Clinical trial NCT03041701
Conditions: Rhabdomyosarcoma Rhabdomyosarcoma, Alveolar Rhabdomyosarcoma, Embryonal
Keywords: ERMS ARMS Monoclonal Antibody YES RMS
Sponsor: National Cancer Institute (NCI)
Start date: 2017-07-07; Completion date: 2021-10-16
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Two types are embryonal RMS (ERMS) and alveolar RMS (ARMS). Dasatinib may block over-expression of a certain enzyme. Ganitumab may block a certain growth factor, which might suppress tumor growth. This drug combination may help slow tumor growth in people with ERMS and ARMS.

Objective:

To see if dasatinib combined with ganitumab is safe and shrinks or slows the growth of tumors in people with ERMS and ARMS.

Eligibility:

People any age who have ERMS or ARMS that did not respond to previous treatment and who can swallow tablets

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Blood, urine, and heart tests
* Scans/x-rays
* Tissue sample: This can be from previous surgery or biopsy.
* Optional biopsy: A small piece of the tumor is removed with a needle.

Participants will be asked to co-enroll in another protocol.

Participants will get a drug interaction handout and wallet card that show what foods and medications to avoid.

Participants will be treated in cycles. The first cycle is 35 days, and the rest are 28 days. Participants will take dasatinib by mouth daily. They will get ganitumab through an intravenous (IV) every 2 weeks. They will have a physical exam every 1-2 weeks, and urine and heart tests before most cycles.

Participants will continue treatment as long as they do not have severe side effects, or their tumors do not get worse.

After ending treatment, participants will have a visit. This includes repeats of the screening tests.

Detailed description:
Background:

* Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. The annual incidence in the United States is 4-7 cases per million children under 15 years, which represents 250 new cases per year. Two major histologic subtypes exist: embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS), the latter of which carries a particularly poor prognosis.
* Over-expression of both the type like growth factor 1 (1 IGF) receptor insulin-like growth factor type 1 receptor (IGF-1R) and its ligands has been observed in multiple malignancies, including pediatric sarcomas, and abnormal activation of this pathway contributes to sarcoma development and progression. Downstream signaling cascades of IGF-1R further regulate tumor cell proliferation, survival, and metastasis through the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK) and phosphatidylinositol 3-kinases (PI3Ks)/mammalian target of rapamycin (mTOR) pathways. In the majority of RMS, IGF-1R is highly expressed.
* Monoclonal antibodies targeting IGF-1R interfere with ligand binding and decrease the expression of the receptor on cell surfaces by internalization and degradation of the receptor. A number of these have been tested in the clinical setting. Results from a phase II trial using monotherapy with monoclonal antibodies against IGF-1R resulted in clinically meaningful responses in about 10-15% of patients with RMS. However, the vast majority of these responses were short-lived with a rapid onset of resistance.
* YES is a member of the SRC family tyrosine kinases (SFKs), non-receptor tyrosine kinases that function in a number of signaling pathways necessary for cell growth, differentiation and survival. Preclinical work suggests involvement of YES in a number of solid tumor types, including colon carcinoma, oral squamous cell carcinoma, glioma, pancreatic cancer, mesothelioma, and RMS.
* Recently, the Helman lab published preclinical work showing that in both embryonal and alveolar RMS models, blockade of IGF-1R results in YES activation and that YES activation is associated with resistance to IGF-1R blockade. In addition, combination blockade of IGF-1R and YES in vitro results in downregulation of phospho-AKT in some cell lines. Treatment blocking both IGF-1R and YES results in enhanced growth inhibition of multiple cell lines of both embryonal and alveolar RMS in vitro and in vivo.

Objectives:

1. Phase I: To determine the safe dose of dasatinib when given with ganitumab in patients with relapsed or refractory embryonal or alveolar RMS.
2. Phase II: To determine if the use of ganitumab plus dasatinib is able to be associated with a modest fraction of patients who experience an objective clinical response (complete response (CR) and partial response (PR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In addition, a second primary objective will estimate the fraction that is without progression at 4 months.

Eligibility:

* Patients must have a diagnosis of relapsed or refractory embryonal or alveolar RMS, be able to swallow tablets, have archival tissue available.
* Patients must have adequate performance status and adequate major organ function and have recovered from acute toxicity of all prior therapies.

Design:

* This is an open label, multi-site, phase I/II study designed to determine if ganitumab given in combination with dasatinib in children and adults with relapsed or refractory embryonal or alveolar RMS for whom no curative options exist.
* In the phase I portion, using a standard 3 + 3 design, limited dose escalations will be performed to define the maximum tolerated dose (MTD) or the highest safe dose tested of dasatinib when given in combination with ganitumab in this patient population.
* In the phase II component, sixteen (16) evaluable patients, including up to 6 patients from the phase I portion treated at the selected phase II dose, will be enrolled to rule out a 5% fraction with a clinical response in favor of a 30% fraction with a clinical response, using a one sided 0.10 significance level exact test for a binomial proportion. In practice, the fraction of the 16 patients that have objective responses will be determined and reported along with 80% and 95% confidence intervals. If there are 3 objective responses in 16 evaluable patients, the lower one-sided exact 90% confidence interval is 7.1%, thus ruling out 5%.
* It is anticipated that approximately 10-15 patients per year may be accrued onto this trial. Thus, 2 to 3 years is expected to completed accrual.
* In all patients, mechanisms of response and resistance will be assessed by analyzing archival tissue for expression of IGF-1R, insulin receptor, IGF-2 expression and phospho-YES expression, and through genomic sequencing (on protocol 10-C-0086). Genomic sequencing of tumor cells from tissue relative to non-tumor cells from whole blood will be profiled to identify the genomic variances that may contribute to response or disease progression and provide an understanding of molecular abnormalities. Ribonucleic acid (RNA) sequencing will be conducted to provide expression data and give relevance to deoxyribonucleic acid (DNA) mutations; Quantitative proteomics analysis will be conducted on all patients to determine the exact amounts of specific proteins and/or to confirm expression of genes that are correlative of response and disease progression. Genomic and transcriptomic analysis will be conducted on patients who consent to protocol 10-C-0086, Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a Repository for Related Biological Studies. All genomic, transcriptomic, and proteomic molecular analyses will be retrospective and exploratory.
* In patients who agree to undergo biopsy of their tumor, provided the tissue is easily accessible and can be biopsied safely with minimal morbidity, mechanisms of response and resistance will be assessed by analyzing biopsy tissue expression of IGF- 1R, insulin receptor, IGF-2 expression and phospho-YES expression, and through genomic sequencing.

Arms: arm 1: Phase I Dose Level 1: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib arm 2: Phase I Dose Level 2: Combination of ganitumab and dasatinib with limited dose escalation of dasatinib arm 3: Phase 2 Dose Level 1: Combination of ganitumab and dasatinib at the maximum tolerated dose (MTD) (or highest safe dose)
Interventions: intervention 1: Dasatinib intervention 2: Dasatinib intervention 3: Ganitumab
Intervention descriptions: intervention 1: Once daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles. intervention 2: Twice daily on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles. intervention 3: Once every 2 weeks beginning on day 0.

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #: 10003 
Version Date: 04/06/2020 
1 
NCI Protocol #: 10003 
Local Protocol #: 17-C-0049 G 
Version Date: 04/06/2020 
ClinicalTrials.gov Identifier: NCT03041701 
Abbreviated Title: Das-Ganit in Rhabdomyosarcoma 
TITLE: A Phase I/II Trial of the Insulin-Like Growth Factor 1 Receptor (IGF-1R) Antibody 
AMG479 (Ganitumab) in Combination with the Src Family Kinase (SFK) Inhibitor 
Dasatinib in Patients with Embryonal and Alveolar Rhabdomyosarcoma 
Corresponding Organization: 
NCICCR / National Cancer Institute CCR 
NIH Principal Investigator: 
Christine Heske, M.D., POB, NCI 
10 Center Drive, MSC 1104 
Bldg. 10 CRC, Rm. 1W-3816 
Bethesda, MD 20892-1104  
Phone: (240) 760-6197  
Email: Christine.heske@nih.gov 
NIH Associate Investigators: 
Brigitte Widemann, M.D., POB, CCR, NCIA-F 
John Glod, M.D., Ph.D., POB, CCR, NCIA-F 
Alice Chen, M.D., DCTD, NCIA-F  
John (Jack) Shern, M.D., POB, CCR, NCIA-F 
Rosandra Kaplan, M.D., POB, CCR, NCIA-F 
Andrea Gross, M.D., POB, CCR, NCIA-F
Marielle Yohe, M.D., POB, CCR, NCIA-F
Donna Bernstein, R.N., OCD, CCR, NCIA-F 
Amanda Carbonell, R.N., OCD, CCR, NCIA-F
Melissa Spencer, R.N., OCD, CCR, NCIA-F
Joanne Derdak, CRNP, POB, CCR, NCIA-F 
Geraldine O'Sullivan, M.D., DCTD, NCIA-F  
Naoko Takebe, M.D., Ph.D., DCTD, NCIA-F
Seth Steinberg, Ph.D., BDMS, CCR, NCIE-F
Eva Dombi, POB, CCR, NCIE-F
Investigator Roles: 
A. Obtain information by intervening or interacting with
living individuals for research purposes
B. Obtaining identifiable private information about
living individuals
C. Obtaining the voluntary informed consent of
individuals to be subjects
D. Makes decisions about subject eligibility


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E. Studying, interpreting, or analyzing identifiable
private information or data/specimens for research
purposes
F. Studying, interpreting, or analyzing coded (linked)
data or specimens for research purposes
G. Some/all research activities performed outside NIH
Participating Organizations 
LAO-CA043 /  City of Hope Comprehensive Cancer Center 
Participation restricted to CA009 - Children’s Hospital of Los Angeles 
FWA Number: 
FWA00001914 
Institutional PI:  
Fariba Navid, MD 
4650 Sunset Blvd.  
Los Angeles, CA 90027 
Phone: 323-361-2762 
Email: fnavid@usc.edu 
Coordinating Center: National Cancer Insititute, Center for Cancer Research 
Responsible Data Safety Monitoring Board (DSMB): N/A   


 
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Statistician: 
Seth Steinberg, Ph.D., OCD, CCR, NCI 
9609 Medical Center Drive RM 2W334 
Rockville, MD 20850 
Phone: 240-276-5563 
Fax: 240-276-7885 
Email: steinbes@mail.nih.gov 
Study Coordinator: 
Donna Bernstein, R.N., OCD, CCR, NCI 
Bldg. 10 CRC, Room 1-3750 
Bethesda, MD 20982-1104 
Phone: 240-760-6189  
Email: bernsted@mail.nih.gov 
Responsible Research Nurse: 
Donna Bernstein, R.N., OCD, CCR, NCI 
Bldg. 10 CRC, Room 1-3750 
Bethesda, MD 20982-1104 
Phone: 240-760-6189  
Email: bernsted@mail.nih.gov 
Responsible Data Manager: 
Isabel Palacio-Yance 
10 Center Drive Rm 1C253 
Bethesda, MD 20892 
Phone: 301-402-9748 
Email: Isabel.palacio-yance@nih.gov 
 
NCI-Supplied Agents: Ganitumab, NSC # 750008, BDP, FNLCR and Dasatinib (BMS-
354825), NSC # 732517, Bristol-Myers-Squibb    
IND #: 12049 
IND Sponsor: DCTD, NCI 
 
 


 
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PRÉCIS 
Background: 
• Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. The 
annual incidence in the United States is 4-7 cases per million children under 15 years, 
which represents 250 new cases per year.(1) Two major histologic subtypes exist: 
embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS), the 
latter of which carries a particularly poor prognosis.(2) 
• Over-expression of both the type 1 IGF receptor (IGF-1R) and its ligands has been 
observed in multiple malignancies, including pediatric sarcomas, and abnormal activation 
of this pathway contributes to sarcoma development and progression.(3-5) Downstream 
signaling cascades of IGF-1R further regulate tumor cell proliferation, survival, and 
metastasis through the MAPK/ERK and PI3K/mTOR pathways.(6) In the majority of 
RMS, IGF-1R is highly expressed.(7, 8) 
• Monoclonal antibodies targeting IGF-1R interfere with ligand binding and decrease the 
expression of the receptor on cell surfaces by internalization and degradation of the 
receptor.(9-12) A number of these have been tested in the clinical setting. Results from a 
phase II trial using monotherapy with monoclonal antibodies against IGF-1R resulted in 
clinically meaningful responses in about 10-15% of patients with RMS. However, the 
vast majority of these responses were short-lived with a rapid onset of resistance.(13, 14) 
• YES is a member of the SRC family tyrosine kinases (SFKs), non-receptor tyrosine 
kinases that function in a number of signaling pathways necessary for cell growth, 
differentiation and survival.(15, 16) Preclinical work suggests involvement of YES in a 
number of solid tumor types, including colon carcinoma, oral squamous cell carcinoma, 
glioma, pancreatic cancer, mesothelioma, and RMS.(17-22) 
• Recently, the Helman lab published preclinical work showing that in both embryonal and 
alveolar RMS models, blockade of IGF-1R results in YES activation and that YES 
activation is associated with resistance to IGF-1R blockade. In addition, combination 
blockade of IGF-1R and YES in vitro results in downregulation of phospho-AKT in some 
cell lines.  Treatment blocking both IGF-1R and YES results in enhanced growth 
inhibition of multiple cell lines of both embryonal and alveolar RMS in vitro and in 
vivo.(23) 
Objectives: 
• Phase I: To determine the safe dose of dasatinib when given with ganitumab in patients 
with relapsed or refractory embryonal or alveolar RMS. 
• Phase II: To determine if the use of ganitumab plus dasatinib is able to be associated with 
a modest fraction of patients who experience an objective clinical response (CR and PR) 
as defined by RECIST criteria. In addition, a second primary objective will estimate the 
fraction that is without progression at 4 months. 
Eligibility: 


 
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• Patients must have a diagnosis of relapsed or refractory embryonal or alveolar RMS, be 
able to swallow tablets, have archival tissue available. 
• Patients must have adequate performance status and adequate major organ function and 
have recovered from acute toxicity of all prior therapies. 
Design: 
• This is an open label, multi site, phase I/II study designed to determine if ganitumab 
given in combination with dasatinib in children and adults with relapsed or refractory 
embryonal or alveolar RMS for whom no curative options exist. 
• In the phase I portion, using a standard 3 + 3 design, limited dose escalations will be 
performed to define the maximum tolerated dose (MTD) or the highest safe dose tested of 
dasatinib when given in combination with ganitumab in this patient population.   
• In the phase II component, sixteen (16) evaluable patients, including up to 6 patients from 
the phase I portion treated at the selected phase II dose, will be enrolled to rule out a 5% 
fraction with a clinical response in favor of a 30% fraction with a clinical response, using 
a one sided 0.10 significance level exact test for a binomial proportion. In practice, the 
fraction of the 16 patients that have objective responses will be determined and reported 
along with 80% and 95% confidence intervals. If there are 3 objective responses in 16 
evaluable patients, the lower one-sided exact 90% confidence interval is 7.1%, thus 
ruling out 5%. 
• It is anticipated that approximately 10-15 patients per year may be accrued onto this trial. 
Thus, 2 to 3 years is expected to completed accrual.  
• In all patients, mechanisms of response and resistance will be assessed by analyzing 
archival tissue for expression of IGF-1R, insulin receptor, IGF-2 expression and 
phospho-YES expression, and through genomic sequencing (on protocol 10-C-0086). 
Genomic sequencing of tumor cells from tissue relative to non-tumor cells from whole 
blood will be profiled to identify the genomic variances that may contribute to response 
or disease progression and provide an understanding of molecular abnormalities.  RNA 
sequencing will be conducted to provide expression data and give relevance to DNA 
mutations; Quantitative proteomics analysis will be conducted on all patients to 
determine the exact amounts of specific proteins and/or to confirm expression of genes 
that are correlative of response and disease progression. Genomic and transcriptomic 
analysis will be conducted on patients who consent to protocol 10-C-0086, 
Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a 
Repository for Related Biological Studies. All genomic, transcriptomic, and proteomic 
molecular analyses will be retrospective and exploratory. 
• In patients who agree to undergo biopsy of their tumor, provided the tissue is easily 
accessible and can be biopsied safely with minimal morbidity, mechanisms of response 
and resistance will be assessed by analyzing biopsy tissue expression of IGF-1R, insulin 
receptor, IGF-2 expression and phospho-YES expression, and through genomic 
sequencing. 


 
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TABLE OF CONTENTS 
 
PRÉCIS .................................................................................................................................. 4 
TABLE OF CONTENTS ......................................................................................................... 6 
1 
INTRODUCTION ......................................................................................................... 10 
1.1 
Study Objectives .................................................................................................. 10 
2 
BACKGROUND AND RATIONALE............................................................................ 10 
2.1 
Inhibiting the insulin-like growth factor type 1 receptor (IGF1-R) in 
rhabdomyosarcoma (RMS): ............................................................................................... 10 
2.2 
YES activation as a bypass resistance pathway to IGF-1R inhibition: ..................... 12 
2.3 
Rationale for combining IGF-1R inhibition and YES/SFK Inhibition in RMS in a 
Phase I/II Study: ................................................................................................................ 12 
2.4 
Dasatinib.............................................................................................................. 13 
2.5 
Ganitumab ........................................................................................................... 17 
2.6 
Proposed trial: ...................................................................................................... 20 
3 
PATIENT SELECTION................................................................................................. 22 
3.1 
Eligibility Criteria ................................................................................................ 22 
3.2 
Screening Evaluation............................................................................................ 25 
4 
RECRUITMENT AND REGISTRATION...................................................................... 26 
4.1 
Recruitment Strategies.......................................................................................... 26 
4.2 
Registration Procedures ........................................................................................ 26 
4.3 
Local Registration for NCI CCR ........................................................................... 30 
4.4 
General Guidelines ............................................................................................... 31 
5 
TREATMENT PLAN .................................................................................................... 31 
5.1 
Agent Administration ........................................................................................... 31 
5.2 
General Concomitant Medication and Supportive Care Guidelines......................... 35 
5.3 
Duration of Therapy (Off Treatment) .................................................................... 37 
5.4 
Duration of Follow Up ......................................................................................... 37 
5.5 
Criteria for Removal from Study........................................................................... 37 
5.6 
Local Off Protocol Treatment and Off-Study Procedure......................................... 38 
6 
DOSING DELAYS/DOSE MODIFICATIONS .............................................................. 38 


 
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6.1 
Definition of Dose Limiting Toxicity (DLT) (Phase I) and Treatment Limiting 
Toxicity (TLT) (Phase II)................................................................................................... 38 
6.2 
Adverse Events Attributed to Ganitumab .............................................................. 39 
6.3 
Hematologic Adverse Events Attributed to Dasatinib or Ganitumab ....................... 39 
6.4 
Pneumonitis Attributed to Dasatinib and Ganitumab.............................................. 40 
6.5 
Additional Adverse Events Attributed to Dasatinib................................................ 41 
6.6 
Additional Adverse Events Attributed to Ganitumab ............................................. 42 
6.7 
Dasatinib Dose Modifications For Toxicity ........................................................... 46 
6.8 
Dosing Delays...................................................................................................... 47 
7 
SPONSOR SAFETY REPORTING................................................................................ 48 
7.1 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS.................... 48 
7.2 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) .................. 48 
7.3 
Adverse Event Characteristics .............................................................................. 58 
7.4 
Expedited Adverse Event Reporting...................................................................... 58 
7.5 
Routine Adverse Event Reporting ......................................................................... 60 
CTEP-AERS 24-hour Notification is required for ≥ Grade 2 pneumonitis. ............................... 60 
7.6 
Secondary Malignancy ......................................................................................... 60 
7.7 
Second Malignancy .............................................................................................. 60 
8 
NIH INTRAMURAL RESEARCH REPORTING........................................................... 61 
8.1 
Definitions ........................................................................................................... 61 
8.2 
OHSRP Office of Compliance and Training/ IRB Reporting .................................. 61 
8.3 
NCI Clinical Director Reporting (For NCI Site Only) ............................................ 61 
8.4 
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials..... 61 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES......................................... 61 
9.1 
Genomics, transcriptomics and Proteomics Molecular Analysis ............................. 61 
9.2 
Biomarker Studies ................................................................................................ 64 
9.3 
Sample Storage, Tracking and Disposition ............................................................ 66 
9.4 
Samples for Genetic/Genomic Testing .................................................................. 67 
10 STUDY CALENDAR .................................................................................................... 69 
11 MEASUREMENT OF EFFECT ..................................................................................... 71 
11.1 
Response Criteria ................................................................................................. 71 


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12 STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS
78 
12.1 
Study Oversight ................................................................................................... 78 
12.2 
Data Reporting ..................................................................................................... 78 
12.3 
Data Sharing Plans ............................................................................................... 80 
13 STATISTICAL CONSIDERATIONS ............................................................................ 81 
13.1 
Phase I ................................................................................................................. 81 
13.2 
Phase II................................................................................................................ 81 
13.3 
Sample Size/Accrual Rate..................................................................................... 82 
14 COLLABORATIVE AGREEMENTS ............................................................................ 82 
14.1 
CTEP Collaborative Agreement (CRADA, CTA, CSA)......................................... 82 
14.2 
Multi-Institutional Guidelines ............................................................................... 84 
15 HUMAN SUBJECTS PROTECTIONS .......................................................................... 84 
15.1 
Rationale For Subject Selection ............................................................................ 84 
15.2 
Participation of Children....................................................................................... 85 
15.3 
Participation of Subjects Unable to Give Consent (NIH CCR Only—Participating 
Sites should follow their Institutional Policy) ...................................................................... 85 
15.4 
Evaluation of Benefits and Risks/Discomforts ....................................................... 86 
15.5 
Consent and Assent Process and Documentation ................................................... 86 
16 PHARMACEUTICAL INFORMATION ........................................................................ 88 
16.1 
Dasatinib  (IND# 120449, NSC# 732517) ............................................................. 88 
16.2 
Ganitumab (IND# 120449, NSC# 750008) ............................................................ 89 
16.3 
Agent Ordering and Agent Accountability............................................................. 91 
17 REFERENCES .............................................................................................................. 93 
18 APPENDICES ............................................................................................................... 99 
18.1 
Appendix 1: Performance Status Criteria............................................................... 99 
18.2 
Appendix 2: Substances Prohibited During Dasatinib Treatment .......................... 100 
18.3 
Appendix 3: Information on Possible Drug Interactions ....................................... 101 
18.4 
Appendix 4: Dosing nomogram for Dasatinib for Phase I/II Trial of 
Rhabdomyosarcoma......................................................................................................... 104 
18.5 
Appendix 5: Patient’s Medication Diary – Dasatinib- Cycle 1 .............................. 105 
18.6 
Appendix 6: Patient’s Medication Diary – Dasatinib- Subsequent Cycles ............. 107 


 
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18.7 
Appendix 7: Patient’s Medication Diary – Dasatinib- Cycle 1 .............................. 109 
18.8 
Appendix 8: Patient’s Medication Diary – Dasatinib- Subsequent Cycles ............. 111 
18.9 
Appendix 9: Processing and Shipping Samples to NIH ........................................ 113 
 
 


 
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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objectives 
1.1.1.1 Phase I: To determine the safe dose of dasatinib when given with ganitumab in patients 
with relapsed or refractory embryonal or alveolar RMS. 
1.1.1.2 Phase II: To determine if the use of ganitumab plus dasatinib is able to be associated 
with a modest fraction of patients who experience an objective clinical response (CR 
and PR) as defined by RECIST criteria. In addition, a second primary objective will 
estimate the fraction that is without progression at 4 months. 
1.1.2 Secondary Objectives 
1.1.2.1 To assess the PFS in patients receiving this combination. 
1.1.2.2 To determine the fraction of patients with stable disease >= 6 months as defined by 
RECIST criteria in patients receiving this combination. 
1.1.2.3 To describe the toxicity and confirm the tolerability of the combination of ganitumab 
and dasatinib in patients with relapsed or refractory RMS. 
1.1.3 Exploratory Objectives 
1.1.3.1 To determine the genomic and proteomic profile of subjects’ tumors to identify gene 
mutations, gene amplifications, RNA-expression levels, and protein-expression levels. 
Correlations between genomic/proteomic profiles and efficacy outcomes will be 
assessed.  
 
The following specific objectives will be explored using genomic/proteomic profiles: 
1.1.3.2 To retrospectively analyze archival tissue for quantitation of IGF-1R and to correlate 
tumor responses with the presence of target. 
1.1.3.3 To examine IGF-1R expression, phospho-YES, insulin receptor expression and IGF-2 
expression in tumor tissue obtained from biopsy samples.  
1.1.3.4 To conduct genomic analysis of archival and relapse biopsy samples and compare them 
to germline samples. For these studies, patients will be co-enrolled on the pediatric 
omics study (10-C-0086). 
2 
BACKGROUND AND RATIONALE 
2.1 
INHIBITING THE INSULIN-LIKE GROWTH FACTOR TYPE 1 RECEPTOR (IGF1-R) IN 
RHABDOMYOSARCOMA (RMS):   
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. The annual 
incidence in the United States is 4-7 cases per million children under 15 years, which represents 
250 new cases per year.(1) Two major histologic subtypes exist: embryonal rhabdomyosarcoma 
(ERMS) and alveolar rhabdomyosarcoma (ARMS), the latter of which carries a particularly poor 
prognosis. Patients with metastatic or recurrent disease are essentially incurable with a 5-year 


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overall survival of less than 20%, and outcomes have only minimally improved over the past 
several decades.(2) Thus, new therapies for RMS are critically needed. 
The insulin-like growth factor (IGF) system plays an important role in the biology of many 
cancers, and for many years, a research focus of the Helman lab in the Pediatric Oncology 
Branch (POB) at the NCI has been to develop an understanding of IGF signaling in pediatric 
sarcomas. Over-expression of both the type 1 IGF receptor (IGF-1R) and its ligands has been 
observed in multiple malignancies, including pediatric sarcomas, and abnormal activation of this 
pathway contributes to sarcoma development and progression.(3-5) Downstream signaling 
cascades of IGF-1R further regulate tumor cell proliferation, survival, and metastasis through the 
MAPK/ERK and PI3K/mTOR pathways.(6) In the majority of RMS, IGF-1R is highly expressed. 
A study by Cao et al. examined 9 tumor samples from patients with ARMS and ERMS and 
found that 5 of these (roughly 60%) highly expressed IGF-1R.(7) Another study of archival tumor 
tissue reported that 90% of pediatric RMS tumors highly expressed IGF-1R by 
immunohistochemistry.(8) Thus, inhibition of IGF-1R is a potentially important therapeutic target 
in RMS.   
Monoclonal antibodies targeting IGF-1R interfere with ligand binding and decrease the 
expression of the receptor on cell surfaces by internalization and degradation of the receptor.(9-12) 
A number of these have been tested in the clinical setting. Results from a phase II trial using 
monotherapy with monoclonal antibodies against IGF-1R resulted in clinically meaningful 
responses in about 10-15% of patients with RMS. However, the vast majority of these responses 
were short-lived with a rapid onset of resistance. Specifically, a study of R1507, a monoclonal 
antibody against IGF-1R, in patients with relapsed or refractory sarcomas (RMS, osteosarcoma, 
synovial sarcoma and soft-tissue sarcoma) reported that in the RMS subset, 1 of 36 (3%) patients 
(embryonal subtype) had a PR by WHO criteria and an additional 3 of 36 (8%) patients (all 
alveolar subtype) had a decrease in tumor size that was greater than 50% noted at 6 weeks, but 
had disease progression at the 12 week time point and responses could thus not be confirmed. 
One additional RMS patient (3%) achieved a PR at 18 weeks that was not confirmed 
thereafter.(13) An additional phase II study that used cixutumumab, another monoclonal antibody 
against IGF-1R, in patients with previously treated advanced or metastatic soft-tissue sarcomas 
or Ewing family of tumors reported a 12 week PFS for RMS patients.(14) 
The development of agents targeting IGF-1R has been abandoned by pharmaceutical companies 
due to the lack of clinical benefit in adult cancers.(24-26) Because of the promising clinical activity 
in pediatric sarcomas, particularly Ewing sarcoma, the NCI (CTEP) was able to negotiate a 
CRADA with Amgen to manufacture the Amgen IGF-1R inhibitor (AMG479) for a phase II trial 
with the Children’s Oncology Group (COG). This study is a randomized phase II trial evaluating 
the addition of ganitumab to multiagent chemotherapy for patients with newly diagnosed 
metastatic Ewing sarcoma. Through this CRADA, ganitumab would also be available for this 
study.  
Work done by the Helman lab in mouse xenograft models of alveolar and embryonal RMS 
revealed a phenomenon similar to that observed in the clinical trials. Mice treated with h7C10, 
another monoclonal antibody against IGF-1R, showed a progression free period of about 9 
weeks, compared to 3 weeks in control animals. Evaluation of the tumor samples from treated 
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phosphorylation, suggesting that resistance was not due to loss of activity of the antibody against 
IGF-1R, but rather the result of a bypass resistance pathway.(7)    
2.2 
YES ACTIVATION AS A BYPASS RESISTANCE PATHWAY TO IGF-1R INHIBITION: 
YES is a member of the SRC family tyrosine kinases (SFKs), non-receptor tyrosine kinases that 
function in a number of signaling pathways necessary for cell growth, differentiation and 
survival.(15, 16) Preclinical work suggests involvement of YES in a number of solid tumor types, 
including colon carcinoma, oral squamous cell carcinoma, glioma, pancreatic cancer, 
mesothelioma, and RMS.(17-22) In RMS, YES is highly expressed in both ERMS and ARMS cell 
lines, xenografted tumors, and human tumors, although the precise mechanism through which it 
functions remains to be described. Recently, the Helman lab published preclinical work showing 
that in both embryonal and alveolar RMS models, blockade of IGF-1R results in YES activation 
and that YES activation is associated with resistance to IGF-1R blockade. In addition, 
combination blockade of IGF-1R and YES in vitro results in downregulation of phospho-AKT in 
some cell lines.  Treatment blocking both IGF-1R and YES results in enhanced growth inhibition 
of multiple cell lines of both embryonal and alveolar RMS in vitro and in vivo. Specifically, in 
vivo experiments showed that mice in groups receiving vehicle, R1507 or dasatinib alone 
reached an endpoint volume of 3000 mm3 by days 39, 45 and 69 (alveolar RMS) and days 69, 78 
and 90 (embryonal RMS), while mice receiving the combination had an average tumor size of 
only 500 mm3 at the end of the experiments (days 69 (alveolar) and 90 (embryonal)).(23) This 
inhibition occurs at concentrations that are achievable in humans. The average dasatinib plasma 
concentration at once daily dosing at 60 mg/m2 (33 nM) exceeds the IC50 of dasatinib in 
combination with R1507 (10 nM) in RMS cell lines.(23, 27) For R1507 the minimum plasma 
concentration on a once per week dosing schedule (3300 µM) exceeds the IC50 (100 nM) in RMS 
cell lines.(23, 28) These data provide the rationale for the clinical evaluation of the combination of 
IGF-1R and YES blockade in RMS.  
2.3 
RATIONALE FOR COMBINING IGF-1R INHIBITION AND YES/SFK INHIBITION IN RMS IN 
A PHASE I/II STUDY:  
Clinical data demonstrate that the activity of IGF-1R antibody therapy in RMS is limited by a 
rapid onset of acquired resistance. Based on preclinical data showing that YES mediates this 
resistance in some embryonal and alveolar RMS and preclinical data demonstrating that the 
combination of IGF-1R inhibition with YES inhibition overcomes this resistance resulting in 
sustained inhibition of RMS growth (23), we are proposing a phase I/II study of the combination 
of ganitumab and dasatinib. As preclinical data do not suggest a difference in response between 
ERMS and ARMS (23), and due to the relative rarity of RMS, we will not stratify this study to 
separate the histologies.  
Inhibition of IGF-1R by ganitumab occurs at concentrations that are achievable in humans.(29) In 
vitro RMS cell growth inhibition by dasatinib occurs at concentrations that are achievable in 
humans.(23, 27) However, there are no human studies that report on the concentrations needed to 
inhibit YES phosphorylation in rhabdomyosarcoma. In addition, while the combination of these 
specific agents has not been evaluated clinically, IGF-1R antibodies have been combined with 
multiple agents at full dose and have been well tolerated. Further, these two agents do not have 


