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8.5 agent accountability

Agent Inventory Records - The investigator, or a responsible party designated by the investigator, must maintain a careful record of the inventory and disposition of all agents received from DCTD using the NCI Drug Accountability Record Form (DARF). (See the CTEP Web site at http://ctep.cancer.gov for Procedures for Drug Accountability and Storage and to obtain a copy of the DARF Clinical Drug Request form.)
Agent Accountability for 89Zr-panitumuab: The organic precursor for 89Zr-panitumumab is purchased commercially in single-use, 200-mg vials that are delivered to the custody of Dr. George Afari, the lead nuclear radiopharmacist for this project. They are stored in a controlled temperature refrigerator in a locked and secure room and they are inventoried with a chain of custody maintained from the time of receipt. Each radiosynthesis is done by Dr. George Afari or his designee and, after passing all required quality control assays, the product 89Zr-panitumumab dose is drawn up under the supervision of Dr. George Afari or the nuclear medicine physician investigators Dr. Peter Choyke, Dr. Karen Kurdziel, or Dr. Liza Lindenberg.  
The quality control tests that must be passed prior to release of the product 89Zr-labeled, EGFR targeting antibody panitumumab for injection include radioactive purity, radiochemical purity, pH, sterilizing filter integrity, and tests for endotoxin and particulates. The dose is drawn up into a syringe, assayed for mCi at time of injection, labeled, and administered to the research subject. Agent Returns: If for any reason the study imaging is unable to be completed, sites will allow the radioactivity of the 89Zr-panitumumab solution to decay and then discard it appropriately per site's policies and procedures, making a record of the event as required. A copy of the policy should be available upon request.
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9 correlative/special studies

We plan to evaluate the effect of modulation of HIF1α inhibition and additional Hsp90 client proteins as a result of combination therapy with ganetespib and ziv-aflibercept. We also plan to pursue 89Zr-panitumumab PET/CT imaging to evaluate tumor distribution of EGFR prior to and following treatment with both agents as an exploratory correlation for evidence of modulation of EGFR, as an indirect biomarker of Hsp90 inhibition, as EGFR is a known Hsp90 client protein. Two core biopsies will be obtained, one on C1D7 prior to administration of ganetespib on C1D8, and 7 days after administration of ziv-aflibercept on C1D1; and again on C2D7, 7 days after treatment with the combination of ganetespib and ziv-aflibercept on C2D1, but before administration of ganetespib on C2D8. One core will be immediately flash frozen for analysis of HIF1α, a second core will be stored and later analyzed for Hsp90 client proteins based on the availability of tissue and various histologies, and availability of assays.  
Circulating tumor cells (CTCs) will be isolated from whole blood samples collected at baseline and then throughout the study for assessment of DNA damage response markers such as γH2AX. These samples will be optional and will be collected from patients on the MTD expansion phase only. We will also evaluate whether we can measure changes in the number and phenotype (epithelial-mesenchymal transition) of CTCs in patients over time to explore any correlation with response to treatment or disease progression. This analysis will be performed in Dr. Kinders' lab with the ApoStream instrument, which uses antibody-independent CTC isolation technology that can isolate viable CTCs from epithelial and non-epithelial cancers. The enriched cells are then stained with a panel of antibodies targeting MUC1 (tumor marker) and CEA (tumor marker), CK (epithelial marker), EpCAM (epithelial marker) and β-catenin (CTNNB1; epithelial-mesenchymal transition marker) and CD45 (PTPRC; leukocyte marker), as an exclusion marker.
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9.1 pharmacodynamic assays assessment of

To determine whether the combination of ganetespib and ziv-aflibercept modulates intratumoral HIF1α expression, tumor biopsies will be analyzed for change in HIF1α expression by  
  
immunofluorescence assay (IFA). Cores will be normalized against the percentage of tumor within the sample. Paired pre- and post-combination treatment samples will be compared for qualitative changes in levels of HIF1α expression.  
Figure 6. IFA showing HIF1α expression in A375 xenograft tumors treated for 2 hours with topotecan and counterstained with DAPI.
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assessment of egfr modulation by

