are required for best response of CR.  Two determinations of PR or better before progression, but 
not qualifying for a CR, are required for a best response of PR.  Two determinations of stable/no 
response or better before progression, but not qualifying as CR or PR, are required for a best 
response of stable/no response; if the first objective status is unknown, only one such 
determination is required.  Patients with an objective status of progression on or before the 
second evaluations (the first evaluation is the first radiographic evaluation after treatment has 
been adminstered) will have a best response of progressive disease.  Best response is unknown 
if the patient does not qualify for a best response of progressive disease and if all objective 
statuses after the first determination and before progression are unknown. 
8.3 Definitions of PFS, OS, and PFS rate and OS rate are defined in 
section 11.0 
 
9.0 STUDY DRUGS INFORMATION 
9.1 Dasatinib [SPRYCEL®] 
9.1.1 
Physical/Chemical: 
N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl] 
amino]-5-thiazolecarboxamide, monohydrate (NSC# 732517) 
 
9.1.2 
Mechanism of Action: 
BMS-354825 is a potent, broad spectrum ATP-competitive inhibitor of 5 critical oncogenic 
tyrosine kinase families: BCR-ABL, SRC family kinases, c-KIT, ephrin (EP) receptor kinases, and 
PDGFβ receptor, each of which has has been strongly linked to multiple forms of human 
malignancies. 
9.1.3 
Molecular Formula: 
C22H26CIN7O2S. H2O 
9.1.4 
Formula Weight: 
BMS-354825 monohydrate: 506.02 daltons and anhydrous free base is 488.01 
9.1.5 
Potential Drug Interactions: 
Dasatinib [SPRYCEL®/ BMS-354825] is primarily metabolized by the human CYP3A4 enzyme, is 
a significant inhibitor of CYP3A4, and is a weak inhibitor of CYP1A2, CYP2D6, CYP2C9, and 
CYP2C19.  It may decrease the metabolic clearance of drugs that are significantly metabolized 
by the CYP3A4 enzyme.  Due to the potential of Dasatinib to prolong the QT/QTc, use caution 
when administering Dasatinib with other potential QTc-prolonging medications. 
Due to the possibility of gastrointestinal, cardiac, and cutaneous hemorrhage, avoid using using 
medications that inhibit platelet function or anticoagulants with Dasatinib. 
Dasatinib is not a p-glycoprotein inhibitor. 
9.1.6 
Source and Pharmacology 
The investigational new drug substance  (an aminothiazole analogue), Dasatinib, is a SRC kinase 
inhibitor that is currently under development for treatment of chronic myelogenous leukemia 
(CML) and as a broad-spectrum antitumor agent against solid  tumors. [SPRYCEL®] is a potent, 
broad spectrum ATP-competitive inhibitor of 5 critical oncogenic tyrosine kinase families: 
BCRABL, SRC family kinases, c-KIT, ephrin (EP) receptor kinases, and PDGFβ receptor.  


 
42 
Each of these protein kinases has been strongly linked to multiple forms of human malignancies. 
Animal studies have shown that Dasatinib is likely to have >50% oral absorption in humans, is 
highly bound to serum proteins (>91%), has extensive extravascular distribution and has a 
moderate rate of blood clearance in the animal species studied. Preclinical studies in humans 
with Dasatinib have demonstrated a mean terminal half-life of around 4 hours (range:2.5-11.1 
hours) and rapid oral absorption with peak levels at 0.5-3 hours on average. Urinary excretion 
plays only a minor role in the elimination of Dasatinib. Dasatinib is primarily metabolized in the 
liver by the human CYP3A4 enzyme, is a significant inhibitor of CYP3A4, and is a weak inhibitor 
of CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Dasatinib may decrease the metabolic clearance 
of drugs that are significantly metabolized by the CYP3A4 enzyme. Due to the potential of 
Dasatinib to prolong the QT/QTc, caution must be used when administering Dasatinib with other 
potential Qtcprolonging medications. Due to the possibility of gastrointestinal, cardiac, and 
cutaneous hemorrhage, avoid using medications that inhibit platelet function or anticoagulants in 
conjunction with Dasatinib. (Dasatinib is not a p-glycoprotein inhibitor.) 
9.1.7 
Formulation and Stability 
Dasatinib is available in the following tablet and bottle sizes: 
Strength 
Description 
5 mg 
round, plain white film-coated tablets containing 30 tablets per bottle. 
20 mg 
biconvex round, white to off-white film-coated tablets containing 30 tablets 
per bottle. The tablet is debossed with “20” on one side and “527” on the 
other side. 
50 mg 
biconvex oval, white to off-white film-coated tablets containing 30 tablets 
per bottle. The tablet is debossed with “50” on one side and “528” on the 
other side. 
70 mg 
 
  
biconvex round, white to off-white film-coated tablets containing 30 tablets 
per bottle.  The table is debossed with “BMS” on one side and either “468” 
or “524” on the other side. 
 
Each bottle will be labeled with the following information at a minimum:  product name, table 
strength, batch number, directions for use, storage conditions, and appropriate caution 
statements. 
Storage: 
The intact bottles should be stored at controlled room temperature 15°-25°C (59°-77°F)  
  
9.1.8 
Guidelines for Administration 
See the Treatment and Dose Modifications Sections of the protocol (Sections 6.3 and 6.7) 
While the risk from dermal exposure is considered minimal, it is advised that protective gloves be 
worn when handling the study medication. A mask is not required when handling the study 
medication. Pregnant women or breastfeeding mothers should not handle Dasatinib. 
9.1.8.1 
Dosing Solution Procedure 
Dasatinib tablets can be allowed to dissolve in solution and mixed with lemonade. The following is 
the procedure for preparation of the lemonade dosing solution: 
1. Mix the contents of one 12 ounce can of Minute Maid Premium Frozen Concentrate with 2 
cans (i.e. the emptied lemonade container) of water. This will produce a lemonade that is a little 


 
43
more than twice as concentrated as the instructions on the can with a sweeter taste. Please keep 
the lemonade solution refrigerated when not in use. 
2. Place 1 ounce (30 mL) of this lemonade solution into a drinking glass. 
3. Place the proper dose of intact tablets into the lemonade. Please be sure to always wear 
protective gloves when handling the medication. A mask is not required when handling the 
medication. Always use the 1 oz of lemonade. Do not increase the lemonade volume. 
4. Start timing for 20 minutes. At approximately the 5 minute mark, swirl the contents of the glass 
well for about 3 seconds. 
5. At approximately the 15 minute mark, swirl the contents of the glass a second time. At the 20 
minute mark, swirl the contents of the glass one last time. Immediately administer the entire 
contents of the glass. 
6. In order to ensure administration of the entire medication dose, a rinsing step is necessary. 
Add 0.5 ounce (15 mL) of lemonade into the same glass that has just been emptied. Swirl the 
contents to remove any remaining signs of tablets from the sides or bottom of the glass. 
7. Administer the washing lemonade to the patient. 
If a young child is unable to swallow a pill, Dasatinib may be administered via a naso-gastric tube 
(NGT) or gastrostomy. 
 
9.1.9 
Dispensing 
It is the responsibility of the Investigator to ensure that dasatinib is only dispensed to study 
subjects.  Dasatinib must be dispensed only from official study sites by authorized personnel 
according to local regulations. 
The Investigator (or assigned designee, i.e., study pharmacist) will dispense the proper number of 
each strength tablet to the the subject to satisfy dosing requirements for the study.  The 
containers provided to the subject should be labeled with proper instructions for use.  The lot 
numbers, dosing start dates and the number of tablets for each dosage strength must be 
recorded on the drug accountability pages of record for the site.  The subject must be instructed 
to return all unused dasatinib in the provided packaging at each subsequent visit. 
9.1.9.1 
Supplier 
Dasatinib [SPRYCEL®] is supplied by Bristol-Myers Squibb. 
9.1.10 Obtaining the Agent 
Initial orders of dasatinib will be requested by the assigned BMS protocol manager.  Initial drug 
supply is provided for a 12 week treatment period per subject. 
 
Re-suppply requests can be obtained by completing the SRC re-supply request form and 
submitting the request form electronically via e-mail to srcsupply@bms.com.  Re-supply requests 
should be submitted at least 5 – 7 business days before the expected delivery date.  Deliveries 
will be made Tuesday through Friday. 
9.1.11 Dasatinib Accountability 
It is the responsibility of the Investigator to ensure that a current record of dasatinib disposition is 
maintained at each study site where dasatinib is inventoried and disposed.  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 and use date or expiring date 


 
44 
- 
Dates and initials of person responsible for each dasatinib inventory entry/movement 
- 
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  (e.g., lost, wasted, broken) 
- 
Amount returned to BMS, if applicable 
- 
Retain samples sent to third party for bioavailability/bioequivalence, if applicable. 
Dasatinib dispensing record/inventory logs and copies of signed packing lists must be maintained 
at the investigational site.  Batch numbers for dasatinib must be recorded in the drug 
accountability records. 
9.1.12 Destruction of Dasatinib 
It is the Investigator/s responsibility to ensure that arrangements have been made for disposal 
and that procedures for proper disposal have been established according to applicable 
regulations, guidelines, and institutional procedures.  Appropriate records of the disposal must be 
maintained. 
 
9.1.13 Dasatinib Toxicity  (revised per IB version IX, dated 11/03/2009) 
System Organ 
Class   
Adverse 
Reaction Very 
Common 
(> 1/10) 
Adverse 
Reaction 
Common 
(≥ 1/100 to 
 < 1/10) 
Adverse 
Reaction 
Uncommon 
(≥ 1/1,000 to 
 < 1/100) 
Adverse 
Reaction 
Rare 
(≥ 1/10,000 to  
< 1/1,000) 
Infections and 
infestations 
• 
Infection 
(including 
bacterial, viral, 
fungal, non-
specified) 
 
• 
Pneumonia 
(including 
bacterial, viral, 
and fungal) 
• 
Upper respiratory 
tract 
infection/inflamm
ation 
• 
Herpes virus 
infection 
• 
Enterocolitis 
infection 
• 
Sepsis (including 
fatal outcomes) 
 
 
 
Neoplasms benign, 
malignant and 
unspecified 
(including cysts and 
polyps) 
 
 
 
• Tumor lysis 
syndrome 
 
 
Blood and lymphatic 
system disorders 
 
 
• 
Febrile 
neutropenia 
• 
Thrombocytopenia 
• 
Anemia 
• 
Leukopenia 
• 
Pancytopenia 
 
 
• 
Aplasia pure red 
cell 
 
Immune system 
disorders 
 
 
 
• 
Hypersensitivity 
(including 
erythema 
nodosum) 
 
 


 
45
System Organ 
Class 
Adverse 
Reaction Very 
Common 
(> 1/10) 
Adverse 
Reaction 
Common 
(≥ 1/100 to  
< 1/10) 
Adverse 
Reaction 
Uncommon 
(≥ 1/1,000 to 
< 1/100) 
Adverse 
Reaction 
Rare 
(≥ 1/10,000 to 
 < 1/1,000) 
Metabolism and 
nutrition disorders 
 
• 
Appetite 
disturbances 
• 
Anorexia 
• 
Hyperuricemia 
 
 
 
Psychiatric disorders 
 
 
• 
Depression 
• 
Insomnia 
 
• 
Anxiety 
• 
Confusional State 
• 
Affect lability 
• 
Libido decreased 
 
 
Nervous system 
disorders 
 
• 
Headache 
• 
Lightheadedness
 
• Dizziness 
• Neuropathy 
(including 
peripheral 
neuropathy) 
• Dysgeusia 
• Somnolence 
 
• 
Reversible 
posterior 
leukoencephalopathy 
syndrome 
• 
Amnesia 
• 
Tremor 
• 
Syncope 
• 
Central nervous 
system 
hemorrhage
a 
 
• 
Transient 
ischemic attack 
• 
Convulsion 
• 
Cerebrovascular 
accident 
Eye disorders 
 
 
• Dry eye 
• Visual disorder 
(including visual 
disturbance, 
vision blurred, 
and visual acuity 
reduced 
 
 
• Conjunctivitis 
 
 
Ear and labyrinth 
disorders 
 
• Tinnitus 
 
• Vertigo 
 
 
Cardiac disorders 
 
 
• Congestive heart 
failure/ Cardiac 
dysfunction 
• Pericardial 
effusion 
• 
Arrhythmia 
(including 
tachycardia) 
• 
Palpitations 
• Cardiomegaly 
• Angina pectoris 
• Myocardial 
infarction 
• Pericarditis 
• Ventricular 
tachycardia 
• Electrocardiogram 
QT prolonged 
• 
Acute coronary 
syndrome 
• 
Myocarditis 
• 
Cor pulmonale 
 
Vascular disorders 
 
• 
Hemorrhage 
 
• 
Hypertension 
• 
Flushing 
• 
Hypotension 
• 
Thrombophlebitis 
 
• 
Livedo reticulares 
Respiratory, thoracic 
and mediastinal 
disorders 
 
• 
Pleural effusion 
• 
Dyspnea 
• 
Cough 
 
• 
Pulmonary 
edema 
• 
Lung infiltration 
• 
Pneumonitis 
• 
Pulmonary 
Hypertension 
 
 
 
 
 
 
• 
Asthma 
• 
Bronchospasm 
• 
Acute respiratory 
distress 
syndrome 
 


 
46 
System Organ 
Class 
Adverse 
Reaction Very 
Common 
(> 1/10) 
Adverse 
Reaction 
Common 
(≥ 1/100 to 
 < 1/10) 
Adverse 
Reaction 
Uncommon 
(≥ 1/1,000 to 
 < 1/100) 
Adverse 
Reaction 
Rare 
(≥ 1/10,000 to  
< 1/1,000) 
Gastrointestinal 
disorders 
 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Abdominal pain 
• 
Gastrointestinal 
hemorrhage 
 
• 
Abdominal pain 
• 
Abdominal 
distension 
• 
Mucosal 
inflammation 
(including 
• 
Mucositis / 
stomatitis) 
• 
Colitis (including 
neutropenic 
colitis) 
• 
Gastritis 
• 
Oral soft tissue 
disorder 
• 
Dyspepsia 
• 
Constipation 
• 
Dehydration 
 
• 
Pancreatitis 
• 
Upper 
gastrointestinal 
ulcer 
• 
Ascites 
• 
Dysphagia 
• 
Anal fissure 
• 
Esophagitis 
 
 
Hepatobiliary 
disorders 
 
 
 
• 
Hepatitis, 
• 
Cholestasis 
• 
Cholecystitis 
Skin and 
subcutaneous tissue 
disorders 
 
• 
Skin rash
a 
 
• 
Pruritus 
• 
Alopecia 
• 
Acne 
• 
Dry skin 
• 
Urticaria 
• 
Hyperhydrosis 
• 
Dermatitis 
(including 
eczema) 
 
 
• 
Acute febrile 
neutrophilic 
dermatosis 
• 
Photosensitivity 
reaction 
• 
Pigmentation 
disorder 
• 
Skin ulcer 
• 
Bullous 
conditions 
(including 
• 
Erythema 
multiforme) 
• 
Nail disorder 
• 
Palmar-plantar 
• 
Erythrodysesthesia 
syndrome 
• 
Panniculitis 
 
 
Musculoskeletal and 
connective tissue 
disorders 
 
• Musculoskeletal 
pain 
 
• 
Arthralgia 
• 
Myalgia 
• 
Muscle 
inflammation 
• 
Muscular 
weakness 
• 
Musculoskeletal 
stiffness 
 
• 
Rhabdomyolysis 
• 
Tendonitis 
Renal and urinary 
disorders 
 
 
 
• 
Renal failure 
• 
Urinary frequency 
proteinuria 
 
 
Reproductive system 
and breast disorders 
 
 
 
 
 
 
 
• 
Gynecomastia 
• 
Menstruation 
irregular 
 


 
47
System Organ 
Class 
Adverse 
Reaction Very 
Common 
(> 1/10) 
Adverse 
Reaction 
Common 
(≥ 1/100 to 
< 1/10) 
Adverse 
Reaction 
Uncommon 
(≥ 1/1,000 to 
< 1/100) 
Adverse 
Reaction 
Rare 
(≥ 1/10,000 to 
< 1/1,000) 
General disorders 
and administration 
site conditions 
• 
Superficial 
edema
b  
• 
Fatigue 
• 
Pyrexia 
 
• 
Pain 
• 
Chest pain 
• 
Chills 
• 
Asthenia 
• 
Malaise 
• 
Temperature 
intolerance 
• 
Lethargy 
 
Investigations 
 
 
• 
Weight decreased 
• 
Weight increased 
• 
Blood creatinine 
phosphokinase 
increased 
 
Injury, poisoning, 
and procedural 
complications 
 
• 
Contusion 
 
 
 
Metabolic/laboratory 
• Hypocalcemia 
 
• 
Hypoalbuminemia 
 
 
a Includes erythema, exfoliative rash, generalized erythema, milia, rash, rash erythematous, rash follicular, 
rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin 
exfoliation, systemic lupus erythematosus rash, urticaria vesiculosa, drug eruption, and rash vesicular. 
b Includes eye edema, eye swelling, eyelid edema, orbital edema, face edema, periorbital edema, swelling 
face, gravitational edema, localized edema, edema peripheral, pitting edema, edema genital, scrotal edema. 
 