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serious overlapping toxicities and there is an unmet need for better therapies for patients with 
embryonal and alveolar RMS, particularly in the setting of metastatic disease or relapse.  
2.4 
DASATINIB 
Dasatinib (BMS-354825), an aminothiazole analogue, is an orally administered (PO) protein 
tyrosine kinase (PTK) inhibitor with specificity for five kinases/kinase families that have been 
strongly linked to multiple forms of human malignancies.(30-32) These targets include:  BCR-
ABL, c-SRC, c-KIT, PDGFβ receptor, and EPHA2.  In vivo and in vitro studies have established 
that dasatinib demonstrates potent antiproliferative activity in a wide spectrum of cancer cell 
lines/types, and clinical results suggest anticancer activity of dasatinib in chronic myelogenous 
leukemia (CML) and solid tumor patients.(33-36) 
Dasatinib potently and selectively inhibits the five oncogenic PTKs/kinase families by 
competing with ATP for the ATP-binding sites in the kinases:  SRC family kinases (IC50:  SRC = 
0.55 nM, LCK = 1.1 nM, YES = 0.41 nM, FYN = 0.2 nM); BCR-ABL (<3 nM); c-KIT (13 nM); 
EPHA2 (17 nM) and PDGF receptor (28 nM).(32) The agent was found to be less potent against 
unrelated PTKs and several serine/threonine kinases.  Dasatinib also demonstrates potent 
inhibition of VEGF- and bFGF-driven proliferation of human umbilical vein endothelial cells 
(HUVECs), with IC50 values of 43 and 248 nM, respectively. 
BCR-ABL, a constitutively active cytoplasmic tyrosine kinase, is present in >90% of all patients 
with CML and in 15-30% of adult patients with acute lymphoblastic leukemia (ALL).  The 
inhibition of BCR-ABL by imatinib, another PTK inhibitor, is effective in the management of 
CML thus providing proof-of-concept for targeting PTKs.  However, resistance to imatinib 
therapy associated with BCR-ABL gene mutation/over-expression and activation of selected 
SRC kinases has been increasingly encountered.(37) Dasatinib has activity in a number of 
imatinib-resistant tumors,(38-42) in addition to being 500-fold more potent than imatinib in 
inhibiting BCR-ABL.  The ability of dasatinib to inhibit imatinib-resistant forms of BCR-ABL is 
presumed to be due to its relaxed binding requirements because, unlike imatinib which binds 
only to the inactive conformation of the BCR-ABL kinase, dasatinib binds to both the active and 
inactive conformations.(43) 
2.4.1 Nonclinical Studies 
2.4.1.1 Efficacy 
Dasatinib inhibits growth of multiple BCR-ABL-dependent leukemic cell lines and also shows 
activity against 14 of 15 imatinib-resistant BCR-ABL kinase mutants.(41) Inhibition of CML cell 
lines established from patients who were resistant to imatinib therapy has also been reported.(36) 
Dasatinib potently inhibits wild-type (IC50:  1-10 nM) and mutant (IC50:  10-100 nM) KIT 
kinases in M07E cells and human mast cell leukemia cell lines, respectively.(34) Also of note, 
dasatinib selectively killed primary neoplastic bone marrow mast cells from patients with 
systemic mastocytosis while sparing other hematopoietic cells.(44) 
Dasatinib demonstrated antiproliferative activity in a wide-spectrum of solid tumor types, 
including mastocytoma, prostate, and breast cell lines with IC50 values ranging from 5.4-103 
nM.(32) The agent also inhibited stem cell factor-driven proliferation of three small cell lung 


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cancer (SCLC) cell lines with IC50 values in the range of 114-220 nM and showed activity in 
head and neck squamous cell carcinoma and non-small cell lung cancer cell lines.(45) 
When dasatinib was administered twice daily (BID) on a 5-days-on/2-days-off schedule for a 
total of 14 to 25 days at doses of 10-50 mg/kg/dose, in vivo antitumor activity of dasatinib was 
seen in prostate, colon, breast, and pancreatic  xenograft models.(32) Similarly, dasatinib was 
effective against K562 and imatinib-resistant K562-R human CML xenografts in SCID mice at 
doses as low as 2.5-5 mg/kg/day.(42) In combination with docetaxel, dasatinib produced 
antitumor effects against PC3 human prostate carcinoma xenografts that were substantially better 
than the effects of either single agent alone.(32)  
Dasatinib at 20 or 50 mg/kg inhibited the T-cell proliferation response in mice following the 
transfer of lymphocytes from allogeneic donor mice.(32) In addition, treatment of mice with 
dasatinib 25 mg/kg BID inhibited the graft-versus-host response in a non-vascularized model of 
murine heart transplant.  The 5-days-on/2-days-off regimen almost completely eliminated 
immunosuppressive activity in this model. 
SRC kinase is known to play a major role in osteoclast function.  In short-term studies, dasatinib 
acted as a potent inhibitor of bone resorption as measured by its ability to reduce the release of 
45calcium into the culture medium by fetal rat long bones in vitro (IC50 = 2 nM).  Dasatinib also 
inhibited parathyroid hormone (PTH)-stimulated release of 45calcium in a dose-dependent 
manner with an apparent IC50 of 2 nM.  At 5 nM, dasatinib completely blocked PTH-stimulated 
bone resorption in thyro-parathyroidectomized rats.  The therapeutic utility of dasatinib in the 
treatment of cancer-related hypercalcemic syndromes has not been fully explored, and the long-
term effects of dasatinib on bone physiology are also unknown. 
2.4.1.2 Nonclinical Pharmacokinetic and Pharmacodynamic Studies 
Nonclinical metabolic and pharmacokinetic (PK) studies were conducted with dasatinib in 
several species including mouse, rat, dog, and monkeys to assess the absorption, distribution, 
metabolism, and excretion of the compound in animals.  These studies showed that dasatinib has 
varying degrees of oral bioavailability, ranging from 15% in monkeys to 34% in dogs.  The 
permeability of dasatinib in the Caco-2 cell model is 102 nm/sec at pH 7.4, suggesting that it has 
the potential for good (>50%) oral absorption in humans.  The agent is highly bound to serum 
proteins (>91%) and has extensive extravascular distribution.  Dasatinib is principally eliminated 
by hepatic metabolism and excreted in feces.  The agent is primarily metabolized by the 
CYP3A4 enzyme to produce multiple metabolites.   
The value of phospho-SRC as a biomarker of dasatinib efficacy has been explored in nonclinical 
studies.(46) In nude mice bearing subcutaneous PC-3 tumors (human prostate), measurement of 
phospho-SRC by western blot in tumor and peripheral blood mononuclear cells (PBMCs) 
following treatment with a single dose of dasatinib (15 or 50 mg/kg) produced similar results in 
both tissues.  Levels of phospho-SRC were maximally inhibited at 3 hours post dose, then 
recovered partially between 7 and 17 hours and returned to the basal level by 24 hours after 
agent administration.  These results were quantitated by image scanning and compared to 
efficacy results when the agent was administered PO BID at 15-50 mg/kg/dose for 14 days on a 
5-days-on/2-days-off schedule.  Efficacy and phospho-SRC inhibition appeared to correlate, and
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dasatinib required to produce 90% inhibition of phospho-SRC would be 164 nM and 91 nM in 
PC-3 tumor and PBMCs, respectively.  Studies to evaluate the clinical utility of phospho-SRC as 
a biomarker are ongoing. 
2.4.1.3 Toxicology 
A range of toxicology studies have been conducted to support the oral administration of dasatinib 
in humans.  The oral studies indicated that dasatinib induced reversible toxicities of the 
gastrointestinal (GI) and lymphoid systems in rats and monkeys, and of the hematopoietic system 
in rats.  Embryofetal development studies in rats and rabbits indicated that dasatinib caused 
embryolethality or skeletal malformations at doses that did not cause maternal toxicity, 
suggesting that it is a selective developmental toxicant.  An in vitro cytogenetics study in CHO 
cells indicated that it was clastogenic at concentrations >5 μg/mL, a level not achievable in vivo.  
The agent is nongenotoxic and did not show significant potential for undesirable functional 
activity in in vitro receptor/ion channel binding and enzyme assays.  In vitro potassium channel 
current (HERG/IKr) and Purkinje fiber assays suggested that dasatinib could potentially prolong 
cardiac ventricular repolarization (QT interval), and a single-dose cardiovascular study in 
monkeys demonstrated that the agent at a dose of 10 mg/kg caused a minimal increase in blood 
pressure for approximately 2 hours post dose.  There were no drug-related neurologic 
observations in rats or monkeys.  Dasatinib was found to be phototoxic in an in vitro assay in 
mouse fibroblasts. 
2.4.2 Clinical Experience 
Over 2000 subjects have received dasatinib, the majority with CML refractory or intolerant to 
imatinib.(32) Studies conducted in healthy volunteers include the following:  PK; formulation 
comparisons; the effect of food; drug interactions; and supportive care.  Data are available from 
11 phase I and phase II studies in patients with CML, Philadelphia chromosome-positive (Ph+) 
ALL, or solid tumors using different dosage regimens and designed to determine PK, 
pharmacodynamics, safety, and efficacy in these populations.  
Dasatinib is a multi-target tyrosine kinase inhibitor that targets SFKs, including YES. Dasatinib 
has been approved for the treatment of certain forms of CML and ALL. In adults with CML, the 
recommended dosing is 100 mg/day (approximately equivalent to 60 mg/m2/day).(27) In a phase I 
study in pediatric patients, the recommended dosing was 85 mg/m2/dose twice daily for patients 
with solid tumors. The dose-limiting toxicities in this study were headache and diarrhea. Several 
patients who received multiple courses of dasatinib experienced pleural effusions.(27) In 
combination studies, 100 mg/day of dasatinib has been the dose when used with gemcitabine or 
CCNU in adults.(47, 48) This is the dose we propose for this combination study. The most common 
toxicities that have been reported with combination use of dasatinib in patients with non-
hematologic malignancies are nausea, fatigue, transaminitis, and cytopenias. Rare pleural 
effusions and rash have also been reported.(27, 33) Dasatinib is available in tablet sizes of 5 mg, 20 
mg, 50 mg, 70 mg, 80 mg and 100 mg. 
2.4.2.1 Pharmacokinetics 
Pharmacokinetic (PK) studies were conducted using a single 100 mg dose of dasatinib 
administered to healthy volunteers in four different formulations:  50 mg clinical tablets x 2, 5 
mg clinical tablets x 20, 20 mg commercial tablets x 5, and 50 mg commercial tablets x 2.  The 


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PK profile of the agent was similar in all four formulations.  The PK profile of dasatinib was also 
assessed in CML and Ph+ ALL patients providing data which showed that the PK parameters in 
the patient population appear to be similar to that in the healthy volunteers.  The agent was 
absorbed rapidly following oral administration; peak plasma concentrations were achieved in 
0.5-3 hours and dose-related increases in plasma concentrations were observed.  The mean 
terminal half-life (t1/2) of dasatinib was 4 hours.  Dosing interval exposures and t1/2 values were 
comparable regardless of whether the agent was administered on a once daily or twice daily 
(BID) 5-day-on/2-day-off schedule, or BID continuously. 
A phase I study has been initiated in solid tumor patients to determine the effect of the CYP3A4 
inhibitor ketoconazole on dasatinib PK.  In a study of 18 patients with solid tumors, 20 mg of 
dasatinib once daily coadministered with 200 mg of ketoconazole twice daily increased the 
dasatinib Cmax and AUC by four- and five-fold, respectively. 
2.4.2.2 Efficacy 
A phase I study treated patients with CML in chronic phase (CP) or advanced disease 
(accelerated phase or blast crisis) or Ph+ ALL who were intolerant or resistant to imatinib.(38, 49) 
Dasatinib was administered once daily at doses ranging from 15 to180 mg/day or BID at doses 
ranging from 25 to 50 mg for 5-7 consecutive days each week.  Complete hematologic response 
was documented in 37 of 40 CP patients (92%) and the rate was similar with both schedules 
(once daily or BID).  Fourteen CP patients (35%) achieved a complete cytogenetic response and 
four (10%) experienced partial responses.  In 44 patients with advanced CML or Ph+ ALL, 31 
major hematologic responses were documented (70%).  Cytogenetic responses were documented 
in 25 advanced CML or ALL patients, including complete responses in 11 patients. 
A phase I study has been conducted in patients with refractory solid tumors in order to evaluate 
the safety, tolerability, and the pharmacologic profile of dasatinib.(33) Patients received escalating 
doses (25 to 120 mg) of dasatinib without food administered BID for 5 consecutive days every 
week followed by 2 days of rest (5D2 schedule), or on a continuous daily dosing (CDD) 
schedule.  There were no objective responses on CT scans, but stable disease (SD) was observed 
in 11 patients (16%), including three gastrointestinal stromal tumor (GIST) patients.  These 11 
were comprised of seven (21%) of 33 patients on the 5D2 schedule and four (12%) of 34 patients 
on the CDD schedule.  The median duration of SD was 3.6 months (range 1.7 – 23.6 months).  
The investigators noted that the clinical benefits of the agent in a subset of imatinib-resistant 
GIST patients have been encouraging. 
In solid tumors, the recommended phase II dose for dasatinib in adult patients was found to be 
120 mg BID on the 5D2 schedule, or 70 mg BID on the CDD regimen.(33) In pediatric patients 
with solid tumors, the recommended phase II dose for dasatinib was found to be 85 mg/m2 
BID.(27) In October 2010, dasatinib was approved by the FDA for treatment of chronic, 
accelerated, and blast phase CML and Ph+ ALL with resistance or intolerance to imatinib.  
Results from two phase 3 dose-optimization studies supported starting doses of 100 mg once/day 
for CP CML and 140 mg once/day for imatinib-resistant accelerated phase CML, myeloid or 
lymphoid blast phase CML, or Ph+ ALL.  A randomized phase 3 trial comparing dasatinib to 
imatinib led to FDA approval of dasatinib (100 mg once/day) for first-line therapy of newly 
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2.4.3 Safety 
Myelosuppression, probably attributable to suppression of the Ph+ clone, was the most frequent 
adverse event (AE) in the phase I study in CML or Ph+ ALL, while the most significant AE was 
grade 3/4 thrombocytopenia (28%).(32) Severe myelosuppression was reversible and easily 
managed with a short dose interruption; about 60% of patients required interruption of treatment, 
and the myelosuppression generally resolved within 3 months, often in association with a 
cytogenetic response.(38) Twenty-five percent of leukemia patients required a dose reduction.  In 
the phase I study in solid tumor patients, hematologic AEs were uncommon:  two patients on the 
5D2 schedule with grade 1 or 2 anemia developed grade 3 anemia while on study drug, whereas 
on the CDD schedule one patient developed grade 4 neutropenia and another grade 3 anemia.(33)  
Non-hematologic AEs from the two phase I trials include GI intolerance (primarily diarrhea, 
nausea, and vomiting), GI hemorrhage, fatigue, dyspnea, anorexia, dehydration, fluid retention, 
pleural and pericardial effusion, a moderate increase in QTcF (with no QTcF >500 msec), 
elevated creatinine, depression, and tumor lysis syndrome.  In addition to these AEs, dasatinib 
treatment has the potential to produce skin rashes, other respiratory events, and CNS 
hemorrhage.  While neither immunosuppression nor osteoclast function abnormalities (e.g., 
osteoporosis) were observed in these short-term studies, SRC kinase inhibitors have the potential 
to cause these types of events.  
As of September 2010 in the overall population of 2840 subjects, a total of 740 (26%) deaths 
were reported in adult dasatinib-treated subjects with CML or Ph+ ALL.  Of these 740 deaths, 
296 occurred within 30 days of the last dose of study therapy.  Of the 740 deaths, 380 (51%) 
were due to disease progression and 11 (1.5%) have been positively attributed to study drug 
toxicity.  
2.4.3.1 Potential Drug Interactions 
Dasatinib is primarily metabolized by CYP3A4 and therefore, potent inhibitors of this enzyme 
are contraindicated.(32) Dasatinib is also a significant inhibitor of this hepatic enzyme but a weak 
inhibitor of other cytochrome enzymes, and the agent does not induce CYP3A4.  Thus, dasatinib 
may decrease the clearance of drugs that are significantly metabolized by the CYP3A4 enzyme, 
and caution should be used with concurrent use of such drugs or substances.  In a study in cancer 
patients, concomitant use of a potent CYP3A4 inhibitor (ketoconazole) produced >5-fold increase 
in exposure to dasatinib, while healthy subjects treated concurrently with dasatinib and a potent 
CYP3A4 inducer experienced a 5-fold decrease in dasatinib exposure.  When the CYP3A4 substrate 
simvastatin was studied in combination with dasatinib, increased simvastatin exposure resulted, 
indicating the necessity of caution when dasatinib is administered with CYP3A4 substrates with a 
narrow therapeutic margin (e.g., cyclosporine). 
2.5 
GANITUMAB 
Ganitumab is a fully human monoclonal antibody directed against IGF-1R that exerts its 
antitumor effect by inhibiting IGF1R activation through blockade of ligand binding (IGF-1 and 
IGF-2) to the extracellular domain of IGF-1R, and induction of receptor internalization and 
degradation, without cross-reacting with the insulin receptor. Blockage of ligand binding inhibits 
cell survival and proliferative signals and, consequently, suppresses tumor cell growth and 
invasion. Inhibition of IGF1R signaling with ganitumab provides a potential mechanism for 


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inhibiting tumor growth either alone or in combination with other anticancer therapy. (50) 
The drug has high affinity for IGF-1R, with a KD of 0.3 nM. The IC50 for blocking IGF-1R 
phosphorylation in the presence of IGF-1 or IGF-2 is 0.6 nM.(50) 
2.5.1 Non-clinical studies 
2.5.1.1 Efficacy 
In vitro studies demonstrated high-affinity binding of ganitumab to human (dissociation constant 
(51) = 0.30 nM), cynomolgus monkey (Kd = 0.15 nM), rat (Kd = 0.25 nM), and mouse (Kd =
0.30 nM) IGF1R. Ganitumab inhibited the interaction of IGF1R with both of its natural ligands
(IGF-1 and IGF-2) equally without cross-reacting with the insulin receptor. Ganitumab inhibited
IGF-1- and IGF-2-mediated IGF1R activation, Akt activation, and DNA synthesis in cells
engineered to express IGF1R and in human cancer cell lines. As monotherapy, ganitumab
demonstrated activity in human sarcoma, breast carcinoma, colon carcinoma, ovarian carcinoma,
and pancreatic carcinoma xenograft models. The activity of ganitumab in vivo was driven by
ligand blockade and receptor down-regulation, which resulted in apoptosis and/or lower rates of
cellular proliferation. In a number of tumor xenograft models, ganitumab also enhanced the
antitumor activity of chemotherapeutic agents, such as irinotecan, gemcitabine, and
cyclophosphamide, and targeted agents, such as rapamycin, panitumumab, and erlotinib. The
treatment of mice with ganitumab led to increased serum levels of IGF 1, insulin-like growth
factor binding protein 3 (IGFBP-3), and growth hormone and to decreased peripheral blood
neutrophils.(50) 
2.5.1.2 Nonclinical Pharmacokinetic and Pharmacodynamic Studies 
Exposure to ganitumab increased approximately dose-proportionally after single and multiple IV 
or intraperitoneal administrations in normal cluster of differentiation 1 (CD-1) mice, Sprague-
Dawley rats (0.12 to 120 mg/kg), and in cynomolgus monkeys (0.1 to 100 mg/kg). Antibodies to 
ganitumab were observed in rats and cynomolgus monkeys, with apparent increased drug 
clearance in some of the antibody-positive animals after IV administration of ganitumab. 
Terminal elimination half-life (t1/2, z) values ranged from 4 to 6 days in cynomolgus monkeys in
the absence of anti-ganitumab antibodies. Toxicokinetics of ganitumab did not markedly differ 
between male and female animals.(50) 
2.5.1.3 Toxicology 
A comprehensive package of toxicology studies was performed, including repeated-dose IV 
toxicity studies of up to 6 months in the rat and 9 months in the cynomolgus monkey, safety 
pharmacology studies (neurobehavioral and cardiovascular/respiratory in the rat and monkey, 
respectively), maternal and embryo-fetal developmental study in the pregnant rat, and tissue 
cross-reactivity studies in tissue sections from humans and the preclinical species. The Sprague-
Dawley rat and cynomolgus monkey were selected as the nonclinical toxicology species because 
the in vitro potency and functional activity of ganitumab in rats and monkeys is similar to the 
potency in humans.  Ganitumab administration primarily affected body weight, food 
consumption, clinical pathology parameters, liver, kidney, thymus, and reproductive organs in 
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evaluated cardiovascular (electrocardiogram parameters including corrected QT interval [QTc]), 
CNS, and respiratory effects of ganitumab at doses up to 300 mg/kg.(50) 
2.5.2 Clinical Experience 
In a phase I study in 53 adults with advanced solid tumors, a dose of 20 mg/kg given IV once 
every 2 weeks was deemed tolerable (MTD was not reached), though biochemical blockade was 
achieved at levels of 12 mg/kg IV every 2 weeks. Four of 23 patients treated at the 20 mg/kg 
dose level developed Grade 3 thrombocytopenia. The only other Grade 3 toxicities noted across 
dose levels were arthralgia (n=1); diarrhea (n=1); and fatigue (n=1). Hyperglycemia and 
hypothyroidism were also reported.(52) An adult phase II study with patients with Ewing family 
tumors and desmoplastic small round cell tumors used a dose of 12 mg/kg given IV once every 2 
weeks and reported similar toxicities, most commonly fatigue, thrombocytopenia, and 
hyperglycemia.(53) When used in combination with other agents including conatumumab, 
gemcitabine, panitumumab, erlotinib, and sorafenib, doses of AMG479 between 12 mg/kg and 
20 mg/kg IV every 2 weeks have been tolerated in adults. Frequent toxicities in the combination 
studies include fatigue, nausea and vomiting. Frequent grade 3 toxicities in these combination 
studies included neutropenia, thrombocytopenia and hyperglycemia.(54-57) The combination of 
ganitumab (12 mg/kg IV every 2 weeks) to gemcitabine improved 6-month overall survival in 
patients with advanced pancreatic cancer in a phase II trial,(58) though a randomized phase 3 trial 
testing this combination in advanced pancreatic cancer was stopped early when futility stopping 
rules were met. 
The pharmacokinetic profile of ganitumab appears to differ somewhat between adult patients 
with various solid tumors and adult patients with Ewing sarcoma and DSRCT treated on a phase 
II trial.(53) Specifically, patients on this phase II trial treated with 12 mg/kg every 2 weeks had 
lower trough concentrations after their first and third doses of ganitumab compared to patients 
with relapsed solid tumors treated on 2 other studies with this same dose and schedule. The mean 
± SD trough concentration after Cycle 1 was 17.5 ± 8.52 μg/mL for EWS/DSRCT vs. 22 ± 11 
μg/mL and 26.1 ± 12.5 μg/mL for other solid tumors. The mean ± SD trough concentration after 
Cycle 3 was 15.9 ± 33.6 μg/mL for EWS/DSRCT vs. 27 ± 15.9 μg/mL and 42.2 ± 18.5 μg/mL 
for other solid tumors.(50) 22 of 29 patients (75%) with EWS/DSRCT had ganitumab trough 
concentrations > 10 μg/mL after a single dose of 12 mg/kg.(53) 
2.5.3 Rationale for Proposed Ganitumab Starting Dose  
While a pediatric phase I clinical trial of ganitumab has not been performed, several points 
suggest that proceeding with the proposed pediatric and adult study based on the adult 
experience with this drug is reasonable. First ganitumab is currently being used in a randomized 
Phase II trial conducted by COG in combination with a standard chemotherapy backbone of 
vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide in pediatric patients with 
newly diagnosed metastatic Ewing Sarcoma (activation data 12/8/2014; NCT02306161).  
Second, IGF-1R monoclonal antibodies as a class have been well tolerated in both adults and 
children. Finally, of the compounds in this class in which adult and pediatric phase I studies have 
been performed, the recommended pediatric dose has not been lower than the adult dose. For 
example, the recommended pediatric phase II dose of IMC-A12 is 9 mg/kg weekly (59), which 
compares favorably to the adult recommended phase II dose of 6 mg/kg weekly.(60) Likewise, for 


 
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dalotuzumab, the recommended pediatric phase II dose (900 mg/m2 IV every 3 weeks) was 
similar to the recommended adult phase II dose.(61) Third, the dose used in this study is below the 
maximum dose evaluated and deemed tolerable in the adult single agent phase I study.  
The starting dose of ganitumab for this study will be 18 mg/kg. This dose was selected for 
several reasons. First, biochemical blockade of IGF-1R signaling is observed at serum 
concentrations > 10 μg/mL.(29) Blockade of IGF-1R epitope binding on neutrophils also begins to 
saturate at serum concentrations of 10 μg/mL.(50) Trough serum concentrations in excess of this 
target trough concentration value of 10 μg/mL are anticipated using 18 mg/kg, extrapolating 
from the experience from the phase II trial of young adults with relapsed Ewing sarcoma treated 
with 12 mg/kg. These trough serum concentrations compare favorably with the IC50 of ganitumab 
in 2 Ewing sarcoma cell lines of 1.6 and 3.7 nanomolar (0.54 μg/mL and 0.23 μg/mL). (62) In in 
vivo studies of ganitumab against mouse Ewing sarcoma xenografts, activity was noted at doses 
of ganitumab that yield steady state serum concentrations of 4.7 μg/mL.(62) Second, experience 
with ganitumab and other IGF-1R monoclonal antibodies have demonstrated clinical activity in 
patients with Ewing sarcoma at doses below maximal evaluated dose levels of 20 mg/kg. (53, 59) 
For example, the phase II trial of ganitumab in patients with relapsed Ewing sarcoma used 12 
mg/kg IV every 2 weeks.(53) Third, combination studies have evaluated doses of 12-20 mg/kg 
every 2 weeks.(58) Fourth, given the risk of thrombocytopenia that has been observed with IGF-
1R monoclonal antibodies,(12, 52, 59) use of maximal studied doses of ganitumab (20 mg/kg) may 
not be feasible in combination with other agents.  
2.6 
PROPOSED TRIAL: 
2.6.1 Dose Selection for Phase I/II Design 
This is a phase I/II trial to test the combination of ganitumab and dasatinib in patients with 
refractory or relapsed embryonal or alveolar rhabdomyosarcoma. The ganitumab dose for both 
the phase I and phase II components will be 18 mg/kg IV every 2 weeks, starting on day 0, based 
on published data indicating that this dose inhibits the target and is tolerable in combination with 
other therapies (see section 2.5.3). The starting dasatinib dose will be 60 mg/m2 daily, which is 
the dose that has historically been used in combination with other therapies. For cycle 1, 
dasatinib dosing will begin on day -7 to preemptively inhibit YES prior to ganitumab dosing. For 
subsequent cycles, both agents will begin on day 0. Based on in vitro data generated in RMS cell 
lines, it is expected that this dose will produce concentrations high enough to inhibit the target. 
However, given the dearth of data on inhibition of YES with dasatinib in human tumors and the 
fact that in solid tumor studies, the recommended phase II doses were significantly higher both 
for adult and pediatric patients, we propose a phase I dose escalation from 60 mg/m2/dose once 
daily (maximum 100 mg/day) to 60 mg/m2/dose BID (maximum 70 mg BID). This higher dose 
is still below the recommended phase II dose in pediatric patients with solid tumors, and 
equivalent to the recommended phase II dose in adult patients with solid tumors.(27, 32)  
The design will be a phase I lead in using a standard 3 + 3 design. Limited dose escalations will 
be performed to define the maximum tolerated dose (MTD) or the highest safe dose tested of 
dasatinib when given in combination with ganitumab in this patient population (see section 5.1.1 
for details). In the phase II component, sixteen (16) evaluable patients, including up to 6 patients 
from the phase I portion treated at the selected phase II dose, will be enrolled. 


