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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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                |
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| 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 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                |  
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*
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participating organizations

| LAO-CA043 / City of Hope Comprehensive Cancer Center Participation restricted to CA009 - Children's Hospital of Los Angeles   |                                                                                                     |
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| 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  
| 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   |
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| 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   |
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NCI-Supplied Agents: Ganitumab, NSC \# 750008, BDP, FNLCR and Dasatinib (BMS354825), NSC \# 732517, Bristol-Myers-Squibb IND \#: 12049  
| Responsible Data Manager: Isabel Palacio-Yance 10 Center Drive Rm 1C253 Bethesda, MD 20892 Phone: 301-402-9748 Email: Isabel.palacio-yance@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   |
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IND Sponsor: DCTD, NCI
3
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precis 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)
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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:
4
- 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.
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design

- This is an open label, multisite, 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 .                        |                                                                                                            |
|---------------------------------|------------------------------------------------------------------------------------------------------------|
| TABLE OF CONTENTS.              |                                                                                                            |
| INTRODUCTION .                  |                                                                                                            |
| l                               |                                                                                                            |
| 1.1                             | Study Objectives .                                                                                         |
| 2                               | BACKGROUND AND RATIONALE                                                                                   |
| 2.1                             | Inhibiting the insulin-like growth factor type 1 receptor (IGF1 -R) in                                     |
| rhabdomyosarcoma (RMS):         |                                                                                                            |
| 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:               |                                                                                                            |
| DASATINIB                       |                                                                                                            |
| 2.4                             |                                                                                                            |
| 2.5                             | Ganitumab                                                                                                  |
| 2.6                             | Proposed trial:                                                                                            |
| 3                               | PATIENT SELECTION                                                                                          |
| 3.1                             | Eligibility Criteria .                                                                                     |
| 3.2                             | Sereening Evaluation                                                                                       |
| 4                               | RECRUITMENT AND REGISTRATION                                                                               |
| 4.1                             | Recruitment Strategies                                                                                     |
| 4.2                             | Registration Procedures                                                                                    |
| 4.3                             | Local Registration for NCI CCR                                                                             |
| 4.4                             | General Guidelines                                                                                         |
| S                               | TREATMENT PLAN .                                                                                           |
| 5.1                             | Agent Administration                                                                                       |
| 5.2                             | General Concomitant Medication and Supportive Care Guidelines                                              |
| 5.3                             | Duration of Therapy (Off Treatment)                                                                        |
| 5.4                             | D Duration of Follow Up                                                                                    |
| Criteria for Removal from Study |                                                                                                            |
| 5.5                             | Local Off Protocol Treatment and Off-Study Procedure....................................................38 |
| 5.6                             |                                                                                                            |
| 6                               | DOSING DELAYS/DOSE MODIFICATIONS .                                                                         |  
| Version Date: 04/06/2020 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   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Version Date: 04/06/2020 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   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 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).
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2 background and rationale 2.1

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 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 mice after regrowth showed persistent down-regulation of IGF-1R, but a rebound in AKT 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)
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2.2 yes activation as a

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.
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2.3 rationale for combining igf-1r

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 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.
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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: BCRABL, 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)
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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 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 longterm 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 this pharmacodynamic model permitted the authors to predict that the plasma concentration of  
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.
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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.
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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 nonhematologic 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.
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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  
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 diagnosed CML.
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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.
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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).
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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 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
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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)*
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2.5.1.2 nonclinical pharmacokinetic and pharmacodynamic

Exposure to ganitumab increased approximately dose-proportionally after single and multiple IV
or intraperitoneal administrations in normal cluster of differentiation 1 (CD-1) mice, SpragueDawley 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)*
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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 rats and/or monkeys. No adverse effects were noted in safety pharmacology studies that evaluated cardiovascular (electrocardiogram parameters including corrected QT interval [QTc]),
CNS, and respiratory effects of ganitumab at doses up to 300 mg/kg.*(50)*
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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)
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2.5.3 rationale for proposed ganitumab

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 dalotuzumab, the recommended pediatric phase II dose (900 mg/m2IV 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 IGF1R monoclonal antibodies,(12, 52, 59)use of maximal studied doses of ganitumab (20 mg/kg) may not be feasible in combination with other agents.
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2.6 proposed trial 2.6.1 dose

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.  
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/kgfor all subsequent patients.
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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.
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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 months. 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 4month disease stabilization fraction (see section 13).
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3 patient selection 3.1 eligibility

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.
- 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%
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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.  
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  
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.
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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)  
  
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. 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.
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4 recruitment and registration 4.1

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.
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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 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 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
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.
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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.
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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.
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4.3 local registration for nci