9.2 Ifosfamide (IFX, IFOS) NSC #109724 
9.2.1 
Source and Pharmacology:  
Ifosfamide (IFOS) is a structural analogue of cyclophosphamide.  Ifosfamide requires hepatic 
microsomal activation for the production of the reactive 4-hydroxyoxazaphorine intermediate 
which serves as a carrier molecule for the ultimate intracellular liberation of phosphoramide 
mustard, an alkylating agent. The occurrence of another reactive metabolite, acrolein, is thought 
to be the cause of the hemorrhagic cystitis, identical to that seen with cyclophosphamide. The 
metabolism of ifosfamide is dose-dependent, with the terminal halflife varying between 7 and 16 
hours at doses of 1.6-2.4g/m² and 3.8-5 g/m², respectively. At 1.6- 2.4g/m²/d, 12 to 18% of the 
dose was excreted in the urine, whereas at 5g/m² single-dose, 61% was excreted in the urine. 
Evidence also exists to suggest that metabolism is inducible, with more rapid clearance occurring 
in the second and later doses of fractionated courses of 3-5 times daily. 
Unlike cyclophosphamide, as much as 50% of a large dose of ifosfamide may be subject to 
alternative metabolic degradation, with the production of reactive but non-cytotoxic species. 
Some of these products (chloracetaldehyde) are suggested as being the cause of ifosfamide 
neurotoxicity. 
9.2.2 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 
children out of every 100 
Rare 
Happens to<5 children out of 
every 100 
Immediate 
Within 1-2 days of 
receiving drug 
Nausea (L), vomiting (L), 
anorexia (L) 
Somnolence, confusion, 
weakness, seizure, 
inappropriate ADH1 
Encephalopathy (L) 
Prompt 
Within 2-3 weeks, 
prior to next course 
Myelosuppression, 
arrhythmia, EKG changes 
Hemorrhagic cystitis, 
cardiac toxicities with 
arrythmias2, myocardial 
necrosis2 
 


 
48 
Delayed 
Any time later during 
therapy, excluding 
the above conditions 
Alopecia 
Fanconi’s renal 
syndrome 
Peripheral neuropathy, acute 
renal failure, pulmonary 
fibrosis (L) 
Late 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy, 
bladder fibrosis 
1 Less common with lower doses 
2 Extremely rare at doses of < 10 g/m2/course 
(L) Toxicity may also occur later 
9.2.3 
Formulation and Stability:  
Available in 1 g and 3 g vials of lyophilized white powder without preservatives. Intact vials should 
be stored at room temperature and bear a stamped 5-year expiration date from the manufacturer. 
Reconstitute with sterile water, 20ml/g, to produce a final solution of 50mg/ml ifosfamide. 
Although the reconstituted product is stable for several days at room temperature, the absence of 
preservatives mandates that all drug be used or discarded  within 8 hours. 
9.2.4 
Guidelines for Administration:  
Ifosfamide will be infused intravenously over 1 hour daily for 5 days every 28 day course.  
9.2.5 
Supplier:  
The 1 g and 3g vials are commercially available. See package inserts for further information. 
 
9.3 Etoposide (VP-16, VePesid) NSC #141540 
ETOPOSIDE (VP-16, VePesid) NSC #141540 Revised: Oct 01. 
Approved roadmap abbreviation: ETOP. 
9.3.1 
Source and Pharmacology:  
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase II and 
DNA which results in a single and double strand DNA breaks. Its main effect appears to be in the 
S and G2 phase of the cell course. The initial t1/2 is 1.5 hours and the mean terminal half-life is 4 
to 11 hours. It is primarily excreted in the urine. There is poor diffusion into the CSF. The 
maximum plasma concentration and area under the concentration time curve (AUC) exhibit a 
high degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily 
serum albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is 
related to toxicity. Preliminary data suggests that systemic exposure for unbound etoposide 
correlates better than total (bound and unbound) etoposide. Etoposide is well absorbed after oral 
administration, but a high degree of interpatient variability has been reported (25 - 75% 
bioavailability). 
9.3.2 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to<5 children out 
of every 100 
Immediate 
Within 1-2 days of receiving 
drug 
Nausea, vomiting 
 
 
Prompt 
Myelosuppression 
Alopecia (L), enhanced 
damage due to radiation, 
Peripheral neuropathy, 


 
49
Within 2-3 weeks, prior to 
next course 
diarrhea 
stomatitis 
Delayed 
Any time later during 
therapy, excluding the 
above conditions 
 
 
 
Late 
Any time after completion of 
treatment 
 
 
Secondary malignancy 
(L)  Toxicity may also occur later 
9.3.3 
Formulation and Stability:  
Supplied as solution in 100 mg ampules (20 mg/ml) containing 5 ml. May be diluted in either 5% 
dextrose (DSW) or 0.9% sodium chloride injection (normal saline) to a final concentration of 0.4. 
mg/ml. When diluted as above, the drug is stable for 48 hourse at room temperature.  
9.3.4 
Supplier:  
Commercially available. See package insert for further information. 
 
9.4 Carboplatin (Paraplatin, CBDCA) NSC #241240 
9.4.1 
Source and Pharmacology:  
The mechanism of action of carboplatin would appear to be similar to that of cisplatin, i.e., it binds 
to replicating DNA causing single strand breaks and cross-links with DNA. Data suggests that 
other factors also contribute to cytotoxicity. The μ t½ is 1.1 to 2 hours and the gamma t½ is 2.6 to 
5.9 hours. Carboplatin is not protein bound. Elimination is dependent on the glomerular filtration 
rate; the dose may require adjustment depending on GFR. 
9.4.2 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to<5 children out 
of every 100 
Immediate 
Within 1-2 days of receiving 
drug 
Nausea (L), vomiting (L) 
 
Metallic taste 
Prompt 
Within 2-3 weeks, prior to 
next course 
Myelosuppression1 
Electrolyte disturbances (L) 
Peripheral neuropathy,  
hepatotoxicity (L), renal 
toxicity (L), ototoxicity (L) 
Delayed 
Any time later during 
therapy, excluding the 
above conditions 
 
 
 
Late 
Any time after completion of 
treatment 
 
 
Secondary leukemia 
1 
Thrombocytopenia is more severe or dose limiting 
(L) 
Toxicity may also occur later 


 
50 
9.4.3 
Formulation and Stability:  
Supplied in amber vials containing 50, 150, and 450 mg of carboplatin, prepared as a white 
lyophilized powder. Store at room temperature (15°-30°C) and away from light. Reconstitute with 
5, 15, or 45ml of sterile water, respectively, each ml containing 10mg carboplatin. Carboplatin 
may be further diluted to 0.5-2 mg/mL with 5% dextrose or 0.9% sodium chloride with a 24 hour 
stability at room temperature. Lower chloride concentrations enhance stability. Sodium 
bicarbonate reduces stability. 
9.4.4 
Guidelines for Administration:  
IV infusion over 15 minutes or longer. Pre-hydration and posthydration with IV fluids (D5W in 0.45 
NaCl) are less important than with cisplatin. Aluminum reacts with carboplatin, causing loss of 
potency; therefore, needles and intravenous sets containing aluminum parts must not be used for 
the preparation or administration of carboplatin. 
9.4.5 
Supplier:  
Commercially available. See package insert for further information. 
 
9.5 Mesna (sodium 2-mercaptoethane sulfonate, MESNA) NSC #113891 
9.5.1 
Source and Pharmacology:  
MESNA is a thiol compound with the capacity of inhibiting the urotoxicity of the 
oxazaphosphorines, ifosfamide and cyclophosphamide. Within 1 hour of administration, MESNA 
is completely oxidized to DiMESNA, a totally inert compound. After an 800mg dose the t½ for 
MESNA and DiMESNA is 0.36 hours and 1.17 hours, respectively. There is little or no tissue 
penetration. Following glomerular filtration DiMESNA is rapidly reduced in the renal tubules back 
to MESNA which inactivates acrolein and the oxazaphosphamides, thus preventing bladder 
toxicity. After 3 hours, negligible amounts of MESNA were present in the urine of rats given 
100mg/kg by IV push. 
9.5.2 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to<5 children out 
of every 100 
Immediate 
Within 1-2 days of receiving 
drug 
Bad taste with oral use 
Nausea, vomiting, stomach 
pain 
Headache, pain in arms, 
legs, and joints; fatigue, 
rash, transient hypotension, 
allergy 
Prompt 
Within 2-3 weeks, prior to 
next course 
 
 
Diarrhea 
Delayed 
Any time later during 
therapy, excluding the 
above conditions 
 
 
 
Late 
Any time after completion of 
treatment 
 
 
 
 


 
51
Young children receiving high doses of benzyl alcohol (> 99 mg/kg/day) may develop the gasping 
syndrome manifested by gasping, metabolic acidosis and multiple organ system failure. Benzyl 
alcohol is the preservative in multidose vials of MESNA. 
9.5.3 
Formulation and Stability:  
Available in 1000 mg/10mL multidose vials which contain 10.4 mg/mL of benzyl alcohol* as a 
preservative, or in 200 mg/2 mL ampules without preservatives for neonates and infants or 
patients with hypersensitivity to benzyl alcohol. In Canada, only the non-preserved ampules are 
available. Store either product at controlled room temperature (15- 30°C). MESNA is not light-
sensitive, but is oxidized to DIMESNA when exposed to oxygen. Non-preserved ampules should 
be used immediately after opening, while benzyl alcohol-preserved vials may be stored and used 
for 8 days. After further dilution for administration, either product is chemically stable for at least 
24 hours. Lack of an antimicrobial preservative suggests that the non-preserved product should 
be used within 6-8 hours after diluted for administration. For IV administration, dilute to 20 mg/mL 
with any of the following fluids: 5% dextrose, 5% dextrose in 0.45% sodium chloride, 0.9% 
sodium chloride or Lactated Ringer’s. MESNA may be mixed with ifosfamide or 
cyclophosphamide. 
*The package insert for MESNA states that multidose vials contain benzyl alcohol 10.4 mg/mL 
(1%) as a preservative, should not be used in neonates or infants, and should be used with 
caution in older pediatric patients. A 200 mg/2 mL ampule remains available free of charge for 
pediatric patients less than 2 years old and for patients with hypersensitivity to benzyl alcohol. It 
may be obtained in the U.S. by calling Bristol-Myers Squibb Oncology at 1-800-437-0994. 
The medical literature includes reports of gasping syndrome in premature infants receiving saline 
flushes with benzyl alcohol at benzyl alcohol doses greater than 99 mg/kg/day. (Gershanik J, et 
al. N Engl J Med 1982;307:1384) There is also a report of metabolic acidosis occurring in a 5 
year old girl receiving continuous infusion diazepam which contained 180 mg/kg/day of benzyl 
alcohol. (Lopez-Herce, et al. Ann Pharmacother 1995;29:632) The syndrome includes gasping 
respiration, severe metabolic acidosis, and multiple organ system failure. It results from inability 
to adequately conjugate benzoic acid with glycine, a metabolic pathway poorly developed under 8 
weeks of age. 
Even if the amount of benzyl alcohol in MESNA is not enough to cause problems in a patient, a 
number of other drug products contain benzyl alcohol and therefore could add to the dose a 
patient is receiving. Your pharmacist can check product contents and calculate the dose of benzyl 
alcohol any patient is receiving. 
9.5.4 
Guidelines for Administration:  
IV 5 does of MESNA per day per dose of ifosfamide, will be given each day of ifosfamide 
treatment.. Can be given orally but has a foul taste. Total dose is usually 60% of the 
oxazaphosphorine dose given in divided doses. Higher doses or continuous infusions are used 
with high dose ifosfamide or cyclophosphamide, or in patients with a history of hemorrhagic 
cystitis. 
9.5.5 
Supplier:  
Commercially available. See package insert for further information. 
9.6 Granulocyte Colony-Stimulating Factor (R-MetHuG-CSF, G-CSF, 
Filgastim, Neupogen) NSC #614629 
9.6.1 
Source and Pharmacology:  
r-metHuG-CSF (produced in E. coli by recombinant DNA technology) stimulates the production of 
neutrophils in the bone marrow and selected end-cell activation. The 175 amino acid protein 
(M.W. of 18,800 daltons) differs from the natural protein in that the N-terminal amino acid is a 
methionine and it is not o-glycosylated. 3.45 ug to 11.5 ug of G-CSF administered 


 
52 
subcutaneously resulted in a maximum serum concentration of 4 ng/ml to 49 ng/ml within 2 to 8 
hours. The elimination half-life is similar for SQ and IV, approximately 3.5 hours. 
9.6.2 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to<5 children out 
of every 100 
Immediate 
Within 1-2 days of receiving 
drug 
 
Local irritation at the 
injection site 
Allergic reaction, low grade 
fever 
Prompt 
Within 2-3 weeks, prior to 
next course 
 
Medullary bone pain, 
increased alkaline 
phosphatiase, increased 
lactate dehydrogenase, 
increased urice acid, 
thrombocytopenia 
Subclinical splenomegaly, 
exacerbation of pre-existing 
skin rashes, alopecia 
Delayed 
Any time later during 
therapy, excluding the 
above conditions 
 
 
Cutaneous vasculitis 
Late 
Any time after completion of 
treatment 
 
 
 
 
9.6.3 
Formulation and Stability:  
Supplied as a clear solution in 300 ug/ml (1 ± 0.6 x 108 U/mg) (1 ml or 1.6 ml) vials. Vials are 
preservative free and are intended to be single-use vials; do not reuse opened vials. Filgrastim 
must be stored between 2° and 8°C. Stability has been demonstrated for at least 24 months 
when stored under these conditions. Do not use if discolored or if there is particulate matter. For 
IV use, dilute in D5W to concentrations > 15 ug/ml; G-CSF is incompatible with normal saline. At 
dilutions from 5 ug/ml to 14 ug/ml, add human serum albumin to a final albumin concentration of 2 
mg/ml to protect against absorption of the G-CSF to container walls (glass or plastic). Filgrastim, 
when diluted as described above, is compatible with a number of plastics commonly used in the 
manufacture of syringes, IV bags, infusion sets, and IV pump cassettes. These include polyvinyl 
chloride, polyolefin, and polypropylene. Diluted filgrastim should be stored at 2° to 8° C and used 
within 24 hours. Do not shake or freeze. 
9.6.4 
Guidelines for Administration:  
Administer once daily, subcutaneously without dilution or if necessary dilute with 5% dextrose in 
water, preferably to concentrations of 15 ug/ml or greater for IV administration. Dilutions should 
be prepared as close to the time of administration as possible (up to 24 hours), since the product 
is preservative-free. When diluting Filgrastim to 5-14 ug/ml in D5W, it is necessary at all times to 
add human serum albumin, to reach a final albumin concentration of 2 mg/ml. The suggested 
starting dose is 5 ug/kg. 
Recommended continue G-CSF until ANC >10,000 after the nadir is reached (usually 10-
14 days)  
9.6.5 
Supplier:  
Commercially available. See package insert for further information. 
 


 
53
10.0 ADVERSE EVENTS 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have 
to have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of dasatinib whether or not considered related to dasatinib. 
 
During clinical trials, 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 adverse events.) 
A serious AE is any untoward medical occurrence that at any dose:   
• 
results in death,  
• 
is life-threatening (defined as an event in which the patient 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,  
• 
results in persistent or significant disability/incapacity,  
• 
is a congenital anomaly/birth defect,  
• 
results in the development of drug dependency or drug abuse,  
• 
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 patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above.)  
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.) For reporting purposes, also consider the occurrences of 
pregnancy or overdose (regardless of adverse outcome) as events which must be 
reported as important medical events. 
10.1 Reporting of SAEs 
Following the subject’s written consent to participate in the study, all SAEs should be collected 
and reported, including those thought to be associated with clinical trial procedures. Following 
study completion, any SAE thought to be related to study drug or clinical trial procedures should 
also be reported to BMS. 
SAE terminology and severity grading will be based on ( i.e., CTCAEv3). 
 
The following categories and definitions of causal relationship to study drug should be considered 
for use for all clinical studies supported by BMS: 
 
• 
Certain: There is a known causal relationship between the study drug and the SAE. The 
event responds to withdrawal of study drug (dechallenge), and recurs with rechallenge when 
clinically feasible. (>95% certainty) 
• 
Probable: There is reasonable causal relationship between the study drug and the SAE. The 
event responds to dechallenge. Rechallenge is not required. (65%-95% probability) 
• 
Possible: There is reasonable causal relationship between the study drug and the SAE. 
Dechallenge information is lacking or unclear. (35%-65% probability of relatedness) 
• 
Not likely: There is temporal relationship to study drug administration, but there is not a 
reasonable causal relationship between the study drug and the SAE. (5-35% probability of 
relatedness) 


 
54 
• 
Not related: There is not a temporal relationship to study drug administration (too early, or 
late, or study drug not taken), or there is known causal relationship between the SAE and 
another drug, concurrent disease, or other circumstance. (<5% chance of relatedness) 
• 
Adverse events classified as “serious” require expeditious handling and reporting to BMS to 
comply with regulatory requirements.  
• 
All SAEs whether related or unrelated to dasatinib, must be immediately reported to BMS (by 
the investigator or designee) within 24 hours of becoming aware of the event.  If only limited 
information is initially available, follow-up reports are required.  The original SAE form must 
be kept on file at the study site. 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number:  609-818-3804 
Email: Worldwide.safety@bms.com 
 
• 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later than 7 
days (death or life-threatening event) or 15 days (all other SAEs) after the investigator’s or 
institution’s initial receipt of the information.  BMS will be provided with a simultaneous copy 
of all adverse events filed with the FDA.  SAEs should be reported on the MedWatch Form 
3500A, which can be accessed at: http://www.accessdata.fda.gov/scripts/medwatch/  
 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
City of Hope National Medical Center 
1500 East Duarte Road, MOB 4th Floor 
Duarte, California 91010 
Fax (626) 256-8787 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number:  609-818-3804 
Email: Worldwide.safety@bms.com 
 
• 
Collection of complete information concerning SAEs is extremely important.  Full descriptions 
of each event will be followed by BMS. Thus, follow-up information which becomes available 
as the SAE evolves, as well as supporting documentation (e.g., hospital discharge 
summaries and autopsy reports), should be collected subsequently, if not available at the 
time of the initial report, and immediately sent using the same procedure as the initial SAE 
report. 
• 
An overdose is defined as the accidental or intentional ingestion of any dose of a product that 
is considered both excessive and medically important.  For reporting purposes, BMS 
considers an overdose, regardless of adverse outcome, as an important medical event. 
• 
AEs should be followed to resolution or stabilization, and reported as SAEs if they become 
serious. This also applies to subjects experiencing AEs that cause interruption or 
discontinuation of dasatinib, or those experiencing AEs that are present at the end of their 
participation in the study; such subjects should receive post-treatment follow-up as 
appropriate. 


 
55
• 
In BMS supported trials, all SAEs must be collected which occur within 30 days of 
discontinuation of dosing or completion of the patient’s participation in the study if the last 
scheduled visit occurs at a later time.  In addition, the Investigator should notify BMS of any 
SAE that may occur after this time period which they believe to be certainly, probably, or 
possibly related to dasatinib. 
 