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Once the recommended phase II dose of dasatinib in combination with ganitumab (18 mg/kg) is 
determined, enrollment on the phase II portion of the trial will commence. We expect that the 18 
mg/kg dose of ganitumab will be tolerated. However, we will limit enrollment to 6 patients 
initially to assess the toxicity of this combination at the recommended dose, since these two 
agents have not been assessed in combination previously. Provided ≤1/6 patients experience 
toxicities clearly attributable to ganitumab, the remainder of the patients will be treated using the 
ganitumab dose of dose of 18 mg/kg. If 2 or more of the initial 6 patients experience toxicity 
requiring a dose modification and the toxicities can be clearly attributed to ganitumab only, the 
ganitumab dose will be reduced to 12 mg/kg for all subsequent patients.  
2.6.2 Patient Selection 
Ideally, this trial would select patients with tumors that express IGF-1R. However, there are a 
number of issues that make prospective identification of these patients impractical. IHC, which 
could be performed as a pre-enrollment evaluation, has not been shown to reliably demonstrate 
IGF-1R expression. The preferred method to detect IGF-1R expression is with selection reaction 
monitoring (SRM) mass spectrometry and this will be done retrospectively in this trial. However, 
it is not feasible to perform this testing and obtain results prior to enrollment of each patient. 
Given that, tumor IGF-1R expression will not be an eligibility criteria. Based on published data, 
we expect the majority of patients to express IGF-1R on their tumors. Once the retrospective data 
on IGF-1R expression is available it will be analyzed and if a significant number of patients are 
identified to have no IGF-1R expression, we will consider amending the trail to enroll more 
patients. 
2.6.3 Endpoint Selection 
Historically, pediatric phase II trials have used tumor shrinkage based on RECIST or WHO 
criteria as a measure of response. However, a number of targeted agents have received FDA 
approval recently based on prolongation of survival or progression free survival, without 
evidence of a substantial number of RECIST responses. We hypothesize that improved 
progression free survival (PFS) may be a more meaningful measurement of clinical activity of 
targeted agents for our population. 
An analysis of 85 patients with RMS enrolled on 7 negative phase II COG trials revealed that 
88% of patients on those trials experienced disease progression by 4 months and 93% progressed 
by 6 months.(63-69) Upon review of the aforementioned studies, 4/7 (irinotecan, vinorelbine, 
rebeccamycin analogue, docetaxel) stated in their eligibility requirements that patients who had 
undergone more than 2 prior regimens were ineligible.  For the remaining 3 studies (oxaliplatin, 
topotecan, ixabepilone), the median number of prior regimens was 2. Additionally, the 
oxaliplatin study analyzed the number of prior regimens patients had received and found no 
significant difference in the number of prior treatments between responders and non-responders. 
It would be unlikely that patients would be referred for enrollment on our trial immediately after 
their first relapse. This trial uses only targeted agents, and most centers first attempt salvage with 
a regimen using a cytotoxic backbone in first relapse or primary refractory rhabdomyosarcoma. 
Thus, we expect the majority of patients enrolling will have been treated with 2 or more prior 
therapies, making them more refractory and likely to have an expected PFS of 12% or less at 4 
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Since our goal is to identify active agents that could be integrated into therapy at earlier time 
points, for example in the upfront setting, standard objective response measurements in the 
setting of relapse and refractory disease may be inadequate methods to detect activity of these 
agents in aggressive tumors such as rhabdomyosarcoma. Hence, we have selected co-primary 
endpoints of objective clinical response (CR and PR) as defined by RECIST criteria and the 4-
month disease stabilization fraction (see section 13). 
3 
PATIENT SELECTION  
3.1 
ELIGIBILITY CRITERIA 
3.1.1 Inclusion Criteria 
3.1.1.1 Patients of any age must have histologically or cytologically confirmed embryonal or 
alveolar rhabdomyosarcoma (RMS) confirmed by the Laboratory of Pathology, NCI or 
by the Department of Pathology and Laboratory Medicine, CHLA. 
3.1.1.2 Patients must have measurable disease as per RECIST (version 1.1). 
3.1.1.3 Patients must be able to undergo appropriate imaging studies to monitor tumor 
response.  
3.1.1.4 Archival tissue of tumors (slides or blocks (blocks preferred) must be available for 
analysis. If tissue is not available, patients willing to undergo a pre-treatment biopsy 
may enroll.  
3.1.1.5 Prior Therapies: 
• There is no maximum number of prior medical therapies. 
• There must be no curative or life prolonging treatments available. 
• Patients who have received other IGF-1R antibodies or inhibitors are eligible, as long as 
an appropriate washout period has elapsed (see below). 
• Participants must have had their last fraction of external beam radiation therapy that is 
local and palliative at least 2 weeks prior to enrollment (except for radiation therapy to 
the lungs as noted below), and had their last substantial bone marrow radiation at least 6 
weeks prior to enrollment.  
• Participants must have had their last radiation therapy of the lungs at least 8 weeks prior 
to enrollment.  
• Participants must have had their last dose of temozolomide at least 4 weeks prior to 
enrollment; their last dose of other cytotoxic chemotherapy at least 3 weeks prior to 
enrollment; their last dose of biological therapy, such as biological response modifiers 
(e.g., cytokines), immunomodulatory agents, vaccines, differentiating agents, used to 
treat their cancer at least 7 days prior to enrollment, their last dose of a monoclonal 
antibody the shorter of  3 half- lives or 28 daysprior to enrollment, and their last dose of 
any investigational agent at least 4 weeks prior to enrollment. 


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•
Participants must have recovered from the acute toxic effects of prior therapy to a grade 1
(CTCAE v.5.0) level prior to enrollment (does not apply to alopecia).
3.1.1.6 Age. There are no age limits for this study, but patients must have the ability to swallow 
tablets. 
3.1.1.7 ECOG performance status <2 or Karnofsky >50% (if ≥ 16 years of age); or children < 
16 years old must have a Lansky performance of ≥50% (see Appendix 1). 
3.1.1.8 Patients must have normal organ and marrow function as defined below: 
−absolute neutrophil count
>1,000/mcL
−platelets
>75,000/mcL
−total bilirubin
≤1.5X upper limit of normal (ULN),
with exception of patients with Gilbert
syndrome
−ALT
≤ 3.0X ULN
−creatinine
within normal institutional limits
OR 
−creatinine clearance
>60 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal.
−Normal blood glucose for age
3.1.1.9 Hematologic parameters for patients undergoing biopsy only: Patients should have INR 
<1.4 and PTT ≤ 40 seconds (unless due to lupus anticoagulant). In patients not meeting 
these parameters, clearance by hematology will be required prior to undergoing a 
biopsy. 
3.1.1.10 Cardiac Function: QTcF < 480 msec (Fridericia correction), and ejection fraction (EF) ≥ 
50% 
3.1.1.11 Contraception 
The effects of these agents on the developing human fetus are unknown.  For this reason, men 
and women of child-bearing potential must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for 4 months after completion of administration of either agent.  Should a 
woman become pregnant or suspect she is pregnant while she or her partner is participating in 
this study, she should inform her treating physician immediately.  
Negative pregnancy test is required for women of childbearing potential. 
3.1.1.12 Ability of subject or Legally Authorized Representative (LAR) to understand and the 
willingness to sign a written informed consent document. 
3.1.1.13 Patients will be strongly encouraged to participate in 10-C-0086. If a patient does not 
agree to enroll on 10-C-0086, germline genetic analysis will not be performed. 
3.1.2 Exclusion Criteria 
3.1.2.1 Patients who are receiving any other investigational agents. 


 
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3.1.2.2 Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
3.1.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to dasatinib or ganitumab or other agents used in study. 
3.1.2.4 Patients who require concurrent treatment with any medications or substances that are 
potent inhibitors or inducers of CYP3A4 are ineligible.  (See Appendix 2 for lists of 
specifically prohibited medications or substances.) 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list or medical reference text such as the Physician’s Desk 
Reference. As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product.  (See Appendix 3)  
3.1.2.5 Patients who require concurrent treatment with antithrombotic and/or anti-platelet 
agents (e.g., warfarin, heparin, low molecular weight heparin, aspirin, and/or 
ibuprofen).  
3.1.2.6 Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to 
take oral medication or a requirement for IV alimentation, prior surgical procedures 
affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow 
and retain dasatinib tablets are excluded. 
3.1.2.7 Patients with a history of radiation pneumonitis. 
3.1.2.8 Patients may not have any clinically significant cardiovascular disease including the 
following: 
• myocardial infarction or ventricular tachyarrhythmia within 6 months 
• major conduction abnormality (unless a cardiac pacemaker is present). 
Patients with any cardiopulmonary symptoms of unknown cause (e.g., shortness of breath, chest 
pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as 
needed in addition to electrocardiogram (EKG) to rule out QTc prolongation.  The patient may 
be referred to a cardiologist at the discretion of the principal investigator.  Patients with 
underlying cardiopulmonary dysfunction should be excluded from the study. 
3.1.2.9 Uncontrolled intercurrent illness including, but not limited to, the following:  ongoing 
or active infection; history of significant bleeding disorder, including congenital (von 
Willebrand’s disease) or acquired (anti-factor VIII antibodies) disorders; large pleural 


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effusions; or psychiatric illness/social situations that would limit compliance with study 
requirements. 
3.1.2.10 Patients with known pre-existing diabetes mellitus will be excluded because of the risk 
of hyperglycemia with ganitumab. 
3.1.2.11 Pregnant women are excluded from this study because animal studies with dasatinib 
have shown embryolethality and fetal skeletal alterations at non-toxic maternal doses.  
Because there is an unknown but potential risk for adverse events in nursing human 
infants secondary to treatment of the mother with dasatinib, breastfeeding should be 
discontinued if the mother is treated with dasatinib.  
3.2 
SCREENING EVALUATION 
3.2.1 Clinical Evaluation (within 7 days of enrollment) 
3.2.1.1 History and Physical Examination:  
A complete history and physical examination, (including vital signs with blood pressure, pulse, 
respiratory rate, temperature, and oxygen saturation), and a description of signs and symptoms is 
required.  
3.2.1.2 Height, Weight and Body Surface Area: 
For patients < 18 years old, the BSA should be calculated from measurement of weight and 
height on the same day by the standard formula in use at the NCI: 
BSA=Weight (kg)0.425*Height (cm)0.725 
139.315 
3.2.1.3 Tanner Stage (pediatric patients) 
3.2.1.4 Performance status determination 
3.2.2 Laboratory studies 
The following laboratory studies will be performed within 7 days of enrollment. 


 
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3.2.2.1 β-HCG pregnancy test on all women of child-bearing potential 
3.2.2.2 Hematology: complete blood count, differential, platelet count, PT, PTT. 
3.2.2.3 Chemistries: BUN, creatinine, electrolytes (sodium, potassium, chloride, CO2), 
calcium, magnesium, phosphorus, uric acid, total protein, albumin, LDH, and glucose.  
3.2.2.4 Fasting triglycerides, cholesterol (total, HDL, LDL) 
3.2.2.5 HbA1C. 
3.2.2.6 Hepatic Panel: Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, (Direct 
Bilirubin, if total bilirubin is elevated) 
3.2.2.7 Urinalysis 
3.2.3 Electrocardiogram (ECG) 
ECG with Calculation of QTcF using Fridericia’s correction (QTcF = QT/ 3√RR).  
Electrocardiograms will be evaluated by suitably qualified personnel for the presence of QTcF 
prolongation or other abnormalities, in particular, any changes in the T-wave morphology that 
would suggest a higher likelihood for the development of any arrhythmia.   
3.2.4 Echocardiogram 
3.2.5 Imaging studies 
Imaging studies of disease sites must be performed within 4 weeks prior to initiating protocol 
therapy. If more than 4 weeks have elapsed between the date imaging studies to determine 
eligibility were obtained and the start date of treatment, then repeat imaging studies must be 
obtained prior to initiating protocol therapy.  
4 
RECRUITMENT AND REGISTRATION 
4.1 
RECRUITMENT STRATEGIES 
This study will be posted on NIH websites and on NIH social media forums. The following 
recruitment strategies will also be employed to elicit potential candidates for this trial: 
1. Listed on www.clinical trials.gov;  
2. Listed in the CHLA flyer for physicians in southern California 
3. In addition, patients from POB, NIH adult clinics and CHLA who are eligible for 
participation will be offered participation in this study 
Prior to distribution of any recruitment materials, such materials will be submitted to the NIH 
Intramural IRB for review. 
4.2 
REGISTRATION PROCEDURES 
4.2.1 Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations  require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to 


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register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to Oncology Patient Enrollment 
Network (OPEN) or Rave or acting as a primary site contact) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
•
Added to a site roster
•
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN
•
Act as the site-protocol PI on the IRB approval
•
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
4.2.2 Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 


 
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CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization  
• A valid IRB approval  
• Compliance with all protocol specific requirements 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
4.2.2.1 Requirements for 10003 Site Registration 
• IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted.) 
4.2.2.2 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
4.2.2.3 Checking Site Registration Status 
You can verify your site registration status on the members’ section of the CTSU website. 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 


 
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Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks.  
4.2.3 Patient Registration 
4.2.3.1 IWRS 
Patient Enrollment will be facilitated using the Interactive Web Response System (IWRS).  
IWRS is a web-based registration system available to users on a 24/7 basis.  On a successful 
registration, IWRS will assign a patient number and assign the treatment.  Patient enrollment 
data entered by Registrars in IWRS will automatically transfer to the NCI’s clinical data 
management system, Medidata Rave.  IWRS will provide a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
• Users must have a valid CTEP-IAM account (i.e., CTEP username and password) to 
access the IWRS system. 
• Users defined with the Registrar role will have the ability to register patient in the study. 
• Users defined with the Client Administrator role will have the ability to manage accrual 
limits, open and close treatment assignments as well as approve slot reservations, if 
applicable to the study. 
4.2.3.2 OPEN / IWRS 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available to users on a 24/7 basis.  It is integrated with 
the CTSU Enterprise System for regulatory and roster data interchange and with the Theradex 
Interactive Web Response System (IWRS) for retrieval of patient registration/randomization 
assignment.  Patient enrollment data entered by Registrars in OPEN / IWRS will automatically 
transfer to the NCI’s clinical data management system, Medidata Rave. 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
4.2.4 OPEN/IWRS User Requirements 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients:  Be on an ETCTN Corresponding or Participating Organization roster 
with the role of Registrar. Registrars must hold a minimum of an AP registration type. 
• Have regulatory approval for the conduct of the study at their site. 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form. 


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4.2.5 OPEN/IWRS Questions? 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.3 
LOCAL REGISTRATION FOR NCI CCR 
Authorized staff must register the eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agent.  Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours. 
4.3.1 For Participating Site Registration 
Registration will be a two part process as patients are screened on this protocol. A protocol 
registration form will be supplied by the CCR study coordinator and updates will be provided as 
needed. To initially register a subject, after the participant has signed consent, complete the top 
portion of the form and send to CCR study coordinator.  Once eligibility is confirmed, after 
completion of screening studies, complete the remainder of the form which is the eligibility 
checklist, indicating that the patient is being registered for treatment and send to CCR study 
coordinator. In addition, source documents supporting the eligibility criteria must be sent to the 
CCR study coordinator. The CCR study coordinator will notify you either by e-mail or fax that 
the protocol registration form has been received which will include the unique patient/subject ID 
number. Questions about eligibility should be directed to the CCR study coordinator or PI.  
Questions related to registration should be directed to the CCR study coordinator.  
Subjects that do not meet screening criteria should be removed from the study following the 
procedure in section 5.6. 
4.3.2 Treatment Assignment Procedures 
4.3.2.1 Cohorts 
Number 
Name 
Description 
1 
Dose Escalation Cohort 
(Phase I) 
Patients (minimum 2 years of age and above) with 
embryonal or alveolar RMS and measurable 
disease. 
2 
Dose Expansion Cohort 
(Phase II) 
Patients (minimum 2 years of age and above) with 
embryonal or alveolar RMS and measurable 
disease. 


 
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3 
Previosly Treated Dose 
Expansion Cohort (Phase II) 
Patients (minimum 2 years of age and above) with 
embryonal or alveolar RMS and measurable 
disease previously treated in the Phase I portion of 
this study. 
4.3.2.2 Arms 
Number 
Name 
Description 
1 
Phase I 
Combination of ganitumab and dasatinib with 
limited dose escalation of dasatinib 
2 
Phase II 
Combination of ganitumab and dasatinib at the 
MTD (or highest safe dose) 
4.3.2.3 Arm Assignment 
The treatment assignment is open-label and non-randomized (i.e., patients in Cohort 1 are 
directly assigned to Arm 1 and patients Cohort 2 and Cohort 3 are directly assigned to Arm 2). 
4.4 
GENERAL GUIDELINES 
Following registration, patients should begin protocol treatment within 7-10 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
5 
TREATMENT PLAN 
5.1 
AGENT ADMINISTRATION 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in section 7.  Appropriate dose modifications are described in section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
5.1.1 Dose Escalation/De-escalation Schedules 
During the Phase I portion of the study, patients will receive dasatinib and ganitumab at the 
following dose levels: 
Phase I Dose Escalation Schedule for Dasatinib  
Dose Level 
Dose of dasatinib 
Dose of ganitumab 
Level -1 
40 mg/m2 once daily (maximum 
dose of 100 mg/day) on days -7 
18 mg/kg every 2 weeks, beginning 
on day 0 


 
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During the Phase II portion of the study, patients will receive dasatinib and ganitumab at level 1, 
as described below. See section 5.1.3 for further details on de-escalation. 
 
5.1.2 Dasatinib administration 
For all dose levels in the phase I and II portions, dasatinib will begin on day -7 for cycle 1 and 
day 0 for subsequent cycles. For the phase I portion, dose escalation will proceed in cohorts of 
3–6 patients, starting at dose Level 1. The MTD is the dose level at which no more than 1 of up 
to 6 patients experience DLT during the first cycle of treatment, and the dose below that at which 
at least 2 (of ≤6) patients have DLT as a result of the drug. If a patient did not experience DLT 
and did not finish treatment in cycle 1, he or she will only be evaluable for the dose escalation 
portion of the study if they received both ganitumab doses and ≥85% of the dasatinib doses in 
cycle 1. Patients who have not met these criteria will be replaced in the dose level.  If ≥2 out of a 
maximum of 6 patients experience DLT at dose Level 1, the dose of dasatinib will be de-
through day 27 during cycle 1, 
and then days 0-27 
for subsequent cycles (28 day 
cycles). 
Level 1 
60 mg/m2 once daily (maximum 
dose of 100 mg/day) on days -7 
through day 27 during cycle 1, 
and then days 0-27 for 
subsequent cycles (28 day 
cycles). 
18 mg/kg every 2 weeks, beginning 
on day 0 
Level 2 
60 mg/m2 BID (maximum dose 
of 70 mg BID) on days -7 
through day 27 during cycle 1, 
and then days 0-27 for 
subsequent cycles (28 day 
cycles). 
18 mg/kg every 2 weeks, beginning 
on day 0 
Phase II Potential Dose De-escalation Schedule for Ganitumab further details in section 2.6.1 
and section 5.1.3 
Dose Level 
Dose of dasatinib 
Dose of ganitumab 
Level -1  
Dasatinib MTD determined 
during phase I  
12 mg/kg every 2 weeks, starting on 
day 0 
Level 1 
Dasatinib MTD determined 
during phase I 
18 mg/kg every 2 weeks, starting on 
day 0 


 
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escalated to dose Level -1.  If 0-1 out of a maximum of 6 patients have DLT at dose Level -1, 
this will be considered the MTD.  If 2 or more out of a maximum of 6 patients experience DLT 
at dose Level -1, the accrual will be suspended pending discussions with the Sponsor and NIH 
Intramural IRB regarding how to proceed with the combination therapy. 
Dose escalation will follow the rules outlined in the Table below. 
Number of Patients with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 patients at the next dose level 
> 2 
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose 
(highest dose administered).  Up to three (3) 
additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously 
at that dose. 
1 out of 3 
Enter up to 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed 
to the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared 
the maximally administered dose.  Up to three (3) 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD and is generally the recommended 
phase II dose.  At least 6 patients must be entered at 
the recommended phase II dose. 
 
The dose determined to be MTD, or the highest dose evaluated if no MTD is established will be 
the dose and schedule administered in the Phase II portion of the study.  Patients who received 
the MTD during Phase I will be included in the analysis of the Phase II objectives. 
See the dosing nomogram in Appendix 4. 
During cycle 1, patients will be observed in the clinic, day hospital or hospital for 2 hours after 
the first dose of dasatinib is taken. 
Dasatinib tablets may be taken with or without food as desired, but should be swallowed with at 
least 8 ounces (240 mL) of water.  A light meal is not required, but may improve gastric 
tolerance for dasatinib.  Tablets must be swallowed whole and may not be broken.  If vomiting 


 
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occurs within 30 minutes of swallowing the tablet(s), the dose may be replaced if the tablets can be 
seen and counted.  Four weeks (28 days) constitutes one cycle of treatment, with the exception of 
cycle 1, which lasts five weeks (35 days).  Treatment continues until one of the criteria in section 
5.3 applies. 
Patients will be provided with a Medication Diary for dasatinib (Appendix 5, Appendix 6, 
Appendix 7, and Appendix 8), instructed in its use, and asked to bring the diary with them to 
each appointment.  A new copy of the Medication Diary will be given to patients whose dose is 
reduced due to adverse events. 
If tablets are accidentally crushed or broken, caregivers should wear disposable chemotherapy 
gloves. Pregnant women should avoid exposure to crushed and/or broken tablets.  
5.1.3 Ganitumab Administration 
Patients receive ganitumab intravenously on an outpatient basis once every 2 weeks on a 
continuous dosing schedule starting on day 0 (1 cycle is 28 days), at a dose of 18 mg/kg per dose 
which is below the MTD determined in the pediatric phase I trial and is the same dose being used 
in a current COG phase II trial for metastatic Ewing sarcoma (AEWS1221) in combination with 
a standard chemotherapy backbone of vincristine, doxorubicin, cyclophosphamide, ifosfamide 
and etoposide. We thus do not expect that the 18 mg/kg dose of ganitumab will not be tolerated. 
However, in addition to toxicity assessment for the phase I dose escalation with dasatinib, 
toxicity from ganitumab will be assessed after the first 6 patients have been enrolled at the phase 
II dasatinib dose, since these two agents have not been assessed in combination previously. 
Provided ≤1/6 patients experience toxicities clearly attributable to ganitumab, the remainder of 
the patients will be treated using the ganitumab dose of dose of 18 mg/kg. If 2 or more of the 
initial 6 patients experience toxicity requiring a dose modification and the toxicities can be 
clearly attributed to ganitumab only, the ganitumab dose will be reduced to 12 mg/kg for all 
subsequent patients. 
The first dose of ganitumab should be administered over an hour. Maximum infusion duration is 
120 minutes. Vital signs should be recorded 30-60 minutes before the dose, 30 minutes (+/- 10 
mins) into the infusion and after the infusion (+/- 10 mins). Temperatures should be taken orally. 
If a temperature is not taken orally and is found to be elevated, it should be repeated with an oral 
reading. During cycle 1, patients will be observed in the clinic, day hospital or hospital for at 
least 1 hour after the first dose of ganitumab is given. 
5.1.4 Criteria for starting subsequent treatment cycles 
Patients who complete a treatment cycle (28 days) may receive another cycle if: 
• Disease Status: If imaging is done, the patient has stable disease or has experienced a PR 
or CR, (see Section 11.1.4).  
• Toxicity: Patients who experienced dose-limiting toxicity in the previous cycle should 
have the dose modified as per Section 6.  
• Conditions for discontinuation of protocol treatment or off-study criteria (Sections 5.3 
and 5.5) have not been met. 


 
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5.2 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
There is a potential for interaction of dasatinib with other concomitantly administered drugs.  
Therefore, all prescription and over-the-counter medications as well as herbal treatments or 
alternative medicines must be fully documented in the Case Report Form (CRF; including 
indication and dates of administration). 
5.2.1 Agents that induce or inhibit CYP3A4 
Agents or substances that strongly induce or inhibit CYP3A4 are prohibited during dasatinib 
treatment because the patient’s exposure to dasatinib is significantly affected by such materials.  
For CYP3A4 inhibitors, a washout period of >7 days is required prior to starting dasatinib.  The 
washout period should be based on the half-life of the particular CYP 3A4 inhibitor which can be 
substantially longer than 7 days in some cases (e.g., amiodarone).  The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential to affect 
selected P450 isoenzymes.  See Appendix 2 for a list of specifically prohibited CYP3A4 
inhibitors and inducers.   
Other inhibitors, inducers, and substrates of CYP3A4 may affect dasatinib metabolism, and 
restriction of their use is recommended.  Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated list or medical reference text 
such as the Physician’s Desk Reference.  
Patients should be advised not to consume substantial quantities of grapefruit or grapefruit juice 
during dasatinib treatment. 
5.2.2 Agents to avoid or agents prohibited 
Because systemic antacids (H2 inhibitors, proton pump inhibitors) decrease dasatinib absorption, 
patients who require antacids should use short-acting, locally-active agents (e.g., Maalox®, 
Mylanta® etc.).  However, these agents should not be taken within either 2 hours before or 2 
hours after the dasatinib dose. 
Use of agents with proarrhythmic potential is not permitted during the study, and a washout period 
of ≥7 days is required prior to starting dasatinib.  The washout period should be based on the half-
life of the particular proarrhythmic agent which can be substantially longer than 7 days in some 
cases (e.g., amiodarone).  See Appendix 2: Substances Prohibited During Dasatinib Treatment 
for a list of proarrhythmic agents that are specifically prohibited during dasatinib treatment.  A 
comprehensive list of agents with the potential to cause QTc prolongation can be found at 
http://torsades.org. 
Thrombocytopenia and hemorrhagic events can occur with dasatinib treatment.  For this reason, 
patients may not take anticoagulants or medications that inhibit platelet function while on study 
including therapeutic warfarin or heparin.  All such medications must have been stopped ≥7 days 
prior to starting dasatinib to allow an appropriate washout period.  If the patient requires any 
surgical (including dental) procedure while on study, dasatinib should be stopped 1 day before 
the procedure and not reinstituted until 1 to 2 days afterward or until adequate hemostasis is 
achieved. 


 
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5.2.3 Support for hypocalcemia 
Bisphosphonate therapy should be withheld for the first 8 weeks of treatment in patients 
receiving such treatment pending assessment of the need for calcium supplementation (see 
below).  If patient’s serum calcium levels remain above the lower limit of normal, patients on 
prior bisphosphonate therapy may be restarted with caution at the investigator’s discretion. 
Calcium supplements (e.g., calcium carbonate, 500 mg PO three times daily) may be required to 
maintain serum calcium levels above the lower limit of normal during dasatinib treatment.  
Vitamin D supplements (e.g., ergocalciferol, 400 IU PO daily) may be appropriate for persistent 
hypocalcemia.  Bisphosphonate therapy should be deferred in the presence of hypocalcemia. 
5.2.4 Antiemetics and Anti-diarrheals 
The nausea, vomiting, and diarrhea that may occur with dasatinib administration can generally 
be managed through the use of appropriate supportive measures (anti-emetics - e.g., 5-HT3 
antagonists, benzodiazepines, prochlorperazine, and anti-diarrheal medications - e.g., 
loperamide).   
Given the risk of hyperglycemia with ganitumab, the use of corticosteroids as an antiemetic is 
strongly discouraged. Corticosteroids should only be considered as an antiemetic if a patient has 
poorly controlled nausea without corticosteroids. Sporadic use of corticosteroids as 
premedication for transfusions is allowed. 
5.2.5 Diuretics 
Fluid retention, including pleural effusions, should be controlled by early institution of diuresis 
(e.g., furosemide, 20-40 mg PO daily and/or spironolactone, 25-50 mg PO, titrated to 
symptoms).  Pleural effusions that remain or become symptomatic despite diuresis should be 
managed with thoracentesis.  Steroid treatment may also be effective for pleural effusion.  Chest 
discomfort may be related to a pericardial effusion; and an echocardiogram should be performed 
to investigate this possibility in such cases. 
5.2.6 Supportive care for inflammation 
Inflammation (e.g., pneumonitis, colitis, skin rash) may be appropriately managed with dasatinib 
interruption and short-term steroid treatment (e.g., 5-7 days methylprednisolone with rapid 
taper).  Concurrent antibiotics are appropriate if there is clinical suspicion of infection.   
5.2.7 Other supportive measures 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive 
care are to be used as necessary.  
Growth factors that support platelet or white cell number or function can only be administered 
for culture proven bacteremia or invasive fungal infection. The PI or protocol AI should be 
notified before growth factors are initiated.  
Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease 
prior to initiating dasatinib and during treatment.   