To evaluate for tumor distribution of EGFR, patients will undergo 89Zr-immuno-PET imaging with 89Zr-labeled EGFR-targeting panitumumab antibody in all patients as a non-invasive exploratory correlative to evaluate modulation of EGFR client protein prior to and after treatment with the combination of ganetespib and ziv-aflibercept. Immunohistochemistry staining to confirm EGFR expression in archival tumor biopsies will be performed prior to pursuing scans. Panitumumab is a fully human monoclonal antibody that targets EGFR and competes with endogenous ligands to block stimulation of EGFR. 89Zr-immuno-PET imaging with panitumumab as a targeting ligand allows for quantification of EGFR expression within tumors. Changes in 89Zr-panitumumab PET/CT avidity (as measured by SUV) can therefore serve as a surrogate biomarker of Hsp90 inhibition, as EGFR is a known Hsp90 client protein.  
Figure 7 Example of Zr89 Panitumumab scan from a patient with  
 colon cancer metastasis to the liver. Note the high physiologic radiotracer activity in the liver with decreased uptake in metastatic lesions.
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9.1.1 laboratory contact

At least 24 hours prior to tumor biopsy or blood sample collection, the research nurse will contact the NCI Phase I/II PK/PD Support Group in NIH Building 10: E-mail NCIPK-PDsupportgroup@mail.nih.gov, Pager: 102-12798 Phone: 301-451-1169 Fax: 301-480-5871. For biopsies, tubes pre-labeled with the information specified in Section 9.1.4, biopsy date, and site of tissue biopsy will be provided. Initial processing and shipping of the samples will be completed as described below.
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9.1.2 tumor biopsies 9.1.2.1 timing

Biopsies will be mandatory during the expansion phase. Biopsies will be collected at the following time points: - On C1D7 before ganetespib administration on C1D8 (baseline)  
- On C2D7 after combination of ganetespib and ziv-aflibercept on C2D1, and before ganetespib administration on C2D8
If tumor biopsies are pursued, the first dose of ganetespib on C1D1 will be omitted.
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9.1.2.2 biopsy procedure

Serial tumor biopsies will be obtained by the Interventional Radiology team by a percutaneous approach. It is preferred that 2-3 core biopsies 18-gauge in diameter and ≥1 cm in length will be obtained during each procedure. It is estimated that there will be between 2 million–5 million cells from each biopsy. If a site is deemed appropriate for biopsy with minimal risk to the participant by agreement between the investigators and Interventional Radiology team, an attempt for biopsy will be made. The use of imaging to facilitate biopsies will be decided by members of the Interventional Radiology team and may include ultrasound, CT scan, or MRI. Should a CT scan be needed for biopsy, the number of scans for each procedure will be limited to the minimum number needed to safely obtain a biopsy. Tumor biopsies and local anesthesia will be administered only if they are considered to be of low risk to the participant, as determined by the investigators and Interventional Radiology. If the participant chooses not to undergo tumor biopsy, he/she will still remain in the study and receive study medication, and all the other correlative studies will be performed. Tumor biopsies are optional during the escalation phase and mandatory during the expansion phase. Baseline biopsies will be performed following patient enrolling on study. If an initial attempt at percutaneous biopsy is unsuccessful, the patient will be given an option to proceed with a repeated attempt at percutaneous biopsy. A separate consent form must be signed for each biopsy procedure, so patients may choose not to undergo subsequent biopsies. If the baseline biopsy is unsuccessful or the patient refuses to undergo subsequent biopsies, no further biopsies will be performed but the patient will remain on study, receive study medication, and other correlative studies will be performed.
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9.1.2.3 solid tumor biopsy processing

At least two tissue cores will be collected. The cores will be transferred into a 1.5-mL pre-chilled cryovial and then flash frozen in liquid nitrogen per DCTD SOP340507 (http://dctd.cancer.gov/ResearchResources/biomarkers/ docs/par/SOP340507_Biopsy_Frozen.pdf). Samples will be submitted to Dr. Kinders' laboratory for evaluation of DNA damage markers, and H&E pathology evaluation. The frozen biopsy specimens are transferred to PADIS on dry ice, where the core biopsy samples are stored at -80°C, or colder, and subsequently processed within 7-10 days for analysis or as directed by the Principal Investigator. Biopsy samples will be analyzed for HIF1α expression as described above; any additional cores will be flash-frozen and kept for future analysis in the Frederick National Laboratories CR Biorepository in liquid nitrogen freezers. Biopsies for PD analysis will be shipped on dry ice to Dr. Kinders' laboratory: Dr. Robert Kinders (PADIS/LHTP/FNLCR)
Bldg. 431, Rm. 129 Frederick, MD 21702-1201 Phone: 301-846-6410 kindersr@mail.nih.gov
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9.1.3 circulating tumor cells

