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9.2 biomarker studies

From the whole-genome sequencing, RNA transcriptomic, and quantitative proteomic profiling, evaluation of biomarkers in tumors and blood samples will include but will not be limited to the following biomarkers:  
| Biomarker Namea              | Assay                                                           | Use (Integral, Integrated,  or Exploratory) AND  Purpose b      | Tissue/Body Fluid  Tested   | M/O   | Funding  Source(s) c   |
|------------------------------|-----------------------------------------------------------------|-----------------------------------------------------------------|-----------------------------|-------|------------------------|
| AND Lead PI and  Site        | (CLIA: Y/N)                                                     | and Timing of Assay                                             |                             |       |                        |
| IGF-1R expression            | Targeted  MS: IGF- 1R                                           | Exploratory                                                     | Archival tumor tissue       | M     | NCI/POB                |
| NantOmics                    | Response assessment                                             | At enrollment                                                   |                             |       |                        |
| CLIA: Y                      |                                                                 |                                                                 |                             |       |                        |
| IGF-1R expression            | Targeted  MS: IGF- 1R                                           | Exploratory                                                     | Biopsied tumor tissue       | O     | NCI/POB                |
| NantOmics                    | Response assessment                                             | At enrollment, during  week 1 of treatment,  and at progression |                             |       |                        |
| CLIA: Y                      |                                                                 |                                                                 |                             |       |                        |
| Insulin receptor  expression | Targeted  MS: IR                                                | Exploratory                                                     | Archival tumor tissue       | M     | NCI/POB                |
| Response assessment          | At enrollment                                                   |                                                                 |                             |       |                        |
| NantOmics                    | CLIA: N                                                         |                                                                 |                             |       |                        |
| Insulin receptor  expression | Targeted  MS: IR                                                | Exploratory                                                     | Biopsied tumor tissue       | O     | NCI/POB                |
| Response assessment          | At enrollment, during  week 1 of treatment,  and at progression |                                                                 |                             |       |                        |
| NantOmics                    | CLIA: N                                                         |                                                                 |                             |       |                        |
| IGF-2 expression             | Targeted  MS: IGF-2                                             | Exploratory                                                     | Archival tumor tissue       | M     | NCI/POB                |
| NantOmics                    | Response assessment                                             | At enrollment                                                   |                             |       |                        |
| CLIA: N                      |                                                                 |                                                                 |                             |       |                        |
| IGF-2 expression             | Targeted  MS: IGF-2                                             | Exploratory                                                     | Biopsied tumor tissue       | O     | NCI/POB                |
| NantOmics                    | Response assessment                                             | At enrollment, during  week 1 of treatment,  and at progression |                             |       |                        |
| CLIA: N                      |                                                                 |                                                                 |                             |       |                        |  
| Biomarker Namea         | Assay                                                           | Use (Integral, Integrated,  or Exploratory) AND  Purpose b   | Tissue/Body Fluid  Tested           | M/O   | Funding  Source(s) c   |
|-------------------------|-----------------------------------------------------------------|--------------------------------------------------------------|-------------------------------------|-------|------------------------|
| AND Lead PI and  Site   | (CLIA: Y/N)                                                     | and Timing of Assay                                          |                                     |       |                        |
| Phospho-YES  expression | Targeted  MS: pSFK                                              | Exploratory Response assessment                              | Archival tumor tissue At enrollment | M     | NCI/POB                |
| NantOmics               | CLIA: N                                                         |                                                              |                                     |       |                        |
| Phospho-YES  expression | Targeted  MS: pSFK                                              | Exploratory                                                  | Biopsied tumor tissue               | O     | NCI/POB                |
| Response assessment     | At enrollment, during  week 1 of treatment,  and at progression |                                                              |                                     |       |                        |
| NantOmics               | CLIA: N                                                         |                                                              |                                     |       |                        |  
The following exploratory biomarker studies will be conducted on archival tissue obtained at the time of enrollment.  
1. IGF-1R expression  
2. Insulin receptor expression 3. IGF-2 expression 4. Phospho-YES expression
In consenting participants when biopsies can be performed safely without additional risk of morbidity, biopsies will be performed to explore mechanisms of response, and resistance will be assessed by analyzing biopsy tissue expression of IGF-1R, insulin receptor, IGF-2 expression and phospho-YES expression, and through genomic sequencing. Biopsies will be taken at enrollment, during week 1 of treatment and at the time of progression. Specimens will be batched and performed retrospectively. 9.2.1 Proteomics There are two key components to the quantitative proteomics approach, which allows for the quantitation of targeted proteins from formalin-fixed paraffin-embedded (FFPE) tumor biopsies.
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liquid tissue (lt) technology

NantOmics uses a proprietary non-contact method of laser microdissection that isolates and collects only the tumor cells of interest for analysis. The accuracy and precision of microdissection ensures that the collected sample is highly enriched for active tumor cells, limiting the presence of necrotic, stromal, or normal cells. The microdissected FFPE tumor tissue is then subjected to Liquid Tissue® processing to solubilize the tumor tissues. The patented Liquid Tissue® technology ensures that formalin cross-links are reversed and all of the proteins in the tumor tissue are solubilized. Mass Spectrometry-based Selected Reaction Monitoring (SRM) Technology The solubilized tumor tissue is then subjected to multiplexed SRM analysis using stable isotope - labeled internal standard peptides for accurate quantitation. Quantitative mass spectrometry represents an emerging clinical method, which is highly specific, reproducible, objectively quantitative, and has reduced sensitivity to pre-analytical variation. In addition, mass spectrometry-based proteomic analysis of FFPE tissue is capable of multiplexing analysis of up to 100 analytes from a small amount of tissue.  
9.2.1.1 Sample requirements for proteomics analyses Refer to NantOmics Sample Collection manual for sample requirements and collection instructions. Ship samples and the Requisition form, as outlined in the NantOmics Sample Collection manual, to:
NantOmics Attention: Sample Receipt 9600 Medical Center Drive Suite 300 Rockville, MD 20850 USA
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9.3 sample storage tracking and

Blood and tissue collected during the course of this study will follow NIH guidelines for the research use of human samples and OHSRP Issues to Consider in the Research Use of Stored Data or Tissues. At the NIH Clinical Center, samples will be ordered and tracked in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without IRB notification and an executed MTA. All tumor samples obtained for research, not directly transported for study analysis, will be transported to Dr. Figg's laboratory to be barcoded. Dr. Figg's laboratory will need the patient's Medical Record Number, name, protocol, date, time, and site of tissue, and a description of the type of tissue (normal versus tumor) to issue a label for the sample. Please e-mail Dr. Figg's lab at NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact Dr. Figg's lab at NCIBloodcore@mail.nih.gov. All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with access to LABrador limited to defined Figg lab personnel, who are issued individual user accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. All Figg lab personnel with access to patient information annually complete the NIH online Protection of Human Subjects course.  
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced back to patients without LABrador access. The data recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and freezer location. Patient demographics associated with the clinical center patient number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.).
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9.3.1 sample storage and destruction

Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in LABrador (aka LabSamples). All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB approved protocol) and that any unused samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval. Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. If, at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the patient, if so requested). Sample barcodes are linked to patient demographics and limited clinical information. This information will only be provided to investigators listed on this protocol, via registered use of the LABrador (aka LabSamples). It is critical that the sample remains linked to patient information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate results with these variables. If the patient withdraws consent the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved. The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section 8.2.
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9.4 samples for genetic/genomic testing

Subjects on this study will be asked to co-enroll on 10-C-0086: Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a Repository for Related Biological Studies. Patients who consent to participate in 10-C-0086 will undergo blood sampling at baseline and prior to each cycle as detailed in the study calendar, as well as genomic analysis as described below. This companion protocol may include the following analyses: analysis for mutations or Single Nucleotide Variants (SNVs) in tumors and germline DNA, comparative genomics hybridization, whole genome, exome, and transcriptome sequencing of tumor and germline DNA, messenger and microRNA sequencing and expression analysis, epigenetic studies including whole methylome analysis using next generation sequencing, metabolomics study of tumor, global mass spectroscopy-based protein and phospho-protein analysis. In addition, NantOmics will run Genomic analysis. 9.4.1 Sequencing 1. Whole Genome Sequencing (WGS) will be done at average depth of 30x for normal samples, and an average depth of 60x for tumor samples. RNA sequencing (RNA-Seq) will be performed on tumor samples to obtain approximately 240 million reads across two technical replicates to assure reproducibility.  
2. NantOmics lab has experience sequencing tumor DNA extracted from formalin-fixed, paraffin embedded (FFPE) blocks and slides, fresh frozen tissue, and purified DNA. The FFPE failure rate is approximately 10%, with most failures occurring when the blocks provided have little to no tumor content remaining. NantOmics requests matched normal sample of all patients, and can handle multiple sample types including whole blood, saliva, buccal swabs, and purified DNA.  
3. Using standard methods, sequencing reads are aligned and duplicate marked, followed by indel realignment and base quality recalibration. NantOmics cancer analytical pipeline takes tumor and matched-normal alignments (BAM format) to call point mutations, small indels, copy number and allele fraction, and structural variants at all scales. Filtering is performed on all variants to reduce false positives while being permissive enough to avoid removing variants of interest. Copy number and allele fraction are integrated to determine regions that exhibit similar copy number and allelic bias, e.g. necessary to discover regions of copy neutral loss-of-heterozygosity (CN-LOH) located inside a region of normal copy number. Using these relative copy number estimates and allele fraction, NantOmics estimates tumor purity and ploidy, and use that to inform more accurate copy number estimates and mutation clonality. They perform local assembly using both unmapped and mapped reads aligned near each putative structural variant to precisely locate (base precision) where the structural variant occurred in the tumor genome. All variants identified are annotated for any effect they may have to gene(s) or their isoforms.  
9.4.2 Sample requirements for genomics analyses
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9.4.2.1 tumor tissue