 
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Symptoms of pulmonary arterial hypertension (PAH) include dyspnea, fatigue, hypoxia, and 
edema.  Since other medical conditions may also cause these symptoms, non-invasive procedures 
(including echocardiogram) should be done first to rule out more the common etiologies of these 
symptoms, such as pleural effusion, pulmonary edema, anemia, and lung infiltration. 
Right heart catheterization can confirm the diagnosis of PAH.  Hypertension is “pre-capillary” 
and not a consequence of left heart failure or chronic lung disease if there is normal pulmonary 
capillary wedge pressure (<15 mm Hg) but elevated pulmonary artery pressure (mean pulmonary 
artery pressure >25 mm Hg).  Since PAH may be reversible upon discontinuation of dasatinib, a 
diagnostic approach of interruption of dasatinib treatment may be considered at the discretion of 
the treating physician; however, if PAH is confirmed, dasatinib should be permanently 
discontinued. 
5.3 
DURATION OF THERAPY (OFF TREATMENT) 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s). Patients required to permanently discontinue one agent 
due to toxicity may continue treatment with the other agent until other off treatment 
criteria are met, 
• Treatment of both agents has been held for a period of 6 weeks, for any reason, 
• Patient decides to withdraw from the treatment, or 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
5.4 
DURATION OF FOLLOW UP 
Patients removed from treatment for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event.  In addition, patients will be followed for at least 
30 days after the last dose of investigational agents and until disease progression, whichever 
occurs last. Refer to section 10 for specific follow up requirements. 
5.5 
CRITERIA FOR REMOVAL FROM STUDY 
Patients will be removed from study when any one of the following criteria is met.  The reason 
for study removal and the date the patient was removed must be documented in the Case Report 
Form. Prior to removal from study, effort must be made to have all subjects complete a safety 
visit approximately 30 days following the last dose of study therapy. 
• Completed study follow-up period 
• Participant requests to be withdrawn from study 
• Death 


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5.6 
LOCAL OFF PROTOCOL TREATMENT AND OFF-STUDY PROCEDURE  
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol treatment and when a subject is taken off-study. A Participant Status Update Form from 
the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 
5.6.1 Participating sites 
The Participant Status Update Form will be supplied by the CCR study coordinator. Send the 
completed form to the CCR study coordinator. 
6 DOSING DELAYS/DOSE MODIFICATIONS 
6.1 
DEFINITION OF DOSE LIMITING TOXICITY (DLT) (PHASE I) AND TREATMENT LIMITING 
TOXICITY (TLT) (PHASE II) 
Toxicity will be evaluated and treatment limited by the toxicities defined below (see also 
sections 6.2 through 6.6 for more information).  This study will utilize the CTEP Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 for toxicity and Adverse Event 
grading and reporting.  An adverse event must be judged to be possibly, probably, or definitely 
related to dasatinib, ganitumab or the combination to be considered a dose limiting toxicity 
(DLT) or treatment limiting toxicity (TLT).  
Dose limiting toxicities (DLT) (Phase I) and treatment limiting toxicities (TLT) (phase II) are 
defined as:  
•
Any toxicity of grade 3 or higher, with the specific exceptions of:
o
Grade 3 nausea and vomiting of < 5 days duration
o
Grade 3 ALT/AST that return to levels that meet initial eligibility criteria within 7
days of study drug interruption and that do not recur upon re-challenge with study
drug.
o
Grade 3 fever or infection < 5 days duration.
o
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia and/or hypomagnesemia
responsive to supplementation, or that are isolated events
o
Grade 3 neutropenia or thrombocytopenia
o
Grade 3 and grade 4 infusion reactions (not considered DLTs because they are not
dose related)
•
Grade 2 hemorrhage/bleeding/coagulopathy (without thrombocytopenia)
•
QTcF prolongation ≥ 550 msec
•
Any toxicity of grade 2 or greater that is considered intolerable to the patient, and cannot
be controlled with standard supportive measures.
Treatment will be held until toxicity improves to less than or equal to grade 1 or baseline. 


 
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Depending on attribution of toxicity, treatment can be restarted with a dose reduction of the 
agent that caused the toxicity, or reduction of both agents if the toxicity cannot clearly be 
attributed to either one. Dose reductions of dasatinib will be performed by a dosing nomogram 
with detailed instructions on dose reduction (See Appendix 4 and section 6.7). Dose reductions 
of ganitumab will be as per section 6.6. 
Adverse events (AEs) should be treated with the appropriate maximum supportive care, and dose 
reductions should be clearly documented in the case report form. 
Patients will be withdrawn from the study treatment if they fail to recover to CTCAE grade 0-1 
or tolerable grade 2 (or within 1 grade of starting values for pre-existing laboratory 
abnormalities) from a treatment-related toxicity within 14 days OR they experience agent- 
related adverse events requiring dose modification despite one previous dose reduction of 
ganitumab (i.e., would require a second dose reduction) or two previous dose reductions of 
dasatinib (i.e., would require a third dose reduction) unless the investigator and CTEP senior 
investigator agree that the patient should remain on the study treatment because of evidence that 
the patient is/may continue deriving benefit from continued study treatment.  Patients required to 
permanently discontinue one agent due to toxicity may continue treatment with the other agent 
until off treatment criteria are met (section 5.3). If both agents have been held for a period of 6 
weeks for any reason, patients will be removed from the study.  
6.2 
ADVERSE EVENTS ATTRIBUTED TO GANITUMAB 
During participation in this study, patients who experience DLT or TLT attributable to 
ganitumab, or to both agents, may have the dose of ganitumab reduced to 12 mg/kg2.   
We do not expect that the 18 mg/kg dose of ganitumab will not be tolerated. However, in 
addition to toxicity assessment for the phase I dose escalation with dasatinib, toxicity from 
ganitumab will be assessed after the first 6 patients have been enrolled at the phase II dasatinib 
dose. If 2 or more of those patients who experience toxicity requiring a dose modification and 
the toxicities can be clearly attributed to ganitumab only, the ganitumab dose will be reduced to 
12 mg/kg for all subsequent patients.  
 
6.3 
HEMATOLOGIC ADVERSE EVENTS ATTRIBUTED TO DASATINIB OR GANITUMAB 
Event 
AE Grade or 
Observation 
Dose modification 
Neutropenia 
Grades 1-3 
Maintain dose 
Grade 4 1 
Hold both agents until < grade 3, then reduce 
dasatinib per Section 6.7 AND ganitumab to 12 
mg/kg/dose and resume treatment  
Thrombocytopenia 
Grades 1-3 
Maintain dose 


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Grade 4 1
Hold both agents until < grade 3, then reduce 
dasatinib per Section 6.7 AND ganitumab to 12 
mg/kg/dose and resume treatment 
1If Grade 4 neutropenia or Grade 4 thrombocytopenia recur or persist for more than 2 weeks, patients 
should be removed from study treatment and bone marrow evaluation considered.  
6.4 
PNEUMONITIS ATTRIBUTED TO DASATINIB AND GANITUMAB 
This patient population may have been treated with thoracic radiation prior to enrollment on this 
study for management of primary tumor (e.g., chest wall primary site) or metastatic disease (e.g., 
whole lung radiation for patients with lung metastasis). Ganitumab treatment may increase the 
risk or severity of pneumonitis, although the extent of this potential interaction is not fully 
known. Dasatinib has also been associated with pneumonitis, both with concurrent lung radiation 
and without radiation. 
It is important to be vigilant for the development of pneumonitis in patients treated with 
ganitumab. Oxygen saturation evaluation at time of protocol mandated physical examinations is 
required. Additional evaluations in patients who have been treated with lung radiation who 
present with unexplained cough, dyspnea, or physical exam findings on lung auscultation should 
be considered.  
Pneumonitis will be managed according to local practice, individualized to each patient’s clinical 
scenario:  
Grade 1: Patients with Grade 1 pneumonitis (asymptomatic) should be monitored according to 
local practice for potential worsening to higher grade pneumonitis (symptomatic).  
Grade 2 or higher: Prompt initiation of steroid therapy is critical and treatment should not be 
delayed in cases of suspected pneumonitis. A typical approach to Grade 2 and higher radiation 
pneumonitis includes a protracted course (2-4 weeks) of high dose corticosteroids 
(methylprednisolone or prednisone) followed by a taper. Prophylaxis for pneumocystis 
pneumonia (PCP) is required for patients receiving > 20 mg prednisone daily for 4 weeks or 
longer. Consultation with pulmonology is strongly encouraged for these patients.  
Sites are to report symptomatic grade 2 or higher pneumonitis in an expedited manner via CTEP-
AERS and through routine reporting.  
Dose modifications for dasatinib and ganitumab are as follows: 


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Pneumonitis Grade 
(per CTCAE, under 
Pneumonitis) 
Action 
Grade 1 
•
Monitor closely for worsening symptoms.
•
Continue dasatinib and ganitumab.
Grade 2 
•
Initiate steroid therapy as indicated.
•
Strongly encourage consultation with pulmonologist.
•
Hold dasatinib and ganitumab until resolution to grade 1.
•
If pneumonitis resolves to tolerable grade 2 or less within 14 days, retreatment
may be considered once it has returned to grade 1, if the patient has not met off-
study criteria. Discussion with the Sponsor is required before retreatment can
occur. If retreatment is permitted1, dasatinib will be resumed per dosing in
Appendix 4 and Section 6.6 and ganitumab will be resumed at 12 mg/kg.
Grade 3 
•
Initiate steroid therapy as indicated.
•
Consultation with pulmonologist.
•
Hold ganitumab until resolution to grade 1.
•
If pneumonitis resolves to tolerable grade 2 or less within 14 days, retreatment
may be considered once it has returned to grade 1, if the patient has not met off-
study criteria. Discussion with the Sponsor is required before retreatment can
occur. If retreatment is permitted1, dasatinib will be resumed per dosing in
Appendix 4 and Section 6.6 and ganitumab will be resumed at 12 mg/kg.
 
Grade 4 
•
Initiate steroid therapy as indicated.
•
Consultation with pulmonologist.
•
Discontinue dasatinib and ganitumab permanently.
*For patients who have already been retreated at a dose reduced dose for pneumonitis, if pneumonitis of
any grade recurs, dasatinib and ganitumab will be permanently discontinued.
In most cases, patients who develop pneumonitis will be receiving treatment with both 
ganitumab and dasatinib. In the event that a patient develops pneumonitis before ganitumab is 
introduced (during week 1 of therapy), initiation of ganitumab must first be discussed with the 
Sponsor.  
6.5 
ADDITIONAL ADVERSE EVENTS ATTRIBUTED TO DASATINIB 
Event 
AE Grade or 
Observation 
Dose modification 
Hemorrhage/Bleeding/ 
Coagulopathy 
Grade 1 
No interruption in treatment; maintain current dose. 
Monitor as clinically indicated 


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Event 
AE Grade or 
Observation 
Dose modification 
(without 
thrombocytopenia) 
Grade 2 
Hold dasatinib until AE resolved to < grade 1; reduce 
dose to next lower dose level, and continue treatment. 
If grade 2 or greater hemorrhage/ bleeding recurs 
following dose reduction, stop dasatinib and remove 
patient from study treatment.  
Follow up per protocol (section 5.4) if patient is 
removed from the study treatment. 
Grade 3 or 4 
Discontinue treatment and follow up per protocol (see 
section 5.4). 
QTcF Prolongation 
>480 but
<550 msec 
Review patient’s concomitant medications for QT 
interval-prolonging agents.  Correct any electrolyte 
abnormalities. 
Continue dasatinib at current dose level and repeat 
ECG. 
>550 msec
Stop dasatinib and any other QT interval-prolonging 
agents immediately.  Correct any electrolyte 
abnormalities, then 
1. If there is a plausible explanation for AE other
than dasatinib treatment, resume dasatinib at
current dose level.
2. If dasatinib may have contributed to the AE:
• Reduce 2 dose levels and restart dasatinib.
• If QTcF remains <480 msec after 14 days at
reduced dose, increase one dose level and
continue dasatinib.
6.6 
ADDITIONAL ADVERSE EVENTS ATTRIBUTED TO GANITUMAB  
6.6.1 Hyperglycemia 
For patients who develop hyperglycemia based on random, non-fasting glucose levels, 
discontinue use of corticosteroids before modifying ganitumab dose. If hyperglycemia occurs 
without use of corticosteroids, fasting glucose level should be checked. If elevated, ganitumab 
therapy modifications should be as follows:  


 
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Hyperglycemia 
Grade 
(per CTCAE, under 
Hyperglycemia) 
Action 
Grade 1  
Continue ganitumab.  
Grade 2  
Continue ganitumab. 
Consider consultation with Pediatric Endocrinologist.  
Grade 3 or 
Urine glucose > 0.1 
g/dL  
• 
Initiate insulin therapy or oral diabetic agent* as indicated.  
• 
Hold ganitumab until resolves to ≤ Grade 2 without glycosuria.  
• 
Resume ganitumab at same dose IF patient is asymptomatic, AND serum 
glucose is consistently < 250 mg/dL (≤ Grade 2) without glycosuria AND 
resolution to < Grade 2 has occurred within 2 weeks of interruption. The patient 
may continue to receive concomitant insulin or an oral diabetic agent for the 
management of hyperglycemia while receiving ganitumab.  
• 
If Grade 3 hyperglycemia recurs despite a stable dose of insulin or oral diabetic 
agent OR if resolution to consistent levels < Grade 2 requires more than 2 weeks 
of interruption, subsequent doses should be administered with a reduced dose of 
12 mg/kg/dose.  
Grade 4  
• 
Initiate insulin therapy as indicated.  
• 
If associated with diabetic ketoacidosis or hyperosmolar nonketotic syndrome, 
discontinue ganitumab permanently. Otherwise, use the following instructions.  
• 
Hold ganitumab until resolves to ≤ Grade 2.  
• 
Resume ganitumab with a reduced dose of 12 mg/kg/dose IF patient is 
asymptomatic, AND serum glucose is consistently < 250 mg/dL (≤ Grade 2) 
without glycosuria AND resolution to ≤ Grade 2 has occurred within 2 weeks of 
interruption. The patient may continue to receive concomitant insulin or an oral 
diabetic agent for the management of hyperglycemia while receiving ganitumab. 
• 
If resolution to consistent levels < Grade 2 requires more than 2 weeks of 
interruption OR if Grade 4 toxicity recurs after re- challenge with 12 mg/kg, then 
discontinue ganitumab permanently.  
* Recommended guidelines for use of oral diabetic agents: 
Initiation of treatment for hyperglycemia should occur under the guidance of a pediatric 
endocrinologist. Metformin may be used per endocrinologist’s recommendations.  
Other oral anti-hyperglycemic agent may be used at the discretion of the pediatric 
endocrinologist. Insulin therapy should be directed by specialists in pediatric diabetes with the 
goal of normal fasting blood sugars <126mg/dL and HgbA1C < 8%.  
6.6.2 Infusion Reactions 
For patients who have allergic or acute infusion reactions, therapy modifications based on grade 
should be as follows. Guidelines for emergency management of infusion reactions are 
recommendations and institutional standard practice may be used as an alternative.  


 
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Grade 
Action 
Grade 1 
Transient flushing or rash,  
drug fever between 37.5 °C 
and 38.0 °C (99.5 °F - 100.4 
°F) taken orally 
• 
Slow infusion rate by 50% and monitor patient for worsening of 
condition. Maximum infusion duration is 120 minutes. 
Grade 2 
Rash, flushing, urticaria, 
dyspnea, drug fever ≥ 38.0 °C 
(≥100.4 °F) taken orally 
• 
Stop infusion; symptom control (diphenhydramine hydrochloride 
1 mg/kg (max 50 mg) IV, acetaminophen 10- 15 mg/kg (max 650 
mg) for fever, and oxygen if needed).  
• 
Resume infusion at 50% of the prior rate once the reaction has 
decreased to ≤ Grade 1. Monitor patient for worsening condition. 
Maximum infusion duration is 120 minutes.  
• 
For subsequent dose, premedicate with diphenhydramine 
hydrochloride 1 mg/kg (max 50 mg) IV.  
• 
If Grade 1-2 infusion reactions reoccur with subsequent dose, add 
dexamethasone 0.2 mg/kg (max 10 mg) IV or equivalent to 
premedications above.  
(Only dose interruption/discontinuation, but not dose reduction, is 
required for allergic/infusional reactions.) 
Grade 3 
Symptomatic bronchospasm 
with or without urticaria, 
allergy-related edema/ 
angioedema, hypotension  
• 
Stop infusion immediately.  
• 
Administer diphenhydramine hydrochloride 1 mg/kg (max: 50 
mg) IV, dexamethasone 0.2 mg/kg (max: 10 mg) IV (or 
equivalent), bronchodilators for bronchospasms, and other 
medications as medically indicated. Hospital admission should be 
considered.  
• 
Discontinue ganitumab treatment permanently.  
Grade 4  
Anaphylaxis  
• 
Stop infusion immediately  
• 
Administer diphenhydramine hydrochloride 1 mg/kg (max 50 
mg) IV, dexamethasone 0.2 mg/kg (max 10 mg) IV (or 
equivalent), and other anaphylaxis medications as indicated. 
Epinephrine or bronchodilators should be administered as 
indicated. Hospital admission for observation may be indicated.  
• 
Discontinue ganitumab treatment permanently.  
6.6.3 Ototoxicity 
Given the rarity of baseline hearing loss and low risk of ototoxicity in the setting of IGF-1R 
inhibition, this protocol does not include serial audiograms. If a patient develops symptoms of 
ototoxicity, such as tinnitus or hearing loss, then an audiogram should be obtained. If Grade 3 or 
4 hearing loss occurs, ganitumab should be held and not resumed without consultation with the 
Sponsor.  
6.6.4 Cardiac Toxicity 
The following ganitumab modifications will apply:  


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Asymptomatic decrease in the ejection fraction to < 50% / decrease in the left ventricular 
shortening fraction to < 27%: hold ganitumab, correct any existing electrolyte or micronutrient 
deficiencies, and repeat tests in 1 week. If abnormality persists after 1 week, discontinue 
ganitumab permanently. If abnormality resolves after 1 week, continue ganitumab at current 
dose. If ganitumab needs to be held more than once due to transient decreases in left ventricular 
systolic dysfunction, discontinue ganitumab permanently. Missed doses of ganitumab due to 
decreases in EF will not be made up. 
Grade 3 (symptomatic) left ventricular systolic dysfunction: hold ganitumab and resume 
ganitumab only if symptoms resolve and LV/SF recover to ≥ 50% / 27% within 4 weeks. If  
Grade 3 toxicity recurs, discontinue ganitumab permanently.  
Grade 4 left ventricular systolic dysfunction: discontinue ganitumab permanently. 
6.6.5 Other Non-Hematologic Toxicities Associated with Ganitumab 
For all other toxicities, the following dose modification guidelines should be followed: 
Grade 
Action 
Grade 1 Continue ganitumab. 
Grade 2 Continue ganitumab. 
Grade 3 
•
Unlikely or unrelated to ganitumab: Continue ganitumab.
Possibly, probably, or definitely related: Hold ganitumab until resolves to ≤ Grade 2. If
toxicity resolves within 2 weeks of interruption, then resume ganitumab with a reduced dose
of 12 mg/kg/dose.
Grade 4 
•
Unlikely or unrelated to ganitumab*: Hold ganitumab until resolves to ≤ Grade 2, then
resume ganitumab at full dose.
•
Possibly, probably, or definitely related: Discontinue ganitumab.
*If Grade 4 toxicity is pre-existing or is specifically attributable to tumor, ganitumab should not
be held. Examples include tumor-related pain, paralysis due to spinal cord compression, and
blindness due to parameningeal tumor.


 
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6.7 
DASATINIB DOSE MODIFICATIONS FOR TOXICITY 
6.7.1 For Daily Dosing  
 
Current Dose (Daily) 
Reduced Dose (Daily) 
% Decrease 
100 MG PER DOSE 
70 MG PER DOSE 
30 
95 MG PER DOSE 
65 MG PER DOSE 
32 
90 MG PER DOSE 
65 MG PER DOSE 
28 
85 MG PER DOSE 
60 MG PER DOSE 
29 
80 MG PER DOSE 
55 MG PER DOSE 
31 
75 MG PER DOSE 
50 MG PER DOSE 
33 
70 MG PER DOSE 
50 MG PER DOSE 
28 
65 MG PER DOSE 
45 MG PER DOSE 
31 
60 MG PER DOSE 
40 MG PER DOSE 
33 
55 MG PER DOSE 
40 MG PER DOSE 
27 
50 MG PER DOSE 
35 MG PER DOSE 
30 
45 MG PER DOSE 
30 MG PER DOSE 
33 
40 MG PER DOSE 
40 MG PER DOSE 
ON M, W, TH, SAT, SUN 
28 
35 MG PER DOSE 
25 MG PER DOSE 
29 
30 MG PER DOSE 
20 MG PER DOSE 
33 
25 MG PER DOSE 
20 MG PER DOSE  
ON M, TU, W, TH, F, SAT 
31 
20 MG PER DOSE 
20 MG PER DOSE 
ON M, W, TH, SAT, SUN 
28 


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6.7.2 For BID Dosing 
Current Dose (BID) 
Reduced Dose (BID) 
% Decrease 
70 MG PER DOSE 
50 MG PER DOSE 
28 
65 MG PER DOSE 
45 MG PER DOSE 
31 
60 MG PER DOSE 
40 MG PER DOSE 
33 
55 MG PER DOSE 
40 MG PER DOSE 
27 
50 MG PER DOSE 
35 MG PER DOSE 
30 
45 MG PER DOSE 
30 MG PER DOSE 
33 
40 MG PER DOSE 
40 MG PER DOSE 
ON M, W, TH, SAT, SUN 
28 
35 MG PER DOSE 
25 MG PER DOSE 
29 
30 MG PER DOSE 
20 MG PER DOSE 
33 
25 MG PER DOSE 
20 MG PER DOSE  
ON M, TU, W, TH, F, SAT 
31 
20 MG PER DOSE 
20 MG PER DOSE 
ON M, W, TH, SAT, SUN 
28 
6.8 
DOSING DELAYS 
Missed doses of dasatinib will not be made up. 
All efforts will be made to adhere to the ganitumab schedule. However, if patients are unable to 
receive ganitumab on the prescribed day due to reasons unrelated to study drug toxicity (eg. an 
inpatient hospitalization at an outside hospital for reasons unrelated to the study agents), the dose 
may be administered within a window of 72 hours prior to or after the scheduled date. The 
subsequent dose of ganitumab would be given per the original schedule. 
Patients scheduled for elective radiotherapy of the lungs should hold ganitumab at least two 
months prior to radiation.  


 
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48 
 
7 
SPONSOR SAFETY REPORTING 
7.1 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (section 7.1) and the characteristics of an observed AE (section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
7.2 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST(S) (CAEPRS) 
7.2.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) for Dasatinib (BMS-
354825, Sprycel, NSC 732517) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification.  Frequency is provided based on 2937 patients. Below is the CAEPR for Dasatinib 
(BMS-354825, Sprycel). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.7, September 10, 20181 
 
 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, Sprycel) 
 (CTCAE 5.0 Term) 
[n= 2937] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 Anemia (Gr 3) 
Febrile neutropenia 
 
CARDIAC DISORDERS 
 
Heart failure 
 
Left ventricular systolic 
dysfunction 
 
Myocardial infarction  
Pericardial effusion 
 


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49 
 Adverse Events with Possible 
 Relationship to Dasatinib (BMS-354825, Sprycel) 
 (CTCAE 5.0 Term) 
[n= 2937] 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
GASTROINTESTINAL DISORDERS 
Abdominal distension 
Abdominal pain 
 Abdominal pain (Gr 3) 
Anal mucositis 
Constipation 
Diarrhea 
 Diarrhea (Gr 3) 
Dyspepsia 
Gastrointestinal 
hemorrhage2
Mucositis oral 
Nausea 
 Nausea (Gr 3) 
Rectal mucositis 
Small intestinal 
mucositis 
Vomiting 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
Edema limbs 
Fatigue 
 Fatigue (Gr 3) 
Fever 
 Fever (Gr 2) 
General disorders and 
administration site 
conditions - Other 
(superficial edema) 
 General disorders and 
administration site conditions 
- Other (superficial edema)
(Gr 2)
Generalized edema 
Non-cardiac chest 
pain 
Pain 
INFECTIONS AND INFESTATIONS 
Infection3 
 Infection3 (Gr 3) 
INVESTIGATIONS 
Alanine 
aminotransferase 
increased 


 
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 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, Sprycel) 
 (CTCAE 5.0 Term) 
[n= 2937] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Aspartate 
aminotransferase 
increased 
 
Electrocardiogram QT 
corrected interval 
prolonged 
 
Neutrophil count 
decreased 
 Neutrophil count decreased 
(Gr 4) 
Platelet count decreased 
 Platelet count decreased (Gr 
4) 
Weight gain 
 
Weight loss 
 
White blood cell 
decreased 
 White blood cell decreased 
(Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 Anorexia (Gr 3) 
Hypocalcemia 
 
Hypokalemia 
 
Hypophosphatemia 
 Hypophosphatemia (Gr 3) 
Tumor lysis syndrome  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS  
Arthralgia 
 
 
Growth suppression4 
 
Musculoskeletal and 
connective tissue 
disorder - Other 
(epiphyses delayed 
fusion)4 
 
Musculoskeletal and 
connective tissue 
disorder - Other 
(osteopenia)4 
 
Myalgia 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 


 
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51 
 
 
 Adverse Events with Possible  
 Relationship to Dasatinib (BMS-354825, Sprycel) 
 (CTCAE 5.0 Term) 
[n= 2937] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Headache 
 Headache (Gr 3) 
Intracranial 
hemorrhage 
 
Leukoencephalopathy  
Reversible posterior 
leukoencephalopathy 
syndrome 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS  
 
Gynecomastia4 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
Dyspnea 
 Dyspnea (Gr 3) 
Laryngeal mucositis 
 
Pharyngeal mucositis 
 
Pleural effusion 
 Pleural effusion (Gr 3) 
Pneumonitis 
 
Pulmonary 
hypertension 
 
Tracheal mucositis 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
Erythema multiforme  
Pruritus 
 
Rash acneiform 
 
Rash maculo-papular 
 Rash maculo-papular (Gr 2) 
Stevens-Johnson 
syndrome 
 
Toxic epidermal 
necrolysis 
 
VASCULAR DISORDERS 
 
Flushing 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 


 
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52 
 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail.  
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
3Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
4Effects on growth and development have been observed in pediatric patients and may include 
epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia. 
5Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, Esophageal ulcer, 
Gastric ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, and Small intestine ulcer under the 
GASTROINTESTINAL DISORDERS SOC. 
Adverse events reported on Dasatinib (BMS-354825, Sprycel) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Dasatinib 
(BMS-354825, Sprycel) caused the adverse event:  
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (cardiomegaly); 
Cardiac disorders - Other (heart rate increased); Chest pain - cardiac; Myocarditis; Palpitations; 
Pericarditis; Sinus tachycardia; Ventricular tachycardia 
CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, familial and 
genetic disorders - Other (Keratosis follicular) 
EAR AND LABYRINTH DISORDERS - Ear pain; Middle ear inflammation; Tinnitus; 
Vertigo 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (optic nerve neuritis); 
Periorbital edema 
GASTROINTESTINAL DISORDERS - Anal fissure; Ascites; Colitis; Dry mouth; Dysphagia; 
Esophagitis; Flatulence; Gastritis; Gastrointestinal disorders - Other (enteritis); Gastrointestinal 
disorders - Other (oral soft tissue disorder); Gastrointestinal disorders - Other (tongue eruption); 
Gastrointestinal ulcer5; Ileus; Oral pain; Pancreatitis; Periodontal disease; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
face; Edema trunk; Flu like symptoms; Gait disturbance; General disorders and administration 
site conditions - Other (temperature intolerance); Localized edema; Malaise 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatobiliary disorders - Other (cholestasis) 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 


 
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INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Cardiac 
troponin T increased; CD4 lymphocytes decreased; CPK increased; Creatinine increased; 
Electrocardiogram T wave abnormal; GGT increased; Investigations - Other (bone 
densitometry); Investigations - Other (thermometry abnormal); Lymphocyte count decreased; 
Lymphocyte count increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperkalemia; 
Hyperuricemia; Hypoalbuminemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; 
Bone pain; Chest wall pain; Generalized muscle weakness; Muscle cramp; Musculoskeletal and 
connective tissue disorder - Other (muscle stiffness); Musculoskeletal and connective tissue 
disorder - Other (nuchal rigidity); Musculoskeletal and connective tissue disorder - Other 
(tendonitis); Myositis; Osteoporosis; Pain in extremity; Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(hemangiomatosis) 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Amnesia; Cognitive 
disturbance; Concentration impairment; Dysarthria; Dysgeusia; Ischemia cerebrovascular; 
Lethargy; Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; 
Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Suicidal ideation 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS – Irregular menstruation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Bronchospasm; Epistaxis; Hypoxia; Oropharyngeal pain; Pulmonary edema; 
Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; Hair 
color changes; Hyperhidrosis; Nail loss; Pain of skin; Palmar-plantar erythrodysesthesia 
syndrome; Photosensitivity; Purpura; Skin and subcutaneous tissue disorders - Other (acute 
febrile neutrophilic dermatosis); Skin and subcutaneous tissue disorders - Other (panniculitis); 
Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypertension; Hypotension; Phlebitis; 
Superficial thrombophlebitis; Thromboembolic event; Vasculitis 
Note: Dasatinib (BMS-354825, Sprycel) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 


 
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7.2.2 Comprehensive Adverse Events and Potential Risks list (CAEPR) for Ganitumab 
(AMG 479, NSC 750008) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for further 
clarification. Frequency is provided based on 334 patients. Below is the CAEPR for Ganitumab 
(AMG 479). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.1, March 26, 20191 
 Adverse Events with Possible  
 Relationship to Ganitumab (AMG 479) 
 (CTCAE 5.0 Term) 
[n= 334] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
Anemia (Gr 3) 
EAR AND LABYRINTH DISORDERS 
 
Hearing impaired2 
GASTROINTESTINAL DISORDERS 
 
Diarrhea 
Diarrhea (Gr 2) 
 
Nausea 
Nausea (Gr 2) 
 
Vomiting 
Vomiting (Gr 2) 


 
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 Adverse Events with Possible  
 Relationship to Ganitumab (AMG 479) 
 (CTCAE 5.0 Term) 
[n= 334] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
Fatigue 
Fatigue (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
Infusion related 
reaction3 
Infusion related reaction3 
(Gr 2) 
INVESTIGATIONS 
 
Alanine 
aminotransferase 
increased 
Alanine aminotransferase 
increased (Gr 2) 
 
Aspartate 
aminotransferase 
increased 
Aspartate aminotransferase 
increased (Gr 2) 
 
Lymphocyte count 
decreased 
 
Neutrophil count 
decreased 
Neutrophil count decreased 
(Gr 3) 
 
Platelet count 
decreased 
Platelet count decreased (Gr 
3) 
 
White blood cell 
decreased 
White blood cell decreased 
(Gr 3) 
METABOLISM AND NUTRITION DISORDERS 


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 Adverse Events with Possible 
 Relationship to Ganitumab (AMG 479) 
 (CTCAE 5.0 Term) 
[n= 334] 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
Anorexia 
Anorexia (Gr 2) 
Hyperglycemia 
Hyperglycemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
Myalgia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Pneumonitis4
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash5 
Rash5 (Gr 2) 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting  PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2Middle to high range sensorineural hearing loss has been reported in patients treated with 
monoclonal antibodies to Insulin-like Growth Factor-1 Receptor (IGF-1R). 
3Infusional reactions may include chills, fever, hypotension, dyspnea, arthralgia, joint swelling, 
headache, dizziness, and cardiac arrhythmia (e.g., atrial fibrillation, tachycardia). 
4The rate and severity of radiation-associated pneumonitis may be increased in patients who 
receive ganitumab shortly before or after radiation to the lungs. 
5Rash includes rash, rash acneiform, rash maculo-papular, skin lesions, and pruritus. 