Whole blood for CTCs will be collected aseptically by venipuncture or from a venous port into two K3 EDTA 4 mL tubes. Samples will be collected at the following times from patients on the expansion cohort only:
- cycle 1 prior to drug administration
- cycle 1 day 8 (+/- 1 day, i.e., prior to the administration of ganetespib on C1D8)
- cycle 1 day 5, 4 hours (+/- 1 hour) after completion of drug administration
- cycle 2 day 8 (+/- 1 day, i.e., prior to the administration of ganetespib on C2D8)
- cycle 2 day 15, 4 hours (+/- 1 hour) after completion of drug administration
- on day 1 of all subsequent cycles before drug administration
One additional blood sample will be collected at time of disease progression. All CTC samples will be shipped to Dr. Kinders' lab.
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9.1.4 sample collection and processing

Biospecimens will be collected and processed using validated SOPs that will ensure both specimen quality and patient confidentiality pursuant to informed consent provisions. Information about each specimen (e.g., blood, tumor biopsy, circulating tumor cells, per specific protocol) will be recorded on a PK/PD collection worksheet. Using a computerized inventory system and a backup hardcopy process, all specimen collection and processing steps will be documented and the specific location of each specimen will be tracked. Each new specimen collected will be assigned a unique barcode identifier that can be linked to the original specimen collected and other relevant information within the inventory system. To ensure patient confidentiality, only containers used for the initial specimen collections will be labeled with patient identifiers. Only the barcode identifier will be applied to all subsequent specimen containers. When specimens are processed and aliquoted, no patient information will be included on the new containers. Original specimen containers will be discarded. Only barcode-labeled specimens without patient identifiers will be shipped for analysis and/or storage. Specimen labels will indicate: CTEP protocol number, unique patient accession number, 3-digit sample number (see list below), collection time, and total volume collected, as appropriate. Samples from sets of at least three patients will be grouped for scientific analysis. Standardized 3-digit sample collection numbers: 400 series: blood for circulating tumor cells (CTCs) 500 series: tumor biopsies The inventory process contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access to the inventory system and associated documents will be restricted to appropriate individuals. Requests to use specimens stored in the repository must be approved. The only patient information available in the inventory system will be the patient sex, diagnosis, and level of informed consent given. SOPs ensure that any changes in informed consent made by a patient and relayed to the PI will be reflected in the inventory system to ensure that specimens are destroyed as appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for high-quality performance. Any new use of these samples will require prospective IRB review and approval. 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), and reported as such to the IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample integrity (i.e., broken freezer allows for extensive sample thawing, etc.) will be reported as such to the IRB.
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9.1.5 immunohistochemistry

Patients undergoing 89Zr-panitumumab PET/CT scans will be required to submit a minimum of 2 unstained slides from archival tumor biopsies to the Laboratory of Pathology, CCR, NCI for confirmation of EGFR expression by immunohistochemistry (IHC) to determine eligibility prior to undergoing scans. IHC staining for EGFR will be performed using the commercially available mouse anti-EGFR antibody from Zymed Laboratories, (Zymed Laboratories, Inc., Invitrogen Immunodetection, South San Francisco, CA) according to the manufacturer's instructions. Positivity will be defined as any membrane staining for EGFR in tumor cells. For enrollment purposes the archival material will be scored solely as positive or negative. Only those patients whose tumors are scored as positive will be eligible for 89Zr-panitumumab scans; scans are optional during the escalation phase and mandatory during the expansion phase of this trial.
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9.1.6 imaging studies