Refer to NantOmics Sample Collection manual for sample requirements and collection instructions and **Appendix 9** if sending samples from a participating site.
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9.4.2.2 blood sample

Refer to NantOmics Sample Collection manual for sample requirements and collection instructions and **Appendix 9** if sending samples from a participating site.
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10 study calendar

Baseline evaluations, including cardiac studies, are to be conducted within 1 week prior to start of protocol therapy. Imaging studies of disease must be done ≤4 weeks prior to the start of therapy. For labs indicating a specific day to be drawn (for example, day 14), labs may be drawn on the day indicated in the table, or up to 2 days earlier.  
| STUDIES TO                                                                                               | Screening                                                      | Baseline              | During                               | During        | At End of   | Off   |
|----------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|-----------------------|--------------------------------------|---------------|-------------|-------|
| BE                                                                                                       | Cycle 1                                                        | Subsequent Cycles     | Therapy1                             | Therapy11     |             |       |
| OBTAINED                                                                                                 |                                                                |                       |                                      |               |             |       |
| History, physical  exama , vital  signs, including  oxygen  saturation                                   | Weekly                                                         |                       |                                      |               |             |       |
| X                                                                                                        | X                                                              | starting from  day -7 | At days 0 and 14 of  each subsequent | X             | Monthly     |       |
| cycle                                                                                                    |                                                                |                       |                                      |               |             |       |
| Tanner stage                                                                                             | X                                                              | X                     | Only if change  from baseline        | X             |             |       |
| Height, weight,                                                                                          | At start of each                                               |                       |                                      |               |             |       |
| BSA                                                                                                      | X                                                              | X                     | subsequent cycle                     | X             |             |       |
| Performance                                                                                              | Only if change                                                 |                       |                                      |               |             |       |
| Status2                                                                                                  | X                                                              | X                     | from baseline                        | X             |             |       |
| Weekly                                                                                                   |                                                                |                       |                                      |               |             |       |
| starting from  day -7                                                                                    | Weekly for cycles 2  and 3, then every  other week  thereafter |                       |                                      |               |             |       |
| CBC,                                                                                                     |                                                                |                       |                                      |               |             |       |
| differential,                                                                                            | X                                                              | X                     |                                      |               |             |       |
| platelets3                                                                                               | X                                                              | Monthly               |                                      |               |             |       |
| BUN, creatinine,  sodium,  potassium,  chloride, CO2,  calcium,  magnesium,  phosphorus, uric  acid, LDH | Weekly                                                         |                       |                                      |               |             |       |
| X                                                                                                        | X                                                              | starting from  day -7 | Prior to each                        |               |             |       |
| subsequent cycle                                                                                         | X                                                              | Monthly               |                                      |               |             |       |
| Weekly for cycles 2  and 3, then every  other week  thereafter                                           |                                                                |                       |                                      |               |             |       |
| Weekly                                                                                                   |                                                                |                       |                                      |               |             |       |
| Serum glucose4                                                                                           | X                                                              | X                     | starting from  day -7                | X             | Monthly     |       |
| HgbA1C5                                                                                                  | X                                                              | X                     | As indicated5                        | As indicated5 | As          |       |
| indicated5                                                                                               |                                                                |                       |                                      |               |             |       |  
| Version Date: 04/06/2020 STUDIES TO  Screening                                                                         | Baseline             | During                 | During                            | At End of     | Off    |
|------------------------------------------------------------------------------------------------------------------------|----------------------|------------------------|-----------------------------------|---------------|--------|
| BE                                                                                                                     | Cycle 1              | Subsequent Cycles      | Therapy1                          | Therapy11     |        |
| OBTAINED Hepatic panel:  Alkaline  phosphatase,  ALT, AST,  Total bilirubin  (Direct bilirubin  if total is  elevated) | Weekly               |                        |                                   |               |        |
| X                                                                                                                      | X                    | starting from  day -7  | Prior to each                     |               |        |
| subsequent cycle                                                                                                       | X                    | Monthly                |                                   |               |        |
| Weekly                                                                                                                 |                      |                        |                                   |               |        |
| Total protein,  albumin                                                                                                | X                    | X                      | starting from  day -7             | Prior to each |        |
| subsequent cycle                                                                                                       | X                    | Monthly                |                                   |               |        |
| Fasting                                                                                                                |                      |                        |                                   |               |        |
| triglycerides,  Cholesterol  (Total, HDL,  and LDL)                                                                    | X                    | X                      | Prior to each                     |               |        |
| subsequent cycle                                                                                                       | X                    | Monthly                |                                   |               |        |
| Weekly                                                                                                                 |                      |                        |                                   |               |        |
| Urinalysis                                                                                                             | X                    | X                      | starting from  day -7             | Prior to each |        |
| subsequent cycle                                                                                                       | X                    | Monthly                |                                   |               |        |
| PT, INR (in  patients  undergoing  biopsy)                                                                             | Within 24            |                        |                                   |               |        |
| X                                                                                                                      | X                    | hours prior to  biopsy | Within 24  hours prior  to biopsy |               |        |
| EKG                                                                                                                    | X                    | X                      | Prior to each                     |               |        |
| subsequent cycle                                                                                                       | Monthly              |                        |                                   |               |        |
| Echocardiogram                                                                                                         | X                    | X                      | Prior to cycle  2,3,5,7 etc.      | Monthly       |        |
| Disease                                                                                                                | Prior to cycle 3, 5, | Every 2                |                                   |               |        |
| Evaluation6                                                                                                            | X                    | X                      | 7, etc.                           | X             | months |
| Pregnancy Test7                                                                                                        | X                    | X                      | Prior to each                     |               |        |
| subsequent cycle                                                                                                       |                      |                        |                                   |               |        |
| Unstained slides  or block  (required at  study entry)                                                                 | X                    | X                      |                                   |               |        |
| Molecular                                                                                                              |                      |                        |                                   |               |        |
| Profiling (see                                                                                                         | X                    |                        |                                   |               |        |
| section 9.1.5) Research Blood  (10 cc EDTA or  Streck tube if at  NIH) 8                                               | X                    | Prior to each          |                                   |               |        |
| subsequent cycle                                                                                                       |                      |                        |                                   |               |        |
| Research Blood                                                                                                         | X                    | Prior to each          |                                   |               |        |
| (10 cc Cell-Free                                                                                                       | subsequent cycle     |                        |                                   |               |        |
| DNA BCT                                                                                                                |                      |                        |                                   |               |        |  
| STUDIES TO                                                                                         | Screening   | Baseline          | During   | During    | At End of   | Off   |
|----------------------------------------------------------------------------------------------------|-------------|-------------------|----------|-----------|-------------|-------|
| BE                                                                                                 | Cycle 1     | Subsequent Cycles | Therapy1 | Therapy11 |             |       |
| OBTAINED tube if outside  NIH) 9 Optional                                                          | During week |                   |          |           |             |       |
| Biopsy10                                                                                           | X           | 1                 | X        |           |             |       |
| NIH Advance  Directives                                                                            | X           |                   |          |           |             |       |
| Form12                                                                                             |             |                   |          |           |             |       |
| 1 Should be performed, if possible, when the patient comes off treatment regardless of the reason. |             |                   |          |           |             |       |  
1 Should be performed, if possible, when the patient comes off treatment regardless of the reason.  
2**Appendix 1**; prior to cycle 1 and then only required to be recorded if there is a change in performance status during the study.  
3If patients develop Grade 4 neutropenia then CBC should be checked every 3 to 4 days until recovery to grade 3.  
4Also obtain for symptoms of polyuria or polydipsia or as otherwise clinically indicated.  
5HgbA1C should be obtained at baseline and if the patient develops hyperglycemia requiring treatment and then every 3 months until hyperglycemia resolves and treatment is no longer required.  
6Imaging studies of each site of disease with appropriate modality.  
7 Patients of childbearing potential require a negative pregnancy test prior to starting treatment and must use an acceptable method of birth control. Abstinence is an acceptable method of birth control.  
8Only perform in patients consented to 10-C-0086 (Omics). Deliver immediately to Donna Bernstein.  
9 Only perform in patients consented to 10-C-0086 (Omics). Ship immediately to Donna Bernstein per guidelines in **Appendix 9**. 10Should be performed at end of therapy only if patient comes off treatment due to progression.  
11Off-therapy studies are required only for patients who are removed by the PI due to drug toxicity or side effects. All patients will be followed for at least 30 days after the last dose of investigational agents and until disease progression, whichever is last.  
12As indicated in section **15.3**, all subjects enrolled at NIH and ≥ age 18 will be offered the opportunity to complete an NIH advance directives form. This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required.  
a A complete standard physical examination will be performed at baseline;subsequent physical exams will be targeted based on signs and symptoms of presenting patient.
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11 measurement of effect 11.1