11.0 STATISTICAL METHODOLOGY 
11.1 Phase I Portion of Study: 
11.1.1 Sample Size and Study Duration 
This trial will seek to determine the toxicity profile and the maximum tolerated dose (MTD) of 
dasatinib in relapsed pediatric solid tumor patients, treated in combination with ICE, excluding 
patients with active brain/CNS involvement.  The DLT will be based on the first course and the 
delay to second course and is defined earlier.  Toxicity will be graded according to the NCI 
CTCAE version 3.0.  To be evaluable for toxicity, a patient must receive at least 1 complete 
course of treatment and be observed for at least 28 days (or until re-treatment) after the start of 
the first course or have experienced a DLT.  All patients enrolled are to be fully followed for DLT 
and any patient who is not evaluable for toxicity will be replaced.  The MTD will be defined as the 
highest dose tested in which fewer than 33% of patients experienced DLT attributable to the 
study drug(s), when at least six patients were treated at that dose and are evaluable for toxicity.  
Dose escalation will proceed according to a standard 3+3 design.  There will be no intra-patient 
dose escalation prior to consolidation, but one intra-patient dose escalation is permitted during 
the post-consolidation treatment with dasatinib.  Three patients will be treated at each new dose 
level.  If 0/3 patients experience a DLT, 3 patients will be treated at the next new dose level (in 
the case of dose level 4, 3 more patients will be added to the same dose level).  If DLT 
attributable to the study drugs is experienced in exactly 1/3 patients, 3 more patients (for a total of 
6) will be treated at that dose level.  If no additional DLT is observed at the expanded dose level 
(i.e., 1/6 with DLT), the dose will be escalated.  Escalation will be terminated as soon as two or 
more patients experience any DLT attributable to the study drugs at a given dose level, or dose 
level five has enrolled 6 patients with <2 DLTs.  The dose finding portion of the Phase I trial will 
be terminated when the MTD has been determined. 
 
Tables will be created to summarize these toxicities and side effects by dose, course, organ and 
severity, along with additional tables documenting the patient characteristics treated in this Phase 
I study.  All responses will be reported.  Note that dose level 5 required patients to be treated at 
85 mg/m2/dose of dasatinib prior to consolidation, start the post-consolidation treatment with 85 
mg/m2/dose and tolerate treatment to permit intrapatient escalation to 110 mg/m2/dose during 
the post-consolidation single agent therapy.  Patients treated at or above the MTD and are 
evaluable for the Phase II portion of this trial, will be counted toward the Phase II portion for the 
appropriate strata. 
 
The POETIC member institutions see a total of approximately 1000 newly diagnosed and 500 
relapsed pediatric cancer patients annually.  In 2006, there were 50 patients enrolled to POETIC 
phase I trials.  This study will be open to an additional four sites: City of Hope Cancer Center, 
Nemours Children Clinic Jacksonville, Moffitt Cancer Center, and All Children’s Hospital.  Based 
on the available patient numbers, an adequate patient base is available to complete this trial in a 
timely manner. POETIC member institutions will not be participating in the Phase I portion of the 
study.  During the Phase II portion of the study, POETIC member institutions may participate.  
 


 
56 
11.2 Phase II Portion of Study: 
11.2.1 Sample Size and Study Duration 
During the phase II portion of the study, there are three strata: 
• 
Stratum A (75 patients): patients with relapsed Osteosarcoma, Ewings Sarcoma, 
Rhabdomyosarcoma; 
• 
Stratum B (max of 25 patients): Patients with relapsed solid tumors not listed above; 
• 
Stratum C (max of 25 patients): Patients with newly diagnosed metastatic sarcomas of 
poor risk 
 
The primary endpoint of the Phase II study targets only Stratum A, whereas Stratum B and C will 
be evaluated only in an exploratory manner, and be limited to a maximum of 25 patients each. 
 
The primary endpoint for this analysis is 1-yr overall survival (OS).  Based on Van Winkle (12), 1-
yr OS was 56%, 41% and 43% for rhabdomyosarcoma, osteosarcoma and Ewing sarcoma, 
respectively.  Based on the percentage of patients in each category accrued, the historical 1-yr 
OS based on their work will be calculated.  For example, in their study there were 28 patients with 
rhabdomyosarcoma, 25 with osteosarcoma, and 22 with Ewings sarcoma, leading to a weighted 
1-yr OS of 46%. 
 
Based on this expected 1-yr OS, this study seeks to detect an 11% improvement in OS at 1-yr.  
Based on an exponential survival model, with 1-yr accrual and 1-yr follow-up, there is greater 
than 81% power (regardless of the patient profiles) to detect an 11% improvement in 1-yr OS with 
a 1-sided type I error of 10% with 75 total patients in this stratum.  There is greater than 90% 
power to detect an improvement of 13% in 1-yr OS. 
 
Secondary endpoints include response rate as defined by RECIST criteria prior to consolidation; 
progression-free survival; further assessment of toxicity; and evaluation of exploratory correlative 
studies. 
 
Review of patient accrual onto recent phase II solid tumor studies suggest that there is an 
adequate patient base to complete this portion of the study in a timely manner. 
 
This portion of the study is expected to take 2 to 3 years to enroll sufficient patients to evaluate 
response in the stated disease groups.  If activity is detected in any category, further trials in 
subcategories of categories may be conducted at the discretion of the Principal Investigator.   
11.2.2 Phase II Study Design: Progression Free Survival 
The prognosis for children with recurrent / refractory sarcomas including rhabdomyosarcoma, 
osteosarcoma, and Ewings sarcoma is poor with a 5- year survival rate between 4% and 31% (2-
4).  As previously stated in this document, ifosfamide/carboplatin/etoposide (ICE) is the most 
effective regimen for relapsed or refractory sarcoma with an overall response rate of 51% (12).  
By disease category: for Rhabdomyosarcoma, the ORR (CR + PR) was 66%, osteosarcoma 
36%, Ewings sarcoma 48%, other sarcomas 60% (12).  The one-year overall survival was 49% 
and the 2-year OS was 28%. 
In the Phase II portion of this study, patients with relapsed sarcomas will be treated at the MTD 
as defined by the Phase I portion of the study.  After consolidative therapy (surgery or radiation), 
all patients will receive 6 months of dasatinib alone.  Time to progression and the median 
progression-free survival rate will be estimated at 12 months and 18 months.  Twenty-five 
patients with osteosarcoma, twenty-five patients with Ewings sarcoma, and twenty-five patients 


 
57
with rhabdomyosarcoma will be evaluated at the MTD.  Other pediatric patients with relapsed 
solid tumors will be enrolled on the study and every attempt will be made to fully accrue enough 
patients into each group.  However, due to the rarity of these other tumors, there is a possibility 
that we will be unable to fulfill accrual goals and complete the evaluations. 
A minimum of 75 patients with relapsed sarcoma will be entered on the phase II portion of this 
study.   This portion of the study is expected to take 2 to 3 years to enroll sufficient patients to 
evaluate response in the stated disease groups.   
11.2.3 Methods of Analysis 
Patients who are considered evaluable for response will be included in an analysis of time to 
progression.  Time to progression will be estimated using the product-limit method of Kaplan and 
Meier (36).  The probability of progression free survival at 12 months and 18 months will be 
summarized.  Response rates will be calculated as the percent of patients whose best response 
is a CR or PR, and the fraction of responses obtained will have a 90% confidence interval.  
Toxicity information will include the type, severity, time of onset, time of resolution, and the 
probable association with the study drugs.    
Time to progression will be taken as the number of days from start of treatment until: (1) 
disease progression; (2) death because of treatment complications; or (3) last patient follow-up 
whichever is first.  Patients will be considered to have experience a progression event if (1) or (2) 
occurs.  Otherwise, the patient will be considered censored for time to progression. 
 
12.0 RECORDS, REPORTING, AND DATA SAFETY 
MONITORING PLAN 
12.1 Research Records 
Research records for this study can be divided into two categories: 
12.1.1  Eligibility Verification  
Pathology Reports, Surgical Reports, Radiation Reports to support eligibility verification. These 
forms are faxed to City of Hope National Medical Center at (626) 256-8787. 
12.1.2 
Case Report Forms 
See separate Data Form Packet, which includes submission schedule.  All other data will be 
faxed over with the aid of schedules and worksheets provided in the data form packet.  
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. 
 
All sites within this study will use the CRFs, provided in the accompanying data packet.  Subjects 
will be identified by an assigned subject number. All requested information must be entered on 
the CRF in the space provided. If an item is not available or is not applicable, it must be 
documented as such; do not leave a space blank.  Spaces may be left blank only in those 
circumstances permitted by the 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). 


 
58 
 
 For paper CRFs, a correction must be made by striking through the incorrect entry with a single 
line and entering the correct information adjacent to the incorrect entry.  The correct must be 
dated, initialed and explained (if necessary) by the person making the correction and must not 
obscure the original entry. 
 
The completed CRF, including any paper SAE CRFs must be promptly reviewed, signed and 
dated by the qualified physician who is an investigator or subinvestigator.  The investigator must 
retain a copy of the CRFs including records of the changes and corrections.   
 
12.2 Compliance 
12.2.1 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, the Study Chair and 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.  Any significant deviation must be 
documented in the CRF.  
 
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; 
• 
Study Chair, Judith K. Sato, M.D.;  
• 
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 Study Chair, Judith K. Sato, M.D..  
 
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 subject prior to enrollment.  
 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
12.3 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 documentation, 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. 
 


 
59
12.4 Records Retention 
The investigator must retain investigational product disposition records, copies of CRFs and 
source documents for the maximum period required by applicable regulation 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 (e.g. relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g. another investigator, IRB). Notice of such 
transfer will be given in writing to BMS. 
 
12.5 CRADA/CTA 
Standard Language to Be Incorporated into All Protocols Involving Agent Covered by a Clinical 
Trials Agreement (CTA) or a Cooperative Research and Development Agreement. 
The agent supplied by Bristol-Myers Squibb (BMS), used in this protocol is provided to the 
Individual institutions under a Collaborative Agreement (CRADA, CTA) between the 
Pharmaceutical Company (hereinafter referred to as Collaborator(s)_).  Therefore, the following 
obligations/guidelines, in addition to the provisions in the _ Intellectual Property Option to 
Collaborator_contained within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent may not be used for any purpose outside the scope of this protocol, nor can Agent 
be transferred or licensed to any party not participating in the clinical study. Collaborator(s) 
data for Agent are confidential and proprietary to Collaborator(s) and shall be maintained as 
such by the investigators. The protocol documents for studies utilizing investigational Agent 
contain confidential information and should not be shared or distributed without the 
permission of BMS. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data._): 
a. BMS must provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NIH, the 
design of the proposed combination protocol, and the existence of any obligations that 
would tend to restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
 


 
60 
3. Clinical Trial Data and Results and Raw Data developed under a collaborative agreement 
will be made available exclusively to Collaborator(s), BMS, and the FDA, as appropriate. All 
data made available will comply with HIPAA regulations. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to 
the Study Chair, Judith K. Sato, M.D., who will then notify BMS of Collaborator's wish to 
contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to BMS for 
immediate delivery to Collaborator(s) for advisory review and comment prior to submission 
for publication. Collaborator(s) will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 
30 days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be 
provided to BMS for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to BMS prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
City of Hope National Medical Center, Judith K. Sato, MD  
1500 E. Duarte Road, Duarte, CA  91010 
Tel: 626 930 5430     Fax: 626 930 5415 
  
 
BMS 
Insert address 
 
The BMS Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of Collaborator_s 
confidential/ proprietary information. 
12.6 Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the Data and Safety 
Monitoring Committee. 
12.6.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the COH/ BMS policy for data and safety 
monitoring of Phase 1 and 2 studies. In brief, the role of the Data and Safety Monitoring 
Committee is to protect the interests of patients and the scientific integrity for all Phase 1 and 2 
studies. The DSMC consists of a chair; a statistician; one external member; one consumer 
representative; the lead statistician of the developmental therapy scientific committee; and a 
member from the NCI. The DSMC meets at least every 6 months to review current study results, 
as well as data available to the DSMC from other related studies. Approximately 6 weeks before 
each meeting of the Phase 1 and 2 DSMC, study chairs will be responsible for working with the 
study statistician to prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the Study Chair and BMS for each study reviewed to change the study or to 
continue the study unchanged. Data and Safety Committee reports for institutional review boards 
can be prepared using the public data monitoring report. 


 
61
12.6.2 Monitoring by the Study Chair and Coordinating Center 
The study chair will monitor the study regularly and enter evaluations of patients’ eligibility, 
evaluability, and dose limiting toxicities into the study database. In addition, study data including 
the study chair’s evaluations will be reviewed by the study chair and Statistician on a weekly 
conference call. 
12.7 Investigational Product Records 
It is the responsibility of the investigator to ensure that a current record of investigational product 
disposition is maintained at each study site where investigational product is inventoried and 
disposed.  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 of batch number and use date or expiration date; 
• 
Dates and initials of person responsible for each investigational product inventory 
entry/movements; 
• 
Amount dispensed to and returned by each subject, including unique subject identifiers; 
• 
Amount transferred to another area/site for dispensing or storage;  
• 
Non-study dispositions (e.g. lost, wasted, broken); 
• 
Amount returned to the sponsor; 
• 
Amount destroyed at study site, if applicable;  
• 
Retain samples sent to third party for bioavailability/bioequivalence, if applicable.  
 
The sponsor will provide forms to facilitate inventory control if the staff at the investigational site 
does not have an established system that meets these requirements.  
 
12.8 Return and Destruction of Investigational Product 
12.8.1 Return of Investigational Product 
Upon completion or termination of the study, all unused and/or partially used investigational 
product must be returned to BMS, if not authorized by BMS to be destroyed at the site. 
 
All investigational product returned to BMS must be accompanied by the appropriate 
documentation and be clearly identified by protocol number and study site number on the 
outermost shipping container.  Returned supplies should be in the original container (e.g. patient 
kits that have clinical labels attached).  Empty containers should not be returned to BMS.  It is the 
investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. The return of unused investigational product(s) should be arranged by the responsible 
Study Monitor. 
12.8.2 Destruction of Investigational Product 
If investigational products are to be destroyed on site, it is the investigator’s responsibility to 
ensure that arrangements have been made for the disposal, written authorization has been 
granted by BMS, procedures for proper disposal have been established according to applicable 
regulations and guidelines and institutional procedures, and appropriate records of the disposal 
have been documented.  The unused investigational products can only be destroyed after being 
inspected and reconciled by the responsible BMS Study Monitor.   
 
 


 
62 
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27. Kung F, Hayes FA, Krischer J, et al. Clinical trial of etoposide (VP-16) in children with 
 
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30. Cairo MS, Shen W-P, Miser J, Krailo M, et al. Prospective randomized trial between two 
 
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64 
APPENDIX 1:  List of Abbreviations 
Abbreviation 
Term 
 
 
ANC 
Absolute Neutrophil Count 
BID 
Twice a Day 
BMS 
Bristol-Myers Squibb Company 
CAT ( or CT scan) 
Computed Axial Tomography 
CBC 
Complete Blood Count 
 
 
CR 
Complete Response 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
EKG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
 
 
 
 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IRB 
Institutional Review Board 
 
 
MRI 
Magnetic Resonance Imaging 
PD 
Progressive Disease 
 
 
PFS 
Progression Free Survival 
PO 
By Mouth 
PR 
Partial Response 
QD 
Once Daily 
QoL 
Quality Of Life 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
 
 
SD 
Stable Disease 
TNM Staging 
Tumor, Node and Metastasis Staging 
 
 
ULN 
Upper Limit of Normal 
WBC 
White Blood Count 
WOCPB 
Women of Child-Bearing Potential 
 
 


 
65 
 
APPENDIX 2:  Dasatinib Subject Diary for Study 
 


 
66
 
APPENDIX 3: COH Specimen Transmittal Form 
1) 
A Specimen Transmittal Form should accompany every specimen shipped to the COH Laboratory. Please complete:  
a.) 
Include one form per specimen per patient 
b.) 
Document the number and type(s) of specimen(s) sent  in shipment (see below) 
2) 
The patient must have a Patient ID number.  The registration number (and a study number if the patient has been enrolled on a study) must be 
recorded on each Specimen Transmittal Form for identification purposes. 
3) 
Biology Specimens must be labeled with a COH Registration Number.  Each patient is assigned a Registration Number at the time of registration 
(see Section 6.2).  If you have any questions about a patient's Registration Number, please contact the PI, Judith K. Sato, MD at 626 930 5430. 
 PATIENT/SPECIMEN INFORMATION 
 
Patient Initials (L,F):________________ 
 
Date of Birth: _________________      
                         (mm/dd/yyyy) 
 
IRB Study #:_________________ 
 
 
Consent Date:__________________ 
                          (mm/dd/yyyy) 
 
    
COH Registration Study #:_________   
 
Diagnosis:_____________________________________________ 
 
_____________________________________________________ 
 
 
Institution of Treatment:____________________________________________ 
 
 
Primary Site:_______________________________________ 
Inst. # _________    Contact Person: _________________________________ 
 
Stage (if applicable):_________________________________ 
 
 
Telephone #:____________________________________ 
 
           
Fed Ex (or other) Tracking Number:____________________________ 
 
 
Permission Questions: 
 
Patient agreed to the use of specimen blood samples to do research to learn about 
how Dasatinib may prevent or treat cancer. 
 
Patient agreed to the use of specimen tumor samples to do research about medical 
characteristics of tumor cells and to evaluate the effect of Dasatinib on the tumor 
cells. 
 
Patient agreed to have specimens stored and used for future research purposes 
that have not yet been determined. 
 