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.
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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  
| Number     | Name                                               | Description                                      |
|------------|----------------------------------------------------|--------------------------------------------------|
| 1          | Dose Escalation Cohort                             | Patients (minimum 2 years of age and above) with |
| (Phase I)  | embryonal or alveolar RMS and measurable  disease. |                                                  |
| 2          | Dose Expansion Cohort                              | Patients (minimum 2 years of age and above) with |
| (Phase II) | embryonal or alveolar RMS and measurable  disease. |                                                  |  
4.3.2.1 Cohorts  
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  
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).
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4.4 general guidelines

| 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)         |  
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.
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5 treatment plan 5.1 agent

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:  
| Dose Level                     | Dose of dasatinib            | Dose of ganitumab                 |
|--------------------------------|------------------------------|-----------------------------------|
| Level -1                       | 40 mg/m2 once daily (maximum | 18 mg/kg every 2 weeks, beginning |
| dose of 100 mg/day) on days -7 | on day 0                     |                                   |  
| 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 |  
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.  
| and section 5.1.3 Dose Level   | Dose of dasatinib        | Dose of ganitumab                   |
|--------------------------------|--------------------------|-------------------------------------|
| Level -1                       | Dasatinib MTD determined | 12 mg/kg every 2 weeks, starting on |
| during phase I                 | day 0                    |                                     |
| Level 1                        | Dasatinib MTD determined | 18 mg/kg every 2 weeks, starting on |
| during phase I                 | day 0                    |                                     |  
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-  
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 Escalation Decision Rule at a Given Dose Level 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 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/kgfor 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

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).
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5.2.1 agents that induce or

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 halflife 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.
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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.
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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. 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.
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5.3 duration of therapy (off

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.
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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.
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5.5 criteria for removal from

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

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.
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6 dosing delays/dose modifications 6.1

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.  
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 agentrelated 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.
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6.2 adverse events attributed to

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.  
| Event            | AE Grade or  Observation                                                       | Dose modification   |
|------------------|--------------------------------------------------------------------------------|---------------------|
| Grades 1-3       | Maintain dose Hold both agents until < grade 3, then reduce                    |                     |
| Grade 4 1        | dasatinib per Section 6.7 AND ganitumab to 12  mg/kg/dose and resume treatment |                     |
| Neutropenia      |                                                                                |                     |
| Thrombocytopenia | Grades 1-3                                                                     | Maintain dose       |  
| Hold both agents until < grade 3, then reduce                                                                                                                                        |                                                                                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|
| Grade 4 1                                                                                                                                                                            | dasatinib per Section 6.7 AND ganitumab to 12  mg/kg/dose and resume treatment |
| 1 If 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. |                                                                                |
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6.4 pneumonitis attributed to dasatinib

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 CTEPAERS and through routine reporting.  
Dose modifications for dasatinib and ganitumab are as follows:  
| Pneumonitis Grade                                                                                                                                                                            | Action                                                    |                                        |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------|----------------------------------------|
| (per CTCAE, under  Pneumonitis) -                                                                                                                                                            | Monitor closely for worsening symptoms.                   |                                        |
| Grade 1                                                                                                                                                                                      | -                                                         | Continue dasatinib and ganitumab.      |
| -                                                                                                                                                                                            | 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 offstudy 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 2                                                                                                                                                                                      | -                                                         | 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 offstudy 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.                          |                                        |
| -                                                                                                                                                                                            | Discontinue dasatinib and ganitumab permanently.          |                                        |
| Grade 4  *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 D**ASATINIB**  
| Event                | AE Grade or  Observation                             | Dose modification   |
|----------------------|------------------------------------------------------|---------------------|
| Hemorrhage/Bleeding/ | No interruption in treatment; maintain current dose. |                     |
| Grade 1              |                                                      |                     |
| Coagulopathy         | Monitor as clinically indicated                      |                     |  
| Version Date: 04/06/2020 Event   | AE Grade or  Observation                                                                                                                                                                                                                                                                                                     | Dose modification   |
|----------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|
| (without                         |                                                                                                                                                                                                                                                                                                                              |                     |
| thrombocytopenia)                | 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.                                                                         |                     |
| Grade 2                          | 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). Review patient's concomitant medications for QT  interval-prolonging agents. Correct any electrolyte  abnormalities.                                                                                                                                     |                     |
| >480 but <550 msec               | Continue dasatinib at current dose level and repeat  ECG. Stop dasatinib and any other QT interval-prolonging  agents immediately. Correct any electrolyte  abnormalities, then                                                                                                                                              |                     |
| QTcF Prolongation                | 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. |                     |
| >550 msec                        |                                                                                                                                                                                                                                                                                                                              |                     |
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6.6 additional adverse events attributed