For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).  
(70) Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST
criteria. 11.1.1 Definitions Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with dasatinib and ganitumab. Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. 11.1.2 Disease Parameters Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded  
and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 11.1.3 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all  
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published.  
(71-73) In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer.  
(74)
Cytology, Histology: These techniques can be used to differentiate between partial responses
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
74 PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image. 11.1.4 Response Criteria 11.1.4.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. 11.1.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.  
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). 11.1.4.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| For Patients with Measurable Disease (i.e., Target Disease) Target  Non-Target  New  Overall  Best Overall Response when  Lesions Lesions Lesions Response Confirmation is Required* CR CR No CR >4 wks. Confirmation** CR NonCR/Non-PD No PR CR Not  No PR evaluated >4 wks. Confirmation** PR NonCR/NonPD/not  evaluated No PR SD NonCR/NonPD/not  evaluated No SD Documented at least once >4  wks. from baseline** PD Any Yes or  PD No Any PD*** Yes or no prior SD, PR or CR PD No Any Any Yes PD * See RECIST 1.1 manuscript for further details on what is evidence of a new  lesion. ** Only for non-randomized trials with response as primary endpoint. *** In exceptional circumstances, unequivocal progression in non-target lesions  may be accepted as disease progression.   |
|---|  
| Target   | Non-Target                                                                                                                                                                                                                                                                                                                   | New     | Overall   | Best Overall Response when   |
|----------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|-----------|------------------------------|
| Lesions  | Lesions                                                                                                                                                                                                                                                                                                                      | Lesions | Response  | Confirmation is Required*    |
| Note:    | Patients with a global deterioration of health status requiring discontinuation of  treatment without objective evidence of disease progression at that time should  be reported as "symptomatic deterioration." Every effort should be made to  document the objective progression even after discontinuation of treatment. |         |           |                              |  
| Non-Target Lesions   | New Lesions   | Overall Response   |
|----------------------|---------------|--------------------|
| CR                   | No            | CR                 |
| Non-CR/non-PD        | No            | Non-CR/non-PD*     |
| Not all evaluated    | No            | not evaluated      |
| Unequivocal PD       | Yes or No     | PD                 |
| Any                  | Yes           | PD                 |  
* 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised 11.1.5 Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).  
The duration of overall CR is measured from the time measurement criteria are first met for CR
until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. 11.1.6 Progression-Free Survival PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
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12 study oversight and data

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7
(Adverse Events: List and Reporting Requirements).
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12.1 study oversight

This protocol is monitored at several levels, as described elsewhere in this section. The Protocol Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious adverse events; reporting of expedited adverse events; and accumulation of reported adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and statistician have access to the data at all times through the CTMS web-based reporting portal. For a Phase 1/2 trial, enrollment to the Phase 2 portion of the trial will not begin until a protocol amendment has been submitted which summarizes the Phase 1 results, the recommended Phase 2 dose, and the rationale for selecting it. The amendment must be reviewed and approved by CTEP before enrollment to the Phase 2 portion can begin. All Study Investigators at participating sites who register/enroll patients on a given protocol are responsible for timely submission of data via Medidata Rave and timely reporting of adverse events for that particular study. This includes timely review of data collected on the electronic CRFs submitted via Medidata Rave.. All studies are also reviewed in accordance with the enrolling institution's data safety monitoring plan.  
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in section 8.2.
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12.2 data reporting

Data collection for this study will be done exclusively through Medidata Rave. Access to the trial in Rave is granted through the iMedidata application to all persons with the appropriate roles assigned in the Regulatory Support System (RSS). To access Rave via iMedidata, the site user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA or Rave Investigator) on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an AP registration type. To hold the Rave Investigator role, the individual must be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave. Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Users that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU members' website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com.
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12.2.1 method

This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if approved by CTEP). Information on CTMS reporting is available at: http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On-site audits will be conducted on an 18-36 months basis as part of routine cancer center site visits. More frequent audits may be conducted if warranted by accrual or due to concerns regarding data quality or timely submission. For CTMS monitored studies, after users have activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 12.2.2 Responsibility for Data Submission Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it is greater than 4 weeks past due. Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as data is received. Queries will be issued by CTMS directly within Rave. The queries will appear on the Task Summary Tab within Rave for the CRA to resolve. Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI policies and procedures with the overarching goal of ensuring the integrity of data generated from NCIsponsored clinical trials, which may be found on the CTEP
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and CTSU websites. An End of Study CRF is to be completed by the PI, and is to include a summary of study endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended phase 2 dose (RP2D) and a description of any dose-limiting toxicities (DLTs). CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-andsemantics/metadata-and-models). Customized eCRFs will be included when appropriate to meet unique study requirements. The PI is encouraged to review the eCRFs, working closely with CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs prior to study activation. CTMS will prepare the eCRFs with built-in edit checks to the extent possible to promote data integrity. CDUS data submissions for trials activated after March 1, 2014, will be carried out by the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly basis. The trial's lead institution is responsible for timely submission to CTMS via Rave, as above. Further information on data submission procedures can be found in the ETCTN Program Guidelines (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm).
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what data will be shared?

I will share human data generated in this research for future research as follows:
- Coded, linked data in an NIH-funded or approved public repository.  
- Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
- Identified or coded, linked data with approved outside collaborators under appropriate agreements.
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how and where will the

Data will be shared through:
- An NIH-funded or approved public repository: clinicaltrials.gov.  
- BTRIS (automatic for activities in the Clinical Center)  
- Approved outside collaborators under appropriate individual agreements.  
- Publication and/or public presentations.  
When will the data be shared?
- Before publication. - At the time of publication or shortly thereafter.  
12.3.2 Genomic Data Sharing Plan Unlinked genomic data will be deposited in public genomic databases according to the plan described in protocol 10-C-0086 in compliance with the NIH Genomic Data Sharing Policy.
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13 statistical considerations 13.1 phase

The primary objective of the phase I component of this study is to determine the safe dose of dasatinib when given with ganitumab in patients with relapsed or refractory embryonal or alveolar RMS. This trial uses a limited dose-escalation design to establish the MTD, or highest safe dose of dasatinib. The starting dose level will be 60 mg/m2 once daily (maximum dose of 100 mg/dose once daily) on days -7 through day 27 during cycle 1 (35 days), and then days 0-27 for subsequent cycles (28 day cycles). This will be followed by one dose escalation to 60 mg/m2 BID (maximum dose of 70 mg/doseBID) on days -7 through day 27 during cycle 1, and then days 0-27 for subsequent cycles. The MTD is defined as the dose level immediately below the level at which ≥33% of patients in a cohort experience a DLT. The MTD will be defined based on toxicities observed during the first treatment cycle in order to capture toxicities during 28 days of administration of both agents. Any patient who receives one or more doses and experiences a DLT will be considered evaluable for definition of the MTD. If a patient did not experience DLT and did not finish treatment in cycle 1, he or she will only be evaluable for the dose escalation portion of the study if they received both ganitumab doses and ≥85% of the dasatinib doses in cycle 1. Patients who have not met these criteria will be replaced in the dose level. If ≥2 out of a maximum of 6 patients experience DLT at dose Level 1, the dose of dasatinib will be de-escalated to dose Level -1. If 0-1 out of a maximum of 6 patients have DLT at dose Level -1, this will be considered the MTD. If 2 or more out of a maximum of 6 patients experience DLT at dose Level -1, the accrual will be suspended pending discussions with the Sponsor and NIH Intramural IRB regarding how to proceed with the combination therapy. Dose escalation and de-escalation rules are specified in section **5.1.1**. Patients who receive dasatinib at the MTD (or highest safe dose) and ganitumab during the phase I portion of the study will be included in the evaluation of the phase II objectives. Toxicities related to the combination therapy will be analyzed and reported descriptively
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13.2 phase ii

The primary objective of the phase II component of the trial is to determine if the use of ganitumab plus dasatinib is able to be associated with a modest fraction of patients who experience an objective clinical response (CR or PR) by RECIST. In addition, a second primary objective will estimate the fraction that is without progression at 4 months and, secondarily, to be able to obtain an approximate estimate of the progression free survival (PFS) of the patients. The phase II component of the trial will be conducted using a single stage design with 16 evaluable patients. With this number, there would be 90% power to rule out a 5% fraction with a clinical response in favor of a 30% fraction with a clinical response, using a one sided 0.10 significance level exact test for a binomial proportion. In practice, the fraction of the 16 patients that have objective responses will be determined and reported along with 80% and 95%
confidence intervals. If there are 3 objective responses in 16 evaluable patients, the lower onesided exact 90% confidence interval is 7.1%, thus ruling out 5%.  
Because the staging evaluations for this trial will take place at approximately 8 week intervals and patients typically progress very rapidly, a Kaplan-Meier curve may potentially be somewhat imprecise with respect to its presentation of PFS, especially at early time points. Thus, the determination of progression or not at the 4-month evaluation will be the preferred co- primary endpoint for the trial rather than PFS. The information obtained on PFS as well as 4 month progression or not will be reported and considered for use in interpreting the results of this study and may be used to guide any subsequent evaluations. This study will also address a set of secondary and exploratory objectives. With the understanding of it limitations, in addition to determining the fraction that are without progression by 4 months, a Kaplan-Meier curve will be constructed as a secondary outcome to at least approximately illustrate the PFS as a function of time, recognizing the limited opportunities to assess the actual time of progression relative to an anticipated rapid progression time. Toxicities related to the combination therapy will be analyzed and reported descriptively by dose level, grade and attribution. In all patients, mechanisms of response and resistance will be assessed by analyzing archival tissue for expression of IGF-1R, insulin receptor, IGF-2 expression and phospho-YES expression, and through genomic sequencing (in patients participating in 10-C-0086). In patients for whom tumor biopsies can be obtained successfully, mechanisms of response and resistance will be assessed by analyzing biopsy tissue expression of IGF-1R, insulin receptor, IGF-2 expression and phospho-YES expression, and through genomic sequencing (in patients participating in 10-C-0086).
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13.3 sample size/accrual rate