 
 
 
____Yes     ____No   ___ N/A 
 
 
____Yes    ____No   ___ N/A 
 
 
____Yes    ____No   ___N/A 
Research Patient Number 
  
  
  
  
  
  
  
  
(Specimens will NOT be banked without a Lab #) 
Specimen Obtained at (check all that apply) 
____Pretreatment/Diagnosis 
 
____Relapse 
     
____During Follow-up 
            
 ___During Therapy (designate time period) 
       Course:________________________ 
        Week #:________________________ 
       Transplant Day #:_________________ 
 
___End of Therapy 
Type of Specimen (check one): 
 
_____  Surgical Resection 
 
______Core Biopsy 
Time Specimen Obtained: (if applicable):______________ 
Record Number of each type/  
of specimen present in shipment.  
(include # of specimens)  
FRESH 
FROZEN 
PARAFFIN 
SLIDES 
FORMALIN 
Surgical Path  
ID (SPID) 
Date Obtained 
Primary Tissue 
 
 
 
 
 
 
 
Metastatic Tissue 
 
specify site: 
 
 
 
 
 
 
 
Normal Tissue 
 
 
 
 
 
 
 
Blood and/or WBC aliquots 
 
 
 
 
 
 
 
Other (specify): 
SPECIMEN SHIPPED TO: 
FORM: 
      
      
Send original form with specimen 
Retain a copy in patient file at institution 
      
LABORATORY CODE (Office use): 
  
 
 
 


 
67 
 
APPENDIX 4:  Submission Of Biological Samples 
COLLECTION TIME  
SPECIMEN 
WHERE TO SHIP * 
STUDIES TO BE DONE 
10 ml PB in EDTA tube  
City of Hope National Medical Center 
Attn:  Dr. Jove’s Laboratory* 
1500 E. Duarte Road, Shapiro/Rm1031 
Duarte, CA 91010 
Phone: (626) 256-7643 x62357 
Fax: (626) 256-8708 
Biomarker analysis  
Microarray gene-expression profiling  
Immunohistochemistry  
Diagnosis 
(pre-treatment) 
Core biopsy and/or surgical biopsy  
- 
1.5 cm x 1 cm x 1 cm snap forzen tumor 
- 
Parrafin-embedded tumor specimens 
Dr. Jove’s Laboratory* 
Quality (absence of necrosis or fibrosis, and % tumor cells) 
 
 
 
 
Pre-Consolidation  
 Course 1: Day 14-21 or when 
WBC > 500 /  Date:    
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Pre-Consolidation  
 Course 2: Day 14-21 or when 
WBC > 500  /  Date:   
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Pre-Consolidation  
 Course 3: Day 14-21 or when 
WBC > 500  /  Date:    
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Pre-Consolidation  
  Course 4: Day 14-21 or when 
WBC > 500  /  Date:     
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Pre-Consolidation  
 Course 5: Day 14-21 or when 
WBC > 500  /  Date:   
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Pre-Consolidation  
 Course 6: Day 14-21 or when 
WBC > 500 /  Date:   
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Microarray gene-expression profiling  
Immunohistochemistry  
Consolidation  
 
Surgical resection  
- 
Parrafin-embedded tumor specimens 
Dr. Jove’s Laboratory* 
Quality (absence of necrosis or fibrosis, and % tumor cells) 
 
 
 
 
Post-Consolidation  
 Course 7: Day 14-21 or when 
WBC > 500  /  Date:   
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Post-Consolidation  
 Course 8: Day 14-21 or when 
WBC > 500  /  Date:    
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Post-Consolidation  
 Course 9: Day 14-21 or when 
WBC > 500 /  Date:    
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Post-Consolidation  
 Course 10: Day 14-21 or when 
WBC > 500 /  Date:    
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Post-Consolidation  
 Course 11:  Day 14-21 or when 
WBC > 500  / Date:    
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
Post-Consolidation  
 Course 12: Day 14-21 or when 
WBC > 500  /  Date:     
10 ml PB in EDTA tube  
Dr. Jove’s Laboratory* 
Biomarker analysis  
10 ml Peripheral Blood in tube 
Dr. Jove’s Laboratory* 
Biomarker analysis  
Microarray gene-expression profiling  
Immunohistochemistry  
Relapse / Progression 
 
Surgical resection   
- 
1.5 cm x 1 cm x 1 cm snap forzen tumor 
- 
Parrafin-embedded tumor specimens 
Dr. Jove’s Laboratory* 
Quality (absence of necrosis or fibrosis, and % tumor cells) 


 
68
APPENDIX 5:  POETIC Consortium 
Responsible Investigators 
Children's Healthcare of Atlanta 
 
Howard Katzenstein, M.D. 
 
Anna Janss, M.D. 
 
Children’s Healthcare of Atlanta at  Egleston 
 
2040 Ridgewood Drive, NE, # 100 
 
Atlanta, GA  30322 
 
Telephone:  (404) 727-4451 
 
Fax:  (404) 727-4455 
 
E-mail:  howard.katzenstein@choa.org 
 
 
 
Anna.Janss@choa.org 
 
MD Anderson Cancer Center 
 
Cynthia Herzog, MD 
 
Joann Ater, MD 
 
Johannes Wolff, MD 
 
MD Anderson Cancer Center 
 
1515 Holcombe Blvd., Box 87 
 
Houston, TX 77030 
 
Telephone: (713) 745-0157 
 
Fax: (713)792-0608 
 
E-mail:  cherzog@mdanderson.org 
 
 
 
jater@mdanderson.org 
 
 
 
jwolff@mdanderson.org 
 
Memorial Sloan-Kettering Cancer Center 
Tanya Trippett, MD 
Ira Dunkel, MD 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
Telephone: (212) 639-8267 
Fax: (212) 717-3239 
E-mail:  
Trippet1@mskcc.org 
 
 
      dunkeli@mskcc.org 
 
Phoenix Children's Hospital 
 
Jessica Boklan, M.D. 
 
Michael Etzl, Jr. M.D. 
 
Phoenix Children’s Hospital 
 
Hematology/Oncology 
 
1919 E. Thomas Road 
 
Phoenix, AZ  85016-7710 
 
Telephone:  (602) 546-0920 
 
Fax:  (602) 546-0276 
 
E-mail:  jboklan@phoenixchildrens.com 
 
 
 
metzl@phoenixchildrens.com 
 
Southern Alberta Children's Cancer Program 
 
Aru Narenderan, M.D., Ph.D. 
 
Alberta Children’s Hospital 
 
18/20 Richmond Road, SW 
 
Calgary, Alberta, Canada D2T2T5C7 
 
Telephone:  (403) 943-7203 
 
Fax: (403) 228-4196 
 
Email: 
a.narendran@ucalgary.ca 
 
 
 
 
Sydney Kimmel Comprehensive Cancer Center at 
John Hopkins 
 
Robert Arceci, M.D., Ph.D. 
 
Kenneth Cohen, M.D. 
 
Johns Hopkins Medical Center  
 
Sidney Kimmel Comprehensive Cancer Ctr 
 
1650 Orleans Street, 2M51 
 
Baltimore, MD  21231-1000 
 
Telephone: (410) 502-7519 
 
Fax:   (410) 502-7223 
 
E-mail: arcecro@jhmi.edu 
 
 
 
kcohen@jhmi.edu 
 
University of Arizona, Health Sciences Center 
 
Rochelle Bagatell, M.D. 
 
Department of Pediatrics 
 
Arizona Health Sciences Center 
 
1501 N. Campbell Avenue 
 
Tucson, AZ  85724 
 
Telephone:  (520) 626-4851 
 
Fax:  (520) 626-4220 
 
Email:  bagatell@peds.arizona.edu 
 
University of Colorado Health Sciences Center 
Lia Gore, MD 
University of Colorado Health Sciences Center & the 
Children’s Hospital, Box B115 
1056 East 19th Avenue 
Denver, CO  80218 
Telephone:  (303) 724-4011 
Fax:  (303) 724-4015 
Email:  lia.gore@uchsc.edu 
 
University of Florida, College of Medicine 
 
Amy A. Smith, MD 
 
POETIC Consortium 
 
Pediatric Hematology Oncology 
 
University of Florida College of Medicine 
 
1600 SW Archer Road 
 
Gainesville, FL  32610-0296 
 
Tel:   (352) 392 8724 
 
Fax:  (352) 392 8725 
 
Email:  smithaa@peds.ufl.edu 
 
Vanderbilt Children's Hospital 
 
James Whitlock, MD 
Vanderbilt Children’s Hospital 
2220 Pierce Avenue 
Room 397 PRB 
Nashville, TN 37232-6310 
Telephone: (615) 936-1762 
Fax: (615) 936-1767 
E-mail:  
jim.whitlock@vanderbilt.edu 
 


 
69
APPENDIX 6:  Performance Status Scales/Scores  
 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
 
Karnofsky for patients > 16 years of age 
Lansky for patients < 16 years of age 
Score Description 
Score
Description 
100 
Normal, no complaints, no 
evidence of disease 
100 
Fully active, normal. 
 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
80 
Active, but tires more quickly 
 
70 
Cares for self, unable to carry 
on normal activity or do active 
work. 
70 
Both greater restriction of and less time 
spent in play activity. 
60 
Required occasional 
assistance, but is able to care 
for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies around much of 
the day; no active play, able to participate 
in all quiet play and activities. 
40 
Disabled, requires special care 
and assistance.  
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
30 
In bed; needs assistance even for quiet 
play. 
 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
 
 
 


 
70 
APPENDIX 7:  Study Calendar 
Course 1 (total course = 28 days) 
Subsequent course (total course = 28 days) 
End of 
therapy / 
relapse 
Post 
Treatment 
Follow-Up 
Study Assessment 
 Pre-
Study
# 
  
Day 
0 
Day 
1 
Day 
3 
Day 
8 
Day 
14 
Day 
22 
Day 
28 
  
Day 
0 
Day 
1 
Day 
8 
Day 
14 
Day 
22 
  
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History 
X 
  
X 
  
  
  
  
  
  
Start of each course 
X  
  
  
  
  
X 
X 
Physical Exam with vital 
signs (BP, HR, and Temp) 
X 
Weekly 
X 
  
  
X 
X 
X 
X 
Days 1 and 14 of each course 
 
X 
  
X 
  
X 
X 
Height, weight, BSA 
X 
  
X 
  
  
  
  
  
  
Start of each course 
X 
  
  
  
  
X 
X 
Performance Status 
X 
  
X 
  
  
  
  
  
  
Start of each course 
X 
  
  
  
  
X 
X 
CBC, differential, platelets 
X 
Twice 
Weekly 
(every 3 to 
4 days)
3 
X 
  
X 
  
  
  
  
Weekly
4 
X 
  
X 
X 
X 
X 
  
Peripheral blood for 
biology studies
1 
X 
Day 14-21 
or when 
WBC > 
500 
  
  
  
  
X 
  
  
Day 14 - 21 or when WBC > 
500 of each course 
  
  
  
X 
  
X 
  
Electrolytes including Ca, 
PO4, Mg 
X 
Weekly 
X 
  
  
X 
X 
X 
X 
Days 1 and 14 of each course
5 
  
X 
  
X 
  
X 
  
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
  
  
X 
X 
X 
X 
Days 1 and 14 of each course
5 
  
X  
  
X 
  
X 
  
Total protein/albumin 
X 
Days 1 
and 14 of 
each 
course 
  
X 
  
  
X 
  
  
Days 1 and 14 of each course
5 
  
X 
  
X 
  
X 
  
Disease Evaluation 
X
$ 
End of 
course 1 
  
  
  
  
  
  
  
Start of every other course
6 
X 
  
  
  
  
X 
X 
Pregnancy Test
2 (must be 
done within 72 hours prior 
to 1st dose of treatment) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG 
X 
  
  
  
  
  
  
  
  
Start of each course prior to 
Consolidation; Start of first 
post-consolidation course & 
any time dasatinib dose 
escalated 
X  
  
  
  
  
  
  
Echocardiogram or MUGA 
X 
  
  
  
  
  
  
  
  
As clinically indicated 
  
  
  
  
  
  
  
Tumor tissue for 
Correlative Studies
1 
X 
  
  
  
  
  
  
  
  
From any surgical specimen; 
At time of progression, if 
possible 
  
  
  
  
  
X 
  
1  See Section 7.2  for details and  timing of biology studies 
 
 
 
 
 
 
2   Patients of child bearing potential require a negative pregnancy test prior to starting treatment and must use an acceptable method of birth control.  Abstinence is an acceptable method of birth control. 
3   If patients develop Grade 4 neutropenia, then CBCs should be checked every other day until recovery to Grade 3. 
 
4   If patient develop Grade 4 neutropenia, then CBCs should be checked every 3 to 4 days until recovery to Grade 3 
 
5   Day 14 Chemistry tests required for the Phase I portion of study only  
 
 
 
 
6   Disease Evaluation should be obtained every other course after initial documentation of either a PR, CR, or SD, or at time of suspected disease relapse or progression.  
 
 
 
 
 
 
#   All entry and eligibility studies must be performed within 2 weeks prior to treatment, unless otherwise specified. 
$  Imaging studies are required within 2 weeks prior to study entry 
 
 
 
 
 
 


 
71 
APPENDIX 8:  Data and Submission Schedule 
 
Data Management Time Frames 
 
At Screening 
Baseline 
Course 1 
Course 2 and all 
subsequent courses 
F/UP 
CRF Title: 
Form Number: 
 
 
 
 
 
ELIGIBILITY SCREENING CHECKLIST 
 
X 
 
 
 
 
 
ACCESSION/DIAGNOSIS RECORD1 
 
COH2574 
 
 
X 
 
 
 
ON STUDY 
COH2689 
 
X 
 
 
 
PRIOR THERAPY SUMMARY 
COH1987 
 
X 
 
 
 
PRIOR DRUG TREATMENT - SINGLE AGENT 
COH2007 
 
X 
 
 
 
PRIOR DRUG TREATMENT - COMBINATION 
COH2008 
 
X 
 
 
 
PRIOR TREATMENT - SURGERY 
COH1991 
 
X 
 
 
 
PRIOR TREATMENT - RADIATION 
COH2009 
 
X 
 
 
 
PRIOR TREATMENT – OTHER THERAPIES 
COH1992 
 
X 
 
 
 
PRE-EXISTING CONDITIONS 
COH1993 
 
X 
 
 
 
PEDIATRIC TREATMENT AND ADVERSE 
EVENTS FORM  
COHxxxx 
PEDIATRIC  
 
 
X 
X 
 
PHASE I TRACKING LOG 
COH1033 
 
 
X 
 
 
TUMOR MEASUREMENT2 
COH2690 
 
X 
 
X2 
 
ADVERSE EVENTS COLLECTION FORM 
COH2000 
 
 
X 
X 
 
 
RESPONSE/OFF-STUDY/FOLLOW-UP FORM 
COH1059 v07 
 
 
X 
X 
X 
 
PEDIATRIC CHEMISTRY FORM 
COH2737 
 
X 
X 
X 
 
 
CONCOMITANT THERAPIES 
COH2691 
 
X 
X 
X 
 
 
PATIENT PILL DIARY FORM 
COH2736  
 
 
X 
X 
 
 
1 - Accession/Diagnosis record will be 
completed by Consortium office for the 
patients outside of COH. 
2 - Tumor measurement form to be 
completed at baseline and every 2 courses 
-please always confirm with protocol study 
calendar. 
 
 
 
 
 
 
 


 
72 
APPENDIX 8:  Data and Submission Schedule 
                                
 
 
 
 
                                                                  BEST RESPONSE CODES FOR PRIOR THERAPY  
 
 
  Response                                                                                      Codes   
 
  NED                                                                                                   ND 
                       
  Complete response                                                                         CR 
 
  Partial response                                                                               PR 
 
  Stable Disease                                                                                  SD 
 
  Progression                                                                                      PD 
  
  Not Assessed/ Not Available                                                           NA 
  
  The following codes should be used only for best response on the following forms: 
 
PRIOR THERAPY SUMMARY 
COH1987 
PRIOR DRUG TREATMENT - SINGLE AGENT 
COH2007 
PRIOR DRUG TREATMENT - COMBINATION 
COH2008 
PRIOR TREATMENT - SURGERY 
COH1991 
PRIOR TREATMENT - RADIATION 
COH2009 


 
73
APPENDIX 9:  Surgical Guidelines  
 
The number of patients eligible for limb salvage will be limited and dependent upon the status of other sites of disease. It 
may be feasible for patients with pulmonary mets who have had a response to undergo limb-sparing procedures in 
addition to aggressive resection of pulmonary mets. 
 
Resection of the residual tumor is a standard of care to be sought in all patients with relapsed sarcoma. Some metastases 
tend to arise in well defined anatomic compartments (Enneking) and may be amenable to limb salvage rather than 
amputative surgery. The general considerations for limb salvage versus amputation have to do with the age of the patient, 
the resectability of the tumor locally, the neurogenic and vascular status of the limb post resection, and the risks that the 
patient and patient's family are willing to take in terms of limb sparing. It is recognized that techniques and availability of 
limb salvage may vary from institution to institution, but in general, the precepts of the Musculoskeletal Tumor Society's 
guidelines for wide or radical margin resectability should be followed. In general, wide margins rather than radical margins 
should be adequate unless skip lesions have been identified. Some judgment will have to be used as to the quality of a 
salvaged limb versus the risk of local recurrence. In general, only patients who experience a good local response to 
systemic chemotherapy are suitable candidates for resection of the primary and limb-sparing surgery. Limb sparing is also 
to be encouraged for patients seeking palliation of metastatic disease (pain control, better function, fracture care). Where 
there has been an excellent response of metastatic foci, allowing successful metastasectomy, local control should be 
achieved in a curative fashion. 
 
1.0   Margins of Resection 
 
1.1   Radical  
Radical margins of resection involve the entire osseous or soft tissue structure. In soft tissues, this should run from the 
tendon of origin to the tendon of insertion, taking the entire fascial casement of the muscle. Whether this is done by 
compartment resection or myectomy is up to the surgeon based on the preoperative studies. The bone should be taken 
out from joint above to joint below to truly get a radical margin. 
 
1.11  Wide Margin 
A wide margin of resection as defined by Enneking, removes normal tissue all the way around the lesion. The thickness or 
depth of this tissue is irrelevant. The wide margin does not eliminate the risk of skip metastases, however. At least 3 cms. 
of normal bone should be resected around the most extensive area of bony abnormality (defined by x-ray, bone scan, 
MRI, or CT). Narrower margins are to be discouraged but may be considered in order to preserve joint function. Unusual 
cases of diaphyseal tumors may allow preservation of the epiphysis, or even the growth plate, while excising the tumor 
widely. Older guidelines for resection of more bony tissue predated accurate imaging studies. Furthermore, it makes little 
sense to resect 7 cms. of a bony margin when the soft tissue margin is only 1 mm at times in the popliteal space. 
 