We are conducting 89Zr-immuno-PET imaging with panitimumab as a targeting ligand in the 10 patients enrolled in the expansion cohort, scans are optional during the escalation phase. 89Zr-panitumumab will be administered at baseline (prior to cycle 1 day 1 of treatment) and PET/CT imaging will be performed 2-6 hours following 89Zr-panitumuab injection. If uptake into tumors is shown to be measurable, a second 89Zr-panitumumab infusion and scan will be performed at the end of cycle 1. Uptake of 89Zr-panitumumab in normal tissue and tumors will be evaluated and human dosimetry values will be calculated.  
89Zr-panitumumab PET/CT will be performed in the NCI Molecular Imaging Clinic (B3B). The injectable dose of 89Zr-panitumumab for this study will be 1.0 mCi
(37 MBq), with an allowable range of 0.75 to 1.0 mCi (28-37 MBq), and with a specific activity greater than 200 Ci/mmol at the time of injection. The injected mass dose is less than or equal to 1 mg (7 nmol). Ordering instructions for 89Zrpanitumumab are provided in Appendix D. Participants with severe claustrophobia not relieved by oral anxiolytic medication or patients weighing >136 kg (weight limit for scanner table) may not undergo 89Zr-panitumumab imaging. 89Zrpanitumumab is a sterile, IV injectable solution that will be administered to subjects over 1 minute by intravenous bolus injection. The infusion and imaging procedure will be terminated in any patient who exhibits anaphylaxis, significant hypotension (systolic blood pressure less than 80 mmHg on 2 measurements obtained within 1-2 minutes of each other), dyspnea, or chest pain.
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9.1.6.1 scanning procedure

The scanning acquisition should include the patient torso, from the mid-ears to the mid-thighs. A corresponding low energy transmission CT will be acquired immediately before each emission scan for attenuation correction and localization purposes. The acquisition time for each PET/CT image is estimated at one hour.  
The injected dose of 89Zr-panitumumab will not exceed 1.0 mCi. The minimum injected dose will be 0.75 mCi, although the total dose administered may be reduced at the discretion of the principal investigator on a case-by-case basis due to unpredictable delays. The reasoning for a reduction in the dose will be clearly documented.
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9.1.6.2 image analysis

- Preliminary analysis will be performed to define human dosimetry and evaluate tumor uptake/image quality (as determined by an experienced nuclear imaging physician).  
- The uptake within an EGFR positive tumor us expected to be greater than mean background activity + 2X the standard deviation of the background tissue.  
- Regions/Volumes of interest (VOIs) will be drawn within the tumor focus/foci and normal solid organs, which will be identified on the transmission CT scan.  
For the tumor foci, an estimated smoothed maximum standard uptake value (SUV; SUVmax) will be reported as the mean SUV value of an automated 80% maximum pixel value threshold based on volume of interest (i.e., the average SUV of the :hottest" 20% of pixels in the user defined lesion). This method reduces the chances of the SUVmax value being dominated by one or more "noisy" pixel values. Additional VOIs will include an anatomic value based on the transmission CT and a metabolic volume using an absolute SUVmax threshold. For the normal solid organs, VOIs will also be drawn and SUVmean will be reported.  
- A small VOI will also be defined within the left ventricular or atrial cavity or over the aorta to obtain the blood pool and SUVmean will be reported.  
- A normal tissue "background" VOI will be drawn by establishing a 50%
maximum pixel value volume of interest (VOI), drawn within a homogeneous non-tumor-involved region within the organ in which the tumor resides. This VOI will be used to determine tumor:background ratios.  
- All regions/volumes of interest will be saved. Region volumes, and SUV values will be output to an Excel spreadsheet using MIM imaging software (www.mimsoftware.com)
- Image data will be used to calculate the dosimetry using OLINDA (Organ Level Internal Dose Assessment Code, sopyright Vanderbilt University, 2003) software and to obtain preliminary tissue uptake variability measurements
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9.1.6.3 data analysis

SUVmax and SUVmean within the tumor and non-tumor areas, and tumor:background will be analyzed. Percent change of SUV between baseline and after the first cycle will be assessed. Based on published PET/CT reproducibility data, a percent change >20% in SUV values will be considered significant.
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9.1.7 human data sharing plan

What data will be shared?  
We will share human data generated in this research for future research as follows: X De-identified data in an NIH-funded or approved public repository X Identified data in BTRIS (automatic for activities in the Clinical Center) X De-identified or identified data with approved outside collaborators under appropriate agreements How and where will the data be shared? Data will be shared through: X An NIH-funded or approved public repository: clinicaltrials.gov X BTRIS (automatic for activities in the Clinical Center) X Approved outside collaborators under appropriate individual agreements X Publication and/or public presentations When will the data be shared? X At the time of publication or shortly thereafter
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10 study calendar