The phase I portion of the study may enroll up to 12 subjects to establish MTD or highest safe dose. Sixteen evaluable patients are required to evaluate the objectives in the phase II component. Up to 6 patients from the phase I component who receive study drugs at the MTD or highest safe dose will be included in the analysis of the 16 patients in the phase II component. Therefore, the maximum patient accrual, allowing for replacement of inevaluable patients (up to 4) as well as to account for screen failures (up to 14), is expected to be 12 + 10 + 4+14, for a total enrollment of 40 patients. It is anticipated that approximately 10-15 patients per year may be accrued onto this trial. Thus, 2 to 3 years is expected to completed accrual. If the actual accrual is slower, we would consider opening the trial at additional sites to improve the accrual rate.
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14 collaborative agreements 14.1 ctep

The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the "Intellectual Property Option to Collaborator" (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of award, apply to the use of the Agent(s) in this study: 1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient's family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 2. For a clinical protocol where there is an investigational Agent used in combination with (an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"): a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NCI, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol. b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own Agent. c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own Agent. 3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order as described in the IP Option to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the *Standards for Privacy of Individually Identifiable Health* Information set forth in 45 C.F.R. Part 164. 4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them. 5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial. 6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group office for Cooperative Group studies or by the principal investigator f or non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: Email: ncicteppubs@mail.nih.gov The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/ proprietary information.
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14.2 multi-institutional guidelines 14.2.1 irb

The PI will provide the NIH Intramural IRB with a copy of the participating institution's approved yearly continuing review. Registration will be halted at any participating institution in which a current continuing approval is not on file at the NIH Intramural IRB. 14.2.2 Amendments and Consents The CCR PI will provide the NIH Intramural IRB with copies of all amendments, consents and approvals from each participating institution.
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15 human subjects protections 15.1

Subjects of both genders and from all racial and ethnic groups are eligible for this trial if they meet the eligibility criteria outlined in section 3.1. No groups are being excluded from participation in the trial. Efforts will be made to extend the accrual to a representative population, but in a small pilot trial which will accrue a maximum of 16 patients, a balance must be struck between the need to evaluate safety and efficacy, and the need to explore gender, racial, and ethnic aspects of clinical research. If differences in outcome that correlate to gender, racial, or ethnic identity are noted, accrual may be expanded or additional studies may be performed to investigate those differences more fully. Projected accrual table:  
| DOMESTIC PLANNED ENROLLMENT REPORT Ethnic Categories   |                        |                    |       |
|--------------------------------------------------------|------------------------|--------------------|-------|
| Racial                                                 |                        |                    |       |
| Categories                                             | Not Hispanic or Latino | Hispanic or Latino | Total |
| Female                                                 | Male                   | Female             | Male  |  
| DOMESTIC PLANNED ENROLLMENT REPORT           |    |    |    |    |    |
|----------------------------------------------|----|----|----|----|----|
| American  Indian/ Alaska  Native             | 0  | 1  | 1  |    |    |
| Asian                                        | 1  | 2  | 3  |    |    |
| Native  Hawaiian or  Other Pacific  Islander | 0  | 0  | 0  |    |    |
| Black or  African  American                  | 4  | 6  | 10 |    |    |
| White                                        | 8  | 13 | 2  | 3  | 26 |
| More Than One                                | 0  | 0  | 0  | 0  | 0  |
| Race Total                                   | 13 | 22 | 2  | 3  | 40 |
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15.2 participation of children

There is no limit to the age of participants in this trial. Children who meet eligibility criteria for this trial will be offered entry in the study. Children will be evaluated and cared for by physicians trained in pediatrics and pediatric oncology, and will be followed in a Pediatric Oncology clinic. The clinical and research staff in the Pediatric Oncology Branch and CHLA have extensive experience caring for patients of younger ages in administering complex research therapies.
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15.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However,re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **15.4**), all subjects enrolled at NIH who are ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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15.4 evaluation of benefits and

The primary risk to patients, including adults who may lose their ability to consent, participating in this research study is from toxicities related to the investigational agents (ganitumab and dasatinib) as described in the protocol, section 7. The primary objective of this study is to determine if the use of ganitumab plus dasatinib is able to be associated with a modest fraction of patients who experience an objective clinical response (CR and PR) as defined by RECIST criteria. In addition, a second primary objective will estimate the fraction that is without progression at 4 months. Patients will thus be treated with therapeutic intent and response to the therapy will be closely monitored. Treatment options for these patients are very limited, as most patients will have received all prior effective therapies. The potential benefits from this therapy are disease stabilization, tumor shrinkage, and a reduction in symptoms caused by rhabdomyosarcoma. Therefore, this protocol involves greater than minimal risk to the patients entered, but presents the potential for direct benefit to individual subjects.  
Pediatric patients: This trial will be open to children under 18 years of age. Given the potential for clinical benefit, participation of children in this study meets 45 CFR 46.405- Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual child subjects involved in the research.
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15.5 consent and assent process

The investigational nature and research objectives of this trial, the procedures and treatments involved and their attendant risks and discomforts and benefits, and potential alternative therapies will be carefully explained to the patient or the patient's parents or guardian if he/she is a child, and a signed informed consent document will be obtained prior to entry onto the study. The PI or an associate investigator on the trial at each site will obtain consent. The PI or associate investigator will meet with the patient, or the patient's parents or guardian, and other family members to discuss the protocol treatment and alternative options in detail. It will be stated clearly that participation in the research study is voluntary and that participants can withdraw from the study without losing benefits they would otherwise be entitled to. The patient and family members will be encouraged to ask questions, and additional meetings to discuss the treatment options will be arranged as necessary. The investigators are requesting a waiver from the IRB to allow only one parent to sign the informed consent to enter a child on the protocol. Because many patients must travel to the NIH or CHLA from long distances at substantial expense, requiring both parents to be present for the consent process could be a financial hardship for many families. When guardianship status of the child is uncertain, documentation of custody status must be obtained.  
In situations where there is joint custody of a child, both parents must sign consent. If only one parent can be present at NIH or CHLA, the other parent's consent can be obtained by telephone via the procedure described in section **15.5.2**.  
Where deemed appropriate by the clinician and the child's parent(s) or guardian, the child will also be included in all discussions about the trial and age-appropriate language will be used to describe the procedures and tests involved in this study, along with the risks, discomforts and benefits of participation. Written assent will not be obtained from children as the study holds out the prospect of direct benefit that is important to the health and well-being of the child and is available only in the context of the research. Verbal assent will be obtained as appropriate for children ages > 7. The child will sign the appropriate line in the consent document to attest to assent. Children under the age of 7 will not be required to provide assent as they typically do not have the cognitive ability to fully understand the nature of research. The consent/assent process will be documented in the child's medical record, including the assessment of the child's ability to provide assent (verbal versus written) as applicable. All children will be contacted after they have reached the age of 18 to determine whether they wish to continue on the trial and informed consent will be obtained from them at that time.  
15.5.1 Consent for minors when they reach the age of majority When a pediatric subject reaches age 18, continued participation (including ongoing interactions with the subject or continued analysis of identifiable data) will require consenting of the now adult with the standard protocol consent document to ensure legally effective informed consent has been obtained. We request waiver of informed consent for those individuals who become lost to follow up after all efforts to reach the subject have failed. We also request waiver of informed cosent for individuals who have been taken off study prior to reaching the age of majority. Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d):
(1) The research involves no more than minimal risk to the subjects.  
a. Analysis of samples and data from this study involves no additional risks to subjects.  
(2) The waiver or alteration will not adversely affect the rights and welfare of the subjects.
a. Retention of these samples or data does not affect the welfare of subjects.  
(3) The research could not practicably be carried out without the waiver or alteration.  
a. Considering the length of time between the minor's last contact with the research team and their age of majority, it will likely be very difficult to locate them again. A significant reduction in the number of samples analyzed is likely to impact the quality of the research.
(4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation.  
a. We only request a waiver of consent for those subjects who have been lost to follow-up or who have been taken off study prior to reaching the age of majority.
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15.5.2 telephone consent

This procedure may be used for initial consent in the event that both parental signatures are required as referenced above. This procedure may also be used for re-consent in the event that a patient needs to re-consent because of changes to the consent document. The informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented in the medical record.
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16 pharmaceutical information 16.1 dasatinib