1.12 Marginal or Intralesional 
In tumors arising in a non-resectable area, such as vertebral body, a surgical debulking of as much tumor as possible 
should be undertaken. Wherever possible, if a margin can be obtained that is at least marginal, the risk of local recurrence 
will be decreased. In those patients where only intralesional surgery can be undertaken, this may still preclude mechanical 
problems and help in decreasing the tumor load. Additional therapy beside surgery and chemotherapy should be 
undertaken in these patients.  
 
1.2   Guidelines for Resection of Metastases 
Resection of pulmonary metastases will be performed, if considered resectable, after a period the pre-consolidation phase 
of chemotherapy.  Decisions should be made based on repeat chest CT obtained and exploration may be performed if 
results are equivocal. Thoracoscopy may be performed. In all patients surgical specimens will be analyzed to determine 
viability and the effects of chemotherapy.  
 
1.3 
Questions regarding surgical aspects of this protocol should be directed to: 
Dominic Femino, M.D. 
City of Hope National Medical Center; Division of Orthopedic Surgery 
1500 E. Duarte Road, MOB 4th Floor, Room 4015; Duarte, California 91010 
Phone: (626) 256-4673 x 65437; Fax: (626) 930-5415 
E-mail: dFemino@coh.org 


 
74
APPENDIX 10:  Radiation Therapy Guidelines 
Radiotherapy may be administered during the consolidation (local control) phase of treatment as determined by the type 
of disease. Radiotherapy is reserved for situations where complete surgery cannot be achieved. Radiotherapy is, 
however, recommended for inoperable sites or those that could only be operated with inadequate margins. It is strongly 
suggested that participating institutions use the information and consulting systems set up by their respective groups 
before assuming inoperability, because some lesions which at first seem inoperable may turn out to be operable for 
specialized tumor surgeons. Further recommendations about how to proceed in specific situations may vary between 
groups.  Non-target, painful lesions may be given palliative radiation.  
 
1.1 Timing of Radiation Therapy 
 
1.1.1 Local Control Variations: 
The timing of radiotherapy will differ according to the local control variation. It is essential that the management team 
including the radiation oncologist and surgeon meet to discuss optimal management of specific patients prior to choosing 
the favored local control variation.  
 
1.1.2 Planned Rests 
Low blood counts during radiotherapy are most commonly due to chemotherapy. Radiation therapy should be interrupted 
for low blood counts only if: 
a.  There is a significant amount of marrow within the radiation portal (for example, a large pelvic field) and 
b.  ANC < 750 and platelets < 75,000 and 
c.  There is uncontrolled infection, or significant (Grade 3 or more) stomatitis or mucositis in the radiation field. 
 
Radiation therapy should be restarted when the blood counts rise above the levels cited and the mucositis has healed. 
Recurrent problems with low blood counts may indicate modification of chemotherapy (See Section 6.7). The hemoglobin 
should be obtained, and the hemoglobin or hematocrit levels recorded on the daily treatment record. 
 
1.1.3 Emergency Radiation Therapy: 
Patients requiring emergency radiotherapy, such as patients with spinal cord compression may be treated immediately as 
deemed necessary by the treating radiation oncologist. The entire course of the emergency radiotherapy should be 
administered consecutively, if possible. 
 
 
1.2 Radiotherapy Dose and Volume 
Type of radiotherapy is to be determined by responsible investigator and institutional treating team. Any modality i.e. 
photon, proton, intensity modulated radiation therapy, brachytherapy may be used in the best interest of the patient.  
 
1.2.1 Dose: 
The daily dose to the prescription points shall be 1.8 Gy with the exception of patients with chest wall tumor and ipsilateral 
cytology positive pleural fluid, and patients with pulmonary metastases, who will receive 1.5 Gy per fraction. 
 
1.2.2 Bony and soft tissue lesions: 
Soft tissue and bony lesions with the exception of vertebral body tumors shall be treated as follows. 
 
For bony and soft tissue tumor sites harboring gross residual disease, dose will be 55.8 Gy in 31 fractions. 
 
A field reduction will be allowed after 45 Gy for soft tissue response to chemotherapy, but is not required. No field 
reduction is allowed for bony disease however sites with both bony and soft tissue components may qualify for field 
reduction. 
 
For sites harboring microscopic residual disease, 50.4 Gy in 28 fractions will be delivered. There will be no field reduction 
for patients with microscopic residual disease. 
 
1.2.3 Regional Lymph Nodes: 
The dose to biopsy proven regional lymph nodes will be 50.4 Gy in 28 fractions if they have been excised and 55.8 Gy if 
biopsied but not excised. 
 
 
1.2.4 Bone Marrow Metastases: 


 
75
The bone marrow will not be treated. 
 
1.2.5 Vertebral Body Metastases: 
Vertebral body metastases shall receive 45 Gy in 25 daily fractions of 1.8 Gy each. 
 
1.2.6 Chest Wall Tumors and Ipsilateral Cytology Positive Pleural Fluid: 
For patients having chest wall tumors and ipsilateral cytology positive pleural fluid, and who are ≥ 6 years of age, 
ipsilateral lung radiation will be given with 15 Gy in 10 daily fractions of 1.5 Gy each.  
 
For patients < 6 years of age the dose shall be 12 Gy in 8 fractions of 1.5 Gy each. Chest wall tumors without positive 
pleural fluid shall be treated as bony/soft tissue lesions. 
 
1.2.7 Pulmonary Metastases and Pleural Effusions: 
For patients having pulmonary metastases and pleural effusion who are ≥ 6 years of age, bilateral lung radiation will be 
given with 15 Gy in 10 daily fractions of 1.5 Gy each. For patients < 6 years of age the dose shall be 12 Gy in 8 fractions 
of 1.5 Gy each. 
 
Surgical management of residual pulmonary tumors after induction chemotherapy is encouraged. Field reduction boost to 
treat individual lesions is allowed. The dose for field reductions will be 27 Gy in 15 daily fractions of 1.8 Gy for all patients 
regardless of age. The total dose will therefore be 15 Gy + 27 Gy = 43 Gy for ≥ 6 years of age, and 12 Gy + 27 Gy = 39 
Gy for < 6 years of age. Strict volume requirements must be met for field reduction boost of pulmonary metastases (see 
below). 
 
1.3 Brachytherapy Dose: 
 
1.3.1 
The dose to the prescription point for low dose-rate brachytherapy will be 5000 cGy if brachytherapy is used alone or 
1200 cGy if brachytherapy is combined with external beam radiation. The prescription point dose-rate is expected to be 
between 40 cGy and 100 cGy per hour. 
 
1.3.2 
The dose to the prescription point for high dose-rate brachytherapy will be 3600 cGy delivered in 12 fractions of 300 cGy 
twice a day with a six hour separation between fractions if brachytherapy is used alone. If high dose-rate brachytherapy is 
used in combination with external beam radiation, the dose to the prescription point will be 900 cGy in 3 fractions of 300 
cGY over 2 days with a minimum of six hours separation between fractions. 
 
1.3.3 
The dose for external beam radiation when combined with brachytherapy will be 45 Gy in 25 daily fractions of 1.8 Gy 
each. 
 
1.4 Absorbed dose specification 
All doses shall be specified as cGy to muscle. 
 
1.4.1 Fractionation: 
All radiation fields should be treated once each day and treatments should be given 5 days per week. 
 
1.4.2 Tissue inhomogeneity consideration:  
No inhomogeneity corrections should be made. 
 
1.4.3 Prescription Points: 
 
Spine fields: 
The dose to the spine shall be prescribed to the isocenter, or along the central axis at a depth representing the mean 
depth to the posterior aspect of the vertebral bodies as determined by cross-table lateral x-rays, by CT scan, or by MRI 
scan. 
 
Conformal Therapy: 
The dose shall be prescribed to the isocenter. The isocenter should be within the target volume. 
 
1.4.4 Volume: 
Conformal Radiation Therapy: 


 
76 
Volume based 3-D conformal radiotherapy technique is encouraged for all sites treated on the current protocol. In specific 
instances simple or intermediate complexity methodology may be appropriate however. ICRU definitions for gross tumor 
volume (GTV), clinical target volume (CTV), and planning target volume (PTV) will be used as appropriate. In the ICRU 
terminology GTV and CTV are anatomically defined and are intended to direct treatment to gross and microscopic 
disease respectively. 
 
The PTV is geometric and not anatomically defined. A margin is added to the CTV in 3-dimensions to create the PTV as 
the purpose of the PTV is to account for uncertainty in immobilization and daily variability in patient positioning. 
Conformal radiation therapy will use 3 dimensional treatment planning techniques. This means that three dimensional 
imaging data (CT and/or MRI) are acquired with the patient in the treatment position and that image data are used to 
delineate and reconstruct a gross target volume, clinical target volume, planning target volume, and specific normal or 
critical structures in 3-dimensions. True conformal therapy further requires that the dose distribution is computable on a 
point-by-point basis in 3-dimensional space. 
 
1.5 Protocol Specific Definition of Target Volumes: 
Site: A site consists of a discrete body area thought to harbor gross residual or microscopic residual disease. Various non-
contiguous sites within the same patient may differ in status regarding residual disease and therefore be treated with 
different radiotherapy dose and fractionation. 
 
1.5.1 
GTV: The radiologically apparent and palpable bony and soft-tissue disease prior to surgical debulking and/or 
chemotherapy. GTV may be defined based on physical examination, X-ray, computed tomography, bone scan, positron 
emission tomography, or magnetic resonance imaging. Magnetic resonance imaging is most often the optimal treatment 
planning modality. The initial GTV shall specifically, be based on the initial pre-operative, pre-chemotherapy, and 
pre-irradiation imaging examinations. The GTV should include adjacent areas of bone destruction and soft tissue 
extension. The GTV should, when possible, be based on T1 signal changes with and without Gadolinium contrast 
enhancement as well as T2 signal changes. The GTV may be modified to account for tumors which exhibit an initial 
“pushing margin” into body cavity if the normal tissues have returned to their natural positions. 
 
Biopsy proven regional disease such as positive lymph nodes draining the primary site will be defined as GTV however 
regional lymph nodes will not be included within GTV unless proven by biopsy to be involved with tumor. 
 
1.5.2 
GTV-P: For sites in which significant tumor response to initial chemotherapy is demonstrated, the GTV-P (for 
“post-chemotherapy GTV”) may be defined. The GTV-P terminology will be used for field reduction after 45 Gy for soft 
tissue tumors, and after 12 or 15 Gy for pulmonary metastases. 
 
1.5.3 
For multiple non-contiguous sites, multiple GTVs (i.e. GTV1, GTV2, GTV3, etc.) will be treated. 
Similarly for field reductions after 45 Gy multiple GTV-Ps may be treated (GTV-P1, GTV-P2, GTV-P3, etc.) Where sites 
are considered as separate target volumes, care must be taken to avoid overlap of entrance and exit beams so that 
normal tissue does not exceed the prescription dose. 
 
1.5.4 
CTV: The clinical tumor volume (CTV) is the GTV together with regions of potential occult tumor involvement. For bony or 
soft tissue tumors, the clinical target volume (CTV) will be an anatomically defined margin of 1.0 cm surrounding the GTV. 
The CTV may be extended when adjacent to a bony interface, for example at the skull. For multiple GTVs, (i.e. GTV1, 
GTV2, GTV3, etc.), multiple CTVs will be created. For ipsilateral or bilateral lung irradiation, the involved lung will be 
arbitrarily defined as the CTV. For field reductions the terminology CTV-P will be used. 
 
1.5.5 
PTV: The planning target volume (PTV) is the CTV together with margin added for daily setup 
variability and organ motion. For conformal radiation therapy on this protocol the PTV will be the CTV plus 0.5 cm. For 
field reductions, the terminology PTV-P will be used. 
 
1.5.5.1 Special PTV Considerations: 
When the PTV includes the epiphysis of an adjacent bone and there is no extension across the joint space, a smaller PTV 
may arbitrarily be chosen, so that the adjacent epiphysis is included. Similarly, with a diaphyseal lesion, every attempt 
should be made to exclude at least one epiphysis of the affected bone. Similarly, every attempt should be made that the 
PTV does not encompass an extremity circumferentially. An adequate strip of tissue should be spared on extremity 
tumors, to avoid lymphatic obstruction. 


 
77
 
1.6 Non-conformal Radiation: 
It is recognized that specific clinical situations will arise in which true conformal radiation is not practical and this will not 
be required for all treatment sites in this study. In specific instances, simple or intermediate complexity methodology may 
be allowed. Such situations may include irradiation of the long bones of the extremity, and vertebral body radiation, for 
example. Nevertheless, the use of ICRU definitions (and conformal treatment) is encouraged for all sites. 
 
1.7 Normal Tissue Tolerance Limitations: 
Normal tissue tolerance limits of liver (50% of volume limited to 30 Gy), heart (50% of volume limited to 30 Gy), small 
bowel (limited to 45 Gy) and bilateral kidneys (limited to 15 Gy) will be respected. Regarding tolerance of lung, it is 
recommended that the total lung volume receiving greater than 20 Gy be limited to 35% or less. 
 
1.8 Special Rule Regarding Volume Limitation for Bone Marrow: 
For patients with widespread metastatic disease, care shall be taken not to allow more than 50% of the active marrow to 
be irradiated. An estimate of the percentage of active marrow within the radiation field can be made by using established 
methodology. If, in order to otherwise comply with the protocol requirements, more than 50% of marrow would be included 
in radiotherapy fields, this situation should be discussed with a pediatric radiotherapist. In cases where all initial 
presenting lesions cannot be treated, the priority for treatment will be those persistent lesions which have not improved on 
follow-up imaging after chemotherapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
78
APPENDIX 11:  Informed Consent Template – Phase I  
 
SAMPLE INFORMED CONSENT / PARENTAL PERMISSION  
FOR PARTICIPATION IN RESEARCH 
 
Dasatinib (SPRYCEL®) with Ifosfamide, Carboplatin, Etoposide: 
A Pediatric Phase I Trial 
 
 
This study is a clinical trial (a research study involving patients, or protocol) of an 
experimental new drug Dasatinib (SPRYCEL®) for cancer. We are asking if you want to 
participate in this study because there is not a standard treatment for your cancer at this 
point. Clinical trials only include patients who choose to take part in them and your 
participation is entirely voluntary. Your participation in this study is entirely voluntary. 
Please read the consent form carefully. You will be given a copy of it to keep if you decide 
to participate in this study. You may discuss your decision with your friends and family if 
you would like.  
 
Bristol-Myers Squibb (BMS) and the Pediatric Cancer Foundation (PCF) are collaborators on this 
clinical trial.  These investigators promote the early clinical development of promising therapies 
for the treatment of children, adolescents and young adults with cancer. There are fourteen large 
academic medical institutions participating in this study. Bristol-Myers Squibb is the manufacturer 
of dasatinib (SPRYCEL®) and supporter of this research study and the Pediatric Cancer 
Foundation is a non-profit, charity organization, dedicated to funding research to eliminate 
childhood cancer worldwide.  
 
This is a Phase I study of the experimental drug called Dasatinib (SPRYCEL®).  Dasatinib 
(SPRYCEL®) is considered experimental because it has not been approved by the Food and 
Drug Administration (FDA) for use in pediatric solid tumors. This is called a Phase I study 
because the goal is to find the highest dose of Dasatinib (SPRYCEL®) that we can give safely 
when given with chemotherapy of Ifosfamide, Carboplatin and Etoposide (ICE).  We are using 
Dasatinib (SPRYCEL®) because it seems to work against cancer in test tubes and animals. 
Dasatinib (SPRYCEL®) has been used in several hundred adults.  Some adults with chronic 
myelogenous leukemia have been helped by Dasatinib (SPRYCEL®).  However, there is a lot 
that we do not know about Dasatinib (SPRYCEL®).    
 
You are being asked to participate in this study because you have a recurrent 
cancer (cancer that has returned) or metastatic solid tumor including recurrent or refractory 
sarcomas, such as rhabdomyosarcoma, osteosarcoma, and Ewing sarcoma, or other solid 
tumors.  
 
 
Why is this study being done? 
 We are testing the safety of Dasatinib (SPRYCEL®)at different dose levels with cytotoxic 
chemotherapy, Ifosfamide, Carboplatin, and Etoposide (D-ICE).  We want to find out what effects, 
good and/or bad, it has on you and your recurrent or progressive solid tumor cancer.  
 
 
 
 
 


 
79
The goals of this study are: 
 
• 
To determine the maximally tolerated dose (MTD) of dasatinib (SPRYCEL®)given 
immediately following ifosfamide, carboplatin and etoposide (D-ICE) as a re-
induction regimen to pediatric patients with recurrent solid tumors 
• 
To describe and define the toxicities of D-ICE 
• 
To determine the safety and feasibility of prolonged administration of single agent 
dasatinib (SPRYCEL®) following completion of 2-6 courses of D-ICE therapy 
• 
To examine the effect of Dasatinb (SPRYCEL®) on the biology of cancer cells 
including 
• 
To determine the phosphotyrosine state by immunohistochemistry of SRC 
family kinases and related signaling pathways including FAK, STAT3, VEGFR, 
AKT, EGFR, KIT, EPHA2 and PDGFR in paraffin-embedded tumor specimens 
prior to and during treatment with dasatinib. 
• 
To identify molecular signatures in tumor cells that may predict response to 
dasatinib by microarray analyis examined by gene expression. 
• 
To correlate the biomarkers and molecular signatures with dasatinib dosage, 
toxicity, and anti-tumor activity. 
• 
To evaluate the effect of dasatinib on phosphorylation of SRC family kinases in 
peripheral blood mononuclear cells (PBMCs) as a surrogate marker of 
response prior to treatment with dasatinib, at day 14 - 21 or when WBC > 500 
during each treatment course, at the time of local control, and at time of 
progression, if any. 
 
 
How many people will take part in the study? 
There will be approximately of 18 patients participating in this study 
overall.  About ___ patients will be treated at this hospital.  
 
 
What will happen if I take part in this research study?   
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in 
the study.  These exams, tests or procedures are part of regular cancer care and may be 
done even if you do not join the study.  If you have had some of them recently, they may 
not need to be repeated.  This decision will be up to your study doctor.   
 