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:  
| Hyperglycemia  Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Action   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|
| (per CTCAE, under  Hyperglycemia) Grade 1 Continue ganitumab.  Grade 2 Continue ganitumab. Consider consultation with Pediatric Endocrinologist.  - 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 3 or Urine glucose > 0.1  g/dL  - 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.  Grade 4 |          |  
* 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%.**
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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.  
| Version Date: 04/06/2020 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.) - 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 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), 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.                                                                                                                                                                                                                                                          |                                                                                                                                                                   |
| Grade 4  Anaphylaxis  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:  
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. - Unlikely or unrelated to ganitumab: Continue ganitumab. Possibly, probably, or definitely related: Hold ganitumab until resolves to ≤ Grade 2. If Grade 3  toxicity resolves within 2 weeks of interruption, then resume ganitumab with a reduced dose of 12 mg/kg/dose. - Unlikely or unrelated to ganitumab*: Hold ganitumab until resolves to ≤ Grade 2, then resume ganitumab at full dose. Grade 4  - 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

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                         | 28                     |              |
| ON M, W, TH, SAT, SUN                  |                        |              |
| 35 MG PER DOSE                         | 25 MG PER DOSE         | 29           |
| 30 MG PER DOSE                         | 20 MG PER DOSE         | 33           |
| 20 MG PER DOSE                         |                        |              |
| 25 MG PER DOSE                         | 31                     |              |
| ON M, TU, W, TH, F, SAT 20 MG PER DOSE |                        |              |
| 20 MG PER DOSE                         | 28                     |              |
| ON M, W, TH, SAT, SUN                  |                        |              |  
| 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                         | 28                 |            |
| ON M, W, TH, SAT, SUN                  |                    |            |
| 35 MG PER DOSE                         | 25 MG PER DOSE     | 29         |
| 30 MG PER DOSE                         | 20 MG PER DOSE     | 33         |
| 20 MG PER DOSE                         |                    |            |
| 25 MG PER DOSE                         | 31                 |            |
| ON M, TU, W, TH, F, SAT 20 MG PER DOSE |                    |            |
| 20 MG PER DOSE                         | 28                 |            |
| ON M, W, TH, SAT, SUN                  |                    |            |
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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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7 sponsor safety reporting 7.1

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.
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7.2 comprehensive adverse events and

7.2.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) for **Dasatinib (BMS354825, 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, 2018                                            |                                                                            |                         |
|----------------------------------------------------------------------------|----------------------------------------------------------------------------|-------------------------|
| 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                                                       |                                                                            |                         |  
| Version Date: 04/06/2020 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                                                      |                         |  
| Version Date: 04/06/2020 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                                                                                                                                                                                                                                      | Neutrophil count decreased                          |                         |
| decreased                                                                                                                                                                                                                                             | (Gr 4)                                              |                         |
| Platelet count decreased                                                                                                                                                                                                                              | Platelet count decreased (Gr  4)                    |                         |
| Weight gain Weight loss White blood cell                                                                                                                                                                                                              | White blood cell decreased                          |                         |
| 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                                                                                                                                                                                                                    |                                                     |                         |  
| Version Date: 04/06/2020 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 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 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.  
7.2.2 Comprehensive Adverse Events and Potential Risks list (CAEPR) **for Ganitumab**
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(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.  
  
| 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)     |                         |  
| 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                  | Neutrophil count decreased                   |                                            |
| decreased                                                     | (Gr 3)                                       |                                            |
| Platelet count                                                | Platelet count decreased (Gr                 |                                            |
| decreased                                                     | 3)                                           |                                            |
| White blood cell                                              | White blood cell decreased                   |                                            |
| decreased                                                     | (Gr 3)                                       |                                            |
| METABOLISM AND NUTRITION DISORDERS                            |                                              |                                            |  
  
| 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.  
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; Noncardiac 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 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.
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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.
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- for expedited reporting purposes

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.
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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://eappsctep.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  
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
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fda reporting requirements for serious

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.  
| via AdEERS within the timeframes detailed in the table below.   | Grade 3-5                      |            |
|-----------------------------------------------------------------|--------------------------------|------------|
| Hospitalization                                                 | Grade 1 and Grade 2 Timeframes | Timeframes |
| Resulting in                                                    |                                |            |
| Hospitalization                                                 | 10 Calendar Days               |            |
| ≥ 24 hrs                                                        | 24-Hour 5 Calendar             |            |
| Not resulting in                                                | Days                           |            |
| Hospitalization                                                 | Not required                   |            |
| ≥ 24 hrs                                                        |                                |            |  
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.
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expedited ae reporting timelines are

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.  
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
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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.
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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.
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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

Please refer to definitions provided in Policy 801: Reporting Research Events found here.
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8.2 ohsrp office of compliance

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.
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8.3 nci clinical director reporting(for

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.
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8.4 nciguidance for reporting expedited

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.
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9 biomarker correlative and special

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 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.
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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.
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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
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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 phosphoYES, 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. 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.  
| 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 |            |  
  
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.