 
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Adverse events reported on ganitumab (AMG 479) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that ganitumab (AMG 479) 
caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (diastolic dysfunction); 
Heart failure; Myocardial infarction 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Cataract; Keratitis 
GASTROINTESTINAL DISORDERS - Abdominal pain; Anal fistula; Anal mucositis; 
Constipation; Dysphagia; Esophagitis; Gastrointestinal disorders - Other (enteritis); Mucositis 
oral; Oral pain; Pancreatitis; Rectal fistula; Rectal hemorrhage; Small intestinal obstruction; 
Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Non-
cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (hepatic function 
abnormal); Hepatobiliary disorders - Other (jaundice cholestatic) 
INFECTIONS AND INFESTATIONS - Anorectal infections; Infections and infestations - 
Other (pneumococcal infection); Lung infection; Myelitis; Sepsis; Skin infection; Soft tissue 
infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Vascular access 
complication 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; Ejection fraction 
decreased; Investigations - Other (electrocardiogram abnormal); Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hyperkalemia; 
Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone 
pain; Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Radiculitis; Reversible posterior leukoencephalopathy 
syndrome; Seizure; Stroke; Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Agitation 
RENAL AND URINARY DISORDERS - Acute kidney injury; Urinary tract obstruction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Cough; Epistaxis; Hypoxia; Pleural effusion; Respiratory, thoracic and mediastinal 
disorders - Other (respiratory hemorrhage) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Palmar-plantar 
erythrodysesthesia syndrome; Skin ulceration 


 
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VASCULAR DISORDERS - Hematoma; Hypertension; Thromboembolic event (venous) 
Note: Ganitumab (AMG 479) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
7.3 
ADVERSE EVENT CHARACTERISTICS  
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
• For expedited reporting purposes only:   
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, section 7.1.1) should be reported through CTEP-AERS only if the grade 
is above the grade provided in the SPEER. 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.4 
EXPEDITED ADVERSE EVENT REPORTING 
7.4.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).   
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
7.4.2 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 


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physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death
2) A life-threatening adverse event
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization
for ≥ 24 hours
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life
functions
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening, or require
hospitalization may be considered serious when, based upon medical judgment, they may
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via AdEERS within the timeframes detailed in the table below. 
Hospitalization
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:   Protocol-specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24
hours of learning of the AE, followed by a complete expedited report within 5 calendar days
of the initial 24-hour report.
o
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10
calendar days of learning of the AE.


 
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1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.5 
ROUTINE ADVERSE EVENT REPORTING 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
7.5.1 Protocol Specific Additional Instructions and Reporting Exceptions  
CTEP-AERS 24-hour Notification is required for ≥ Grade 2 pneumonitis.  
7.6 
SECONDARY MALIGNANCY 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.7 
SECOND MALIGNANCY 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 


 
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8 
NIH INTRAMURAL RESEARCH REPORTING  
8.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
8.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING/ IRB REPORTING 
8.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
8.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
8.3 
NCI CLINICAL DIRECTOR REPORTING (FOR NCI SITE ONLY) 
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
8.4 
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER 
TRIALS 
Report events to the Reviewing IRB as per its policy. Please also notify the coordinating center 
PI and study coordinator of your submission at the time you make it.  
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
9.1 
GENOMICS, TRANSCRIPTOMICS AND PROTEOMICS MOLECULAR ANALYSIS  
Proteomic, genomic and transcriptomic molecular profiling will be conducted by NantOmics.   
Proteomic molecular profiling is mandatory for study participation.  Patients will be strongly 
encouraged to participate in genomic and transcriptomic molecular profiling under POB protocol 
10-C-0086, Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a 
Repository for Related Biological Studies.  CHLA patients will be given the option to enroll 
remotely on 10-C-0086 at the time of their enrollment on this study. They will be contacted by 
an NCI investigator to discuss participation. Only patients who consent to 10-C-0086 will have 
tumor tissue and whole blood samples collected and sent to NantOmics for genomic and 
transcriptomic analysis.  If patients do NOT consent to genomic and transcriptomic molecular 


 
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profiling under protocol 10-C-0086, their samples will be sent to NantOmics for proteomic 
analysis only. 
Collection of FFPE tumor tissue and whole blood at screening/baseline is preferred for the 
molecular analysis.  In the event the tissue cannot be collected at screening/baseline, a historic 
FFPE tissue block of the specimen taken ≤ 6 months from the date of the screening visit is the 
second preferred option.  In the event this is not available, an archival tissue may be used.    
In the event that there is not sufficient tissue to perform all desired analyses, priority will be 
given to performing NantOmics proteomics first, followed by NantOmics genomics and 
transcriptomics, followed by NCI protocol 10-C-0086 exploratory studies. 
9.1.1 Rationale 
Genomic sequencing of tumor cells relative to non-tumor cells from whole blood will be profiled 
to identify the genomic variances that may contribute to response or disease progression and 
provide an understanding of molecular abnormalities.  RNA sequencing will be conducted to 
provide expression data and give relevance to DNA mutations.  Quantitative proteomics will be 
conducted to determine the exact amounts of specific proteins and to confirm expression of 
genes that are correlative of response and disease progression.  All genomic, transcriptomic, and 
proteomic molecular analysis will be retrospective. 
9.1.2 Sampling 
Genomics and proteomics molecular profiling will be performed on formalin-fixed, paraffin 
embedded (FFPE) tumor tissue and whole blood (subject matched normal comparator against the 
tumor tissue) by next-generation sequencing and mass spectrometry-based quantitative 
proteomics.   
9.1.3 Sampling Times 
9.1.3.1 Archival Tumor Tissue 
Tumor tissues and whole blood will be obtained at baseline.   
9.1.3.2 Biopsies 
In consenting participants (when biopsies can be performed safely without additional risk of 
morbidity), biopsies will be performed to explore mechanisms of response, and resistance will be 
assessed by analyzing biopsy tissue expression of IGF-1R, insulin receptor, IGF-2, and phospho-
YES, and through genomic and proteomic analysis.  Optional biopsies will be taken at 
enrollment, during week 1 of treatment and at the time of progression.  Biopsies will be 
formalin-fixed and paraffin embedded. 
Specimens will be batched and performed retrospectively.  
9.1.4 General Information for Collection of Tumor Tissues and Whole Blood 
Tumor tissue and whole blood samples are to be collected according to the NantOmics Sample 
Collection Manual, or instruction cards included in the Tissue Specimen Kit and Blood 
Specimen Kit.  The kits include the materials necessary to collect and ship FFPE tumor tissue 
samples and whole blood samples.   


 
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NCI investigators are responsible for obtaining the subject’s written Informed Consent Form for 
genomic and transcriptomic analysis (on protocol 10-C-0086); the NCI investigators are to 
confirm that the written informed consent was obtained before submitting genomic samples. 
The investigational site(s) are responsible for completing the protocol # 10003 Clinical Trial 
Requisition Form with the following information: 
- Clinical Site Information 
- Patient Information  
- Specimen Information 
- Specimen Collection Information 
The investigational site(s) will return a hard copy of the completed Clinical Trial Requisition 
Form with the kit shipment per the instructions provided on the form. An electronic copy of this 
form may be downloaded from the study portal (NantOmics). 
Fresh biopsies will be formalin-fixed and paraffin-embedded for molecular profiling. Detailed 
specimen requirements and procedural instructions for FFPE tumor tissue samples and whole 
blood samples are provided in the CTEP #10003 NantOmics Sample Collection Manual.    
9.1.5 Genomic and Proteomic Analysis of Tumor Tissue and Whole Blood 
A single FFPE tumor tissue block is preferred for the extraction of tumor DNA, tumor RNA, and 
tumor protein (see Table 1 below).  A whole blood sample is required for the extraction of 
subject normal DNA.  Refer to the NantOmics Sample Collection Manual for details.  Tumor 
tissue and whole blood will be processed in the NantOmics, LLC CLIA-registered and CAP 
accredited/CLIA certified laboratories.   
Table 1: Schedule of Collection for Molecular Profiling 
Molecular Profiling 
Baseline 
Whole blood (normal comparator against tumor) 
1 PAXgene Blood DNA tube (2.5 mL)a 
 
Formalin-fixed, paraffin-embedded tumor tissue blockb 
A minimum tissue surface area of 25 mm2, 75 µm thick, 
with at least 30% malignant tissue 
 
 
a Whole blood to be collected at baseline only for genomic sequencing. Requires 2.5 mL of subject's whole blood in  1 PAXgene 
Blood DNA tube, provided in the Blood Specimen Kit (see CTEP #10003 NantOmics Sample Collection Manual).  
b FFPE tissue blocks to be collected at baseline for genomic sequencing, RNAseq, and proteomic analysis.  A single block 
meeting the minimum requirements for genomics and proteomics is required. FFPE tissue blocks to be collected per local 
pathology laboratory procedures; detailed specimen and procedural instructions are provided in the CTEP #10003 NantOmics 
Sample Collection Manual. 


 
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9.1.6 Genomic and Proteomic Analysis Results 
The individual subject’s summary report of cancer-related genomic and proteomic data can be 
provided to the investigator upon request after the individual subject has completed or 
discontinued the clinical study. Procedural instructions for requesting the cancer-related genomic 
and proteomic summary report are provided in the CTEP #10003 NantOmics Sample Collection 
Manual. 
9.2 
BIOMARKER STUDIES 
From the whole-genome sequencing, RNA transcriptomic, and quantitative proteomic profiling, 
evaluation of biomarkers in tumors and blood samples will include but will not be limited to the 
following biomarkers: 
 
Biomarker Namea 
AND Lead PI and 
Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, 
or Exploratory) AND 
Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  Funding 
Source(s) c 
IGF-1R expression 
NantOmics 
Targeted 
MS: IGF- 1R 
CLIA: Y 
Exploratory 
Response assessment 
Archival tumor tissue 
At enrollment 
M 
NCI/POB 
IGF-1R expression 
NantOmics 
Targeted 
MS: IGF- 1R 
CLIA: Y 
Exploratory 
Response assessment 
Biopsied tumor tissue 
At enrollment, during 
week 1 of treatment, 
and at progression 
O 
NCI/POB 
Insulin receptor 
expression 
NantOmics 
Targeted 
MS: IR 
CLIA: N 
Exploratory 
Response assessment 
Archival tumor tissue 
At enrollment 
M 
NCI/POB 
Insulin receptor 
expression 
NantOmics 
Targeted 
MS: IR 
CLIA: N 
Exploratory 
Response assessment 
Biopsied tumor tissue 
At enrollment, during 
week 1 of treatment, 
and at progression 
O 
NCI/POB 
IGF-2 expression 
NantOmics 
Targeted 
MS: IGF-2 
CLIA: N 
Exploratory 
Response assessment 
Archival tumor tissue 
At enrollment 
M 
NCI/POB 
IGF-2 expression 
NantOmics 
Targeted 
MS: IGF-2 
CLIA: N 
Exploratory 
Response assessment 
Biopsied tumor tissue 
At enrollment, during 
week 1 of treatment, 
and at progression 
O 
NCI/POB 


 
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Biomarker Namea 
AND Lead PI and 
Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, 
or Exploratory) AND 
Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  Funding 
Source(s) c 
Phospho-YES 
expression 
NantOmics 
Targeted 
MS: pSFK 
CLIA: N 
Exploratory 
Response assessment 
Archival tumor tissue 
At enrollment 
M 
NCI/POB 
Phospho-YES 
expression 
NantOmics 
Targeted 
MS: pSFK 
CLIA: N 
Exploratory 
Response assessment 
Biopsied tumor tissue 
At enrollment, during 
week 1 of treatment, 
and at progression 
O 
NCI/POB 
The following exploratory biomarker studies will be conducted on archival tissue obtained at the 
time of enrollment.   
1. IGF-1R expression 
2. Insulin receptor expression 
3. IGF-2 expression 
4. Phospho-YES expression 
In consenting participants when biopsies can be performed safely without additional risk of 
morbidity, biopsies will be performed to explore mechanisms of response, and resistance will be 
assessed by analyzing biopsy tissue expression of IGF-1R, insulin receptor, IGF-2 expression 
and phospho-YES expression, and through genomic sequencing.  Biopsies will be taken at 
enrollment, during week 1 of treatment and at the time of progression. 
Specimens will be batched and performed retrospectively.  
9.2.1 Proteomics 
There are two key components to the quantitative proteomics approach, which allows for the 
quantitation of targeted proteins from formalin-fixed paraffin-embedded (FFPE) tumor biopsies. 
Liquid Tissue® (LT) Technology 
NantOmics uses a proprietary non-contact method of laser microdissection that isolates and 
collects only the tumor cells of interest for analysis. The accuracy and precision of 
microdissection ensures that the collected sample is highly enriched for active tumor cells, 
limiting the presence of necrotic, stromal, or normal cells.  The microdissected FFPE tumor 
tissue is then subjected to Liquid Tissue® processing to solubilize the tumor tissues. The patented 
Liquid Tissue® technology ensures that formalin cross-links are reversed and all of the proteins 
in the tumor tissue are solubilized. 
Mass Spectrometry-based Selected Reaction Monitoring (SRM) Technology 
The solubilized tumor tissue is then subjected to multiplexed SRM analysis using stable isotope-
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represents an emerging clinical method, which is highly specific, reproducible, objectively 
quantitative, and has reduced sensitivity to pre-analytical variation. In addition, mass 
spectrometry-based proteomic analysis of FFPE tissue is capable of multiplexing analysis of up 
to 100 analytes from a small amount of tissue. 
9.2.1.1 Sample requirements for proteomics analyses 
Refer to NantOmics Sample Collection manual for sample requirements and collection 
instructions. 
 
Ship samples and the Requisition form, as outlined in the NantOmics Sample Collection manual, 
to: 
NantOmics 
Attention: Sample Receipt 
9600 Medical Center Drive 
Suite 300 
Rockville, MD 20850 
USA 
9.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Blood and tissue collected during the course of this study will follow NIH guidelines for the 
research use of human samples and OHSRP Issues to Consider in the Research Use of Stored 
Data or Tissues. At the NIH Clinical Center, samples will be ordered and tracked in CRIS and 
tracked through a Clinical Trial Data Management system.  Should a CRIS screen not be 
available, the CRIS downtime procedures will be followed.  Samples will not be sent outside 
NIH without IRB notification and an executed MTA.  
All tumor samples obtained for research, not directly transported for study analysis, will be 
transported to Dr. Figg’s laboratory to be barcoded. Dr. Figg’s laboratory will need the patient’s 
Medical Record Number, name, protocol, date, time, and site of tissue, and a description of the 
type of tissue (normal versus tumor) to issue a label for the sample. 
Please e-mail Dr. Figg’s lab at NCIBloodcore@mail.nih.gov at least 24 hours before transporting 
samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Dr. Figg’s lab at 
NCIBloodcore@mail.nih.gov. 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user 
accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These 
computers all have a password restricted login screen. All Figg lab personnel with access to 
patient information annually complete the NIH online Protection of Human Subjects course.  


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LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
9.3.1 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador (aka 
LabSamples). All researchers are required to sign a form stating that the samples are only to be 
used for research purposes associated with this trial (as per the IRB approved protocol) and that 
any unused samples must be returned to the BPC. It is the responsibility of the NCI Principal 
Investigator to ensure that the samples requested are being used in a manner consistent with IRB 
approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested). 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador (aka LabSamples). It is critical that the sample remains linked to patient information 
such as race, age, dates of diagnosis and death, and histological information about the tumor, in 
order to correlate results with these variables. 
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 8.2. 
9.4 
SAMPLES FOR GENETIC/GENOMIC TESTING 
Subjects on this study will be asked to co-enroll on 10-C-0086: Comprehensive Omics Analysis 
of Pediatric Solid Tumors and Establishment of a Repository for Related Biological Studies.  
Patients who consent to participate in 10-C-0086 will undergo blood sampling at baseline and 
prior to each cycle as detailed in the study calendar, as well as genomic analysis as described 
below.   


 
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This companion protocol may include the following analyses: analysis for mutations or Single 
Nucleotide Variants (SNVs) in tumors and germline DNA, comparative genomics hybridization, 
whole genome, exome, and transcriptome sequencing of tumor and germline DNA, messenger 
and microRNA sequencing and expression analysis, epigenetic studies including whole 
methylome analysis using next generation sequencing, metabolomics study of tumor, global 
mass spectroscopy-based protein and phospho-protein analysis. 
In addition, NantOmics will run Genomic analysis. 
9.4.1 Sequencing 
1. Whole Genome Sequencing (WGS) will be done at average depth of 30x for normal 
samples, and an average depth of 60x for tumor samples. RNA sequencing (RNA-Seq) 
will be performed on tumor samples to obtain approximately 240 million reads across 
two technical replicates to assure reproducibility. 
2. NantOmics lab has experience sequencing tumor DNA extracted from formalin-fixed, 
paraffin embedded (FFPE) blocks and slides, fresh frozen tissue, and purified DNA. The 
FFPE failure rate is approximately 10%, with most failures occurring when the blocks 
provided have little to no tumor content remaining. NantOmics requests matched normal 
sample of all patients, and can handle multiple sample types including whole blood, 
saliva, buccal swabs, and purified DNA. 
3. Using standard methods, sequencing reads are aligned and duplicate marked, followed by 
indel realignment and base quality recalibration. NantOmics cancer analytical pipeline 
takes tumor and matched-normal alignments (BAM format) to call point mutations, small 
indels, copy number and allele fraction, and structural variants at all scales. Filtering is 
performed on all variants to reduce false positives while being permissive enough to 
avoid removing variants of interest. Copy number and allele fraction are integrated to 
determine regions that exhibit similar copy number and allelic bias, e.g. necessary to 
discover regions of copy neutral loss-of-heterozygosity (CN-LOH) located inside a 
region of normal copy number. Using these relative copy number estimates and allele 
fraction, NantOmics estimates tumor purity and ploidy, and use that to inform more 
accurate copy number estimates and mutation clonality. They perform local assembly 
using both unmapped and mapped reads aligned near each putative structural variant to 
precisely locate (base precision) where the structural variant occurred in the tumor 
genome. All variants identified are annotated for any effect they may have to gene(s) or 
their isoforms.  
9.4.2 Sample requirements for genomics analyses 
9.4.2.1 Tumor tissue 
Refer to NantOmics Sample Collection manual for sample requirements and collection 
instructions and Appendix 9 if sending samples from a participating site. 
9.4.2.2 Blood sample 
Refer to NantOmics Sample Collection manual for sample requirements and collection 
instructions and Appendix 9 if sending samples from a participating site. 


 
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10 STUDY CALENDAR 
Baseline evaluations, including cardiac studies, are to be conducted within 1 week prior to start 
of protocol therapy.  Imaging studies of disease must be done ≤4 weeks prior to the start of 
therapy.   
 
For labs indicating a specific day to be drawn (for example, day 14), labs may be drawn on the 
day indicated in the table, or up to 2 days earlier. 
 
STUDIES TO 
BE 
OBTAINED 
Screening 
Baseline 
During 
Cycle 1 
During 
Subsequent Cycles 
At End of 
Therapy1 
Off 
Therapy11 
History, physical 
exama, vital 
signs, including 
oxygen 
saturation 
X 
X 
Weekly 
starting from 
day -7 
At days 0 and 14 of 
each subsequent 
cycle 
X 
Monthly 
Tanner stage 
X 
X 
 
Only if change 
from baseline 
X 
 
Height, weight, 
BSA 
X 
X 
 
At start of each 
subsequent cycle 
X 
 
Performance 
Status2 
X 
X 
 
Only if change 
from baseline 
X 
 
CBC, 
differential, 
platelets3 
X 
X 
Weekly 
starting from 
day -7 
 
Weekly for cycles 2 
and 3, then every 
other week 
thereafter 
X 
Monthly 
BUN, creatinine, 
sodium, 
potassium, 
chloride, CO2, 
calcium, 
magnesium, 
phosphorus, uric 
acid, LDH 
X 
X 
Weekly 
starting from 
day -7 
Prior to each 
subsequent cycle 
 
X 
Monthly 
Serum glucose4 
X 
X 
Weekly 
starting from 
day -7 
Weekly for cycles 2 
and 3, then every 
other week 
thereafter 
X 
Monthly 
HgbA1C5 
X 
X 
As indicated5 
As indicated5 
As 
indicated5 
 


 
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STUDIES TO 
BE 
OBTAINED 
Screening 
Baseline 
During 
Cycle 1 
During 
Subsequent Cycles 
At End of 
Therapy1 
Off 
Therapy11 
Hepatic panel: 
Alkaline 
phosphatase, 
ALT, AST, 
Total bilirubin 
(Direct bilirubin 
if total is 
elevated) 
X 
X 
Weekly 
starting from 
day -7 
Prior to each 
subsequent cycle 
 
X 
Monthly 
Total protein, 
albumin 
X 
X 
Weekly 
starting from 
day -7 
Prior to each 
subsequent cycle 
X 
Monthly 
Fasting 
triglycerides, 
Cholesterol 
(Total, HDL, 
and LDL)  
X 
X 
 
Prior to each 
subsequent cycle 
X 
Monthly 
Urinalysis  
X 
X 
Weekly 
starting from 
day -7 
Prior to each 
subsequent cycle 
X 
Monthly 
PT, INR (in 
patients 
undergoing 
biopsy) 
X 
X 
Within 24 
hours prior to 
biopsy 
 
Within 24 
hours prior 
to biopsy 
 
EKG 
X 
X 
 
Prior to each 
subsequent cycle 
 
Monthly 
Echocardiogram 
X 
X 
 
Prior to cycle 
2,3,5,7 etc. 
 
Monthly 
Disease 
Evaluation6 
X 
X 
 
Prior to cycle 3, 5, 
7, etc. 
X 
Every 2 
months 
Pregnancy Test7 
X 
X 
 
Prior to each 
subsequent cycle 
 
 
Unstained slides 
or block 
(required at 
study entry) 
X 
X 
 
 
 
 
Molecular 
Profiling (see 
section 9.1.5) 
 
X 
 
 
 
 
Research Blood 
(10 cc EDTA or 
Streck tube if at 
NIH)8 
 
X 
 
Prior to each 
subsequent cycle 
 
 
Research Blood 
(10 cc Cell-Free 
DNA BCT 
 
X 
 
Prior to each 
subsequent cycle 
 
 


 
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STUDIES TO 
BE 
OBTAINED 
Screening 
Baseline 
During 
Cycle 1 
During 
Subsequent Cycles 
At End of 
Therapy1 
Off 
Therapy11 
tube if outside 
NIH)9 
Optional 
Biopsy10 
 
X 
During week 
1 
 
X 
 
NIH Advance 
Directives 
Form12 
 
X 
 
 
 
 
1 Should be performed, if possible, when the patient comes off treatment regardless of the reason. 
2Appendix 1; prior to cycle 1 and then only required to be recorded if there is a change in 
performance status during the study. 
3 If patients develop Grade 4 neutropenia then CBC should be checked every 3 to 4 days until 
recovery to grade 3. 
4Also obtain for symptoms of polyuria or polydipsia or as otherwise clinically indicated. 
5HgbA1C should be obtained at baseline and if the patient develops hyperglycemia requiring 
treatment and then every 3 months until hyperglycemia resolves and treatment is no longer 
required.  
6 Imaging studies of each site of disease with appropriate modality. 
7 Patients of childbearing 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. 
8Only perform in patients consented to 10-C-0086 (Omics). Deliver immediately to Donna 
Bernstein. 
9 Only perform in patients consented to 10-C-0086 (Omics). Ship immediately to Donna 
Bernstein per guidelines in Appendix 9. 
10Should be performed at end of therapy only if patient comes off treatment due to progression. 
 11Off-therapy studies are required only for patients who are removed by the PI due to drug 
toxicity or side effects. All patients will be followed for at least 30 days after the last dose of 
investigational agents and until disease progression, whichever is last. 
12As indicated in section 15.3, all subjects enrolled at NIH and ≥ age 18 will be offered the 
opportunity to complete an NIH advance directives form.  This should be done preferably at 
baseline but can be done at any time during the study as long as the capacity to do so is retained.  
The completion of the form is strongly recommended, but is not required. 
a A complete standard physical examination will be performed at baseline; subsequent physical 
exams will be targeted based on signs and symptoms of presenting patient. 
11 MEASUREMENT OF EFFECT   
11.1 RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 


 
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Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).(70) Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
11.1.1 Definitions 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with dasatinib and ganitumab. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
11.1.2 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 


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and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 


 
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scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published.(71-73) In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.(74)  
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-


 
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PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
11.1.4 Response Criteria 
11.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
11.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     


 
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Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
11.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 


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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
11.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
11.1.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since
SD is increasingly used as an endpoint for assessment of efficacy in some trials
so to assign this category when no lesions can be measured is not advised


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12 STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
12.1 STUDY OVERSIGHT  
This protocol is monitored at several levels, as described elsewhere in this section.  The Protocol 
Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, 
including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine 
and serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal. 
For a Phase 1/2 trial, enrollment to the Phase 2 portion of the trial will not begin until a protocol 
amendment has been submitted which summarizes the Phase 1 results, the recommended Phase 2 
dose, and the rationale for selecting it.  The amendment must be reviewed and approved by 
CTEP before enrollment to the Phase 2 portion can begin. 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave..   
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 8.2. 
12.2 DATA REPORTING 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA or 
Rave Investigator) on either the LPO or participating organization roster at the enrolling site. To 
the hold Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an 
AP registration type.  To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR. Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 


 
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using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
12.2.1 Method 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18-36 months basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
12.2.2 Responsibility for Data Submission 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA to resolve.  Monthly web-based reports are 
posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will be conducted by 
the CTMS to ensure compliance with regulatory requirements, GCP, and NCI policies and 
procedures with the overarching goal of ensuring the integrity of data generated from NCI-
sponsored clinical trials, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D) and a description of any dose-limiting toxicities (DLTs).  CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-


 
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semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
CDUS data submissions for trials activated after March 1, 2014, will be carried out by the CTMS 
contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly basis.  The 
trial’s lead institution is responsible for timely submission to CTMS via Rave, as above. 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
12.3 DATA SHARING PLANS 
12.3.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
• Coded, linked data in an NIH-funded or approved public repository.   
• Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
• Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared?  
Data will be shared through: 
• An NIH-funded or approved public repository: clinicaltrials.gov. 
• BTRIS (automatic for activities in the Clinical Center) 
• Approved outside collaborators under appropriate individual agreements. 
• Publication and/or public presentations. 
When will the data be shared?  
• Before publication. 
• At the time of publication or shortly thereafter. 
12.3.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases according to the plan 
described in protocol 10-C-0086 in compliance with the NIH Genomic Data Sharing Policy. 