Other names: BMS-354825, Sprycel® 16.1.1 Chemical Name: N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2 methyl-4pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate 16.1.2 Mechanism of Action: Dasatinib is a potent, broad spectrum ATP-competitive inhibitor of 5 critical oncogenic tyrosine kinase families: BCR-ABL, SRC family kinases, c-KIT, ephrin (EP) receptor kinases, and PDGFβ receptor. Overexpression or activation of these kinases plays critical roles in the etiology of various cancer types. 16.1.3 Molecular Formula:
C22H26CIN7O2S· H20 **MW:** Dasatinib monohydrate: 506.02 daltons 16.1.4 Approximate Solubility: Dasatinib's solubility ranged from 18.42 mg/mL at pH 2.6 to < 0.001 mg/mL at pH 7. 16.1.5 How Supplied: BMS supplies and CTEP, NCI, DCTD distributes dasatinib. Dasatinib is available in the following tablet/bottle sizes:
- 5 mg round, plain white film-coated tablets.  
- 20 mg biconvex round, white to off-white film-coated tablets. The tablet is debossed with "20" on one side and "527" on the other side.  
- 50 mg biconvex oval, white to off-white film-coated tablets. The tablet is debossed with
"50" on one side and "528" on the other side.
Inactive ingredients include lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate. The film-coating contains hypromellulose, titanium dioxide, glycerol triacetate (in the 5 mg), and polyethylene glycol (in the 20 mg tablets and 50 mg tablets).  
Tablets are supplied in high-density polyethylene (HDPE) bottles with desiccant and cotton. The bottles are heat-induction sealed with child-resistant caps. 16.1.6 Storage: Store the intact bottles at controlled room temperature (15°C-25°C) and protect from light. 16.1.7 Stability: Stability studies are ongoing. 16.1.8 Route of Administration:
Oral. Tablets may be taken with or without food. They should be swallowed whole and not crushed or broken. 16.1.9 Potential Drug Interactions Dasatinib is primarily metabolized by the human CYP3A4 enzyme; therefore, potent CYP3A4 inducers and inhibitors are prohibited on dasatinib trials. Concomitant use of dasatinib and a CYP3A4 substrate may increase exposure to the CYP3A4 substrate. Therefore, caution is warranted when dasatinib is co-administered with CYP3A4 substrates of narrow therapeutic index.  
Systemic antacids (both H2 receptor antagonists and proton pump inhibitors) are prohibited on dasatinib trials. Locally acting antacids can be given up to two hours prior or two hours following dasatinib administration. Dasatinib may prolong the QT/QTc interval. Use caution when administering dasatinib with other potential QTc-prolonging medications. Due to the possibility of CNS, gastrointestinal, cardiac, and cutaneous hemorrhage, use caution in patients who require medications that inhibit platelet function or anticoagulants.  
16.1.10Special Handling: Dasatinib tablets consist of a core tablet (containing the active drug) surrounded by a film coating to prevent exposure to the active drug substance. If tablets are accidentally crushed or broken, caregivers should wear disposable chemotherapy gloves. Pregnant women should avoid exposure to crushed and/or broken tablets.
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16.2 ganitumab (ind# 120449nsc# 750008)

16.2.1 Other Names: AMG 479 16.2.2 Classification: Monoclonal antibody 16.2.3 M.W.: 146 kilodaltons (kD)
16.2.4 Mode of Action:
Ganitumab exerts its anti-tumor activity by blocking ligand binding (IGF-1 and IGF-2) and inducing receptor internalization and degradation without cross-reacting with the insulin receptor. 16.2.5 Description: Fully human recombinant IgG1 monoclonal antibody targeting IGF-1R 16.2.6 How Supplied: Ganitumab will be supplied by NantBio and distributed by the PMB, CTEP, NCI as a sterile, clear, colorless liquid with 70 mg/mL (210 mg/3 mL or 700 mg/10 mL) vial of ganitumab. The single-use vials also contain the following excipients; 10 mM sodium acetate, 5% w/v sorbitol, 0.004% w/v polysorbate 20, pH 5.2. *Once the 700 mg vial size is available, the 210 mg vial size* will no longer be available for this trial. 16.2.7 Preparation: The prescribed dose of ganitumab should be further diluted in 0.9% sodium chloride to a concentration between 3 mg/mL and 20 mg/mL. 16.2.8 Storage: Store at 2°C to 8°C. Do not shake or freeze. Protect from light. 16.2.9 Stability Once the ganitumab is injected into the infusion bag, the infusion must be completed within 8 hours. The total time between removal of ganitumab intact vials from the refrigerator and completion of infusion must not exceed 24 hours. Vials contain no preservatives and any solution remaining in the vials after the dose is prepared should be discarded. 16.2.10 Route(s) of Administration Intravenous infusion. 16.2.11 Method of Administration The infusion line should be thoroughly flushed with saline before and after administration of ganitumab to avoid mixing with other drug products or IV solutions. The first dose should be administered over 60 ± 10 minutes without premedication. If well tolerated, subsequent infusions may be administered over 30 minutes, at the investigator's discretion. Infusion times can be extended to a maximum of 120 minutes for subjects unable to tolerate the 60 minute infusion. Doses over 2100 mg should be infused over 120 minutes.
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16.3 agent ordering and agent

NCI-supplied agents may be requested by the Principal Investigator (or their authorized designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of agents between institutions (unless prior approval from PMB is obtained). The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The responsible investigator at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEPsupplied investigational agents for the study should be ordered under the name of one lead investigator at that institution. In general, sites may order initial agent supplies when a subject is being screened for enrollment onto the study. Active CTEP-registered investigators and investigator-designated shipping designees and ordering designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status and a "current" password. For questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the PMB's website for specific policies and guidelines related to agent management. 16.3.2 Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol. 16.3.3 Investigator Brochure Availability The current versions of the IBs for the agents will be accessible to site investigators and research staff through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status and a "current" password. Questions about IB access may be directed to the PMB IB coordinator via email.  
16.3.4 Useful Links and Contacts
- CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
- NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov - PMB policies and guidelines:
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
- PMB Online Agent Order Processing (OAOP) application: https://eappsctep.nci.nih.gov/OAOP/pages/login.jspx
- CTEP Identity and Access Management (IAM) account: https://eappsctep.nci.nih.gov/iam/
- CTEP Associate Registration and IAM account help:
ctepreghelp@ctep.nci.nih.gov
- PMB email: PMBAfterHours@mail.nih.gov
- IB Coordinator: IBCoordinator@mail.nih.gov
- PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET)
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17 references

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28. Bagatell R, Herzog CE, Trippett TM, et al. Pharmacokinetically Guided Phase 1 Trial of the IGF-1 Receptor Antagonist RG1507 in Children with Recurrent or Refractory Solid Tumors. Clin Cancer Research. 2011;17(3):611-9. 29. Tolcher AW, Rothenberg ML, Rodon J, et al. A phase I pharmacokinetic and pharmacodynamic study of AMG 479, a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R), in advanced solid tumors. J Clin Oncol 2007;25(18S):Abstr. 3002. 30. Hunter T. Oncoprotein networks. Cell. 1997;88(3):333-46. 31. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6- (4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47(27):6658-61. 32. Investigator's Brochure. Dasatinib. BMS-354825. Bristol-Myers Squibb.Version No: 10. Version Date: November 2010. 33. Demetri GD, Lo Russo P, MacPherson IR, et al. Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res. 2009;15(19):6232-40. 34. Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 2006;66(1):473-81. 35. Li S, Hu Y, Swerdlow SJ, et al. Simultaneous targeting of SRC and BCR-ABL kinases by BMS-354825 cures Ph+ acute lymphoblastic leukemia in mice. Blood. 2004;104(11):Abstr. 1976. 36. Wu JY, Donato NJ, Hong DS, et al. The SRC/ABL kinase inhibitor BMS-354825 induces apoptosis and overcomes imatinib resistance in chronic myelogenous leukemia cell lines and patient specimens. Proc Am Assoc Can Res. 2004;45:Abstr. 3850.  
37. Hochhaus A, Hughes T. Clinical resistance to imatinib: mechanisms and implications.  
Hematol Oncol Clin North Am. 2004;18(3):641-56, ix. 38. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-41. 39. Shah NP. Loss of response to imatinib: mechanisms and management. Hematology Am Soc Hematol Educ Program. 2005:183-7. 40. Donato NJ, Wu J, Kong LY, et al. The SRC/ABL inhibitor BMS-354825 overcomes resistance to imatinib mesylate in chronic myelogenous leukemia cells through multiple mechanisms. Blood. 2004;104(11):Abstr. 1989. 41. Shah NP, Tran C, Lee FY, et al. BMS-354825 is a novel orally bioavailable small molecule ABL tyrosine kinase inhibitor that successfully and safely inhibits the kinase activity of  
multiple imatinib-resistant BCR-ABL isoforms in vitro and in vivo. Proc Am Assoc Can Res. 2004;45:Abstr. 5624. 42. Lee FY, Lombardo L, Borzilleri R, et al. BMS-354825 - A potent dual SRC/ABL kinase inhibitor possessing curative efficacy against imatinib sensitive and resistant human CML models in vivo. Proc Am Assoc Cancer Res. 2004;45:Abstr. 3987.  
43. Tokarski JS, Newitt J, Lee FY, et al. The crystal structure of Abl kinase with BMS354825, a dual SRC/ABL kinase inhibitor. Blood. 2004;104(11):Abstr. 553.  
44. Shah NP, Lee FY, Luo R, et al. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood. 2006;108(1):286-91. 45. Johnson FM, Saigal B, Talpaz M, et al. Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 2005;11(19 Pt 1):6924-32. 46. Luo FR, Yang Z, Camuso A, et al. Pharmacodynamic biomarker. Proc Am Assoc Cancer Res. 2005;46:Abstr. 4183. 47. Franceschi E, Stupp R, van den Bent MJ, et al. EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma. Neuro Oncol. 2012;14(12):1503-10. 48. Hong DS, Choe JH, Naing A, et al. A phase 1 study of gemcitabine combined with dasatinib in patients with advanced solid tumors. Invest New Drugs. 2013;31(4):918-26. 49. Sawyers CL, Shah NP, Kantarjian HM, et al. A phase I study of BMS-354825 in patients with imatinib-resistant and intolerant accelerated and blast phase chronic myeloid leukemia (CML): Results from CA180002. Journal of Clinical Oncology. 2005;23(16S):Abstr. 6520. 50. Investigator's Brochure. Ganitumab. AMG 479. Amgen Inc. Version No: 9. Version Date: November 2013.  
51. Vassal G, Couanet D, Stockdale E, et al. Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol. 2007;25(4):356-61. 52. Tolcher AW, Sarantopoulos J, Patnaik A, et al. Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. J Clin Oncol. 2009;27(34):5800-7.  
53. Tap WD, Demetri G, Barnette P, et al. Phase II study of ganitumab, a fully human antitype-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol. 2012;30(15):1849-56. 54. Rosen LS, Puzanov I, Friberg G, et al. Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors. Clin Cancer Res. 2012;18(12):3414-27.  
55. Kindler HL, Richards DA, Garbo LE, et al. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol. 2012;23(11):2834-42.  
56. Fuchs CS, Azevedo S, Okusaka T, et al. A phase 3 randomized, double-blind, placebocontrolled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015;26(5):921-7. 57. Tabernero J, Chawla SP, Kindler H, et al. Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab. Target Oncol. 2015;10(1):65-76. 58. Kindler HL, Richards DA, Stephenson J, et al. A placebo-controlled, randomized phase II study of conatumumab or AMG 479 or placebo plus gemcitabine in patients wiht metastatic pancreatic cancer. J Clin Oncol 2010;28(15s):Abstr. 4035. 59. Malempati S, Weigel B, Ingle AM, et al. Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012;30(3):256-62. 60. Higano CS, Yu EY, Whiting SH, et al. A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol 2007;25(18s):Abstr. 3505. 61. Frappaz D, McGregor LM, Pearson ADJ, et al. A phase I study of the anti-insulin like growth factor type 1 receptor (IGF-1R) antibody dalotuzumab in pediatric patients with advanced solid tumors. J Clin Oncol. 2013;31:Abstr. 10026. 62. Beltran PJ, Chung YA, Moody G, et al. Efficacy of ganitumab (AMG 479), alone and in combination with rapamycin, in Ewing's and osteogenic sarcoma models. J Pharmacol Exp Ther. 2011;337(3):644-54. 63. Beaty O, 3rd, Berg S, Blaney S, et al. A phase II trial and pharmacokinetic study of oxaliplatin in children with refractory solid tumors: a Children's Oncology Group study. Pediatr Blood Cancer. 2010;55(3):440-5.  
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18 appendices 18.1 appendix 1performance