Your doctor will also review your current medications with you. Since Dasatinib (SPRYCEL®) 
interacts with some medications, your doctor may stop or change some of your medications. You 
should talk to your doctor before taking any prescription or over the counter medications while on 
this study. 
 
• 
A medical history 
• 
Physical exam 
• 
Vital signs (blood pressure, pulse, temperature) 
• 
Blood tests 
• 
Pregnancy test (if you are female and of childbearing age) 
• 
Tests to evaluate heart function  
• 
CT scans, MRI, X-rays  and/or bone scans of disease sites, will be done to measure 
tumor, or other tests are needed to check your tumor. 
 
 
 
During the study … 


 
80 
If the exams, tests and procedures show that you can be in the study, and you choose to 
take part 
 
Study Plan… 
You will receive Ifosfamide, Carboplatin, Etoposide and Dasatinib (SPRYCEL®) (D-ICE) every 28 
days in this study. The whole tablet of dasatinib (SPRYCEL®) may be placed (and allowed to 
dissolve) in lemonade, preservative free orange juice, or preservative free apple juice before 
swallowing.  This 28 day time period is called a course.  The course will be repeated up to 6 times 
prior to consolidation.  Each course is numbered in order.   
 
The chart below shows what will happen to you during Course 1 and future treatment 
courses as explained previously.    
 
Course may be repeated up to 6 times, each course will last for 28 days 
Drug 
Route 
Schedule 
Method of Administration 
Ifosfamide (IFOS) 
Intravenous (IV) 
Day 0 - 4 
IV infusion over 60 minutes daily for 5 days  
Carboplatin (CBDCA) 
Intravenous (IV) 
Day 0 - 1 
IV infusion over 60 minutes daily for 2 days 
Etoposide (VP-16) 
Intravenous (IV) 
Day 0 - 4 
IV infusion over 60 minutes (every day) daily 
for 5 days 
Dasatinib 
(SPRYCEL®) 
By mouth (oral) 
Day 5 - 21 
Oral BID (twice a day) for 17 days 
Mesna 
Intravenous (IV) 
Day 0 - 4 
IV infusion over 15 minutes 
MESNA and fluids will be used with Ifosfamide as a bladder protectant 
REST 
 
Day 22 - 28 
 
G-CSF 
Subcutaneously 
(Subq) 
Day 5 
Daily starting day 5, until ANC ≥10,000, first 
course only. Neulasta may be given for 
subsequent courses to subjects > 50 kg. 
 
The dose for the first 3 children enrolled on the study will be based on the side effects seen in 
adults.  Between 3 and 6 children will receive Dasatinib at each dose. If the side effects are not 
too severe, the next group of children will receive a higher dose. Up to four different doses may 
be studied. Your dose will not be increased.  If you have bad side effects, your drug will be 
stopped.  If you are a patient enrolled early in this study you may receive a lower dose than those 
who are enrolled later. It is therefore possible that you may receive a dose that is less likely to 
have any effect on your tumor. If you are a patient enrolled in this study at a high dose level it is 
possible that you will receive a dose that is more likely to cause side effects.  Dosing is done this 
way because we do not yet know the best dose to use in children.   
 
You may be required to stay in the hospital if the treatment makes you sick, or you are sick 
because of your tumor. 
 
Another way to find out what will happen to you during the study is to read the chart below.  Start 
reading at the top and read down the list, following the lines and arrows. 
 
 
 
 
 
 
 


 
81
EXPERIMENTAL DESIGN SCHEMA*:   
 
 
 
 
 
 
 
 
 
 
 
ON STUDY 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
D-ICE x 2 
(level x of Dasatinib 
as determined by P.I.) 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR# 
 
 
 
CR 
↓ 
 
↓ 
 
 
 
↓  
Off Protocol 
Therapy 
 
D-ICE x 2 
 
 
 
Consolidation 
Radiation &/or 
Surgery 
 
 
↓ 
 
 
 
  
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR# 
 
 
CR 
 
↓ 
 
↓ 
 
 
↓ 
 
Off Protocol 
Therapy 
 
D-ICE x 2 
 
  
Consolidation 
Radiation &/or 
Surgery 
 
 
 
↓ 
 
 
  
 
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR 
 
CR 
 
 
↓ 
 
↓ 
 
↓ 
 
 
Off Protocol 
Therapy 
 
Consolidation 
Radiation &/or Surgery
 
Consolidation 
Radiation &/or 
Surgery 
  
 
 
 
↓ 
 
↓ 
 
 
 
 
Dasatinib alone start at (level x) 2 months  
 
 
 
 
↓ 
 
 
Legend: 
 
After 2 months then may increase Dasatinib to level (x + 1) 
CR – Complete Response 
 
 
↓ 
 
 
PR – Partial Response 
Continue x 4 more months (total 6 months) Dasatinib alone 
SD – Stable Disease 
 
 
↓ 
 
 
PD – Progressive Disease 
 
END OF THERAPY 
 
 
*  
Phase I:  Dasatinib (SPRYCEL®) dose escalation per Table 3 
# 
At Investigators discretion subject may proceed to consolidation, radiation and/or surgery 
 
 
 


 
82 
You will need the following tests and procedures during the study.  These exams, tests or 
procedures are part of regular cancer care.  
 
• A medical history 
• Physical exam 
• Vital signs (blood pressure, pulse, temperature) 
• Blood tests 
• Test to evaluate the heart function 
 
We will also do whatever x-rays, CT scans, or other tests as needed to check your tumor. 
 
You will also be asked to keep a diary of when you take Dasatinib (SPRYCEL®). This diary 
will help document study compliance.  
 
You will be asked to tell your doctor about other medications and nutritional supplements 
that you take. 
 
When I am finished taking D-ICE  
After you are finished taking Dasatinib, the study doctor will ask you to visit the office for follow-up 
exams and tests. These exams, tests or procedures are all part of regular cancer care:  
  
First year off-therapy (reporting every 6 months) 
• 
Physical examination every month x 6 months then every 2 months x 6 months 
• 
Imaging studies that were positive at study entry every 3 months 
 
Second and subsequent years off-therapy (reporting every year) 
• 
Physical examination every 3 months 
• 
Imaging studies that were positive at study entry every 6 months until progressive disease 
 
 
Biology Studies:  Blood and Tumor 
We would also like to do some extra tests called biology studies and tumor studies.  These tests 
will help us learn more about Dasatinib and may help children who receive this drug in the future. 
The information learned will not change the way you are treated, and the results of these tests will 
not be returned to you.  Although these tests are a very important part of how we will better learn 
to use this drug, it is your decision as to whether or not you agree to participate in these tests. 
 
During the study blood samples will be collected to evaluate the biological effects of Dasatinib on 
your blood cells. The amount of blood for each sample is about 10 mL (which is the about the 
same as 2 teaspoons) and will be collected on Day 14 - 21 or when WBC > 500 of each course 
during pre-consolidation treatment, and on Day 14 - 21 or when WBC > 500 of each course 
during post-consolidation treatment for all patients.  
 
The tests will help us to better learn how Dasatinib (SPRYCEL®)may work.  
 
Please indicate by checking and initialing below whether you choose to participate in the biology 
studies. 
 
/      Yes, I agree to participate in the biology studies. 
 
/      No, I do not agree to participate in the biology studies. 
 
 
 


 
83
 
Tumor biology studies: 
If a biopsy is done for clinical reasons at any time before or during the study, we would like to 
have a piece of tumor tissue for research. The tumor samples will be sent to a research 
laboratory to measure the characteristics of the tumor cell and to evaluate the effect of Dasatinib 
(SPRYCEL®) on the tumor cells.  
 
Please indicate by checking and initialing below whether you choose to participate in the tumor 
biology studies. 
 
/      Yes, I agree to participate in the tumor biology studies if a tumor biopsy is done for 
clinical reasons. 
 
/      No, I do not agree to participate in the tumor biology studies if a tumor biopsy is done 
for clinical reasons. 
 
 
How long will I be in the study? 
You may be in the study for up to 12 courses (about 12 months), if your tumor responds to this 
therapy and the treatment does not cause bad side effects. You may receive an additional 6 months of 
Dasatinib (SPRYCEL®)alone if you successfully complete the pre-consolidation phase of treatment.  
 
Your doctor may decide to take you off study if any of the following occur: 
 
• The side effects of Dasatinib (SPRYCEL®)and ICE are too harmful for you 
• You need a treatment that is not allowed on this study 
• Your tumor does not improve or worsens 
• You are not able to follow study-related treatment instructions 
• New information becomes available 
• The study is not in your best interest 
• The study is stopped 
 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
Dasatinib and ICE chemotherapy can be evaluated by your doctor.  Another reason to tell 
your doctor that you are thinking about stopping is to discuss what follow-up care and 
testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. 
 
 
What side effects or risks can I expect from being in the study?  
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, doctors don’t know all the side effects 
that may happen.  Side effects may be mild or very serious. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after you 


 
84 
stop taking the Dasatinib. In some cases, side effects can be serious, long lasting, or may 
never go away.  
 
You should talk to your study doctor about any side effects that you have while taking part 
in the study.    
 
Risks and side effects related to the DASATINIB (SPRYCEL®) include: 
 
Likely 
• 
Headache 
• 
Hemorrhage  
• 
Thrombocytopenia (Low platelet count which may lead to bleeding or bruising) 
• 
Pleural effusion  
• 
Dyspnea 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Abdominal pain 
• 
Gastrointestinal hemorrhage 
• 
Skin rash 
• 
Musculoskeletal pain 
• 
Superficial edema 
• 
Fatigue 
• 
Pyrexia 
• 
Hypocalcemia 
• 
Infection (including bacterial, viral, fungal, non-specified) 
• 
Cough 
 
 Less Likely   
• 
Pneumonia (including bacterial, viral, and fungal) 
• 
Upper respiratory tract infection/inflammation 
• 
Herpes virus infection 
• 
Enterocolitis infection 
• 
Febrile neutropenia 
• 
Anemia 
• 
Leukopenia 
• 
Depression 
• 
Insomnia 
• 
Dizziness 
• 
Neuropathy (including peripheral neuropathy) 
• 
Dysgeusia 
• 
Dry eye 
• 
Congestive heart failure/ Cardiac dysfunction 
• 
Pericardial effusion 
• 
Arrhythmia (including tachycardia) 
• 
Palpitations 
• 
Hypertension 
• 
Flushing 
• 
Pulmonary edema 
• 
Lung infiltration 
• 
Pneumonitis 
• 
Abdominal distension 
• 
Mucosal inflammation (including Mucositis/stomatitis) 
• 
Colitis (including neutropenic colitis) 


 
85
• 
Gastritis 
• 
Oral soft tissue disorder dyspepsia 
• 
Constipation 
• 
Dehydration 
• 
Pruritus 
• 
Alopecia 
• 
Acne 
• 
Dry skin 
• 
Urticaria 
• 
Hyperhydrosis 
• 
Arthralgia 
• 
Myalgia 
• 
Muscle inflammation 
• 
Muscular weakness 
• 
Pain 
• 
Chest pain 
• 
Chills 
• 
Weight decreased 
• 
Weight increased 
• 
Contusion 
• 
Thrombophlebitis 
• 
Anorexia 
• 
Asthenia 
• 
Sepsis (including fatal outcome) 
• 
Pancytopenia 
• 
Hyperuricemia 
• 
Somnolence 
• 
Pulmonary hypertension 
• 
Dermatitis (including eczema) 
• 
Musculoskeletal stiffness 
 
Rare but serious 
• 
Tumor lysis syndrome 
• 
Aplasia pure red cell 
• 
Hypersensitivity (including erythema nodosum, a type of skin inflammation) 
• 
Transient ischemic attack 
• 
Reversible posterior leukoencephalopathy syndrome 
• 
Convulsion 
• 
Amnesia 
• 
Tremor 
• 
Syncope 
• 
Central nervous system hemorrhage 
• 
Cardiomegaly 
• 
Angina pectoris 
• 
Myocardial infarction 
• 
Pericarditis 
• 
Acute coronary syndrome 
• 
Myocarditis 
• 
Ventricular tachycardia 
• 
Hypotension 
• 
Livedo reticulares 
• 
Asthma 
• 
Acute respiratory distress syndrome 
• 
Pancreatitis 


 
86 
• 
Upper gastrointestinal ulcer 
• 
Ascites 
• 
Dysphagia 
• 
Hepatitis 
• 
Cholestasis 
• 
Cholecystitis 
• 
Acute febrile neutrophilic dermatosis 
• 
Photosensitivity reaction 
• 
Pigmentation disorder 
• 
Skin ulcer 
• 
Bullous conditions (including Erythema multiforme) 
• 
Nail disorder 
• 
Palmar-plantar erythrodysesthesia syndrome 
• 
Rhabdomyolysis 
• 
Tendonitis 
• 
Blood creatine phosphokinase increased 
• 
Renal failure 
• 
Urinary frequency proteinuria 
• 
Gynecomastia 
• 
Menstruation irregular 
• 
Malaise 
• 
Temperature intolerance 
• 
Lethargy 
• 
Lightheadedness 
• 
Tinnitus 
• 
Tendonitis 
• 
Cor pulmonale   
• 
Cerebrovascular accident 
• 
Tendonitis 
• 
Hypoalbuminemia 
• 
Conjunctivitis 
• 
Vertigo 
• 
Bronchospasm 
• 
Anal fissure 
• 
Anxiety  
• 
Confusional State 
• 
Affect lability 
• 
Libido decreased 
• 
Electrocardiogram QT prolonged 
• 
Esophagitis 
• 
Panniculitis 
 
 
Risks and side effects related to the IFOSFAMIDE include: 
 
Likely 
• 
Nausea  
• 
Vomiting  
• 
Hair loss 
• 
Fewer red and white blood cells and platelets in the blood  
o 
A low number of red blood cells can make you feel tired and weak 
o 
A low number of white blood cells can make it easier to get infections 
o 
A low number of platelets causes you to bruise and bleed more easily 
• 
Decreased ability of the body to fight infection 


 
87
• 
Absence or decrease in the number of sperm which may be temporary or permanent 
which may decrease the ability to have children 
• 
Slight decrease in kidney function  
 
Less Likely 
• 
Drowsiness  
• 
Confusion  
• 
Depression  
• 
Loss of appetite 
• 
Diarrhea or constipation  
• 
Seizures  
• 
Abnormal hormone function affecting levels of salt in the blood and urine  
• 
Abnormal heartbeat or rhythm. This side effect may require frequent evaluations of the 
hearts function and a heart specialist consult  
• 
Blood in the urine that is only seen under the microscope  
• 
Body loss of certain important salts and minerals  
• 
Failure of the ovaries to function normally which may be permanent and which may 
decrease the ability to have children   
• 
Inflammation and burning along the vein where the medicine is given  
• 
Temporary elevation in the blood of certain enzymes found in the liver  
 
Rare but Serious 
• 
Damage to brain tissue with very high doses that may lead to coma    
• 
Kidney failure or damage  
• 
Damage to the bladder, which can lead to large amounts of blood in the urine, pain and 
the urge to urinate frequently and also permanent scarring of the bladder   
• 
A new cancer or leukemia resulting from this treatment  
• 
Damage to heart muscle which may make you tired, weak, feel short of breath, and 
retain fluid 
• 
Abnormal bone growth and development 
 
 
Risks and side effects related to the ETOPOSIDE include: 
 
Likely 
• 
Nausea  
• 
Hair loss 
• 
A feeling of weakness or tiredness  
• 
Fewer red and white blood cells and platelets in the blood 
o 
A low number of red blood cells can make you feel tired and weak 
o 
A low number of white blood cells can make it easier to get infections 
o 
A low number of platelets causes you to bruise and bleed more easily 
 
Less Likely 
• 
Loss of appetite  
• 
Decreased blood pressure during the infusion which may require treatment 
• 
Rashes 
• 
Diarrhea or constipation 
• 
Pain in the abdomen 
• 
Mouth sores 
• 
Tingling sensation or loss of sensation in fingers or toes 
• 
A feeling of extreme tiredness or weakness 
• 
The finger or toe nails may loosen from their nail beds 
• 
Inflammation and burning along the vein through which the medication was given  
• 
Chest pain 


 
88 
 
Rare but Serious 
• 
Damage to the liver 
• 
Severe allergic reaction which can be life threatening with shortness of breath, low 
blood pressure, rapid heart rate chills and fever 
• 
A new cancer or leukemia resulting from this treatment  
• 
Temporary severe rashes which can result in loss of skin and damage to mucous 
membranes   
• 
Absence or decrease monthly periods  
• 
Damage to heart muscle which may make you tired, weak, feel short of breath, and 
retain fluid  
 
 
Risks and side effects related to the CARBOPLATIN include: 
     
Likely 
• 
Bone Marrow Suppression (as described for Ifosfamide) - Fewer red and white blood 
cells and platelets in the blood  
o 
A low number of red blood cells can make you feel tired and weak 
o 
A low number of white blood cells can make it easier to get infections 
o 
A low number of platelets causes you to bruise and bleed more easily 
• 
Nausea and vomiting 
 
Less Likely 
• 
Kidney and liver damage   
 
Rare but Serious 
• 
Tingling and discomfort in arms and legs and weakness may occur rarely 
• 
Local allergic reactions at the IV site.  Itching, a skin rash, lightheadedness, facial 
flushing or trouble breathing  
• 
Hearing loss 
• 
A new cancer or leukemia resulting from this treatment  
 
 
Risks and side effects related to the MESNA include: 
 
Likely 
• 
Bad taste when taken by mouth. 
 