Baseline evaluations are to be conducted within 72 hours prior to start of protocol therapy. Scans and x-rays must be done ≤4 weeks prior to the start of therapy. Start of next cycle may be delayed for up to 1 week to accommodate scheduling conflicts. Treatments within a cycle may be delayed up to +/- 1 day to accommodate scheduling conflicts. History and physical examination and laboratory evaluations can be performed up to 3 days before the start of the next cycle.  
| Study Treatment                |                                                               |                                                                           |      |      |      |      |      |
|--------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|------|------|------|------|------|
| Cycle 1                        | Cycle 2 and subsequent                                        | Off                                                                       |      |      |      |      |      |
| cycles                         | Treatment                                                     |                                                                           |      |      |      |      |      |
| W1                             | W2                                                            | W3                                                                        | Wk 4 | Wk 1 | Wk 2 | Wk 3 | Wk 4 |
| Ganetespiba                    | Xb                                                            | X                                                                         | X    | X    | X    | X    |      |
| Study Procedure                | Screen                                                        |                                                                           |      |      |      |      |      |
| Ziv-Aflibercept                | X                                                             | X                                                                         | X    | X    |      |      |      |
| Informed consent               | X                                                             |                                                                           |      |      |      |      |      |
| Demographics                   | X                                                             |                                                                           |      |      |      |      |      |
| Medical history                | X                                                             |                                                                           |      |      |      |      |      |
| Concurrent meds                | X                                                             | X-----------------------------------------------------------------------X |      |      |      |      |      |
| Physical examd                 | X                                                             | X                                                                         | X    | X    | X    | X    | X    |
| Vital signsd                   | X                                                             | X                                                                         | X    | X    | X    | X    | X    |
| Heightd                        | X                                                             |                                                                           |      |      |      |      |      |
| Weightd                        | X                                                             | X                                                                         | X    | X    | X    | X    | X    |
| Performance statusd            | X                                                             | X                                                                         | X    | X    | X    | X    | X    |
| CBC w/diff, pltse              | X                                                             | X                                                                         | X    | X    | X    | X    | X    |
| Serum chemistrye               | X                                                             | X                                                                         | X    | X    | X    | X    | X    |
| Urine  protein/creatininee     | X                                                             | X                                                                         | X    | X    | X    |      |      |
| PT, INR, PTTf                  | X                                                             | X                                                                         | X    |      |      |      |      |
| β-HCGg                         | X                                                             |                                                                           |      |      |      |      |      |
| Electrocardiogramh             | X                                                             | X                                                                         | X    | X    | X    | X    | X    |
| Echocardiogrami                | X                                                             |                                                                           |      |      |      |      |      |
| Ophthalmologic examj           | X                                                             |                                                                           |      |      |      |      |      |
| Adverse event  evaluation      | X                                                             | X----------------------------------------------------------------------X  |      |      |      |      |      |
| Tumor                          | Tumor measurements are repeated every 2 cycles. Documentation |                                                                           |      |      |      |      |      |
| measurements                   | X                                                             | (radiologic) must be provided for patients removed from study for         | X    |      |      |      |      |
| progressive disease.           |                                                               |                                                                           |      |      |      |      |      |
| Tumor biopsyk                  |                                                               | X                                                                         | X    |      |      |      |      |
| 89Zr-panitumumab  PET/CT scanl |                                                               | X                                                                         | X    |      |      |      |      |
| PD blood collectionm           | X                                                             | X                                                                         | X    | X    | X    |      |      |  
a. Ganetespib will be administered intravenously on D1, 8, and 15 of a 28-day cycle.  
b. In order to accommodate biopsies, D1 administration of ganetespib may be omitted during cycle 1 only.  
c. Ziv-aflibercept will be administered intravenously on D1 and 15 of a 28-day cycle. d. Physical examination, including vitals, weight, and performance status, will be performed at the Clinical Center at the start of each cycle or treatment (up to 3 days before start of a new cycle or treatment).  
Height will be performed at enrollment and will not need to be repeated prior to each treatment.  
e. Serum chemistry (albumin, total bilirubin, calcium, creatinine, phosphorus, magnesium, potassium, sodium, SGOT [AST], SGPT [ALT], amylase, lipase); CBC w/diff, and platelets should be performed within 72 hours of enrollment and weekly thereafter on weeks of treatment, prior to the first treatment of that week. If clinically indicated, labs may be obtained with more frequency with subsequent cycles. Urine protein/creatinine ratio will be checked prior to treatment with ziv-aflibercept.  
f. PT/INR, PTT prior to biopsy.  
g. Serum pregnancy test (women of childbearing potential) within 1 week prior to enrollment and as clinically indicated.  
h. Electrocardiogram will be performed prior to each ganetespib treatment and approximately 24 hours after each treatment during the first cycle, and will be repeated as indicated until QTc is less than 500 msec. With subsequent cycles, electrocardiogram will be performed prior to each treatment, and repeated after treatment if clinically indicated.  
i. Echocardiogram must be performed within 4 weeks prior to enrollment and as clinically indicated thereafter.  
j. Ophthalmologic exams must be performed within 4 weeks prior to enrollment and as clinically indicated thereafter.  
k. Tumor biopsies will be obtained on Cycle 1 D7 prior to administration of ganetespib on C1D8, and again on C2D7 before administration of ganetespib on C2D8. Tumor biopsies are optional during the escalation phase and mandatory during the expansion phase. If tumor biopsies are collected, the first dose of ganetespib on C1D1 will be omitted.  
l. 89Zr-panitumumab scan will be performed in patients with confirmed EGFR expression on archival tumor tissue prior to initiation of treatment on C1D1. If there is evidence of measurable uptake on baseline scans, patients will receive a second 89Zr-panitumumab PET/CT scan after completion of C1D15 treatment, on C1D16 ± 1 day. If patients are unable to have a second scan during cycle 1 due to scheduling conflicts, scans may be performed during C2D16 ± 1 day. Scans will be optional during the escalation phase and mandatory during the expansion phase.  
m. Blood for circulating tumor cells (optional) will be collected on the expansion phase only per Section 9.1.3
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11 measurement of effect 11.1