| PERFORMANCE STATUS CRITERIA Karnofsky and Lansky performance scores are intended to be multiples of 10 Karnofsky (> 16 years of age) Lansky (≤16 years of age)   | ECOG                                                                        |                                                                                                                                                                                           |                                                                                                                                                               |                                     |                                                                                                    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|----------------------------------------------------------------------------------------------------|
| Score                                                                                                                                                            | Description                                                                 | Score                                                                                                                                                                                     | Description                                                                                                                                                   |                                     |                                                                                                    |
| 100                                                                                                                                                              | Normal, no complaints, no evidence of disease                               | 100                                                                                                                                                                                       | Fully active, normal.                                                                                                                                         | 0                                   | Normal activity. Fully active, able to  carry on all pre-disease performance  without restriction. |
| 90                                                                                                                                                               | Able to carry on normal activity, minor signs                               | 90                                                                                                                                                                                        | Minor restrictions in physically strenuous                                                                                                                    |                                     |                                                                                                    |
| or symptoms of disease.                                                                                                                                          | activity.                                                                   |                                                                                                                                                                                           |                                                                                                                                                               |                                     |                                                                                                    |
| 80                                                                                                                                                               | Normal activity with effort; some signs or                                  | 80                                                                                                                                                                                        | Active, but tires more quickly                                                                                                                                |                                     |                                                                                                    |
| symptoms of disease.                                                                                                                                             | 1                                                                           | Symptoms, but ambulatory. Restricted  in physically strenuous activity, but  ambulatory and able to carry out work  of a light or sedentary nature (e.g., light  housework, office work). |                                                                                                                                                               |                                     |                                                                                                    |
| 70                                                                                                                                                               | Cares for self, unable to carry on normal                                   | 70                                                                                                                                                                                        | Both greater restriction of and less time                                                                                                                     |                                     |                                                                                                    |
| activity or do active work.                                                                                                                                      | spent in play activity.                                                     |                                                                                                                                                                                           |                                                                                                                                                               |                                     |                                                                                                    |
| 60                                                                                                                                                               | Required occasional assistance, but is able to                              | 60                                                                                                                                                                                        | Up and around, but minimal active play;                                                                                                                       |                                     |                                                                                                    |
| care for most of his/her needs.                                                                                                                                  | keeps busy with quieter activities.                                         | 2                                                                                                                                                                                         | In bed <50% of the time. Ambulatory  and capable of all self-care, but unable  to carry out any work activities. Up  and about more than 50% of waking  hours |                                     |                                                                                                    |
| 50                                                                                                                                                               | Requires considerable assistance and frequent                               | 50                                                                                                                                                                                        | Gets dressed, but lies around much of the                                                                                                                     |                                     |                                                                                                    |
| medical care.                                                                                                                                                    | day; no active play, able to participate in all  quiet play and activities. |                                                                                                                                                                                           |                                                                                                                                                               |                                     |                                                                                                    |
| 40                                                                                                                                                               | Disabled, requires special care and assistance.                             | 40                                                                                                                                                                                        | Mostly in bed; participates in quiet                                                                                                                          | In bed >50% of the time. Capable of |                                                                                                    |
| activities.                                                                                                                                                      | 3                                                                           | only limited self-care, confined to bed  or chair more than 50% of waking  hours.                                                                                                         |                                                                                                                                                               |                                     |                                                                                                    |
| 30                                                                                                                                                               | Severely disabled, hospitalization indicated.                               | 30                                                                                                                                                                                        | In bed; needs assistance even for quiet play.                                                                                                                 |                                     |                                                                                                    |
| Death not imminent.                                                                                                                                              |                                                                             |                                                                                                                                                                                           |                                                                                                                                                               |                                     |                                                                                                    |
| 20                                                                                                                                                               | Very sick, hospitalization indicated. Death not                             | 20                                                                                                                                                                                        | Often sleeping; play entirely limited to very                                                                                                                 |                                     |                                                                                                    |
| imminent.                                                                                                                                                        | passive activities.                                                         | 4                                                                                                                                                                                         | 100% bedridden. Completely disabled.  Cannot carry on any self-care. Totally  confined to bed or chair.                                                       |                                     |                                                                                                    |
| 10                                                                                                                                                               | Moribund, fatal processes progressing rapidly.                              | 10                                                                                                                                                                                        | No play; does not get out of bed.                                                                                                                             |                                     |                                                                                                    |  
18.2 APPENDIX 2:SUBSTANCES PROHIBITED DURING DASATINIB TREATMENT
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cyp3a4 inhibitors

➢ itraconazole, ketoconazole, miconazole, voriconazole ➢ amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir ➢ ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, isoniazid, ketamine nefazodone, nicardipine, propofol, quinidine, telithromycin
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cyp3a4 inducers

➢ aminoglutethimide, primidone, rifabutin, rifampin, St. John's wort ➢ carbamazepine, nevirapine, oxcarbazepine, rifapentine ➢ fosphenytoin, pentobarbital, phenobarbital, phenytoin
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agents with proarrhythmic potential

➢ quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide
➢ erythromycins, clarithromycin ➢ chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide ➢ cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine Because the lists of these agents are constantly changing, your prescribers should consult a frequently-updated list or medical reference text such as the Physician's Desk Reference to see if any medicine they want to prescribe is on a list of drugs to avoid. 18.3 APPENDIX 3:INFORMATION ON POSSIBLE DRUG I**NTERACTIONS** Information on Possible Interactions with Other Agents for Patients and Their Caregivers and Non-Study Healthcare Team The patient ____________________________ is enrolled on a clinical trial using the experimental agent **dasatinib and ganitumab**. This clinical trial is sponsored by the National Cancer Institute. This form is addressed to the patient, but includes important information for others who care for this patient.  
Dasatinib interacts with many drugs that are processed by your liver. Because of this, it is very important to tell your study doctors about all of your medicine before you start this study. It is also very important to tell them if you stop taking any regular medicine, or if you start taking a new medicine while you take part in this study. When you talk about your medicine with your study doctor, include medicine you buy without a prescription at the drug store (over-the-counter remedy), or herbal supplements such as St. John's wort. Many health care prescribers can write prescriptions. You must also tell your other prescribers (doctors, physicians' assistants or nurse practitioners) that you are taking part in a clinical trial.  
Bring this paper with you and keep the attached information card in your wallet. These are the things that you and they need to know:
Dasatinib interacts with (a) certain specific enzyme(s) in your liver.  
- The enzyme(s) in question is/are *CYP3A4 Inhibitor* (because it may increase your blood level of dasatinib) and *CYP3A4 Inducer* (because dasatinib is broken down by this enzyme in order to be cleared from your body)
- **Dasatinib** must be used very carefully with other medicines that need these liver enzymes to be effective or to be cleared from your system.  
- Other medicines may also affect the activity of the enzyme.  
o Substances that increase the enzyme's activity ("inducers") could reduce the effectiveness of the drug, while substances that decrease the enzyme's activity
("inhibitors") could result in high levels of the active drug, increasing the chance of harmful side effects.  
o Dasatinib may affect the heart's electrical activity (QTc prolongation). o Use caution when administering dasatinib with other potential QTc-prolonging medications.  
o Because antacids (H2 inhibitors, proton pump inhibitors) decrease your ability to absorb dasatinib, antacids should be limited to short-acting, locally-active agents (e.g., Maalox®, Mylanta® etc.). However, these agents should not be taken within either 2 hours before or 2 hours after the dasatinib dose.  
o Substances that effect platelet function should be avoided such as aspirin, nonsteroidal anti-inflammatory drugs (like motrin, ibuprofen), some antibiotics, some cardiovascular and lipid-lowering drugs, some antidepressants. It is important that you discuss any new drugs (prescription or over the counter) with your doctor before starting.  
- You and healthcare providers who prescribe drugs for you must be careful about adding or removing any drug in this category.  
- Before you start the study, your study doctor will work with your regular prescriber to switch any medicines that are considered CYP3A4 Inhibitor or *CYP3A4 Inducer.* Examples of these medicines are listed on the next page.  
- Because the lists of these agents are constantly changing, your prescribers should consult a frequently-updated list or medical reference text such as the Physician's Desk Reference to see if any medicine they want to prescribe is on a list of drugs to avoid.  
- Please be very careful! Over-the-counter drugs have a brand name on the label—it's usually big and catches your eye. They also have a generic name—it's usually small and located above or below the brand name, and printed in the ingredient list. Find the generic name and determine, with the pharmacist's help, whether there could be an adverse interaction.  
- Be careful:
o If you take acetaminophen regularly: You should not take more than 3.25 grams a day if you are an adult. Read labels carefully! Acetaminophen is an ingredient in many medicines for pain, flu, and cold.  
o If you drink grapefruit juice or eat grapefruit: Avoid these until the study is over.  
o If you take herbal medicine regularly: You should not take St. John's wort while you are taking **Dasatinib**.  
Other medicines can be a problem with your study drugs.  
- You should check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplement.  
- Your regular prescriber should check a medical reference or call your study doctor before prescribing any new medicine for you. Your study doctor's name is _____________________________________ and he or she can be contacted at_____________________________
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cyp3a4 inhibitors