Less Likely 
• 
Nausea. 
• 
Vomiting 
• 
Stomach pain 
• 
Headache 
• 
Pain in arms, legs and joints 
• 
Tired feeling 
• 
Rash 
• 
Temporary low blood pressure  
• 
Diarrhea 
• 
Fever 
• 
Facial flushing with red cheeks 
• 
Nervousness 
• 
Dizziness  
• 
Confusion  
• 
Swelling around the eyes  


 
89
• 
Coughing 
• 
Rapid heart rate  
 
Rare but Serious 
• 
Severe allergic reaction which can be life threatening with shortness of breath, low 
blood pressure, rapid heart rate chills and fever    
 
 
Risks and side effects related to the G-CSF (Growth factor, Filgrastim, Neupogen) include: 
 
Most patients who receive G-CSF have little or no side effects.  However, some patients 
may experience the following: 
 
Likely 
• 
Mild to moderate aching or pain inside the bones 
 
Less Likely 
• 
Local irritation at the site of the injection  
• 
Mild headache  
• 
Higher than normal levels of liver enzymes   
• 
Lower number of platelets in the blood  
• 
Low fever 
• 
Enlargement of the spleen  
• 
Worsening of skin rashes  
• 
Inflammation of a blood vessel in the skin leading to a raised purple rash and bruising  
• 
Higher than normal white blood count  
 
Rare but Serious 
• 
Allergic reactions which can be life threatening with shortness of breath, low blood 
pressure, rapid heart rate, hives and facial swelling 
• 
If you are known to have sickle cell disease, filgrastim may cause a sickle cell crisis. 
• 
A blood disorder or leukemia that has only been seen in patients with certain immune 
disorders who are treated for a very long time 
• 
Severe damage to the spleen 
• 
Difficulty breathing and lung damage that may be due to the white blood cells that are 
stimulated by filgrastim traveling to the lungs when they are inflamed or infected  
 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed 
a baby while on this study.  It is important you understand that you need to use birth 
control while on this study.  The long-term effects of Dasatinib on fertility are unknown.  
Check with your study doctor about what kind of birth control methods to use and how long to use 
them.  Some methods might not be approved for use in this study.  Pregnancy tests will be 
obtained in women interested in participating in this study. 
 
Risks of blood drawing or placing an intravenous catheter for blood drawing: 
Risks associated with drawing blood are slight, but some risks include: pain, excessive bleeding, fainting or 
feeling lightheaded, bruising, infection (a slight risk any time the skin is broken), and multiple punctures to 
locate veins. 
 
Risk of Surgery 
Some patients on this study will undergo surgery before starting therapy or during this study. You 
will be asked to sign a separate consent form for the surgical procedure. The planned surgery will 
be explained to you and your questions about it answered by your surgeon when you sign the 
consent for the surgical procedure. 


 
90 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your cancer to stop growing or shrink for a period of 
time.  While doctors hope the treatment proposed in this study will be more useful against cancer 
compared to the usual treatment, there is no proof of this yet. We do know that the information from 
this study will help doctors learn more about Dasatinib when given with ICE chemotherapy, as a 
treatment for cancer.  This information could help future cancer patients 
 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• No further treatment and 
• 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not 
treat the cancer directly, but instead tries to improve how you feel.  Comfort care tries 
to keep you as active and comfortable as possible.   
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given out 
if required by law.  If information from this study is published or presented at scientific meetings, 
your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: 
 
• 
Pediatric Cancer Foundation 
• 
Bristol-Myers Squibb (sponsor/supplier of Dasatinib) 
• 
Representatives of the  National Cancer Institute (NCI) and other government 
agencies, like the Food and Drug Administration (FDA), involved in keeping 
research safe for people 
 
 
What are the costs of taking part in this study? 
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking part 
in studies.  Check with your health plan or insurance company to find out what they will pay for.  
Taking part in this study may or may not cost your insurance company more than the cost of getting 
regular cancer treatment.  
 
Bristol-Myers Squibb (BMS) is supplying Dasatinib at no cost to you.  However, you or your 
health plan may need to pay for costs of the supplies and personnel who give you the Dasatinib. 
 
The study agent, Dasatinib, will be provided free of charge while you are participating in 
this study.  However, if you should need to take the study agent much longer than is 
usual, it is possible that the supply of free study agent that has been supplied to could run 


 
91
out.  If this happens, your study doctor will discuss with you how to obtain additional drug 
from the manufacturer and you may be asked to pay for it. 
 
You will not be paid for taking part in this study. 
 
There will be no cost to you for any tissue collected and banked.  You will not be paid for allowing 
your leftover tissue to be used in research, even though it is possible that new cancer tests or 
treatments may be developed as a result of the research. 
 
For more information on clinical trials and insurance coverage, you can visit the National 
Cancer 
Institute’s 
Web 
site 
at 
http://www.cancer.gov/clinicaltrials/understanding/insurance-coverage.    You can print a 
copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask 
them to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], 
if you feel that you have been injured because of taking part in this study.  You can tell the 
doctor in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or 
your health plan will be charged for this treatment.   The study will not pay for medical treatment.   
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the 
study.  If you decide to take part in this study, you may leave the study at any time.   No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits.  
Leaving the study will not affect your medical care.  You can still get your medical care from our 
institution.    
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form.   
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the 
study.  If you decide to take part in this study, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits.  
Leaving the study will not affect your medical care.  You can still get your medical care from our 
institution.    
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form.   
 
Whether you participate or not, you will continue to get the best medical care this hospital can 
provide. 
 


 
92 
 
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this 
study.  Contact your study doctor __________________ [name(s)] at __________________ 
[telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ 
[name of center] Institutional Review Board (a group of people who review the research to protect 
your rights) at __________________ (telephone number).  [Note to Local Investigator: Contact 
information for patient representatives or other individuals in a local institution who are not on the IRB or 
research team but take calls regarding clinical trial questions can be listed here.]    
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
• 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
• 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form. You will be given a copy of the protocol (full study plan) 
upon request.   
 
If you want more information about this study, ask your study doctor. 
 
Signature 
I have been given a copy of all # pages of this form.   
I have read it or it has been read to me.  
 
I understand the information and have had my questions answered.  I agree to take part in 
this study. 
Participant _______________________________________ 
Parent (or Guardian) ________________________________ 
 
Date ______________________________________  
 
Signature of Physician or Responsible Investigator  
 
___________________________________________ 
 
Date ______________________________________ 
 
 
 
 
 


 
93
 
FOR SUBJECTS/PARTICIPANTS 7-17 YEARS OF AGE 
 
 
The undersigned physician, _____________________________, M.D., hereby certifies that 
he/she has discussed the research project with the subject/participant and has explained 
all the information contained in the informed consent form to the subject/participant, 
including any risks that may reasonably be expected to occur. The undersigned further 
certifies that the subject/participant was encouraged to ask questions and that all 
questions were answered. 
 
 
__________________________      __________________________ 
Date                                         
Physician's Signature 
 


 
94
APPENDIX 12:  Informed Consent Template – Phase II 
 
SAMPLE INFORMED CONSENT / PARENTAL PERMISSION  
FOR PARTICIPATION IN RESEARCH 
 
Dasatinib (SPRYCEL®) with Ifosfamide, Carboplatin, Etoposide: 
A Pediatric Phase II Trial 
 
 
This study is a clinical trial (a research study involving patients, or protocol) of an 
experimental new drug Dasatinib (SPRYCEL®) for cancer. We are asking if you want to 
participate in this study because there is not a standard treatment for your cancer at this 
point. Clinical trials only include patients who choose to take part in them and your 
participation is entirely voluntary. Your participation in this study is entirely voluntary. 
Please read the consent form carefully. You will be given a copy of it to keep if you decide 
to participate in this study. You may discuss your decision with your friends and family if 
you would like  
 
Bristol-Myers Squibb (BMS) and the Pediatric Cancer Foundation (PCF) are collaborators on this 
clinical trial.  These investigators promote the early clinical development of promising therapies 
for the treatment of children, adolescents and young adults with cancer. There are fourteen large 
academic medical institutions participating in this study. Bristol-Myers Squibb is the manufacturer 
of dasatinib and supporter of this research study and the Pediatric Cancer Foundation is a non-
profit, charity organization, dedicated to funding research to eliminate childhood cancer 
worldwide. 
 
This is a Phase II study of the experimental drug called Dasatinib (SPRYCEL®) when given with 
chemotherapy including Ifosfamide, Carboplatin and Etoposide (ICE).  A Phase II study is 
done to measure the response of a disease to an experimental drug. A tolerable dose (the 
highest dose without bad side effects) for children with recurrent solid tumors was found in a 
phase I clinical trial that has been completed. Dasatinib (SPRYCEL®) is considered experimental 
because it has not been approved by the Food and Drug Administration (FDA) for use in pediatric 
solid tumors. This is called a Phase II study because the goal is to find out what effects, good 
and/or bad. Dasatinib (SPRYCEL®) with ICE has on you and your recurrent and/or progressive 
solid tumor cancer.  We are using Dasatinib (SPRYCEL®) because it seems to work against 
cancer in test tubes and animals. Dasatinib (SPRYCEL®) has been used in several hundred 
adults.  Some adults with chronic myelogenous leukemia have been helped by Dasatinib 
(SPRYCEL®).  However, there is a lot that we do not know about Dasatinib (SPRYCEL®).   
Although Dasatinib (SPRYCEL®) has been given to a small number of children, we do not know 
if it will work against the type of tumor you have. 
 
 
You are being asked to participate in this study because you have a recurrent 
cancer (cancer that has returned) or relapsed childhood solid tumor including Sarcomas 
(Rhabdomyosarcoma, Osteosarcoma, Ewing sarcoma and other Soft Tissue sarcomas), Kidney 
Tumors, Lymphoma, CNS Tumors (pending toxicity analysis in any Phase I study, including 
Dasatinib), and other solid tumors (neuroblastoma, gonadal, germ cell tumors, liver tumors, and 
miscellaneous tumors). 
 
 
 


 
95
Why is this study being done? 
We are testing a new experimental drug such as Dasatinib, and combination chemotherapy of 
Ifosfamide, Carboplatin and Etoposide in the hopes of finding a drug that may be effective against 
recurrent or refractory solid tumors.  The combination of Dasatinib, Ifosfamide, Carboplatin and 
Etoposide is referred throughout this protocol as D-ICE  
 
The purpose of this study is to….    
We are testing the safety of Dasatinib at different dose levels with cytotoxic chemotherapy, 
Ifosfamide, Carboplatin, and Etoposide (D-ICE).  We want to find out what effects, good and/or 
bad, it has on you and your recurrent or progressive solid tumor cancer.  
 
The goals of this study are: 
 
• 
In the phase II portion of the study, to estimate the overall progression free survival 
and time to progression in patients with recurrent sarcoma and other solid tumors 
(including primary CNS tumors), to D-ICE given at the MTD, plus dasatinib alone given 
after consolidative therapy. 
• 
In the phase II portion of the study, to estimate the response rate to 2 courses of D-
ICE, given at the MTD. 
• 
To examine the effect of Dasatinb (SPRYCEL®) on the biology of cancer cells 
including 
• 
To determine the phosphotyrosine state by immunohistochemistry of SRC family 
kinases and related signaling pathways including FAK, STAT3, VEGFR, AKT, 
EGFR, KIT, EPHA2 and PDGFR in paraffin-embedded tumor specimens prior to and 
during treatment with dasatinib (SPRYCEL®). 
• 
To identify molecular signatures in tumor cells that may predict response to 
dasatinib by microarray analyis examined by gene expression. 
• 
To correlate the biomarkers and molecular signatures with dasatinib dosage, 
toxicity, and anti-tumor activity. 
• 
To evaluate the effect of dasatinib on phosphorylation of SRC family kinases in 
peripheral blood mononuclear cells (PBMCs) as a surrogate marker of response 
prior to treatment with dasatinib, at day 14 - 21 or when WBC > 500 during each 
treatment course, at the time of local control, and at time of progression, if any. 
 
 
How many people will take part in the study? 
There will be approximately 125 subjects participating in this study overall.  Subjects will be 
stratified (grouped) by their diagnosis: Stratum A (75 patients with Osteosarcoma, Ewing 
Sarcoma and Rhabdomyosarcoma tumors); Stratum B (25 other solid tumors); and Stratum C (25 
patients with newly diagnosed metastatic sarcomas of poor risk). 
 
What will happen if I take part in this research study?   
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in 
the study.  These exams, tests or procedures are part of regular cancer care and may be 
done even if you do not join the study.  If you have had some of them recently, they may 
not need to be repeated.  This will be up to your study doctor.   
 
Your doctor will also review your current medications with you. Since Dasatinib interacts with 
some medications, your doctor may stop or change some of your medications. You should talk to 
your doctor before taking any prescription or over the counter medications while on this study. 
 
• 
A medical history 
• 
Physical exam 
• 
Vital signs (blood pressure, pulse, temperature) 


 
96 
• 
Blood tests 
• 
Pregnancy test (if you are female and of childbearing age) 
• 
Tests to evaluate heart function  
• 
CT scans, MRI, X-rays and/or bone scans of disease sites, will be done to measure 
tumor, or other tests are needed to check your tumor. 
 
During the study … 
If the exams, tests and procedures show that you can be in the study, and you choose to 
take part 
 
Study Plan… 
You will receive Ifosfamide, Carboplatin, Etoposide and Dasatinib (D-ICE) every 28 days in this 
study. The whole tablet of dasatinib may be placed (and allowed to dissolve) in lemonade, 
preservative free orange juice, or preservative free apple juice before swallowing.  This 28 day time 
period is called a course.  The course will be repeated up to 6 times prior to consolidation.  Each 
course is numbered in order.   
 
The chart below shows what will happen to you during Course 1 and future treatment 
courses as explained previously.    
 
Course may be repeated up to 6 times, each course will last for 28 days 
Drug 
Route 
Schedule 
Method of Administration 
Ifosfamide (IFOS) 
Intravenous (IV) 
Day 0 - 4 
IV infusion over 60 minutes daily for 5 days  
Carboplatin (CBDCA) 
Intravenous (IV) 
Day 0 - 1 
IV infusion over 60 minutes daily for 2 days 
Etoposide (VP-16) 
Intravenous (IV) 
Day 0 - 4 
IV infusion over 60 minutes (every day) daily 
for 5 days 
Dasatinib  
By mouth (oral) 
Day 5 - 21 
Oral BID (twice a day) for 17 days 
Mesna 
Intravenous (IV) 
Day 0 - 4 
IV infusion over 15 minutes 
MESNA and fluids will be used with Ifosfamide as a bladder protectant 
REST 
 
Day 22 - 28 
 
G-CSF 
Subcutaneously 
(Subq) 
Day 5 
Daily starting day 5, until ANC ≥10,000, first 
course only. Neulasta may be given for 
subsequent courses to subjects > 50 kg. 
Another way to find out what will happen to you during the study is to read the chart below.  Start 
reading at the top and read down the list, following the lines and arrows.  
 
The dose for the first 3 children enrolled on the study will be based on the side effects seen in 
adults.  Between 3 and 6 children will receive Dasatinib at each dose. If the side effects are not 
too severe, the next group of children will receive a higher dose. Up to four different doses may 
be studied. Your dose will not be increased.  If you have bad side effects, your dose will be 
stopped.  If you are a patient enrolled early in this study you may receive a lower dose than those 
who are enrolled later. It is therefore possible that you may receive a dose that is less likely to 
have any effect on your tumor. If you are a patient enrolled in this study at a high dose level it is 
possible that you will receive a dose that is more likely to cause side effects.  Dosing is done this 
way because we do not yet know the best dose to use in children.   
 
You may be required to stay in the hospital if the treatment makes you sick, or you are sick 
because of your tumor. 
 


 
97
EXPERIMENTAL DESIGN SCHEMA*:   
 
 
 
 
 
 
 
 
 
 
 
ON STUDY 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
D-ICE x 2 
(level x of Dasatinib 
as determined by P.I.) 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR# 
 
 
 
CR 
↓ 
 
↓ 
 
 
 
↓  
Off Protocol 
Therapy 
 
D-ICE x 2 
 
 
 
Consolidation 
Radiation &/or 
Surgery 
 
 
↓ 
 
 
 
  
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR# 
 
 
CR 
 
↓ 
 
↓ 
 
 
↓ 
 
Off Protocol 
Therapy 
 
D-ICE x 2 
 
  
Consolidation 
Radiation &/or 
Surgery 
 
 
 
↓ 
 
 
  
 
 
 
EVALUATION 
 
 
 
 
 
 
↓ 
 
 
 
 
 PD 
 
SD / PR 
 
CR 
 
 
↓ 
 
↓ 
 
↓ 
 
 
Off Protocol 
Therapy 
 
Consolidation 
Radiation &/or Surgery
 
Consolidation 
Radiation &/or 
Surgery 
  
 
 
 
↓ 
 
↓ 
 
 
 
 
Dasatinib alone start at (level x) 2 months  
 
 
 
 
↓ 
 
 
Legend: 
 
After 2 months then may increase Dasatinib to level (x + 1) 
CR – Complete Response 
 
 
↓ 
 
 
PR – Partial Response 
Continue x 4 more months (total 6 months) Dasatinib alone 
SD – Stable Disease 
 
 
↓ 
 
 
PD – Progressive Disease 
 
END OF THERAPY 
 
 
*  Phase II:  Dasatinib (SPRYCEL®) dose will be administered at the maximally tolerated dose, as determined by            
  
the Phase I portion of this study. 
# At Investigators discretion subject may proceed to consolidation, radiation and/or surgery 
 
 


 
98 
You will need the following tests and procedures during the study.  These exams, tests or 
procedures are part of regular cancer care.  
 
• A medical history 
• Physical exam 
• Vital signs (blood pressure, pulse, temperature) 
• Blood tests 
• Tests to evaluate heart function 
 
We will also do whatever x-rays, CT scans, or other tests as needed to check your tumor. 
 
You will also be asked to keep a diary of when you take Dasatinib. This diary will help 
document study compliance.  
 
You will be asked to tell your doctor about other medications and nutritional supplements 
that you take. 
 
 
When I am finished taking D-ICE  
After you are finished taking Dasatinib (SPRYCEL®), the study doctor will ask you to visit the 
office for follow-up exams and tests. These exams, tests or procedures are all part of regular 
cancer care:  
  
First year off-therapy (reporting every 6 months) 
• 
Physical examination every month x 6 months then every 2 months x 6 months 
• 
Imaging studies that were positive at study entry every 3 months 
 
Second and subsequent years off-therapy (reporting every year) 
• 
Physical examination every 3 months 
• 
Imaging studies that were positive at study entry every 6 months 
 
Biology Studies: Blood and Tumor 
We would also like to do some extra tests called biology studies and tumor studies.  These tests 
will help us learn more about Dasatinib (SPRYCEL®) and may help children who receive this 
drug in the future. The information learned will not change the way you are treated, and the 
results of these tests will not be returned to you.  Although these tests are a very important part of 
how we will better learn to use this drug, it is your decision as to whether or not you agree to 
participate in these tests. 
Another way to find out what will happen to you during the study is to read the chart below.  Start 
reading at the top and read down the list, following the lines and arrows. 
 