Although response is not the primary endpoint of this trial, patients with measurable disease will be assessed by standard criteria. For the purposes of this study, patients should be re-evaluated for response every 8 weeks (every 2 cycles). In addition to a baseline scan, confirmatory scans should also be obtained at least 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) [*Eur J Ca* 45:228-247, 2009]. 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.
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11.1.1 definitions

Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with the combination of ganetespib and zivaflibercept.  
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.
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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 or as ≥10 mm with CT scan, MRI, or 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 nonmeasurable.  
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.
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11.2 guidelines for evaluation of

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). 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 PETCT 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 [*JNCI* 96:487-488, 2004; *J Clin Oncol* 17, 3461-3467, 1999; *J Clin Oncol* 26:1148-1159, 2008]. 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 [*JNCI* 92:1534-1535, 2000]. 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-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.
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11.3response criteria

| 11.3.1 Evaluation of Target Lesions  Complete Response (CR): Disappearance of all target lesions. Any  pathological lymph nodes (whether target or nontarget) 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  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 diameters while on study. 11.3.2 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).
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11.3.3 evaluation of best overall

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.  
| Target    | Non-Target                                                                                                                                                                                                                                                                                                                    | New     | Overall                                            | Best Overall Response           |
|-----------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|----------------------------------------------------|---------------------------------|
| Lesions   | Lesions                                                                                                                                                                                                                                                                                                                       | Lesions | Response                                           | when Confirmation is  Required* |
| CR        | CR                                                                                                                                                                                                                                                                                                                            | No      | CR                                                 | ≥ 4 wks. Confirmation**         |
| CR        | Non                                                                                                                                                                                                                                                                                                                               |         |                                                    |                                 |
| CR/Non-PD | No                                                                                                                                                                                                                                                                                                                            | PR      |                                                    |                                 |
| CR        | Not                                                                                                                                                                                                                                                                                                                           | No      | PR                                                 |                                 |
| evaluated | ≥ 4 wks. Confirmation**                                                                                                                                                                                                                                                                                                       |         |                                                    |                                 |
| PR        | Non                                                                                                                                                                                                                                                                                                                               |         |                                                    |                                 |
| CR/NonPD/not  evaluated           | No                                                                                                                                                                                                                                                                                                                            | PR      |                                                    |                                 |
| SD        | Non                                                                                                                                                                                                                                                                                                                               |         |                                                    |                                 |
| CR/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.                                                                                                                                                                                                          |         |                                                    |                                 |
| 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 |               |                    |  
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
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11.4 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.
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12 data reporting / regulatory