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13 STATISTICAL CONSIDERATIONS  
13.1 PHASE I 
The primary objective of the phase I component of this study is to determine the safe dose of 
dasatinib when given with ganitumab in patients with relapsed or refractory embryonal or 
alveolar RMS.  This trial uses a limited dose-escalation design to establish the MTD, or highest 
safe dose of dasatinib.  The starting dose level will be 60 mg/m2 once daily (maximum dose of 
100 mg/dose once daily) on days -7 through day 27 during cycle 1 (35 days), and then days 0-27 
for subsequent cycles (28 day cycles).  This will be followed by one dose escalation to 60 mg/m2 
BID (maximum dose of 70 mg/dose BID) on days -7 through day 27 during cycle 1, and then 
days 0-27 for subsequent cycles. The MTD is defined as the dose level immediately below the 
level at which ≥33% of patients in a cohort experience a DLT.  The MTD will be defined based 
on toxicities observed during the first treatment cycle in order to capture toxicities during 28 
days of administration of both agents.  Any patient who receives one or more doses and 
experiences a DLT will be considered evaluable for definition of the MTD. If a patient did not 
experience DLT and did not finish treatment in cycle 1, he or she will only be evaluable for the 
dose escalation portion of the study if they received both ganitumab doses and ≥85% of the 
dasatinib doses in cycle 1. Patients who have not met these criteria will be replaced in the dose 
level.  If ≥2 out of a maximum of 6 patients experience DLT at dose Level 1, the dose of 
dasatinib will be de-escalated to dose Level -1.  If 0-1 out of a maximum of 6 patients have DLT 
at dose Level -1, this will be considered the MTD.  If 2 or more out of a maximum of 6 patients 
experience DLT at dose Level -1, the accrual will be suspended pending discussions with the 
Sponsor and NIH Intramural IRB regarding how to proceed with the combination therapy. Dose 
escalation and de-escalation rules are specified in section 5.1.1.  Patients who receive dasatinib at 
the MTD (or highest safe dose) and ganitumab during the phase I portion of the study will be 
included in the evaluation of the phase II objectives. 
Toxicities related to the combination therapy will be analyzed and reported descriptively 
13.2 PHASE II 
The primary objective of the phase II component of the trial is to determine if the use of 
ganitumab plus dasatinib is able to be associated with a modest fraction of patients who 
experience an objective clinical response (CR or PR) by RECIST. In addition, a second primary 
objective will estimate the fraction that is without progression at 4 months and, secondarily, to be 
able to obtain an approximate estimate of the progression free survival (PFS) of the patients. 
The phase II component of the trial will be conducted using a single stage design with 16 
evaluable patients. With this number, there would be 90% power to rule out a 5% fraction with a 
clinical response in favor of a 30% fraction with a clinical response, using a one sided 0.10 
significance level exact test for a binomial proportion. In practice, the fraction of the 16 patients 
that have objective responses will be determined and reported along with 80% and 95% 
confidence intervals. If there are 3 objective responses in 16 evaluable patients, the lower one-
sided exact 90% confidence interval is 7.1%, thus ruling out 5%. 
Because the staging evaluations for this trial will take place at approximately 8 week intervals 
and patients typically progress very rapidly, a Kaplan-Meier curve may potentially be somewhat 


 
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imprecise with respect to its presentation of PFS, especially at early time points. Thus, the 
determination of progression or not at the 4-month evaluation will be the preferred co- primary 
endpoint for the trial rather than PFS. The information obtained on PFS as well as 4 month 
progression or not will be reported and considered for use in interpreting the results of this study 
and may be used to guide any subsequent evaluations. 
This study will also address a set of secondary and exploratory objectives. 
With the understanding of it limitations, in addition to determining the fraction that are without 
progression by 4 months, a Kaplan-Meier curve will be constructed as a secondary outcome to at 
least approximately illustrate the PFS as a function of time, recognizing the limited opportunities 
to assess the actual time of progression relative to an anticipated rapid progression time.  
Toxicities related to the combination therapy will be analyzed and reported descriptively by dose 
level, grade and attribution. 
In all patients, mechanisms of response and resistance will be assessed by analyzing archival 
tissue for expression of IGF-1R, insulin receptor, IGF-2 expression and phospho-YES 
expression, and through genomic sequencing (in patients participating in 10-C-0086). In patients 
for whom tumor biopsies can be obtained successfully, mechanisms of response and resistance 
will be assessed by analyzing biopsy tissue expression of IGF-1R, insulin receptor, IGF-2 
expression and phospho-YES expression, and through genomic sequencing (in patients 
participating in 10-C-0086). 
13.3 SAMPLE SIZE/ACCRUAL RATE  
The phase I portion of the study may enroll up to 12 subjects to establish MTD or highest safe 
dose.  Sixteen evaluable patients are required to evaluate the objectives in the phase II 
component. Up to 6 patients from the phase I component who receive study drugs at the MTD or 
highest safe dose will be included in the analysis of the 16 patients in the phase II component.  
Therefore, the maximum patient accrual, allowing for replacement of  inevaluable patients (up to 
4) as well as to account for screen failures (up to 14), is expected to be 12 + 10 + 4+14, for a total 
enrollment of 40 patients.  
It is anticipated that approximately 10-15 patients per year may be accrued onto this trial. Thus, 2 
to 3 years is expected to completed accrual. If the actual accrual is slower, we would consider 
opening the trial at additional sites to improve the accrual rate.  
14 COLLABORATIVE AGREEMENTS  
14.1 CTEP COLLABORATIVE AGREEMENT (CRADA, CTA, CSA) 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 


 
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1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators. The protocol documents for studies utilizing Agents 
contain confidential information and should not be shared or distributed without the permission 
of the NCI.  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 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.   NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, 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 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 Agent. 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
4.   When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) 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 CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-Cooperative 
Group studies 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 


 
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addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must 
be provided to CTEP 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 CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov  
The 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. 
14.2 MULTI-INSTITUTIONAL GUIDELINES 
14.2.1 IRB Approvals 
The PI will provide the NIH Intramural IRB with a copy of the participating institution’s 
approved yearly continuing review.  Registration will be halted at any participating institution in 
which a current continuing approval is not on file at the NIH Intramural IRB. 
14.2.2 Amendments and Consents 
The CCR PI will provide the NIH Intramural IRB with copies of all amendments, consents and 
approvals from each participating institution. 
15 HUMAN SUBJECTS PROTECTIONS  
15.1 RATIONALE FOR SUBJECT SELECTION 
Subjects of both genders and from all racial and ethnic groups are eligible for this trial if they 
meet the eligibility criteria outlined in section 3.1.  No groups are being excluded from 
participation in the trial.  Efforts will be made to extend the accrual to a representative 
population, but in a small pilot trial which will accrue a maximum of 16 patients, a balance must 
be struck between the need to evaluate safety and efficacy, and the need to explore gender, 
racial, and ethnic aspects of clinical research.  If differences in outcome that correlate to gender, 
racial, or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully.   
Projected accrual table: 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 


 
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DOMESTIC PLANNED ENROLLMENT REPORT 
American 
Indian/ Alaska 
Native 
0 
1 
 
 
1 
Asian 
1 
2 
 
 
3 
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
0 
 
 
0 
Black or 
African 
American 
4 
6 
 
 
10 
White 
8 
13 
2 
3 
26 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
13 
22 
2 
3 
40 
 
15.2 PARTICIPATION OF CHILDREN 
There is no limit to the age of participants in this trial.  Children who meet eligibility criteria for 
this trial will be offered entry in the study.  Children will be evaluated and cared for by 
physicians trained in pediatrics and pediatric oncology, and will be followed in a Pediatric 
Oncology clinic.  The clinical and research staff in the Pediatric Oncology Branch and CHLA 
have extensive experience caring for patients of younger ages in administering complex research 
therapies. 
15.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT (NIH CCR ONLY—
PARTICIPATING SITES SHOULD FOLLOW THEIR INSTITUTIONAL POLICY) 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 15.4), all subjects enrolled at NIH who are ≥ age 18 will be 
offered the opportunity to fill in their wishes for research and care, and assign a substitute 
decision maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation” form so that another person can make decisions about their medical care in the 
event that they become incapacitated or cognitively impaired during the course of the study. 
Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation as needed for the following: an independent assessment of whether an individual has 


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the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate 
when indicated; and/or an assessment of the capacity to appoint a surrogate.  For those subjects 
that become incapacitated and do not have pre-determined substitute decision maker, the 
procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult 
subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable 
power of attorney, will be followed. 
15.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The primary risk to patients, including adults who may lose their ability to consent, participating 
in this research study is from toxicities related to the investigational agents (ganitumab and 
dasatinib) as described in the protocol, section 7.  The primary objective of this study is to 
determine if the use of ganitumab plus dasatinib is able to be associated with a modest fraction of 
patients who experience an objective clinical response (CR and PR) as defined by RECIST 
criteria. In addition, a second primary objective will estimate the fraction that is without 
progression at 4 months.  Patients will thus be treated with therapeutic intent and response to the 
therapy will be closely monitored.  Treatment options for these patients are very limited, as most 
patients will have received all prior effective therapies.  The potential benefits from this therapy 
are disease stabilization, tumor shrinkage, and a reduction in symptoms caused by 
rhabdomyosarcoma.  Therefore, this protocol involves greater than minimal risk to the patients 
entered, but presents the potential for direct benefit to individual subjects. 
Pediatric patients: This trial will be open to children under 18 years of age.  Given the potential 
for clinical benefit, participation of children in this study meets 45 CFR 46.405- Research 
involving greater than minimal risk but presenting the prospect of direct benefit to the individual 
child subjects involved in the research. 
15.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The investigational nature and research objectives of this trial, the procedures and treatments 
involved and their attendant risks and discomforts and benefits, and potential alternative 
therapies will be carefully explained to the patient or the patient’s parents or guardian if he/she is 
a child, and a signed informed consent document will be obtained prior to entry onto the study.   
The PI or an associate investigator on the trial at each site will obtain consent.  The PI or 
associate investigator will meet with the patient, or the patient’s parents or guardian, and other 
family members to discuss the protocol treatment and alternative options in detail.  It will be 
stated clearly that participation in the research study is voluntary and that participants can 
withdraw from the study without losing benefits they would otherwise be entitled to. The patient 
and family members will be encouraged to ask questions, and additional meetings to discuss the 
treatment options will be arranged as necessary.   
The investigators are requesting a waiver from the IRB to allow only one parent to sign the 
informed consent to enter a child on the protocol. Because many patients must travel to the NIH 
or CHLA from long distances at substantial expense, requiring both parents to be present for the 
consent process could be a financial hardship for many families. When guardianship status of the 
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In situations where there is joint custody of a child, both parents must sign consent. If only one 
parent can be present at NIH or CHLA, the other parent’s consent can be obtained by telephone 
via the procedure described in section 15.5.2. 
Where deemed appropriate by the clinician and the child’s parent(s) or guardian, the child will 
also be included in all discussions about the trial and age-appropriate language will be used to 
describe the procedures and tests involved in this study, along with the risks, discomforts and 
benefits of participation.  Written assent will not be obtained from children as the study holds out 
the prospect of direct benefit that is important to the health and well-being of the child and is 
available only in the context of the research. Verbal assent will be obtained as appropriate for 
children ages > 7. The child will sign the appropriate line in the consent document to attest to 
assent.  Children under the age of 7 will not be required to provide assent as they typically do not 
have the cognitive ability to fully understand the nature of research. The consent/assent process 
will be documented in the child’s medical record, including the assessment of the child’s ability 
to provide assent (verbal versus written) as applicable. All children will be contacted after they 
have reached the age of 18 to determine whether they wish to continue on the trial and informed 
consent will be obtained from them at that time. 
15.5.1 Consent for minors when they reach the age of majority 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require consenting of the now 
adult with the standard protocol consent document to ensure legally effective informed consent 
has been obtained. We request waiver of informed consent for those individuals who become lost 
to follow up after all efforts to reach the subject have failed. We also request waiver of informed 
cosent for individuals  who have been taken off study prior to reaching the age of majority. 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to 
subjects. 
(2) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects. 
a. Retention of these samples or data does not affect the welfare of subjects.  
(3) The research could not practicably be carried out without the waiver or alteration. 
a. Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again.  A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research.  
(4) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We only request a waiver of consent for those subjects who have been lost to 
follow-up or who  have been taken off study prior to reaching the age of 
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15.5.2 Telephone consent 
This procedure may be used for initial consent in the event that both parental signatures are 
required as referenced above. This procedure may also be used for re-consent in the event that a 
patient needs to re-consent because of changes to the consent document. The informed consent 
document will be sent to the subject.  An explanation of the study will be provided over the 
telephone after the subject has had the opportunity to read the consent form.  The subject will 
sign and date the informed consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented in the medical record. 
16 PHARMACEUTICAL INFORMATION 
16.1 DASATINIB  (IND# 120449, NSC# 732517)  
Other names: BMS-354825, Sprycel® 
16.1.1 Chemical Name:  
N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2 methyl-4-
pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate 
16.1.2 Mechanism of Action: 
Dasatinib 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.  Overexpression or activation of these kinases plays critical roles in the 
etiology of various cancer types. 
16.1.3 Molecular Formula:   
C22H26CIN7O2S· H20 MW:  Dasatinib monohydrate: 506.02 daltons  
16.1.4 Approximate Solubility:  
Dasatinib’s solubility ranged from 18.42 mg/mL at pH 2.6 to < 0.001 mg/mL at pH 7. 
16.1.5 How Supplied:   
BMS supplies and CTEP, NCI, DCTD distributes dasatinib. Dasatinib is available in the 
following tablet/bottle sizes: 
•
5 mg round, plain white film-coated tablets.
•
20 mg biconvex round, white to off-white film-coated tablets.  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.  The tablet is debossed with
“50” on one side and “528” on the other side.


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Inactive ingredients include lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, hydroxypropyl cellulose, magnesium stearate. The film-coating contains 
hypromellulose, titanium dioxide, glycerol triacetate (in the 5 mg), and polyethylene glycol (in 
the 20 mg tablets and 50 mg tablets).  
Tablets are supplied in high-density polyethylene (HDPE) bottles with desiccant and cotton. The 
bottles are heat-induction sealed with child-resistant caps. 
16.1.6 Storage:   
Store the intact bottles at controlled room temperature (15°C-25°C) and protect from light. 
16.1.7 Stability:   
Stability studies are ongoing.  
16.1.8 Route of Administration:  
 Oral. Tablets may be taken with or without food.   They should be swallowed whole and not 
crushed or broken.  
16.1.9 Potential Drug Interactions 
Dasatinib is primarily metabolized by the human CYP3A4 enzyme; therefore, potent CYP3A4 
inducers and inhibitors are prohibited on dasatinib trials. 
Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 
substrate. Therefore, caution is warranted when dasatinib is co-administered with CYP3A4 
substrates of narrow therapeutic index. 
Systemic antacids (both H2 receptor antagonists and proton pump inhibitors) are prohibited on 
dasatinib trials.  Locally acting antacids can be given up to two hours prior or two hours 
following dasatinib administration.   
Dasatinib may prolong the QT/QTc interval.  Use caution when administering dasatinib with 
other potential QTc-prolonging medications. 
Due to the possibility of CNS, gastrointestinal, cardiac, and cutaneous hemorrhage, use caution 
in patients who require medications that inhibit platelet function or anticoagulants.  
16.1.10Special Handling: 
Dasatinib tablets consist of a core tablet (containing the active drug) surrounded by a film 
coating to prevent exposure to the active drug substance.  If tablets are accidentally crushed or 
broken, caregivers should wear disposable chemotherapy gloves. Pregnant women should avoid 
exposure to crushed and/or broken tablets.  
16.2 GANITUMAB (IND# 120449, NSC# 750008)  
16.2.1 Other Names:  
AMG 479 
16.2.2 Classification: 
Monoclonal antibody 


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16.2.3 M.W.:  
146 kilodaltons (kD) 
16.2.4 Mode of Action: 
Ganitumab exerts its anti-tumor activity by blocking ligand binding (IGF-1 and IGF-2) and 
inducing receptor internalization and degradation without cross-reacting with the insulin 
receptor. 
16.2.5 Description:  
Fully human recombinant IgG1 monoclonal antibody targeting IGF-1R 
16.2.6 How Supplied:  
Ganitumab will be supplied by NantBio and distributed by the PMB, CTEP, NCI as a sterile, 
clear, colorless liquid with 70 mg/mL (210 mg/3 mL or 700 mg/10 mL) vial of ganitumab.  The 
single-use vials also contain the following excipients; 10 mM sodium acetate, 5% w/v sorbitol, 
0.004% w/v polysorbate 20, pH 5.2. Once the 700 mg vial size is available, the 210 mg vial size 
will no longer be available for this trial. 
16.2.7 Preparation: 
The prescribed dose of ganitumab should be further diluted in 0.9% sodium chloride to a 
concentration between 3 mg/mL and 20 mg/mL. 
16.2.8 Storage:  
Store at 2°C to 8°C.  Do not shake or freeze. Protect from light. 
16.2.9 Stability 
Once the ganitumab is injected into the infusion bag, the infusion must be completed within 8 
hours. The total time between removal of ganitumab intact vials from the refrigerator and 
completion of infusion must not exceed 24 hours.   
Vials contain no preservatives and any solution remaining in the vials after the dose is prepared 
should be discarded. 
16.2.10 Route(s) of Administration 
Intravenous infusion. 
16.2.11 Method of Administration  
The infusion line should be thoroughly flushed with saline before and after administration of 
ganitumab to avoid mixing with other drug products or IV solutions. 
The first dose should be administered over 60 ± 10 minutes without premedication. If well 
tolerated, subsequent infusions may be administered over 30 minutes, at the investigator’s 
discretion.  Infusion times can be extended to a maximum of 120 minutes for subjects unable to 
tolerate the 60 minute infusion.  Doses over 2100 mg should be infused over 120 minutes. 


 
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16.3 AGENT ORDERING AND AGENT ACCOUNTABILITY 
16.3.1 Agent Ordering  
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
In general, sites may order initial agent supplies when a subject is being screened for enrollment 
onto the study. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a “current” 
password.  For questions about drug orders, transfers, returns, or accountability, call or email 
PMB any time.  Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
16.3.2 Agent Inventory Records –  
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
16.3.3 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status and a “current” 
password.  Questions about IB access may be directed to the PMB IB coordinator via 
email. 
16.3.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  


 
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• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 


 
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Wu JY, Donato NJ, Hong DS, et al. The SRC/ABL kinase inhibitor BMS-354825
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and patient specimens. Proc Am Assoc Can Res. 2004;45:Abstr. 3850.
37.
Hochhaus A, Hughes T. Clinical resistance to imatinib: mechanisms and implications.
Hematol Oncol Clin North Am. 2004;18(3):641-56, ix.
38.
Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia
chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-41.
39.
Shah NP. Loss of response to imatinib: mechanisms and management. Hematology Am
Soc Hematol Educ Program. 2005:183-7.
40.
Donato NJ, Wu J, Kong LY, et al. The SRC/ABL inhibitor BMS-354825 overcomes
resistance to imatinib mesylate in chronic myelogenous leukemia cells through multiple
mechanisms. Blood. 2004;104(11):Abstr. 1989.
41.
Shah NP, Tran C, Lee FY, et al. BMS-354825 is a novel orally bioavailable small
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multiple imatinib-resistant BCR-ABL isoforms in vitro and in vivo. Proc Am Assoc Can Res. 
2004;45:Abstr. 5624. 
42.
Lee FY, Lombardo L, Borzilleri R, et al. BMS-354825 - A potent dual SRC/ABL kinase
inhibitor possessing curative efficacy against imatinib sensitive and resistant human CML
models in vivo. Proc Am Assoc Cancer Res. 2004;45:Abstr. 3987.
43.
Tokarski JS, Newitt J, Lee FY, et al. The crystal structure of Abl kinase with BMS-
354825, a dual SRC/ABL kinase inhibitor. Blood. 2004;104(11):Abstr. 553.
44.
Shah NP, Lee FY, Luo R, et al. Dasatinib (BMS-354825) inhibits KITD816V, an
imatinib-resistant activating mutation that triggers neoplastic growth in most patients with
systemic mastocytosis. Blood. 2006;108(1):286-91.
45.
Johnson FM, Saigal B, Talpaz M, et al. Dasatinib (BMS-354825) tyrosine kinase
inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck
squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 2005;11(19 Pt
1):6924-32.
46.
Luo FR, Yang Z, Camuso A, et al. Pharmacodynamic biomarker. Proc Am Assoc Cancer
Res. 2005;46:Abstr. 4183.
47.
Franceschi E, Stupp R, van den Bent MJ, et al. EORTC 26083 phase I/II trial of dasatinib
in combination with CCNU in patients with recurrent glioblastoma. Neuro Oncol.
2012;14(12):1503-10.
48.
Hong DS, Choe JH, Naing A, et al. A phase 1 study of gemcitabine combined with
dasatinib in patients with advanced solid tumors. Invest New Drugs. 2013;31(4):918-26.
49.
Sawyers CL, Shah NP, Kantarjian HM, et al. A phase I study of BMS-354825 in patients
with imatinib-resistant and intolerant accelerated and blast phase chronic myeloid leukemia
(CML):  Results from CA180002. Journal of Clinical Oncology. 2005;23(16S):Abstr. 6520.
50.
Investigator's Brochure. Ganitumab. AMG 479. Amgen Inc. Version No:  9.  Version
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51.
Vassal G, Couanet D, Stockdale E, et al. Phase II trial of irinotecan in children with
relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric
Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol.
2007;25(4):356-61.
52.
Tolcher AW, Sarantopoulos J, Patnaik A, et al. Phase I, pharmacokinetic, and
pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth
factor receptor 1. J Clin Oncol. 2009;27(34):5800-7.
53.
Tap WD, Demetri G, Barnette P, et al. Phase II study of ganitumab, a fully human anti-
type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family
tumors or desmoplastic small round cell tumors. J Clin Oncol. 2012;30(15):1849-56.
54.
Rosen LS, Puzanov I, Friberg G, et al. Safety and pharmacokinetics of ganitumab (AMG
479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced
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Kindler HL, Richards DA, Garbo LE, et al. A randomized, placebo-controlled phase 2
study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine
in patients with metastatic pancreatic cancer. Ann Oncol. 2012;23(11):2834-42.
56.
Fuchs CS, Azevedo S, Okusaka T, et al. A phase 3 randomized, double-blind, placebo-
controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for
metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015;26(5):921-7.
57.
Tabernero J, Chawla SP, Kindler H, et al. Anticancer activity of the type I insulin-like
growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist,
conatumumab. Target Oncol. 2015;10(1):65-76.
58.
Kindler HL, Richards DA, Stephenson J, et al. A placebo-controlled, randomized phase II
study of conatumumab or AMG 479 or placebo plus gemcitabine in patients wiht metastatic
pancreatic cancer. J Clin Oncol 2010;28(15s):Abstr. 4035.
59.
Malempati S, Weigel B, Ingle AM, et al. Phase I/II trial and pharmacokinetic study of
cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report
from the Children's Oncology Group. J Clin Oncol. 2012;30(3):256-62.
60.
Higano CS, Yu EY, Whiting SH, et al. A phase I, first in man study of weekly IMC-A12,
a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with
advanced solid tumors. J Clin Oncol 2007;25(18s):Abstr. 3505.
61.
Frappaz D, McGregor LM, Pearson ADJ, et al. A phase I study of the anti-insulin like
growth factor type 1 receptor (IGF-1R) antibody dalotuzumab in pediatric patients with
advanced solid tumors. J Clin Oncol. 2013;31:Abstr. 10026.
62.
Beltran PJ, Chung YA, Moody G, et al. Efficacy of ganitumab (AMG 479), alone and in
combination with rapamycin, in Ewing's and osteogenic sarcoma models. J Pharmacol Exp Ther.
2011;337(3):644-54.
63.
Beaty O, 3rd, Berg S, Blaney S, et al. A phase II trial and pharmacokinetic study of
oxaliplatin in children with refractory solid tumors: a Children's Oncology Group study. Pediatr
Blood Cancer. 2010;55(3):440-5.
64.
Bomgaars LR, Bernstein M, Krailo M, et al. Phase II trial of irinotecan in children with
refractory solid tumors: a Children's Oncology Group Study. J Clin Oncol. 2007;25(29):4622-7.
65.
Hawkins DS, Bradfield S, Whitlock JA, et al. Topotecan by 21-day continuous infusion
in children with relapsed or refractory solid tumors: a Children's Oncology Group study. Pediatr
Blood Cancer. 2006;47(6):790-4.
66.
Jacobs S, Fox E, Krailo M, et al. Phase II trial of ixabepilone administered daily for five
days in children and young adults with refractory solid tumors: a report from the children's
oncology group. Clin Cancer Res. 2010;16(2):750-4.
67.
Kuttesch JF, Jr., Krailo MD, Madden T, et al. Phase II evaluation of intravenous
vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children's Oncology
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Langevin AM, Bernstein M, Kuhn JG, et al. A phase II trial of rebeccamycin analogue 
(NSC #655649) in children with solid tumors: a Children's Oncology Group study. Pediatr Blood 
Cancer. 2008;50(3):577-80. 
69. 
Zwerdling T, Krailo M, Monteleone P, et al. Phase II investigation of docetaxel in 
pediatric patients with recurrent solid tumors: a report from the Children's Oncology Group. 
Cancer. 2006;106(8):1821-8. 
70. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
71. 
Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to 
treatment in solid tumors (ovarian cancer). J Natl Cancer Inst. 2004;96(6):487-8. 
72. 
Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-
Specific Antigen Working Group. J Clin Oncol. 1999;17(11):3461-7. 
73. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-59. 
74. 
Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines to evaluate the response 
to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst. 
2000;92(18):1534-5. 
 


 
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18 APPENDICES 
18.1 APPENDIX 1: PERFORMANCE STATUS CRITERIA 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
Karnofsky (> 16 years of age) 
Lansky (≤16 years of age) 
ECOG 
Score 
Description 
Score 
Description 
 
100 
Normal, no complaints, no evidence of disease 
100 
Fully active, normal. 
 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
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 
 
1 
Symptoms, but ambulatory.  Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light 
housework, office work). 
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. 
 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up 
and about more than 50% of waking 
hours 
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. 
 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
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. 
 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
10 
Moribund, fatal processes progressing rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 
 
 


 
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18.2 APPENDIX 2: SUBSTANCES PROHIBITED DURING DASATINIB TREATMENT 
 
CYP3A4 Inhibitors: 
➢ itraconazole, ketoconazole, miconazole, voriconazole 
➢ amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir 
➢ ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, isoniazid, 
ketamine nefazodone, nicardipine, propofol, quinidine, telithromycin 
 
CYP3A4 Inducers: 
➢ aminoglutethimide, primidone, rifabutin, rifampin, St. John’s wort 
➢ carbamazepine, nevirapine, oxcarbazepine, rifapentine 
➢ fosphenytoin, pentobarbital, phenobarbital, phenytoin 
 
Agents with Proarrhythmic Potential 
➢ quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide 
➢ erythromycins, clarithromycin 
➢ chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide 
➢ cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, 
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine 
 
Because the lists of these agents are constantly changing, your prescribers should consult a 
frequently-updated list or medical reference text such as the Physician’s Desk Reference to 
see if any medicine they want to prescribe is on a list of drugs to avoid.   
 
 
 


 
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18.3 APPENDIX 3: INFORMATION ON POSSIBLE DRUG INTERACTIONS 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent dasatinib and ganitumab.  This clinical trial is sponsored by the National 
Cancer Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.  
Dasatinib interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
Dasatinib interacts with (a) certain specific enzyme(s) in your liver.  
• The enzyme(s) in question is/are CYP3A4 Inhibitor (because it may increase your 
blood level of dasatinib) and CYP3A4 Inducer (because dasatinib is broken down by 
this enzyme in order to be cleared from your body)  
• Dasatinib must be used very carefully with other medicines that need these liver 
enzymes to be effective or to be cleared from your system.   
• Other medicines may also affect the activity of the enzyme.   
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
o Dasatinib may affect the heart’s electrical activity (QTc prolongation).   
o Use caution when administering dasatinib with other potential QTc-prolonging 
medications. 
o Because antacids (H2 inhibitors, proton pump inhibitors) decrease your ability to 
absorb dasatinib, antacids should be limited to short-acting, locally-active agents 
(e.g., Maalox®, Mylanta® etc.).  However, these agents should not be taken 
within either 2 hours before or 2 hours after the dasatinib dose. 
o Substances that effect platelet function should be avoided such as aspirin, 
nonsteroidal anti-inflammatory drugs (like motrin, ibuprofen), some antibiotics, 
some cardiovascular and lipid-lowering drugs, some antidepressants.  It is 
important that you discuss any new drugs (prescription or over the counter) with 
your doctor before starting. 
• You and healthcare providers who prescribe drugs for you must be careful about 


 
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adding or removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered CYP3A4 Inhibitor or CYP3A4 Inducer. 
Examples of these medicines are listed on the next page. 
• Because the lists of these agents are constantly changing, your prescribers should 
consult a frequently-updated list or medical reference text such as the Physician’s 
Desk Reference to see if any medicine they want to prescribe is on a list of drugs to 
avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small 
and located above or below the brand name, and printed in the ingredient list.  Find 
the generic name and determine, with the pharmacist’s help, whether there could be 
an adverse interaction.   
• Be careful:  
o If you take acetaminophen regularly:  You should not take more than 3.25 grams 
a day if you are an adult. Read labels carefully!  Acetaminophen is an ingredient 
in many medicines for pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking Dasatinib. 
Other medicines can be a problem with your study drugs.  
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
• Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is _____________________________________ and he or 
she can be contacted at_____________________________  
 
 


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CYP3A4 Inhibitors: 
➢itraconazole, ketoconazole, miconazole, voriconazole
➢amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir
➢ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, isoniazid,
ketamine nefazodone, nicardipine, propofol, quinidine, telithromycin
CYP3A4 Inducers: 
➢aminoglutethimide, primidone, rifabutin, rifampin, St. John’s wort
➢carbamazepine, nevirapine, oxcarbazepine, rifapentine
➢fosphenytoin, pentobarbital, phenobarbital, phenytoin
Agents with Proarrhythmic Potential 
➢quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide
➢erythromycins, clarithromycin
➢chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
➢cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine
_____________________________________. 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
dasatinib and ganitumab.  This clinical trial is sponsored by the NCI.  
These drugs may interact with drugs that are processed by your liver.  
Because of this, it is very important to: 
➢Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial.
➢Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.
Dasatinib interacts with a specific liver enzyme called CYP3A4, and must 
be used very carefully with other medicines that interact with this 
enzyme.  
➢Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered “strong 
inducers/inhibitors or substrates of CYP3A4.”
➢Dasatinib may affect the heart’s electrical activity (QTc prolongation). 
Use caution when administering dasatinib with other potential QTc-
prolonging medications. 
➢Avoid aspirin, antacids, and NSAIDS, 
➢Before prescribing new medicines, your regular prescribers should
consult a frequently-updated list or medical reference text such as the
Physician’s Desk Reference for a list of drugs to avoid, or contact your 
study doctor. 
➢Your study doctor’s name is Dr. Christine Heske and can be contacted
at 240-760-6197.