➢ itraconazole, ketoconazole, miconazole, voriconazole  
➢ amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir
_____________________________________.  
➢ ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, isoniazid, ketamine nefazodone, nicardipine, propofol, quinidine, telithromycin
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cyp3a4 inducers

➢ aminoglutethimide, primidone, rifabutin, rifampin, St. John's wort  
➢ carbamazepine, nevirapine, oxcarbazepine, rifapentine ➢ fosphenytoin, pentobarbital, phenobarbital, phenytoin
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agents with proarrhythmic potential

➢ quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide ➢ erythromycins, clarithromycin  
➢ chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide ➢ cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine
18.4 APPENDIX 4:DOSING NOMOGRAM FOR DASATINIB FOR PHASE I/IITRIAL OF R**HABDOMYOSARCOMA**  
| Dose level 2 (60  mg/m2 /do se BID)   | BSA*                            | 0.5- 0.54   | 0.55- 0.62   | 0.63- 0.71   | 0.72- 0.79   | 0.8- 0.87   | 0.88- 0.96   | 0.97- 1.04   | 1.05- 1.12   | ≥1.13      |            |           |            |            |            |       |       |       |
|---------------------------------------|---------------------------------|-------------|--------------|--------------|--------------|-------------|--------------|--------------|--------------|------------|------------|-----------|------------|------------|------------|-------|-------|-------|
| Dose†                                 | 30                              | 35          | 40           | 45           | 50           | 55          | 60           | 65           | 70           |            |            |           |            |            |            |       |       |       |
| 1 (60                                 |                                 |             |              |              |              |             |              |              |              |            |            |           |            |            |            |       |       |       |
| mg/m2 /dos e once  daily)             | BSA*                            | 0.5- 0.54   | 0.55- 0.62   | 0.63- 0.71   | 0.72- 0.79   | 0.8- 0.87   | 0.88- 0.96   | 0.97- 1.04   | 1.05- 1.12   | 1.13- 1.21 | 1.22-      | 1.3-      |            |            |            |       |       |       |
| 1.29                                  | 1.37                            | 1.38-       | 1.47-        |              |              |             |              |              |              |            |            |           |            |            |            |       |       |       |
| 1.46                                  | 1.54                            | 1.55- 1.62  | ≥1.63        |              |              |             |              |              |              |            |            |           |            |            |            |       |       |       |
| Dose†                                 | 30                              | 35          | 40           | 45           | 50           | 55          | 60           | 65           | 70           | 75         | 80         | 85        | 90         | 95         | 100        |       |       |       |
| -1 (40                                |                                 |             |              |              |              |             |              |              |              |            |            |           |            |            |            |       |       |       |
| mg/m2 /do se once  daily)             | BSA*                            | 0.5- 0.56   | 0.57- 0.69   | 0.70- 0.81   | 0.8- 0.94    | 0.95- 1.06  | 1.07- 1.19   | 1.2- 1.31    | 1.3- 1.44    | 1.45- 1.56 | 1.57- 1.69 | 1.7- 1.81 | 1.82- 1.94 | 1.95- 2.06 | 2.07- 2.18 | 2.19- | 2.32- | ≥2.45 |
| 2.31                                  | 2.44                            |             |              |              |              |             |              |              |              |            |            |           |            |            |            |       |       |       |
| Dose†                                 | 20                              | 25          | 30           | 35           | 40           | 45          | 50           | 55           | 60           | 65         | 70         | 75        | 80         | 85         | 90         | 95    | 100   |       |
| -                                     | *BSA, body surface area in m2 . |             |              |              |              |             |              |              |              |            |            |           |            |            |            |       |       |       |  
- *BSA, body surface area in m2.  
•†Actual dose in mg (tablet sizes 5 mg, 20 mg, and 50 mg).  
The dosing nomogram will not be used to make dose reductions for toxicity due to overlap in dose levels for certain BSA. Section 6 describes dose reductions for toxicity.  
18.5 APPENDIX 5:PATIENT'S MEDICATION DIARY– DASATINIB-C**YCLE** 1
(For once per day dosing)
Today's date __________________________________ **Agent** _____Dasatinib _
Patient Name_____________________ (*initials acceptable)* **Patient Study ID**____________
INSTRUCTIONS TO THE PATIENT: **CYCLE** 1 1. Complete one form for each 5 week-period while you take **dasatinib**. 2. You will take your dose of **dasatinib** daily (unless instructed otherwise due to dose reduction). You will take ____5mg tablets, ____20 mg tablets, and ____ 50 mg tablets. You may take the tablets with or without food as you wish.  
3. Record the date, the number of tablets of each size you took, and when you took them.  
4. If you have any comments or notice any side effects, please record them in the Comments column.  
5. Please return this form to your physician when you go for your next appointment.  
| 3.                                                | Record the date, the number of tablets of each size you took, and when you took them.                                                   |      |
|---------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|------|
| 4.                                                | If you have any comments or notice any side effects, please record them in the Comments column.                                         |      |
| 5.                                                | Please return this form to your physician when you go for your next appointment. # of tablets taken 5 mg 20  50  Comments mg mg Time of |      |
| Day                                               | Date                                                                                                                                    | dose |
| -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 |                                                                                                                                         |      |  
| # of tablets taken                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Comments   |               |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|---------------|
| 5 mg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 20         | 50            |
| mg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | mg         |               |
| Day                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Date       | Time of  dose |
| 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27                                                                                                                                                                                                                                                                                                                                                                                                                                              |            |               |
| POB will complete this section: 1. Date patient started protocol treatment________________________________________________ 2. Date patient was removed from study_________________________________________________ 3. Patient's planned total daily dose_____________________________________________________ 4. Total number of tablets taken this month (each size)______________________________________ 5. Reviewing Physician/Nurse's Signature ____________________________________ |            |               |  
| Patient / Parent Signature:                                                                                  | Date:   |
|--------------------------------------------------------------------------------------------------------------|---------|
| Number of Tablets Returned: ___5 mg tablets, ____20 mg tablets, ____ 50 mg tablets. RN / MD Signature: Date: |         |  
18.6 APPENDIX 6:PATIENT'S MEDICATION DIARY– DASATINIB-SUBSEQUENT CYCLES
(For once per day dosing) **for Cycle \# ______**
Today's date __________________________________ **Agent** _____**Dasatinib _**
Patient Name_____________________ (*initials acceptable)* **Patient Study ID**____________
INSTRUCTIONS TO THE PATIENT: CYCLE **____**
1. Complete one form for each 4 week-period while you take **dasatinib**. 2. You will take your dose of **dasatinib** daily (unless instructed otherwise due to dose reduction). You will take ____5mg tablets, ____20 mg tablets, and ____ 50 mg tablets. You may take the tablets with or without food as you wish.  
3. Record the date, the number of tablets of each size you took, and when you took them. 4. If you have any comments or notice any side effects, please record them in the Comments column. 5. Please return this form to your physician when you go for your next appointment.  
| 4.                                             | If you have any comments or notice any side effects, please record them in the Comments column.                                         |      |
|------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|------|
| 5.                                             | Please return this form to your physician when you go for your next appointment. # of tablets taken Comments 5 mg 20  50  mg mg Time of |      |
| Day                                            | Date                                                                                                                                    | dose |
| 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 |                                                                                                                                         |      |  
| 19 20 21                                                                                                                                                                                                                                                                                                                                                                                                                                              | # of tablets taken   |               |          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|---------------|----------|
| Day                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Date                 | Time of  dose | Comments |
| 5 mg                                                                                                                                                                                                                                                                                                                                                                                                                                                  | 20                   | 50            |          |
| mg                                                                                                                                                                                                                                                                                                                                                                                                                                                    | mg                   |               |          |
| 22 23 24 25 26 27                                                                                                                                                                                                                                                                                                                                                                                                                                     |                      |               |          |
| POB will complete this section: 1. Date patient started protocol treatment_______________________________________ 2. Date patient was removed from study_________________________________________ 3. Patient's planned total daily dose______________________________________________ 4. Total number oftablets taken this month (each size)___________________________ 5. Reviewing Physician/Nurse's Signature ____________________________________ |                      |               |          |  
| Patient / Parent Signature:                                                                                   | Date:   |
|---------------------------------------------------------------------------------------------------------------|---------|
| Number of Tablets Returned: ___5 mg tablets, ____20 mg tablets, ____ 50 mg tablets.  RN / MD Signature: Date: |         |  
18.7 APPENDIX 7:PATIENT'S MEDICATION DIARY - DASATINIB-C**YCLE** 1
(For twice per day dosing)
Today's date __________________________________ **Agent** _____**Dasatinib _**
Patient Name_____________________ (*initials acceptable)* **Patient Study ID**____________
INSTRUCTIONS TO THE PATIENT: **CYCLE** 1 1. Complete one form for each 5 week-period while you take **dasatinib**. 2. You will take your dose of **dasatinib** twice daily in the morning and evening (unless instructed otherwise due to dose reduction). You will take ____5mg tablets, ____20 mg tablets, and ____50 mg tablets.You may take the tablets with or without food as you wish.  
3. Record the date, the number of tablets of each size you took, and when you took them. 4. If you have any comments or notice any side effects, please record them in the Comments column.  
5. Please return this form to your physician when you go for your next appointment.  
| 4.                                                | If you have any comments or notice any side effects, please record them in the Comments column.      |          |    |    |    |
|---------------------------------------------------|------------------------------------------------------------------------------------------------------|----------|----|----|----|
| 5.                                                | Please return this form to your physician when you go for your next appointment. # of tablets  taken | Comments |    |    |    |
| 5                                                 | 20                                                                                                   | 50       | 5  | 20 | 50 |
| mg mg mg                                          | mg                                                                                                   | mg       | mg |    |    |
| # of tablets  taken                               | Time of PM  dose                                                                                     |          |    |    |    |
| Time of                                           |                                                                                                      |          |    |    |    |
| Day                                               | Date                                                                                                 | AM dose  |    |    |    |
| -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 |                                                                                                      |          |    |    |    |  
| # of tablets  taken                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Comments         |                  |    |    |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|------------------|----|----|----|
| 5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | 20               | 50               | 5  | 20 | 50 |
| mg mg mg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | mg               | mg               | mg |    |    |
| # of tablets  taken                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Time of PM  dose |                  |    |    |    |
| Day                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Date             | Time of  AM dose |    |    |    |
| 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27                                                                                                                                                                                                                                                                                                                                                                                                                                              |                  |                  |    |    |    |
| POB will complete this section: 1. Date patient started protocol treatment________________________________________________ 2. Date patient was removed from study_________________________________________________ 3. Patient's planned total daily dose_____________________________________________________ 4. Total number of tablets taken this month (each size)______________________________________ 5. Reviewing Physician/Nurse's Signature ____________________________________ |                  |                  |    |    |    |
| Patient / Parent Signature:                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Date:            |                  |    |    |    |
| Number of Tablets Returned: ___5 mg tablets, ____20 mg tablets, ____ 50 mg tablets.  RN / MD Signature: Date:                                                                                                                                                                                                                                                                                                                                                                             |                  |                  |    |    |    |  
18.8 APPENDIX 8:PATIENT'S MEDICATION DIARY– DASATINIB-SUBSEQUENT CYCLES
(For twice per day dosing) for Cycle \# ______
Today's date __________________________________ **Agent** _____Dasatinib _
Patient Name_____________________ (*initials acceptable)* **Patient Study ID**____________
INSTRUCTIONS TO THE PATIENT: CYCLE **_____**
1. Complete one form for each 4 week-period while you take **dasatinib**. 2. You will take your dose of **dasatinib** twice daily in the morning and evening (unless instructed otherwise due to dose reduction). You will take ____5mg tablets, ____20 mg tablets,and ____50 mg. You may take the tablets with or without food as you wish.  
3. Record the date, the number of tablets of each size you took, and when you took them. 4. If you have any comments or notice any side effects, please record them in the Comments column.  
5. Please return this form to your physician when you go for your next appointment.  
| 4.                                                | If you have any comments or notice any side effects, please record them in the Comments column.                      |         |         |                    |          |
|---------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|---------|---------|--------------------|----------|
| 5.                                                | Please return this form to your physician when you go for your next appointment. # of tablets taken Time of  Time of |         |         |                    |          |
| Day                                               | Date                                                                                                                 | AM dose | PM dose | # of tablets taken | Comments |
| 5 mg                                              | 20                                                                                                                   | 50      | 20      | 50                 |          |
| mg                                                | 5 mg                                                                                                                 |         |         |                    |          |
| mg                                                | mg                                                                                                                   | mg      |         |                    |          |
| 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 |                                                                                                                      |         |         |                    |          |  
| 20 21                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | # of tablets taken   | Time of          |         |                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|------------------|---------|--------------------|
| Day                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Date                 | Time of  AM dose | PM dose | # of tablets taken |
| 5 mg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 20                   | mg               | 5 mg    | 20                 |
| 50                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | 50                   | Comments         |         |                    |
| mg                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | mg                   | mg               |         |                    |
| 22 23 24 25 26 27                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                      |                  |         |                    |
| POB will complete this section: 1. Date patient started protocol treatment________________________________________________ 2. Date patient was removed from study_________________________________________________ 3. Patient's planned total daily dose_____________________________________________________ 4. Total number of tablets taken this month (each size)______________________________________ 5. Reviewing Physician/Nurse's Signature ____________________________________ |                      |                  |         |                    |  
| Patient / Parent Signature:                                                                                   | Date:   |
|---------------------------------------------------------------------------------------------------------------|---------|
| Number of Tablets Returned: ___5 mg tablets, ____20 mg tablets, ____ 50 mg tablets.  RN / MD Signature: Date: |         |
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18.9 appendix 9processing and shipping