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 data reporting 12.1.1 method

This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 31.  
Note: **All** adverse events that have occurred on the study, including those reported through CTEP-AERS, must be reported via the monitoring method identified above.  
12.1.2 Responsibility for Data Submission  
N/A
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12.2 ctep multicenter guideline n/a

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 for non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential and proprietary data, in 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:
E-mail: 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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13 statistical considerations 13.1 study

This Phase I study will use a standard 3+3 design. The MTD dose for the combination of ganetespib and ziv-aflibercept is defined as the dose level at which no more than 1 of 6 patients experience a DLT during the first cycle of the treatment, and the dose level below that at which at least 2 (of < 6) patients have DLT as a result of the drug. Patients will receive ganetespib intravenously on a weekly basis, on days 1, 8, and 15, for 3 weeks out of 4, every 28 days, and ziv-aflibercept intravenously every 2 weeks, on days 1 and 15, during a 28-day cycle. Once the MTD is established, 10 additional patients will be enrolled to the expansion phase of the trial, at the MTD and tumor biopsies will be obtained to assess for pharmacodynamic endpoints. Patients will also undergo an 89Zr-panitumumab PET/CT
scan to evaluate tumor distribution of EGFR prior to and following treatment with both study agents.
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13.2 sample size/accrual rate

We plan to accrue a total of 22 patients in this study. To allow for some patients who may have only evaluable and not measurable disease, the accrual ceiling is set at 26. It is anticipated that 2-3 patients may be enrolled per month onto this study. It is expected that 14-21 months will be required to accrue the number of patients necessary to complete the trial.
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13.3 analysis of secondary endpoints

At the maximal tolerated dose (MTD), we will enroll an additional 10 patients, with mandatory tumor biopsies, for further assessment of pharmacodynamics and imaging endpoints. HIF1α expression and EGFR expression (as measured by SUV, using 89Zrlabeled, EGFR-targeting panitumumab antibody PET/CT imaging) will all be assessed similarly, in an exploratory fashion. For each endpoint, the mean difference (or mean logdifference, if such a transformation appears appropriate) between pre- and post-treatment values, paired by patient, will be assessed by the 1-sample paired t-test, at the 1-sided .05 significance level, if the differences (or log-differences) appear distributed in approximately normal (uni-modal) fashion. This test will have 90% power to detect a treatment related change, in any individual endpoint, equivalent to approximately 0.92SD associated with the natural variation over repeated measures in the absence of treatment. If the differences are not distributed in approximately normal (uni-modal) fashion, the nonparametric sign test will be used to assess whether the observed treatment related changes are in a reliably negative direction (this test will have low power, since it requires that at least 8 of the 10 changes be in the negative direction, to achieve statistical significance at the 1-sided .05 level).
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14 human subjects protections 14.1

This study will be open to all individuals regardless of gender, ethnicity, or race, provided that the aforementioned inclusion and exclusion criteria are met. Patients for this study will be recruited through internal referral, our physician referral base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer). To date, there is no information that suggests that differences in drug metabolism or effect on tumor would be expected in one ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but a balance must be struck between participant safety considerations and limitations on the number of individuals exposed to potentially ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to ethnic identity are noted, a follow-up study may be written to investigate those differences more fully.  
Due to lack of knowledge of the effects of the combination of ganetespib and zivaflibercept on the fetus or infants, as well as the possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial. Patients with unstable or serious medical conditions are excluded due to the possibility that the combination of ganetespib and ziv-aflibercept may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events to ganetespib and ziv-aflibercept. HIV-positive patients on combination antiretroviral therapy are excluded from the study because of possible PK interactions with the combination of ganetespib and ziv-aflibercept.
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14.1.1 participation of children

This study includes patients 18 years of age and older. Because insufficient dosing or adverse event data are currently available on the use of combination of ganetespib and ziv-aflibercept in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials. Studies will be performed in patients <18 years of age when it is appropriate to do so.
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14.2 evaluation of benefits and