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18.4 APPENDIX 4: DOSING NOMOGRAM FOR DASATINIB FOR PHASE I/II TRIAL OF RHABDOMYOSARCOMA 
Dose level 
2 
(60 
mg/m2/do
se BID) 
BSA* 
0.5- 
0.54 
0.55- 
0.62 
0.63- 
0.71 
0.72- 
0.79 
0.8- 
0.87 
0.88- 
0.96 
0.97- 
1.04 
1.05- 
1.12 
≥1.13 
Dose† 
30 
35 
40 
45 
50 
55 
60 
65 
70 
1 
(60 
mg/m2/dos
e once 
daily) 
BSA* 
0.5- 
0.54 
0.55- 
0.62 
0.63- 
0.71 
0.72- 
0.79 
0.8- 
0.87 
0.88- 
0.96 
0.97- 
1.04 
1.05- 
1.12 
1.13- 
1.21 
1.22-
1.29 
1.3- 
1.37 
1.38-
1.46 
1.47- 
1.54 
1.55- 
1.62 
≥1.63 
Dose† 
30 
35 
40 
45 
50 
55 
60 
65 
70 
75 
80 
85 
90 
95 
100 
-1
(40 
mg/m2/do
se once 
daily) 
BSA* 
0.5- 
0.56 
0.57- 
0.69 
0.70- 
0.81 
0.8- 
0.94 
0.95- 
1.06 
1.07- 
1.19 
1.2- 
1.31 
1.3- 
1.44 
1.45- 
1.56 
1.57- 
1.69 
1.7- 
1.81 
1.82- 
1.94 
1.95- 
2.06 
2.07- 
2.18 
2.19-
2.31 
2.32-
2.44 
≥2.45 
Dose† 
20 
25 
30 
35 
40 
45 
50 
55 
60 
65 
70 
75 
80 
85 
90 
95 
100 
•
*BSA, body surface area in m2.
• 
†Actual dose in mg (tablet sizes 5 mg, 20 mg, and 50 mg). 
The dosing nomogram will not be used to make dose reductions for toxicity due to overlap in dose levels for certain BSA. Section 6 describes dose reductions for 
toxicity.


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18.5 APPENDIX 5: PATIENT’S MEDICATION DIARY – DASATINIB- CYCLE 1 
(For once per day dosing) 
Today’s date __________________________________ 
Agent _____Dasatinib _ 
Patient Name_____________________ (initials acceptable) 
Patient Study ID____________ 
INSTRUCTIONS TO THE PATIENT: CYCLE 1 
1.
Complete one form for each 5 week-period while you take dasatinib.
2.
You will take your dose of dasatinib daily (unless instructed otherwise due to dose reduction).  You will
take ____5 mg tablets, ____20 mg tablets, and ____ 50 mg tablets. You may take the tablets with or
without food as you wish.
3.
Record the date, the number of tablets of each size you took, and when you took them.
4.
If you have any comments or notice any side effects, please record them in the Comments column.
5.
Please return this form to your physician when you go for your next appointment.
Day 
Date 
Time of 
dose 
# of tablets taken 
Comments 
5 mg 
20 
mg 
50 
mg 
-7
-6
-5
-4
-3
-2
-1
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 


 
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Day 
Date 
Time of 
dose 
# of tablets taken 
Comments 
5 mg 
20 
mg 
50 
mg 
13  
 
 
 
 
 
14  
 
 
 
 
 
15  
 
 
 
 
 
16  
 
 
 
 
 
17  
 
 
 
 
 
18  
 
 
 
 
 
19  
 
 
 
 
 
20  
 
 
 
 
 
21  
 
 
 
 
 
22  
 
 
 
 
 
23  
 
 
 
 
 
24  
 
 
 
 
 
25  
 
 
 
 
 
26  
 
 
 
 
 
27  
 
 
 
 
 
POB will complete this section: 
1. Date patient started protocol treatment________________________________________________ 
2. Date patient was removed from study_________________________________________________ 
3. Patient’s planned total daily dose_____________________________________________________ 
4. Total number of tablets taken this month (each size)______________________________________ 
5. Reviewing Physician/Nurse’s Signature ____________________________________ 
 
Patient / Parent Signature:  
  Date:  
 
 
Number of Tablets Returned:  ___5 mg tablets, ____20 mg tablets, ____ 50 mg tablets. 
RN / MD Signature:  
  Date:  
 
 
 
 
 
 


 
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18.6 APPENDIX 6: PATIENT’S MEDICATION DIARY – DASATINIB- SUBSEQUENT CYCLES  
(For once per day dosing) for Cycle # ______ 
Today’s date __________________________________ 
Agent _____Dasatinib _ 
Patient Name_____________________ (initials acceptable) 
Patient Study ID____________ 
INSTRUCTIONS TO THE PATIENT: CYCLE ____ 
1. 
Complete one form for each 4 week-period while you take dasatinib. 
2. 
You will take your dose of dasatinib daily (unless instructed otherwise due to dose reduction).  You will 
take ____5 mg tablets, ____20 mg tablets, and ____ 50 mg tablets. You may take the tablets with or 
without food as you wish. 
3. 
Record the date, the number of tablets of each size you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please return this form to your physician when you go for your next appointment. 
 
Day 
 
Date 
Time of 
dose 
# of tablets taken 
Comments 
5 mg 
20 
mg 
50 
mg 
0 
 
 
 
 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10  
 
 
 
 
 
11  
 
 
 
 
 
12  
 
 
 
 
 
13  
 
 
 
 
 
14  
 
 
 
 
 
15  
 
 
 
 
 
16  
 
 
 
 
 
17  
 
 
 
 
 
18  
 
 
 
 
 


 
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19  
 
 
 
 
 
20  
 
 
 
 
 
21  
 
 
 
 
 
Day 
Date 
Time of 
dose 
# of tablets taken 
Comments 
5 mg 
20 
mg 
50 
mg 
22  
 
 
 
 
 
23  
 
 
 
 
 
24  
 
 
 
 
 
25  
 
 
 
 
 
26  
 
 
 
 
 
27  
 
 
 
 
 
POB will complete this section: 
1. Date patient started protocol treatment_______________________________________ 
2. Date patient was removed from study_________________________________________ 
3. Patient’s planned total daily dose______________________________________________ 
4. Total number of tablets taken this month (each size)___________________________ 
5.    Reviewing Physician/Nurse’s Signature ____________________________________ 
 
Patient / Parent Signature:  
  Date:  
 
 
Number of Tablets Returned:  ___5 mg tablets, ____20 mg tablets, ____ 50 mg tablets.  
 
RN / MD Signature:  
  Date:  
 
 
 
 
 
 


 
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18.7 APPENDIX 7: PATIENT’S MEDICATION DIARY – DASATINIB- CYCLE 1  
(For twice per day dosing) 
Today’s date __________________________________ 
Agent _____Dasatinib _ 
Patient Name_____________________ (initials acceptable) 
Patient Study ID____________ 
INSTRUCTIONS TO THE PATIENT: CYCLE 1 
1. 
Complete one form for each 5 week-period while you take dasatinib. 
2. 
You will take your dose of dasatinib twice daily in the morning and evening (unless instructed otherwise 
due to dose reduction).  You will take ____5 mg tablets, ____20 mg tablets, and ____ 50 mg tablets. You 
may take the tablets with or without food as you wish. 
3. 
Record the date, the number of tablets of each size you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please return this form to your physician when you go for your next appointment. 
 
Day 
 
Date 
Time of 
AM dose 
# of tablets 
taken 
Time of PM 
dose  
# of tablets 
taken 
Comments 
5 
mg 
20 
mg 
50 
mg 
5 
mg 
20 
mg 
50 
mg 
-7 
 
 
 
 
 
 
 
 
 
 
-6 
 
 
 
 
 
 
 
 
 
 
-5 
 
 
 
 
 
 
 
 
 
 
-4 
 
 
 
 
 
 
 
 
 
 
-3 
 
 
 
 
 
 
 
 
 
 
-2 
 
 
 
 
 
 
 
 
 
 
-1 
 
 
 
 
 
 
 
 
 
 
0 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
10  
 
 
 
 
 
 
 
 
 
11  
 
 
 
 
 
 
 
 
 
12  
 
 
 
 
 
 
 
 
 


NCI Protocol #: 10003 
Version Date: 04/06/2020 
110 
Day 
Date 
Time of 
AM dose 
# of tablets 
taken 
Time of PM 
dose 
# of tablets 
taken 
Comments 
5 
mg 
20 
mg 
50 
mg 
5 
mg 
20 
mg 
50 
mg 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
POB will complete this section: 
1.
Date patient started protocol treatment________________________________________________
2.
Date patient was removed from study_________________________________________________
3.
Patient’s planned total daily dose_____________________________________________________
4.
Total number of tablets taken this month (each size)______________________________________
5.
Reviewing Physician/Nurse’s Signature ____________________________________
Patient / Parent Signature: 
  Date: 
Number of Tablets Returned:  ___5 mg tablets, ____20 mg tablets, ____ 50 mg tablets. 
RN / MD Signature: 
  Date: 


 
NCI Protocol #: 10003 
 
Version Date: 04/06/2020 
 
111 
 
18.8 APPENDIX 8: PATIENT’S MEDICATION DIARY – DASATINIB- SUBSEQUENT CYCLES   
(For twice per day dosing) for Cycle # ______ 
Today’s date __________________________________ 
Agent _____Dasatinib _ 
Patient Name_____________________ (initials acceptable) 
Patient Study ID____________ 
INSTRUCTIONS TO THE PATIENT: CYCLE _____ 
1. 
Complete one form for each 4 week-period while you take dasatinib. 
2. 
You will take your dose of dasatinib twice daily in the morning and evening (unless instructed otherwise due to 
dose reduction).  You will take ____5 mg tablets, ____20 mg tablets ,and ____50 mg. You may take the tablets 
with or without food as you wish. 
3. 
Record the date, the number of tablets of each size you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please return this form to your physician when you go for your next appointment. 
 
Day 
 
Date 
Time of 
AM dose 
# of tablets taken 
Time of 
PM dose  
# of tablets taken 
Comments 
5 mg 20 
mg 
50 
mg 
5 mg 
20 
mg 
50 
mg 
0 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
10  
 
 
 
 
 
 
 
 
 
11  
 
 
 
 
 
 
 
 
 
12  
 
 
 
 
 
 
 
 
 
13  
 
 
 
 
 
 
 
 
 
14  
 
 
 
 
 
 
 
 
 
15  
 
 
 
 
 
 
 
 
 
16  
 
 
 
 
 
 
 
 
 
17  
 
 
 
 
 
 
 
 
 
18  
 
 
 
 
 
 
 
 
 
19  
 
 
 
 
 
 
 
 
 


 
NCI Protocol #: 10003 
 
Version Date: 04/06/2020 
 
112 
 
20  
 
 
 
 
 
 
 
 
 
21  
 
 
 
 
 
 
 
 
 
Day 
Date 
Time of 
AM dose 
# of tablets taken 
Time of 
PM dose 
# of tablets taken 
Comments 
5 mg 20 
mg 
50 
mg 
5 mg 
20 
mg 
50 
mg 
22  
 
 
 
 
 
 
 
 
 
23  
 
 
 
 
 
 
 
 
 
24  
 
 
 
 
 
 
 
 
 
25  
 
 
 
 
 
 
 
 
 
26  
 
 
 
 
 
 
 
 
 
27  
 
 
 
 
 
 
 
 
 
POB will complete this section: 
1. Date patient started protocol treatment________________________________________________ 
2. Date patient was removed from study_________________________________________________ 
3. Patient’s planned total daily dose_____________________________________________________ 
4. Total number of tablets taken this month (each size)______________________________________ 
5. Reviewing Physician/Nurse’s Signature ____________________________________ 
 
Patient / Parent Signature:  
  Date:  
 
 
Number of Tablets Returned:  ___5 mg tablets, ____20 mg tablets, ____ 50 mg tablets.  
 
RN / MD Signature:  
  Date:  
 
 
 


NCI Protocol #: 10003 
Version Date: 04/06/2020 
113 
18.9 APPENDIX 9: PROCESSING AND SHIPPING SAMPLES TO NIH 
At least one week in advance, please obtain study kits from:  
Donna Bernstein, RN 
Research Nurse Specialist 
NIH/NCI/POB 
10 Center Drive 
Building 10/Room 1-3750 
Bethesda, MD 20892 
18.9.1 Collection and Shipping Instructions Pathology 
Samples should only be drawn Sunday through Thursday and sent via overnight courier. 
Refer to NantOmics Sample Collection manual pages 20-23 for sample requirements and collection 
instructions. 
Page 9 of the NantOmics Sample Collection manual MUST be filled out and returned with the pathology. 
Please also include:  
•
Patient ID: This should be the protocol specific number given to the patient:  site number followed by the
patient number enrolled (ie: MD004-004)
•
Specimen ID: this is the path identifier (ie: SS17-NO041)
•
Container type:  (block or slides)
In addition please provide a redacted pathology report with specimen ID (that matches the pathology identifier) 
Ship at room temperature to: 
Donna Bernstein, RN 
Research Nurse Specialist 
NIH/NCI/POB 
10 Center Drive 
Building 10/Room 1-3750 
Bethesda, MD 20892 
18.9.2 Collection and Shipping Instructions for Whole Blood Samples 
Samples should only be drawn Sunday through Thursday and sent via overnight courier. 
Refer to NantOmics Sample Collection manual pages 19 for sample requirements and collection instructions. 
Page 9 of the NantOmics Sample Collection manual MUST be filled out and returned with the pathology. 
Please also include: 
•
Patient ID: This should be the protocol specific number given to the patient: site number followed by the
patient number enrolled (ie: MD004-001)
•
Container type:  blood
Ship at room temperature to: 


NCI Protocol #: 10003 
Version Date: 04/06/2020 
114 
Donna Bernstein, RN 
Research Nurse Specialist 
NIH/NCI/POB 
10 Center Drive 
Building 10/Room 1-3750 
Bethesda, MD 20892 
18.9.3 Instructions for Use of the Streck Cell-Free DNA BCT tube 
Samples should only be drawn Sunday through Thursday and sent via overnight courier. 
For a video demonstration, visit www.streck.com/mixing.  
•
Collect specimen by venipuncture according to CLSI GP41-A61 . Prevention of Backflow - Since Cell-
Free DNA BCT contains chemical additives, it is important to avoid possible backflow from the tube.
To guard against backflow, observe the following precautions: a. Keep patient’s arm in the downward
position during the collection procedure. b. Hold the tube with the stopper in the uppermost position so
that the tube contents do not touch the stopper or the end of the needle during sample collection. c.
Release tourniquet once blood starts to flow in the tube, or within 2 minutes of application.
•
Follow recommendations for order of draw outlined in CLSI GP41-A61 . Cell-Free DNA BCT should
be drawn after the EDTA tube and before the fluoride oxalate (glycolytic inhibitor) tube. If a CellFree
DNA BCT tube immediately follows a heparin tube in the draw order, Streck recommends collecting a
non-additive or EDTA tube as a waste tube prior to collection in the Cell-Free DNA BCT.
•
Fill tube completely.
•
Remove tube from adapter and immediately mix by gentle inversion 8 to 10 times. Inadequate or
delayed mixing may result in incorrect analytical results or poor product performance. One inversion is a
complete turn of the wrist, 180 degrees.
•
Ship overnight on wet ice to:
Donna Bernstein, RN 
Research Nurse Specialist 
NIH/NCI/POB 
10 Center Drive 
Building 10/Room 1-3750 
Bethesda, MD 20892 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 1 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Christine Heske, MD
STUDY TITLE:
A Phase I/II Trial of the Insulin-like Growth Factor 1 
Receptor (IGF-1R) Antibody AMG479 (Ganitumab) in 
Combination with the Src Family Kinase (SFK) Inhibitor 
Dasatinib in Patients with Embryonal and Alveolar 
Rhabdomyosarcoma
STUDY SITE:
National Cancer Institute
Cohort: 
Affected Patient 
Consent Version:  
March 3, 2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Christine Heske, MD
Email: Christine.heske@nih.gov
Phone: 240-760-6197
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time 
needed to ask any questions and discuss this study with NIH staff, and with your family, friends, 
and personal health care providers. Taking part in research at the NIH is your choice.
If the individual being enrolled is a minor then the term “you” refers to “you and/or your child” 
throughout the remainder of this document.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may 
change your mind and stop participating in the study at any time and for any reason. In either 
case, you will not lose any benefits to which you are otherwise entitled. However, to be seen at 
the NIH, you must be taking part in a study or are being considered for a study. If you do choose 
to leave the study, please inform your study team to ensure a safe withdrawal from the research.  
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 2 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
WHAT IS THE USUAL APPROACH TO MY DIAGNOSIS?
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood.  Two major 
types of RMS are embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma 
(ARMS). The treatments for RMS include surgery, radiation therapy or chemotherapy.  Some of 
the agents used to treat rhabdomyosarcoma are approved by the U.S. Food and Drug 
Administration (FDA) for other indications. New types of treatments being tested in clinical 
trials include high-dose chemotherapy with stem cell transplant, immunotherapy, or targeted 
therapy.  
The insulin-like growth factor (IGF) system plays an important role in many cancers.  Over-
expression of the type 1 IGF receptor (IGF-1R) has been observed in sarcoma.  An enzyme 
called YES is also highly expressed in both ERMS and ARMS.  Treatment blocking both IGF 
and YES appears to slow tumor growth of ERMS and ARMS cells studied in the laboratory.
Dasatinib is an enzyme inhibitor that may block over-expression of YES.  Dasatinib also appears 
to have anticancer activity in some cancers.  Ganitumab is a monoclonal antibody directed 
specifically against IGF-1R to suppress tumor growth.  
WHAT IS THE USUAL APPROACH TO MY CANCER?
You are being asked to participate in this trial because you have ERMS or ARMS and the other 
known treatments for your disorder, such as surgery, radiation therapy or chemotherapy, have 
not proven effective for you.  People who are not in a study are usually treated with surgical 
removal of their tumor, radiation, and/or chemotherapy. You may decide not to receive any 
treatment directed at shrinking your tumor(s) at this point in time.
WHAT ARE MY OTHER CHOICES IF I DO NOT TAKE PART IN THIS STUDY?
If you decide not to take part in this study, you have other choices. For example:

you may choose to have the usual approach described above

you may choose to take part in a different study, if one is available

or you may choose not to be treated for cancer but you may want to receive comfort
care to relieve symptoms.
Please talk to your doctor about these and other options.
WHY IS THIS STUDY BEING DONE? 
The purposes of this research study are:
1. To find the safe dose of dasatinib when given with ganitumab in patients with ERMS and
ARMS.
2. To assess if the combination of ganitumab and dasatinib is helpful in the treatment of
your type of tumor(s) (causes your tumor to shrink or slow down the growth), or can
increase survival.
3. To study the side effects of the combination of ganitumab and dasatinib.
4. To study how ganitumab and dasatinib act on the tumors of people with RMS.
5. To do genomic analysis of tissue samples of patients with ERMS and ARMS (you will be
asked to participate in another POB study for this called protocol 10-C-0086:
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 3 of 17
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a 
Repository for Related Biological Studies)
Ganitumab is being used in clinical studies and has been given to adults and children with 
different types of tumors.  Dasatinib was approved by the U.S. Food and Drug Administration 
(FDA) for treatment of adults with a type of chronic myeloid leukemia (CML).  Ganitumab has 
not been approved by the U.S. Food and Drug Administration (FDA) for any indication. 
Ganitumab and the combination of ganitumab and dasatinib are experimental, meaning they have 
not been approved by the FDA, but are approved for use in this clinical trial.
Up to 24 evaluable patients may take part in this study.
WHAT ARE THE STUDY GROUPS?
All study participants will get the same study intervention.  You will take the dasatinib pills by 
mouth every day.  The treatment will be divided into cycles.  The first cycle will be 35 days long 
(from day -7 through day 27) and the rest of the cycles will be 28 days long (from day 0 through 
day 27).  Ganitumab will be given in an IV (a small plastic catheter put into a vein in your arm) 
in the clinic once every 2 weeks, starting on day 0.  
There will be two phases to the study: Phase I and Phase II.  In the Phase I portion of the study, 
the highest safe dose of dasatinib will be tested when given with ganitumab.  Between 3 and 6 
people will receive dasatinib at the first dose level, dasatinib once per day.  If the side effects are 
acceptable, the next group of 3 to 6 people will receive the dose of dasatinib twice per day (dose 
level 2).  If dose level 2 does not have unacceptable side effects, this will be the dose that will be 
used in the Phase II portion of the study
If unacceptable side effects are seen at the first dose level, additional patients will receive a 
lower dose of dasatinib (dose level -1) to make sure we find the maximum dose that is tolerated.  
If you are a patient enrolled early in this study you may receive a lower dose than those who are 
enrolled later.     
In the Phase II portion of the study, up to an additional 10 people will be given the highest safe 
dose of dasatinib tested and the same dose of ganitumab as was given in Phase I.
Everyone will take dasatinib with at least 8 ounces of water, with or without food.  Tablets 
should be swallowed whole; do not break or chew the tablets.  If the dasatinib causes stomach 
upset, you should take it with a light meal.  If you vomit within 30 minutes of swallowing the 
tablet(s), you can repeat the dose.  But if you vomit later than 30 minutes after taking the dose, 
do not repeat it.  Wait until the next day to take your next dose.  We ask that you keep a 
medication diary to record when you get the study medication at home, and any symptoms that 
you may have as a result of the study medication, including how you treat the symptoms. 
Complete this medication diary every day and bring it to clinic with you when you come. Also 
bring the medication bottle and any remaining tablets to each clinic visit. If tablets are 
accidentally crushed or broken, caregivers should wear disposable chemotherapy gloves, which will 
be provided. Pregnant women should avoid exposure to crushed and/or broken tablets. 
Because the dasatinib has the potential to interact with other medications and some foods, you 
will be given a drug interaction handout and wallet card as a resource for yourself, caregivers 
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 4 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
and other health care providers. Do not take any new medications, even over the counter 
medications, without first talking to your study doctor.  
Because some antacids may affect the way your body absorbs dasatinib, you should only take 
certain types of them (such as Maalox®, or Mylanta®).  Please discuss this with your study 
doctor before beginning to take them. When taking the antacid your study doctor prescribes, do 
NOT take them within 2 hours before or 2 hours after your dasatinib dose.  
Substances that affect your blood’s ability to form clots, such as aspirin, nonsteroidal anti-
inflammatory drugs (like motrin, ibuprofen), some antibiotics, some cardiovascular and lipid-
lowering drugs, and some antidepressants should be avoided.  It is important that you discuss any 
new drugs (prescription or over the counter) with your study doctor before starting.  
Avoid drinking grapefruit juice or eating grapefruit until the study is over.  You should not take 
St. John’s wort while you are taking dasatinib.
You will come to the POB clinic every two weeks and be given the ganitumab in an IV. The first 
infusion will be given to you over about 1 hour.  If you tolerate the first infusion, the second and 
subsequent infusions can be given over about 30 minutes.  Let your study staff know if you 
experience any unusual feelings during the infusion (such as chills, difficulty breathing, 
headache or dizziness), because the infusion can be slowed or temporarily stopped to reduce 
these effects.
HOW LONG WILL I BE IN THIS STUDY?
You will take the dasatinib every day for 35 days during the first cycle, and for 28 days in 
subsequent cycles.  You will be given the ganitumab once every 2 weeks.  You can continue to 
take dasatinib-ganitumab as long as you do not have unacceptable toxicities or your tumor(s) do 
not get worse.  If you have side effects the dose of dasatinib and/or ganitumab may be held for a 
short time and the dose(s) may be reduced to prevent return of the side effect.  Two dose 
reductions for dasatinib and one dose reduction for ganitumab are allowed on this study.  If the 
side effect(s) is too severe, or side effect(s) recur after the dose reductions, dasatinib-ganitumab 
may need to be stopped.  
WHAT EXTRA TESTS AND PROCEDURES WILL I HAVE IF I TAKE PART IN THIS 
STUDY?
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer. However, there are some extra tests and procedures that you will need to have if you take 
part in this study.
Before you begin the study:
You will need to have the following extra tests to find out if you can be in the study:

Pregnancy test (if you are a woman who could have children)

EKG (electrocardiogram), a test that checks the electrical activity of your heart

Echocardiogram (a sonogram [uses sounds waves] of the heart that allows us to
identify any problems with the heart valves or muscle movement.)

Optional biopsy of tumor. This will be further discussed later in the consent.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 5 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
During the study:

EKG will be done before each cycle.

Echocardiogram will be performed prior to cycles 1 and 2, and then before each scan
to evaluate your tumor(s), (i.e. before cycles 3, 5, 7), and repeated more frequently if
your doctor thinks it is needed.

Pregnancy test will be performed before starting treatment and then before each scan
to evaluate your tumor(s), (i.e. before cycles 3, 5, 7), if you are a female who can get
pregnant.

Tissue studies (tissue obtained during a previous surgery or biopsy): everyone
participating will have tissue requested to study the changes in cell activities of
patients with ERMS and ARMS. Your name will not be attached to your tissue; it will
be identified using a study number.  Only the investigator and research team will have
access to the information that links your personal information to your tissue sample.
At the end of treatment with dasatinib-ganitumab you will have an evaluation at the NIH.  At this 
visit you will have a physical exam, blood and urine tests and scans/x-rays to measure your 
tumor.
A STUDY CALENDAR THAT SHOWS HOW OFTEN THESE TESTS AND 
PROCEDURES WILL BE DONE IS ATTACHED.
WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS STUDY?
If you choose to take part in this study, there is a risk that ganitumab (AMG 479) and dasatinib 
may not be as good as the usual approach for your cancer or condition at shrinking or stabilizing 
your cancer.
 You also may have the following discomforts:

Spend more time in the hospital or doctor’s office.

Be asked sensitive or private questions which you normally do not discuss

May not be able to take part in future studies
The ganitumab (AMG 479) and dasatinib used in this study may affect how different parts of 
your body work such as your liver, kidneys, heart, and blood. The study doctor will test your 
blood and will let you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drugs.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go
away.

Some side effects may interfere with your ability to have children.

Some side effects may be mild. Other side effects may be very serious and even result in
death.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 6 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You can ask your study doctor questions about side effects at any time.  Here are important 
points about how you and the study doctor can make side effects less of a problem:

If you notice or feel anything different, tell your study doctor.  He or she can check to see
if it is a side effect.