During the study blood samples will be collected to evaluate the biological effects of Dasatinib on 
your blood cells. The amount of blood for each sample is about 10 mL (which is the about the 
same as 2 teaspoons) and will be collected on Day 14 - 21 or when WBC > 500 of each course 
during pre-consolidation treatment, and on Day 14 - 21 or when WBC > 500 of each course 
during post-consolidation treatment for all patients.  
 
The tests will help us to better learn how Dasatinib (SPRYCEL®) may work.  
 
Please indicate by checking and initialing below whether you choose to participate in the biology 
studies. 
 
/      Yes, I agree to participate in the biology studies. 
 


 
99
/      No, I do not agree to participate in the biology studies. 
 
Tumor biology studies: 
If a biopsy is done for clinical reasons at any time before or during the study, we would like to 
have a piece of tumor tissue for research. The tumor samples will be sent to a research 
laboratory to measure the characteristics of the tumor cell and to evaluate the effect of Dasatinib 
(SPRYCEL®) on the tumor cells.  
 
Please indicate by checking and initialing below whether you choose to participate in the tumor 
biology studies. 
 
/      Yes, I agree to participate in the tumor biology studies if a tumor biopsy is done for 
clinical reasons. 
 
/      No, I do not agree to participate in the tumor biology studies if a tumor biopsy is done 
for clinical reasons. 
 
How long will I be in the study?  
You will be asked to take D-ICE (Dasatinib (SPRYCEL®), Ifosfamide, Carboplatin and Etoposide) 
for as long as you show to have stable disease, or objective tumor response, you will be allowed to 
continue treatment as long as there is a clinical benefit that is observed.  
 
Your doctor may decide to take you off study if any of the following occur: 
 
• The side effects of Dasatinib (SPRYCEL®)and ICE are too harmful for you 
• You need a treatment that is not allowed on this study 
• Your tumor does not improve or worsens 
• You are not able to follow study-related treatment instructions 
• New information becomes available 
• The study is not in your best interest 
• The study is stopped 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
Dasatinib can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss follow-up care and testing could be most helpful for 
you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
 
 
What side effects or risks can I expect from being in the study?  
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, doctors don’t know all the side effects 
that may happen.  Side effects may be mild or very serious. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after you 
stop taking the Dasatinib. In some cases, side effects can be serious, long lasting, or may 
never go away.  
 


 
100
You should talk to your study doctor about any side effects that you have while taking part 
in the study.    
 
Risks and side effects related to the DASATINIB (SPRYCEL®) include: 
 
Likely 
• 
Headache 
• 
Hemorrhage  
• 
Thrombocytopenia (Low platelet count which may lead to bleeding or bruising) 
• 
Pleural effusion  
• 
Dyspnea 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Abdominal pain 
• 
Gastrointestinal hemorrhage 
• 
Skin rash 
• 
Musculoskeletal pain 
• 
Superficial edema 
• 
Fatigue 
• 
Pyrexia 
• 
Hypocalcemia 
• 
Infection (including bacterial, viral, fungal, non-specified) 
• 
Cough 
 
 Less Likely   
• 
Pneumonia (including bacterial, viral, and fungal) 
• 
Upper respiratory tract infection/inflammation 
• 
Herpes virus infection 
• 
Enterocolitis infection 
• 
Febrile neutropenia 
• 
Anemia 
• 
Leukopenia 
• 
Depression 
• 
Insomnia 
• 
Dizziness 
• 
Neuropathy (including peripheral neuropathy) 
• 
Dysgeusia 
• 
Dry eye 
• 
Congestive heart failure/ Cardiac dysfunction 
• 
Pericardial effusion 
• 
Arrhythmia (including tachycardia) 
• 
Palpitations 
• 
Hypertension 
• 
Flushing 
• 
Pulmonary edema 
• 
Lung infiltration 
• 
Pneumonitis 
• 
Abdominal distension 
• 
Mucosal inflammation (including Mucositis/stomatitis) 
• 
Colitis (including neutropenic colitis) 
• 
Gastritis 
• 
Oral soft tissue disorder dyspepsia 
• 
Constipation 


 
101
• 
Dehydration 
• 
Pruritus 
• 
Alopecia 
• 
Acne 
• 
Dry skin 
• 
Urticaria 
• 
Hyperhydrosis 
• 
Arthralgia 
• 
Myalgia 
• 
Muscle inflammation 
• 
Muscular weakness 
• 
Pain 
• 
Chest pain 
• 
Chills 
• 
Weight decreased 
• 
Weight increased 
• 
Contusion 
• 
Thrombophlebitis 
• 
Sepsis (including fatal outcome) 
• 
Pancytopenia 
• 
Anorexia 
• 
Hyperuricemia 
• 
Somnolence 
• 
Visual disorder (including visual disturbance, vision blurred, and visual acuity 
reduced) 
• 
Pulmonary hypertension 
• 
Dermatitis (including eczema) 
• 
Musculoskeletal stiffness 
• 
Asthenia 
 
 
Rare but serious 
• 
Tumor lysis syndrome 
• 
Aplasia pure red cell 
• 
Hypersensitivity (including erythema nodosum, a type of skin inflammation)) 
• 
Transient ischemic attack 
• 
Reversible posterior leukoencephalopathy syndrome 
• 
Convulsion 
• 
Amnesia 
• 
Tremor 
• 
Syncope 
• 
Central nervous system hemorrhage 
• 
Cardiomegaly 
• 
Angina pectoris 
• 
Myocardial infarction 
• 
Pericarditis 
• 
Acute coronary syndrome 
• 
Myocarditis 
• 
Ventricular tachycardia 
• 
Hypotension 
• 
Livedo reticulares 
• 
Asthma 
• 
Acute respiratory distress syndrome 
• 
Pancreatitis 


 
102
• 
Upper gastrointestinal ulcer 
• 
Ascites 
• 
Dysphagia 
• 
Hepatitis 
• 
Cholestasis 
• 
Cholecystitis 
• 
Acute febrile neutrophilic dermatosis 
• 
Photosensitivity reaction 
• 
Pigmentation disorder 
• 
Skin ulcer 
• 
Bullous conditions (including Erythema multiforme) 
• 
Nail disorder 
• 
Palmar-plantar erythrodysesthesia syndrome 
• 
Rhabdomyolysis 
• 
Tendonitis 
• 
Blood creatine phosphokinase increased 
• 
Renal failure 
• 
Urinary frequency proteinuria 
• 
Gynecomastia 
• 
Menstruation irregular 
• 
Malaise 
• 
Temperature intolerance 
• 
Lethargy 
• 
Lightheadedness 
• 
Tinnitus 
• 
Tendonitis 
• 
Cor pulmonale   
• 
Cerebrovascular accident 
• 
Tendonitis 
• 
Hypoalbuminemia 
• 
Anxiety  
• 
Confusional State 
• 
Affect lability 
• 
Libido decreased 
• 
Conjunctivitis 
• 
Vertigo 
• 
Electrocardiogram QT prolonged 
• 
Bronchospasm 
• 
Anal fissure 
• 
Esophagitis 
• 
Panniculitis 
 
 
Risks and side effects related to the IFOSFAMIDE include: 
 
Likely 
• 
Nausea  
• 
Vomiting  
• 
Hair loss 
• 
Fewer red and white blood cells and platelets in the blood  
o 
A low number of red blood cells can make you feel tired and weak 
o 
A low number of white blood cells can make it easier to get infections 
o 
A low number of platelets causes you to bruise and bleed more easily 
• 
Decreased ability of the body to fight infection 


 
103
• 
Absence or decrease in the number of sperm which may be temporary or permanent 
which may decrease the ability to have children 
• 
Slight decrease in kidney function  
 
Less Likely 
• 
Drowsiness  
• 
Confusion  
• 
Depression  
• 
Loss of appetite 
• 
Diarrhea or constipation  
• 
Seizures  
• 
Abnormal hormone function affecting levels of salt in the blood and urine  
• 
Abnormal heartbeat or rhythm. This side effect may require frequent evaluations of the 
hearts function and a heart specialist consult  
• 
Blood in the urine that is only seen under the microscope  
• 
Body loss of certain important salts and minerals  
• 
Failure of the ovaries to function normally which may be permanent and which may 
decrease the ability to have children   
• 
Inflammation and burning along the vein where the medicine is given  
• 
Temporary elevation in the blood of certain enzymes found in the liver  
 
Rare but Serious 
• 
Damage to brain tissue with very high doses that may lead to coma    
• 
Kidney failure or damage  
• 
Damage to the bladder, which can lead to large amounts of blood in the urine, pain and 
the urge to urinate frequently and also permanent scarring of the bladder   
• 
A new cancer or leukemia resulting from this treatment  
• 
Damage to heart muscle which may make you tired, weak, feel short of breath, and 
retain fluid 
• 
Abnormal bone growth and development 
 
 
Risks and side effects related to the ETOPOSIDE include: 
 
Likely 
• 
Nausea  
• 
Hair loss 
• 
A feeling of weakness or tiredness  
• 
Fewer red and white blood cells and platelets in the blood 
o 
A low number of red blood cells can make you feel tired and weak 
o 
A low number of white blood cells can make it easier to get infections 
o 
A low number of platelets causes you to bruise and bleed more easily 
 
Less Likely 
• 
Loss of appetite  
• 
Decreased blood pressure during the infusion which may require treatment 
• 
Rashes 
• 
Diarrhea or constipation 
• 
Pain in the abdomen 
• 
Mouth sores 
• 
Tingling sensation or loss of sensation in fingers or toes 
• 
A feeling of extreme tiredness or weakness 
• 
The finger or toe nails may loosen from their nail beds 
• 
Inflammation and burning along the vein through which the medication was given  
• 
Chest pain 


 
104
 
Rare but Serious 
• 
Damage to the liver 
• 
Severe allergic reaction which can be life threatening with shortness of breath, low 
blood pressure, rapid heart rate chills and fever 
• 
A new cancer or leukemia resulting from this treatment  
• 
Temporary severe rashes which can result in loss of skin and damage to mucous 
membranes   
• 
Absence or decrease monthly periods  
• 
Damage to heart muscle which may make you tired, weak, feel short of breath, and 
retain fluid  
 
Risks and side effects related to the CARBOPLATIN include: 
     
Likely 
• 
Bone Marrow Suppression (as described for Ifosfamide) - Fewer red and white blood 
cells and platelets in the blood  
o 
A low number of red blood cells can make you feel tired and weak 
o 
A low number of white blood cells can make it easier to get infections 
o 
A low number of platelets causes you to bruise and bleed more easily 
• 
Nausea and vomiting 
 
Less Likely 
• 
Kidney and liver damage   
 
Rare but Serious 
• 
Tingling and discomfort in arms and legs and weakness may occur rarely 
• 
Local allergic reactions at the IV site.  Itching, a skin rash, lightheadedness, facial 
flushing or trouble breathing  
• 
Hearing loss 
• 
A new cancer or leukemia resulting from this treatment  
 
 
Risks and side effects related to the MESNA include: 
 
Likely 
• 
Bad taste when taken by mouth. 
 
Less Likely 
• 
Nausea. 
• 
Vomiting 
• 
Stomach pain 
• 
Headache 
• 
Pain in arms, legs and joints 
• 
Tired feeling 
• 
Rash 
• 
Temporary low blood pressure  
• 
Diarrhea 
• 
Fever 
• 
Facial flushing with red cheeks 
• 
Nervousness 
• 
Dizziness  
• 
Confusion  
• 
Swelling around the eyes  


 
105
• 
Coughing 
• 
Rapid heart rate  
 
Rare but Serious 
• 
Severe allergic reaction which can be life threatening with shortness of breath, low 
blood pressure, rapid heart rate chills and fever    
 
Risks and side effects related to the G-CSF (Growth factor, Filgrastim, Neupogen) include: 
 
Most patients who receive G-CSF have little or no side effects.  However, some patients 
may experience the following: 
 
Likely 
• 
Mild to moderate aching or pain inside the bones 
 
Less Likely 
• 
Local irritation at the site of the injection  
• 
Mild headache  
• 
Higher than normal levels of liver enzymes   
• 
Lower number of platelets in the blood  
• 
Low fever 
• 
Enlargement of the spleen  
• 
Worsening of skin rashes  
• 
Inflammation of a blood vessel in the skin leading to a raised purple rash and bruising  
• 
Higher than normal white blood count  
 
Rare but Serious 
• 
Allergic reactions which can be life threatening with shortness of breath, low blood 
pressure, rapid heart rate, hives and facial swelling 
• 
If you are known to have sickle cell disease, filgrastim may cause a sickle cell crisis. 
• 
A blood disorder or leukemia that has only been seen in patients with certain immune 
disorders who are treated for a very long time 
• 
Severe damage to the spleen 
• 
Difficulty breathing and lung damage that may be due to the white blood cells that are 
stimulated by filgrastim traveling to the lungs when they are inflamed or infected  
 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed 
a baby while on this study.  It is important you understand that you need to use birth 
control while on this study.  The long-term effects of Dasatinib on fertility are unknown.  
Check with your study doctor about what kind of birth control methods to use and how long to use 
them.  Some methods might not be approved for use in this study.  Pregnancy tests will be 
obtained in women interested in participating in this study. 
 
Risks of blood drawing or placing an intravenous catheter for blood drawing: 
Risks associated with drawing blood are slight, but some risks include: pain, excessive bleeding, fainting or 
feeling lightheaded, bruising, infection (a slight risk any time the skin is broken), and multiple punctures to 
locate veins. 
 
 
Risk of Surgery 
Some patients on this study will undergo surgery before starting therapy or during this study. You 
will be asked to sign a separate consent form for the surgical procedure. The planned surgery will 
be explained to you and your questions about it answered by your surgeon when you sign the 
consent for the surgical procedure. 


 
106
 
For more information about risks and side effects, ask your study doctor. 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your tumor to stop growing.  The potential 
benefit of the treatment with Dasatinib is that it may cause your cancer to stop growing or 
to shrink for a period of time. It may lessen the symptoms, such as pain, that are caused 
by the cancer. Because there is not much information about Dasatinib, we know that the 
information from this study will help doctors learn more about Dasatinib as a treatment for 
cancer in children. However, we do not know if you will benefit from taking part in this 
study.  Information learned from this study may help future patients with cancer. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• No further treatment and 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not 
treat the cancer directly, but instead tries to improve how you feel.  Comfort care tries 
to keep you as active and comfortable as possible.   
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given out 
if required by law.  If information from this study is published or presented at scientific meetings, 
your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: 
 
• 
Pediatric Cancer Foundation 
• 
Bristol-Myers Squibb (sponsor/supplier of Dasatinib) 
• 
Representatives of the  National Cancer Institute (NCI) and other government 
agencies, like the Food and Drug Administration (FDA), involved in keeping 
research safe for people 
 
What are the costs of taking part in this study? 
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking part 
in studies.  Check with your health plan or insurance company to find out what they will pay for.  
Taking part in this study may or may not cost your insurance company more than the cost of getting 
regular cancer treatment.  
 
Bristol-Myers Squibb (BMS) is supplying Dasatinib at no cost to you.  However, you or your 
health plan may need to pay for costs of the supplies and personnel who give you the Dasatinib.  
The study agent, Dasatinib, will be provided free of charge while you are participating in 
this study.  However, if you should need to take the study agent much longer than is 
usual, it is possible that the supply of free study agent that has been supplied to [the NCI 
or other study sponsor, as appropriate] could run out.  If this happens, your study doctor will 


 
107
discuss with you how to obtain additional drug from the manufacturer and you may be 
asked to pay for it. 
 
You will not be paid for taking part in this study. 
 
There will be no cost to you for any tissue collected and banked.  You will not be paid for allowing 
your leftover tissue to be used in research, even though it is possible that new cancer tests or 
treatments may be developed as a result of the research. 
 
For more information on clinical trials and insurance coverage, you can visit the National 
Cancer 
Institute’s 
Web 
site 
at 
http://www.cancer.gov/clinicaltrials/understanding/insurance-coverage.    You can print a 
copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask 
them to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], 
if you feel that you have been injured because of taking part in this study.  You can tell the 
doctor in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this 
study.  You and/or your health plan will be charged for this treatment.   The study 
will not pay for medical treatment.   
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the 
study.  If you decide to take part in this study, you may leave the study at any time.   No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits.  
Leaving the study will not affect your medical care.  You can still get your medical care from our 
institution.    
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form.   
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the 
study.  If you decide to take part in this study, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits.  
Leaving the study will not affect your medical care.  You can still get your medical care from our 
institution.    
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form.   
 
Whether you participate or not, you will continue to get the best medical care this hospital can 
provide. 


 
108
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this 
study.  Contact your study doctor __________________ [name(s)] at __________________ 
[telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ 
[name of center] Institutional Review Board (a group of people who review the research to protect 
your rights) at __________________ (telephone number).  [Note to Local Investigator: Contact 
information for patient representatives or other individuals in a local institution who are not on the IRB or 
research team but take calls regarding clinical trial questions can be listed here.]    
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
• 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
• 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form. You will be given a copy of the protocol (full study plan) 
upon request.   
 
If you want more information about this study, ask your study doctor. 
 
Signature 
I have been given a copy of all # pages of this form.   
I have read it or it has been read to me.  
 
I understand the information and have had my questions answered.  I agree to take part in 
this study. 
Participant _______________________________________ 
Parent (or Guardian) ________________________________ 
 
Date ______________________________________  
 
Signature of Physician or Responsible Investigator  
 
___________________________________________ 
 
Date ______________________________________ 
 
 
 
 
 
 


 
109
FOR SUBJECTS/PARTICIPANTS 7-17 YEARS OF AGE 
 
 
The undersigned physician, _____________________________, M.D., hereby certifies that 
he/she has discussed the research project with the subject/participant and has explained 
all the information contained in the informed consent form to the subject/participant, 
including any risks that may reasonably be expected to occur. The undersigned further 
certifies that the subject/participant was encouraged to ask questions and that all 
questions were answered. 
 
 
__________________________      __________________________ 
Date                                         
Physician's Signature