At least one week in advance, please obtain study kits from:
Donna Bernstein, RN
Research Nurse Specialist NIH/NCI/POB 10 Center Drive Building 10/Room 1-3750 Bethesda, MD 20892 18.9.1 Collection and Shipping Instructions Pathology Samples should only be drawn Sunday through Thursday and sent via overnight courier. Refer to NantOmics Sample Collection manual pages 20-23 for sample requirements and collection instructions. Page 9 of the NantOmics Sample Collection manual MUST be filled out and returned with the pa thology. Please also include:
- Patient ID: This should be the protocol specific number given to the patient: site number followed by the patient number enrolled (ie: MD004-004)
- Specimen ID: *this is the path identifier (ie: SS17-NO041)*
- Container type: *(block or slides)*
In addition please provide a redacted pathology report with specimen ID (that matches the pathology identifier) Ship at room temperature to: Donna Bernstein, RN Research Nurse Specialist NIH/NCI/POB 10 Center Drive Building 10/Room 1-3750 Bethesda, MD 20892 18.9.2 Collection and Shipping Instructions for Whole Blood Samples Samples should only be drawn Sunday through Thursday and sent via overnight courier. Refer to NantOmics Sample Collection manual pages 19 for sample requirements and collection instructions. Page 9 of the NantOmics Sample Collection manual MUST be filled out and returned with the pathology. Please also include:
- Patient ID: This should be the protocol specific number given to the patient: site number followed by the patient number enrolled (ie: MD004-001)
- Container type: *blood* Ship at room temperature to:
Donna Bernstein, RN Research Nurse Specialist NIH/NCI/POB
10 Center Drive Building 10/Room 1-3750 Bethesda, MD 20892 18.9.3 Instructions for Use of the Streck Cell-Free DNA BCT tube Samples should only be drawn Sunday through Thursday and sent via overnight courier. For a video demonstration, visit www.streck.com/mixing.  
- Collect specimen by venipuncture according to CLSI GP41-A61 . Prevention of Backflow - Since CellFree DNA BCT contains chemical additives, it is important to avoid possible backflow from the tube.  
To guard against backflow, observe the following precautions: a. Keep patient's arm in the downward position during the collection procedure. b. Hold the tube with the stopper in the uppermost position so that the tube contents do not touch the stopper or the end of the needle during sample collection. c. Release tourniquet once blood starts to flow in the tube, or within 2 minutes of application.  
- Follow recommendations for order of draw outlined in CLSI GP41-A61 . Cell-Free DNA BCT should be drawn after the EDTA tube and before the fluoride oxalate (glycolytic inhibitor) tube. If a CellFree DNA BCT tube immediately follows a heparin tube in the draw order, Streck recommends collecting a non-additive or EDTA tube as a waste tube prior to collection in the Cell-Free DNA BCT.  
- Fill tube completely.  
- Remove tube from adapter and immediately mix by gentle inversion 8 to 10 times. Inadequate or delayed mixing may result in incorrect analytical results or poor product performance. One inversion is a complete turn of the wrist, 180 degrees.  
- Ship overnight on wet ice to:
Donna Bernstein, RN Research Nurse Specialist NIH/NCI/POB
10 Center Drive Building 10/Room 1-3750 Bethesda, MD 20892