Your study doctor will work with you to treat your side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects doctors know about. 
There might be other side effects doctors do not yet know about. If important new side effects 
are found, the study doctor will discuss these with you.
Risks of Dasatinib
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving dasatinib, more than 20 and up to 100 may have:

Anemia which may require blood transfusion

Diarrhea, nausea

Tiredness

Bruising, bleeding

Pain

Headache

Shortness of breath

Fluid in the body

Rash
OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving dasatinib, from 4 to 20 may have:

Infection, especially when white blood cell count is low

Bloating, constipation, heartburn, vomiting

Bleeding from multiple sites

Internal bleeding which may cause black tarry stool or blood in vomit

Sores in the mouth which may cause difficulty swallowing

Swelling of the body

Fever

Weight gain

Weight loss, loss of appetite

Dizziness
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving dasatinib, from 4 to 20 may have:

Cough, sore throat

Damage to organs (lungs, brain, others) which may cause shortness of breath,
changes in thinking

Hair loss, itching, acne

Flushing
RARE, AND SERIOUS
In 100 people receiving dasatinib, 3 or fewer may have:

Heart failure, heart attack which may cause shortness of breath, swelling of ankles,
and tiredness

Change in the heart rhythm

Kidney damage which may require dialysis

Bone growth may stop early in teenagers leading to short stature

Loss of bone tissue

Decreased height in children and adolescents

Enlarged breasts in males

Bleeding in the brain which may cause confusion

Brain damage which may cause headache, seizure, blindness (also known as
Reversible Posterior Leukoencephalopathy Syndrome)

Severe skin rash with blisters and peeling which can involve mouth and other parts of
the body

Inflammation of the lungs which can cause shortness of breath and difficulty
breathing
Risks of Ganitumab
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Ganitumab (AMG 479), more than 20 and up to 100 may have:

Tiredness

Reaction during or following a drug infusion which may cause fever, chills, low blood
pressure
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 8 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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.  Both male and female participants must use effective birth control measures while 
participating in this study and for at least 4 months after the last dose of dasatinib-ganitumab.  
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.  Optional birth control 
methods include, but are not limited to, abstinence, oral birth control pills, an IUD, or condoms 
with spermicide.  If you are a woman and become pregnant or suspect you are pregnant while 
participating in this study, please inform your treating physician immediately.  A patient who 
becomes pregnant while on study will immediately be taken off study.
WHAT POSSIBLE BENEFITS CAN I EXPECT FROM TAKING PART IN THIS 
STUDY?
Treatment with dasatinib-ganitumab may cause your tumor(s) to stop growing or shrink or it may 
lessen the symptoms, such as pain, that are caused by the tumor.  However, because there is not 
much information about the combination of the drugs’ effects on your type of tumor, we do not 
know if you will benefit from taking part in this study, although the knowledge gained from this 
study may benefit others.  Your samples may be helpful to research. The researchers, using the 
samples from you and others, might make discoveries that could help people in the future.
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Ganitumab (AMG 479), from 4 to 20 may have:

Anemia which may require blood transfusion

Diarrhea, nausea, vomiting

Bruising, bleeding

Infection, especially when white blood cell count is low

Loss of appetite

Pain in muscles

Rash
RARE, AND SERIOUS
In 100 people receiving Ganitumab (AMG 479), 3 or fewer may have:

Hearing loss

Ganitumab may cause damage to the lung that may cause shortness of breath when
receiving radiotherapy to the lungs shortly before or after treatment with ganitumab.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 9 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CAN I STOP TAKING PART IN THIS STUDY?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization helping the investigators to run the study.
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study.
The study doctor may take you out of the study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study rules

If the study is stopped by the sponsor, IRB or FDA.
CONFLICT OF INTEREST 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH.
ADDITIONAL STUDIES SECTION 
This part of the consent form is about optional studies that you can choose to take part in. You 
will not get health benefits from any of these studies. The researchers leading this optional study 
hope the results will help other people with cancer in the future.
The results will not be added to your medical records and you or your study doctor will not know 
the results.
You will not be billed for these optional studies. You can still take part in the main study even if 
you say ‘no’ to any or all of these studies. If you sign up for but cannot complete any of the 
studies for any reason, you can still take part in the main study.
Circle your choice of “yes” or “no” for each of the following studies.
TUMOR BIOPSY   
Biopsy of your tumor (optional): a biopsy of your tumor (take a small piece of your tumor tissue 
using a large needle) will be done before you start the study drugs, sometime during the first 
week of treatment and again if your tumor(s) begin to enlarge. This biopsy will only be requested 
if you are 12 years old or older, and provided the biopsy can be obtained safely, and are willing 
to participate in our companion protocol 10-C-0086.  This tumor biopsy is optional. With this 
biopsy tissue we will study the changes that these study agents cause in the tumor of people with 
ERMS and ARMS.  You can agree now to allow us to biopsy your tumor and change your mind 
later.  This tissue will also undergo genomic analysis at a laboratory called NantOmics.  Your 
name will not be attached to your tissue; it will be identified using a study number.  Only the 
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 10 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
investigator and research team will have access to the information that links your personal 
information to your tissue sample.
What is involved?
A doctor will use a hollow needle attached to a syringe to enter a tumor, then withdraw (aspirate) 
a small amount of tissue from the tumor.  The doctor may use a scan or ultrasound to guide the 
needle directly to the tumor.  Depending upon the location of the tumor, the doctor may use 
numbing medicine (called local anesthetic) to numb the area before the biopsy.  
What are the possible risks?
The risks will be explained to you fully in a different consent.  In general, the risks include 
bleeding, pain, scarring and infection.  If there is bleeding under the skin, a hematoma or 
collection of blood at the biopsy site may occur. Other risks depend on the location of the tumor 
being sampled.  The doctor will discuss these specific risks with you before the procedure.  
How will information about me be kept private?
Your tumor samples will be identified and stored using a number and not your name.  Only the 
study investigator and research team taking care of you on this study will have access to your 
name. 
What are the possible benefits?
The use of your biopsy specimens will be for research purposes only and will not benefit you.  
Results of research done on your tumor specimens will not be available to you or your doctor, 
but it will help us better understand how this study drug works on tumors, and it might help 
people who have these types of tumors in the future.
Are there any costs or payments? 
There are no costs to you.  You will not be paid for your tissue.  The cost of biopsy, storage and 
testing will be paid by the study investigators or collaborators in this study.
What if I change my mind?
If you decide now that you will undergo the biopsy, you can change your mind at any time. Just 
let us know at the time of the biopsy or contact us (office of Dr. Heske, Principal Investigator: 
240-760-6197) and let us know that you do not want to have the biopsy.
What if I have more questions?
If you have additional questions, please contact the office of Dr. Heske, Principal Investigator:
240-760-6197.
Please circle your answer: I choose to take part in the tumor biopsy:
YES
NO
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 11 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
BLOOD AND TISSUE STORAGE
What is involved?
Should any leftover blood remain after completing the studies described in earlier sections, we 
would like to keep the remaining blood for future research. 
What are the possible risks?
There are no known risks as your blood and tissue samples have already been collected.  No 
additional procedures will be performed.
How will information about me be kept private?
These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for 
research purposes.  The remaining specimens and your data will be identified by a number only.  
Only the study investigator and research team taking care of you on this study will have access to 
your name.
What are the possible benefits?
The use of your specimens and data will be for research purposes only and will not benefit you. 
It is also possible that the stored specimens and data may never be used. Results of research done 
on your specimens and data will not be available to you or your doctor. It might help people who 
have these types of tumors and other diseases in the future.
Are there any costs or payments? 
There are no costs to you.  You will not be paid for your tissue or data.  The cost of storage and 
testing will be paid by the study investigators or collaborators in this study.
What if I change my mind?
If you decide now that your specimens and data can be kept for research, you can change your 
mind at any time. Just contact us (office of Dr. Heske, Principal Investigator: 240-760-6197) and 
let us know that you do not want us to use your specimens and/or data. Then any specimens that 
remain will be destroyed, and your data will not be used for future research. 
What if I have more questions?
If you have additional questions, please contact the office of Dr. Heske, Principal Investigator: 
240-760-6197.
Please circle your answer: My specimens and data may be used for future research:
YES
NO
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 12 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
STUDY CALENDAR
Test/Procedure
Pre-
treatment
During Cycle 
1
During Cycles 2 through end 
of treatment
Completion/ 
Stopping 
treatment
Medical history, 
Physical exam, vital 
signs 
X
Weekly 
starting from 
day -7
On days 0 and 14
X
Standard blood tests
X
Weekly 
starting from 
day -7
Weekly for cycles 2 and 3, 
then every other week 
thereafter
X
Urine test
X
Weekly 
starting from 
day -7
Prior to each subsequent cycle
X
EKG
X
Prior to each subsequent cycle
Echocardiogram
X
At the start of cycles 1,2, 3, 5, 
7, 9, 11 etc. 
Dasatinib, swallow 
tablets(s); record in the 
diary
Days -7 
through Day 
28
Day 0 through Day 28
Ganitumab, IV every 2 
weeks
Day 0 and 
Day 14
Day 0 and Day 14
Tumor biopsy 
(optional if you are 12 
years of age or older)
X
During week 1
If your tumor(s) 
grow
Pregnancy test
X
Prior to cycle 3, 5, 7, 9, 11, etc
Tumor evaluations
X
Prior to cycle 3, 5, 7, 9, 11, etc
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The 
amount of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
The NCI generally does not cover expenses during screening.  If you are scheduled for and begin 
treatment, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid.  Someone will work 
with you to provide more information.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 13 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

There are limited funds available to cover the cost of some tests and
procedures performed outside the Clinical Center, NIH.  You may have to
pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or
paid for by the Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no
longer be provided by the Clinical Center, NIH.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your 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.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA),
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study sponsor and any drug company supporting the study.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release 
any information about your research involvement without your written permission.  However, if 
you sign a release of information form, for example, for an insurance company, the NIH will 
give the insurance company information from your medical record.  This information might 
affect (either favorably or unfavorably) the willingness of the insurance company to sell you 
insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 14 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Your study records also will be stored for future use.  However, your name and other personal 
information will not be used.  Some types of future research may include looking at your records 
and those of other patients to see who had side effects across many studies or comparing new 
study data with older study data.  However, we don’t know what research may be done in the 
future using your information.  This means that:

You will not be asked if you agree to take part in the specific future research studies
using your health information.

You and your study doctor will not be told when or what type of research will be done.

You will not get reports or other information about any research that is done using your
information.
Where can I get more information?
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237).
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent.
The Certificate does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self 
or others including, for example, child abuse and neglect, and by signing below you consent to 
those disclosures. Other permissions for release may be made by signing NIH forms, such as the 
Notice and Acknowledgement of Information Practices consent.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 15 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your medical record without your permission, for 
example, if it is requested by Congress. Information may also be released for certain research 
purposes with due consideration and protection, to those engaged by the agency for research 
purposes, to certain federal and state agencies, for HIV partner notification, for infectious disease 
or abuse or neglect reporting, to tumor registries, for quality assessment and medical audits, or 
when the NIH is involved in a lawsuit.  However, NIH will only release information from your 
medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action. 
Your insurance company may not be willing to pay for study-related injury. If you have no 
insurance, you may be responsible for any costs.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Christine 
Heske, MD, Christine.heske@nih.gov, 240-760-6197. You may also call the NIH Clinical Center 
Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, 
if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 16 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally 
authorized to make research decisions on behalf of the adult participant unable to consent and have the 
authority to provide consent to this study. As applicable, the information in the above consent was described 
to the adult participant unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Parent/Guardian of a Minor Participant: I have read the explanation about this study and have been given 
the opportunity to discuss it and to ask questions. I give permission for my child to take part in this study.
Signature of Parent/Guardian
Print Name of Parent/Guardian
Date
Signature 
of 
Parent/Guardian 
(as 
applicable)
Print Name of Parent/Guardian
Date
Assent: (Use this section only when this process is approved by an IRB for older minors. Do not use if an 
IRB requires a separate assent form for this population.)
I have had this study explained to me in a way that I understand, I have been given the opportunity to discuss 
it, and I have had the chance to ask questions. I agree to take part in this study.
Assent of Minor: (as applicable)
Signature of Minor
Print Name of Minor
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/03/2020
Page 17 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


1 of 14
NOTES FOR LOCAL INVESTIGATORS*:

The goal of the informed consent process is to provide people with sufficient information 
for making informed choices about participating in research. The consent form provides 
a summary of the study, of the individual's rights as a study participant, and documents 
their willingness to participate. The consent form is, however, only one piece of an 
ongoing exchange of information between the investigator and study participant. For 
more information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared by 
the Comprehensive Working Group on Informed Consent in Cancer Clinical Trials for 
the National Cancer Institute. The Web site address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-docs/

A blank line, “__________”, indicates that the local investigator should provide the 
appropriate information before submitting to the IRB.
*These notes for investigators are instructional and should not be included in the consent form 
sent to IRBs.
Consent Form
Study Title for Study Participants: Das-Ganit in Rhabdomyosarcoma
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: Protocol 10003: A 
Phase I/II Trial of the Insulin-like Growth Factor 1 Receptor (IGF-1R) Antibody AMG479 
(Ganitumab) in Combination with the Src Family Kinase (SFK) Inhibitor Dasatinib in Patients 
with Embryonal and Alveolar Rhabdomyosarcoma
What is the usual approach to my diagnosis?
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood.  Two major 
types of RMS are embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma 
(ARMS). The treatments for RMS include surgery, radiation therapy or chemotherapy.  Some of 
the agents used to treat rhabdomyosarcoma are approved by the U.S. Food and Drug 
Administration (FDA) for other indications. New types of treatments being tested in clinical 
trials include high-dose chemotherapy with stem cell transplant, immunotherapy, or targeted 
therapy.  
The insulin-like growth factor (IGF) system plays an important role in many cancers.  Over-
expression of the type 1 IGF receptor (IGF-1R) has been observed in sarcoma.  An enzyme 
called YES is also highly expressed in both ERMS and ARMS.  Treatment blocking both IGF 
and YES appears to slow tumor growth of ERMS and ARMS cells studied in the laboratory.
Dasatinib is an enzyme inhibitor that may block over-expression of YES.  Dasatinib also appears 
to have anticancer activity in some cancers.  Ganitumab is a monoclonal antibody directed 
specifically against IGF-1R to suppress tumor growth.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


What is the usual approach to my cancer?
You are being asked to participate in this trial because you have ERMS or ARMS and the other 
known treatments for your disorder, such as surgery, radiation therapy or chemotherapy, have 
not proven effective for you.  People who are not in a study are usually treated with surgical 
removal of their tumor, radiation, and/or chemotherapy. You may decide not to receive any 
treatment directed at shrinking your tumor(s) at this point in time.
What are my other choices if I do not take part in this study?
If you decide not to take part in this study, you have other choices. For example:

you may choose to have the usual approach described above

you may choose to take part in a different study, if one is available

or you may choose not to be treated for cancer but you may want to receive
comfort care to relieve symptoms.
Please talk to your doctor about these and other options.
Can I stop taking part in this study?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study.
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study.
The study doctor may take you out of the study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you are not able to meet the study requirements for taking selumetinib or keep your
appointments

If the study is stopped by the sponsor, IRB or FDA. Even though it probably won’t
happen, it is possible that the manufacturer may not continue to provide the selumetinib
to the NCI for some reason.  If this would occur, the study will be closed and your study
doctor will talk to you about other treatment options (including continuing selumetinib if
it becomes commercially available).
Why is this study being done? 
The purposes of this research study are:
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


1. To find the safe dose of dasatinib when given with ganitumab in patients with ERMS and 
ARMS.
2. To assess if the combination of ganitumab and dasatinib is helpful in the treatment of 
your type of tumor(s) (causes your tumor to shrink or slow down the growth), or can 
increase survival.
3. To study the side effects of the combination of ganitumab and dasatinib.
4. To study how ganitumab and dasatinib act on the tumors of people with RMS.
5. To do genomic analysis of tissue samples of patients with ERMS and ARMS (you will be 
asked to participate in another study for this called protocol 10-C-0086: Comprehensive 
Omics Analysis of Pediatric Solid Tumors and Establishment of a Repository for Related 
Biological Studies)
Ganitumab is being used in clinical studies and has been given to adults and children with 
different types of tumors.  Dasatinib was approved by the U.S. Food and Drug Administration 
(FDA) for treatment of adults with a type of chronic myeloid leukemia (CML).  Ganitumab has 
not been approved by the U.S. Food and Drug Administration (FDA) for any indication. 
Ganitumab and the combination of ganitumab and dasatinib are experimental, meaning they have 
not been approved by the FDA, but are approved for use in this clinical trial.
Up to 24 evaluable patients may take part in this study.
What are the study groups?
All study participants will get the same study intervention.  You will take the dasatinib pills by 
mouth every day.  The treatment will be divided into cycles.  The first cycle will be 35 days long 
(from day -7 through day 27) and the rest of the cycles will be 28 days long (from day 0 through 
day 27).  Ganitumab will be given in an IV (a small plastic catheter put into a vein in your arm) 
in the clinic once every 2 weeks, starting on day 0.  
There will be two phases to the study: Phase I and Phase II.  In the Phase I portion of the study, 
the highest safe dose of dasatinib will be tested when given with ganitumab.  Between 3 and 6 
people will receive dasatinib at the first dose level, dasatinib once per day.  If the side effects are 
acceptable, the next group of 3 to 6 people will receive the dose of dasatinib twice per day (dose 
level 2).  If dose level 2 does not have unacceptable side effects, this will be the dose that will be 
used in the Phase II portion of the study
If unacceptable side effects are seen at the first dose level, additional patients will receive a 
lower dose of dasatinib (dose level -1) to make sure we find the maximum dose that is tolerated.  
If you are a patient enrolled early in this study you may receive a lower dose than those who are 
enrolled later.     
In the Phase II portion of the study, up to an additional 10 people will be given the highest safe 
dose of dasatinib tested and the same dose of ganitumab as was given in Phase I.
Everyone will take dasatinib with at least 8 ounces of water, with or without food.  Tablets 
should be swallowed whole; do not break or chew the tablets.  If the dasatinib causes stomach 
upset, you should take it with a light meal.  If you vomit within 30 minutes of swallowing the 
tablet(s), you can repeat the dose.  But if you vomit later than 30 minutes after taking the dose, 
do not repeat it.  Wait until the next day to take your next dose.  We ask that you keep a 
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


medication diary to record when you get the study medication at home, and any symptoms that 
you may have as a result of the study medication, including how you treat the symptoms. 
Complete this medication diary every day and bring it to clinic with you when you come. Also 
bring the medication bottle and any remaining tablets to each clinic visit. If tablets are 
accidentally crushed or broken, caregivers should wear disposable chemotherapy gloves, which 
will be provided. Pregnant women should avoid exposure to crushed and/or broken tablets. 
Because the dasatinib has the potential to interact with other medications and some foods, you 
will be given a drug interaction handout and wallet card as a resource for yourself, caregivers 
and other health care providers. Do not take any new medications, even over the counter 
medications, without first talking to your study doctor.  
Because some antacids may affect the way your body absorbs dasatinib, you should only take 
certain types of them (such as Maalox®, or Mylanta®).  Please discuss this with your study 
doctor before beginning to take them. When taking the antacid your study doctor prescribes, do 
NOT take them within 2 hours before or 2 hours after your dasatinib dose.  
Substances that affect your blood’s ability to form clots, such as aspirin, nonsteroidal anti-
inflammatory drugs (like motrin, ibuprofen), some antibiotics, some cardiovascular and lipid-
lowering drugs, and some antidepressants should be avoided.  It is important that you discuss any 
new drugs (prescription or over the counter) with your study doctor before starting.  
Avoid drinking grapefruit juice or eating grapefruit until the study is over.  You should not take 
St. John’s wort while you are taking dasatinib.
You will come to the clinic every two weeks and be given the ganitumab in an IV. The first 
infusion will be given to you over about 1 hour.  If you tolerate the first infusion, the second and 
subsequent infusions can be given over about 30 minutes.  Let your study staff know if you 
experience any unusual feelings during the infusion (such as chills, difficulty breathing, 
headache or dizziness), because the infusion can be slowed or temporarily stopped to reduce 
these effects.
How Long Will I Be in This Study?
You will take the dasatinib every day for 35 days during the first cycle, and for 28 days in 
subsequent cycles.  You will be given the ganitumab once every 2 weeks.  You can continue to 
take dasatinib-ganitumab as long as you do not have unacceptable toxicities or your tumor(s) do 
not get worse.  If you have side effects the dose of dasatinib and/or ganitumab may be held for a 
short time and the dose(s) may be reduced to prevent return of the side effect.  Two dose 
reductions for dasatinib and one dose reduction for ganitumab are allowed on this study.  If the 
side effect(s) is too severe, or side effect(s) recur after the dose reductions, dasatinib-ganitumab 
may need to be stopped.
What extra tests and procedures will I have if I take part in this study?
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer. However, there are some extra tests and procedures that you will need to have if you take 
part in this study.
Before you begin the study:
You will need to have the following extra tests to find out if you can be in the study:
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020



Pregnancy test (if you are a woman who could have children)

EKG (electrocardiogram), a test that checks the electrical activity of your heart

Echocardiogram (a sonogram [uses sounds waves] of the heart that allows us to 
identify any problems with the heart valves or muscle movement.)

Optional biopsy of tumor. This will be further discussed later in the consent.
During the study:

EKG will be done before each cycle.

Echocardiogram will be performed prior to cycles 1 and 2, and then before each scan 
to evaluate your tumor(s), (i.e. before cycles 3, 5, 7), and repeated more frequently if 
your doctor thinks it is needed.

Pregnancy test will be performed before starting treatment and then before each scan 
to evaluate your tumor(s), (i.e. before cycles 3, 5, 7), if you are a female who can get 
pregnant.

Tissue studies (tissue obtained during a previous surgery or biopsy): everyone 
participating will have tissue requested to study the changes in cell activities of 
patients with ERMS and ARMS. Your name will not be attached to your tissue; it will 
be identified using a study number.  Only the investigator and research team will have 
access to the information that links your personal information to your tissue sample.
At the end of treatment with dasatinib-ganitumab you will have an evaluation at 
______________.  At this visit you will have a physical exam, blood and urine tests and scans/x-
rays to measure your tumor.
A study calendar that shows how often these tests and procedures will be done is attached.
What possible risks can I expect from taking part in this study?
If you choose to take part in this study, there is a risk that ganitumab (AMG 479) and dasatinib 
may not be as good as the usual approach for your cancer or condition at shrinking or stabilizing 
your cancer.
 You also may have the following discomforts:

Spend more time in the hospital or doctor’s office.

Be asked sensitive or private questions which you normally do not discuss

May not be able to take part in future studies
The ganitumab (AMG479) and dasatinib used in this study may affect how different parts of 
your body work such as your liver, kidneys, heart, and blood. The study doctor will test your 
blood and will let you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drugs.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020



Some side effects may go away soon, some may last a long time, or some may never go
away.

Some side effects may interfere with your ability to have children.

Some side effects may be mild. Other side effects  may be very serious and even result in
death.
You can ask your study doctor questions about side effects at any time. Here are important points 
about how you and the study doctor can make side effects less of a problem:

If you notice or feel anything different, tell your study doctor.  He or she can check to see
if it is a side effect.

Your study doctor will work with you to treat your side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects doctors know about. 
There might be other side effects doctors do not yet know about. If important new side effects 
are found, the study doctor will discuss these with you.
Risks of Dasatinib
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving dasatinib, more than 20 and up to 100 may have:

Anemia which may require blood transfusion

Diarrhea, nausea

Tiredness

Bruising, bleeding

Pain

Headache

Shortness of breath

Fluid in the body

Rash
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving dasatinib, from 4 to 20 may have:

Infection, especially when white blood cell count is low

Bloating, constipation, heartburn, vomiting

Bleeding from multiple sites

Internal bleeding which may cause black tarry stool or blood in vomit

Sores in the mouth which may cause difficulty swallowing

Swelling of the body

Fever

Weight gain

Weight loss, loss of appetite

Dizziness

Cough, sore throat

Damage to organs (lungs, brain, others) which may cause shortness of breath,
changes in thinking

Hair loss, itching, acne

Flushing
RARE, AND SERIOUS
In 100 people receiving dasatinib, 3 or fewer may have:

Heart failure, heart attack which may cause shortness of breath, swelling of ankles,
and tiredness

Change in the heart rhythm

Kidney damage which may require dialysis

Bone growth may stop early in teenagers leading to short stature

Loss of bone tissue

Decreased height in children and adolescents

Enlarged breasts in males

Bleeding in the brain which may cause confusion

Brain damage which may cause headache, seizure, blindness (also known as
Reversible Posterior Leukoencephalopathy Syndrome)

Severe skin rash with blisters and peeling which can involve mouth and other parts of
the body

Inflammation of the lungs which can cause shortness of breath and difficulty
breathing
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


Risks of Ganitumab
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.  Both male and female participants must use effective birth control measures while 
participating in this study and for at least 4 months after the last dose of dasatinib-ganitumab.  
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.  Optional birth control 
methods include, but are not limited to, abstinence, oral birth control pills, an IUD, or condoms 
with spermicide.  If you are a woman and become pregnant or suspect you are pregnant while 
participating in this study, please inform your treating physician immediately.  A patient who 
becomes pregnant while on study will immediately be taken off study.
  COMMON, SOME MAY BE SERIOUS                                             
 In 100 people receiving Ganitumab (AMG 479), more than 20 and up to 100 may have:

Tiredness

Reaction during or following a drug infusion which may cause fever, chills, low blood 
pressure
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Ganitumab (AMG 479), from 4 to 20 may have:

Anemia which may require blood transfusion

Diarrhea, nausea, vomiting

Bruising, bleeding

Infection, especially when white blood cell count is low

Loss of appetite

Pain in muscles

Rash
RARE, AND SERIOUS
In 100 people receiving Ganitumab (AMG 479), 3 or fewer may have:

Hearing loss

Ganitumab may cause damage to the lung that may cause shortness of breath when 
receiving radiotherapy to the lungs shortly before or after treatment with ganitumab.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


What possible benefits can I expect from taking part in this study?
Treatment with dasatinib-ganitumab may cause your tumor(s) to stop growing or shrink or it may 
lessen the symptoms, such as pain, that are caused by the tumor.  However, because there is not 
much information about the combination of the drugs’ effects on your type of tumor, we do not 
know if you will benefit from taking part in this study, although the knowledge gained from this 
study may benefit others.  Your samples may be helpful to research. The researchers, using the 
samples from you and others, might make discoveries that could help people in the future.
Can I stop taking part in this study?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization helping the investigators to run the study.
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study.
The study doctor may take you out of the study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study rules
If the study is stopped by the sponsor, IRB or FDA.
What are my rights in this study?
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights.
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number). 
(Note to Local Investigator: Contact information for patient representatives or other individuals 
at a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can also be listed here.)
What are the costs of taking part in this study?
Study treatment will be supplied at no charge while you take part in this study. You and/or your 
health plan/insurance company will need to pay for all of the other costs of treating your tumors 
while in this study, including the cost of tests, procedures, or medicines to manage any side 
effects, unless you are told that certain tests are supplied at no charge. Before you decide to be in 
the study, you should check with your health plan or insurance company to find out exactly what 
they will pay for.
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


You will not be paid for taking part in this study.
(Note to consent form authors and investigators: Insert a description of any compensation for 
participation or reimbursement for expenses.)
What happens if I am injured or hurt because I took part in this study?
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The study sponsors will not offer to pay for medical treatment for 
injury.  Your insurance company may not be willing to pay for study-related injury.  If you have 
no insurance, you would be responsible for any costs.
If you feel this injury was a result of medical error, you keep all your legal rights to receive  
payment for this even though you are in a study.
Who will see my medical information?
The NCI has recommended that HIPAA regulations be addressed by the local institution. 
Language pertaining to HIPAA compliance may or may not be included in the local consent 
form, depending on local institutional policy.
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 
you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database.
There are organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis. These organizations are required to make sure your information is 
kept private, unless required by law to provide information. Some of these organizations are:

Qualified representatives from the pharmaceutical collaborator, maker of selumetinib. 

The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study.

Representatives of the National Cancer Institute (NCI) and other government agencies, 
like the Food and Drug Administration (FDA), involved in overseeing research 
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


Where can I get more information?
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237).
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
Who can answer my questions about this study?
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number).
ADDITIONAL STUDIES SECTION
This section is about optional studies you can choose to take part in
Biopsy of your tumor (optional): a biopsy of your tumor (take a small piece of your tumor tissue 
using a large needle) will be done before you start the study drugs, sometime during the first 
week of treatment and again if your tumor(s) begin to enlarge. This biopsy will only be requested 
if you are 12 years old or older, and provided the biopsy can be obtained safely, and are willing 
to participate in our companion protocol 10-C-0086.  This tumor biopsy is optional. With this 
biopsy tissue we will study the changes that these study agents cause in the tumor of people with 
ERMS and ARMS.  You can agree now to allow us to biopsy your tumor and change your mind 
later.  This tissue will also undergo genomic analysis at a laboratory called NantOmics.  Your 
name will not be attached to your tissue; it will be identified using a study number.  Only the 
investigator and research team will have access to the information that links your personal 
information to your tissue sample.
What is involved?
A doctor will use a hollow needle attached to a syringe to enter a tumor, then withdraw (aspirate) 
a small amount of tissue from the tumor.  The doctor may use a scan or ultrasound to guide the 
needle directly to the tumor.  Depending upon the location of the tumor, the doctor may use 
numbing medicine (called local anesthetic) to numb the area before the biopsy.  
What are the possible risks?
The risks will be explained to you fully in a different consent.  In general, the risks include 
bleeding, pain, scarring and infection.  If there is bleeding under the skin, a hematoma or 
collection of blood at the biopsy site may occur. Other risks depend on the location of the tumor 
being sampled.  The doctor will discuss these specific risks with you before the procedure.  
How will information about me be kept private?
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


Your tumor samples will be identified and stored using a number and not your name. Only the 
study investigator and research team taking care of you on this study will have access to your 
name. 
What are the possible benefits?
The use of your biopsy specimens will be for research purposes only and will not benefit you.  
Results of research done on your tumor specimens will not be available to you or your doctor, 
but it will help us better understand how this study drug works on tumors, and it might help 
people who have these types of tumors in the future.
Are there any costs or payments? 
There are no costs to you.  You will not be paid for your tissue.  The cost of biopsy, storage and 
testing will be paid by the study investigators or collaborators in this study.
What if I change my mind?
If you decide now that you will undergo the biopsy, you can change your mind at any time. Just 
let us know at the time of the biopsy or contact us ________________________ (insert name of 
center) Institutional Review Board at __________________ (insert telephone number) and let us 
know that you do not want to have the biopsy. 
What if I have more questions?
If you have additional questions, please contact the office of Dr. Heske, Principal Investigator: 
240-760-6197.
Yes
No
NA
 Initials:_______ Date: ________
This is the end of the section about optional studies.
Blood and Tissue Storage
What is involved?
Should any leftover blood remain after completing the studies described in earlier sections, we 
would like to keep the remaining blood for future research. 
What are the possible risks?
There are no known risks as your blood and tissue samples have already been collected.  No 
additional procedures will be performed.
How will information about me be kept private?
These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for 
research purposes.  The remaining specimens and your data will be identified by a number only.  
Only the study investigator and research team taking care of you on this study will have access to 
your name.
What are the possible benefits?
The use of your specimens and data will be for research purposes only and will not benefit you. 
It is also possible that the stored specimens and data may never be used. Results of research done 
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


on your specimens and data will not be available to you or your doctor. It might help people who 
have these types of tumors and other diseases in the future.
Are there any costs or payments? 
There are no costs to you.  You will not be paid for your tissue or data.  The cost of storage and 
testing will be paid by the study investigators or collaborators in this study.
What if I change my mind?
If you decide now that your specimens and data can be kept for research, you can change your 
mind at any time. Just contact us (office of ________________________ (insert name of center) 
Institutional Review Board at __________________ (insert telephone number)) and let us know 
that you do not want us to use your specimens and/or data. Then any specimens that remain will 
be destroyed, and your data will not be used for future research. 
What if I have more questions?
If you have additional questions, please contact the office of ________________________ 
(insert name of center) Institutional Review Board at __________________ (insert telephone 
number).
Study Calendar
Test/Procedure
Pre-
treatment
During Cycle 
1
During Cycles 2 through end 
of treatment
Completion/ 
Stopping 
treatment
Medical history, 
Physical exam, vital 
signs 
X
Weekly 
starting from 
day -7
On days 0 and 14
X
Standard blood tests
X
Weekly 
starting from 
day -7
Weekly for cycles 2 and 3, 
then every other week 
thereafter
X
Urine test
X
Weekly 
starting from 
day -7
Prior to each subsequent cycle
X
EKG
X
Prior to each subsequent cycle
Echocardiogram
X
At the start of cycles 1,2, 3, 5, 
7, 9, 11 etc. 
Dasatinib, swallow 
tablets(s); record in the 
diary
Days -7 
through Day 
28
Day 0 through Day 28
Ganitumab, IV every 2 
weeks
Day 0 and 
Day 14
Day 0 and Day 14
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020


Tumor biopsy 
(optional if you are 12 
years of age or older)
X
During week 1
If your tumor(s) 
grow
Pregnancy test
X
Prior to cycle 3, 5, 7, 9, 11, etc
Tumor evaluations
X
Prior to cycle 3, 5, 7, 9, 11, etc
My Signature Agreeing to Take Part in the Main Study
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’. 
Participant’s signature________________________________
Date of signature_____________________________________
Signature of person(s) conducting the informed consent 
discussion___________________________________
Date of signature_____________________________________
IRB NUMBER: 17C0049
IRB APPROVAL DATE: 04/13/2020