There may or may not be any clinical benefit to a patient from participation in this trial. Their participation will benefit future cancer patients. Potential risks include the possible occurrence of any of a range of side effects that are listed in the consent document. The procedure for protecting against or minimizing risks will be to medically evaluate patients as described in Section 5 and Section 6. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which participants are entitled under applicable regulations.
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14.3 consent and assent process

An associate or principal investigator on the trial will inform patients of the purpose, alternatives, drug administration plan, research objectives, and follow-up of this trial. The patient will be provided an IRB-approved consent for review and signature and his/her questions will be answered. After a decision is made to enroll into the study, a signature will be obtained from the patient. The original signed consent goes to Medical Records; a copy will be placed in the research record. All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on study.
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14.4 procedure for protecting against

All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. This study may involve risks to patients, which are currently unforeseeable. All patients will be monitored for side effects from taking study medication. This research represents a greater than minimal risk to participants, but presents the prospect of direct benefit to individual subjects. The research component of this study required to obtain 2 CT tumor biopsies confers radiation exposure at an effective dose of 0.29 rem. This dose is below NIH RSC guidelines of less than 5.0 rem per year in adults, and represents a slightly greater than minimal risk to patients. The imaging component of the study using 89Zr-panitumumab PET/CT confers an effective dose up to 6.9 rem, and adds a radiation risk which is slightly greater than minimal risk to subjects and offers no direct benefit to individual subjects.
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14.5 patient advocate

The patients' rights representative is available to patients receiving treatment on this protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical Research Center, Room 1-3521, on the Bethesda NIH campus. Patients will be informed that they can contact the study PI or RN at any time with questions about their medical care, and that the patients' rights representative is also available to answer non-medical questions about the study.
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37. Holland, J.P., Y. Sheh, and J.S. Lewis, Standardized methods for the production of high specific-activity zirconium-89. Nucl Med Biol, 2009. 36(7): p. 729-39.  
38. Perk, L.R., et al., Preparation and evaluation of (89)Zr-Zevalin for monitoring of (90)YZevalin biodistribution with positron emission tomography. Eur J Nucl Med Mol Imaging, 2006.  
33(11): p. 1337-45. 39. Borjesson, P.K., et al., Performance of immuno-positron emission tomography with zirconium-89-labeled chimeric monoclonal antibody U36 in the detection of lymph node metastases in head and neck cancer patients. Clin Cancer Res, 2006. 12(7 Pt 1): p. 2133-40. 40. Bhattacharyya, S., et al., Zirconium-89 labeled panitumumab: a potential immuno-PET probe for HER1-expressing carcinomas. Nuclear Medicine and Biology, 2013. 40(4): p. 451-457.
untitled h1
appendix a performance status criteria

| ECOG Performance Status Scale   |                                                                                                                                                                                                                                                                                             |
|---------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                           | Descriptions                                                                                                                                                                                                                                                                                |
| 0                               | Normal activity. Fully active, able to carry on  all pre-disease performance without restriction. 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). |
| 1                               | 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.                                                                                                                               |
| 2                               | In bed >50% of the time. Capable of only                                                                                                                                                                                                                                                    |
| 3                               | limited self-care, confined to bed or chair more  than 50% of waking hours. 100% bedridden. Completely disabled. Cannot                                                                                                                                                                     |
| 4                               | carry on any self-care. Totally confined to bed  or chair.                                                                                                                                                                                                                                  |
| 5                               | Dead.                                                                                                                                                                                                                                                                                       |
untitled h1
appendix b potential drug interactions

| CYP3A4 Inhibitors           | Modafinil                    |                      |               |                     |
|-----------------------------|------------------------------|----------------------|---------------|---------------------|
| Acetaminophen               | Cyclosporine                 | Glyburide            | Ranolazine    |                     |
| Acetazolamide               | Danazol                      | Grapefruit juice (2) | Nefazodone    | Risperidone         |
| Amiodarone                  | Dasatinib (1)                | Haloperidol          | Nelfinavir    | Ritonavir           |
| Amlodipine                  | Delavirdine                  | Hydralazine          | Nevirapine    | Saquinavir          |
| Amprenavir                  | Desipramine                  | Ifosfamide           | Nicardipine   | Selegiline          |
| Sertraline                  |                              |                      |               |                     |
| Anastrozole                 | Dexmedetomidine              | Imatinib             | Nifedipine    |                     |
| Aprepitant                  | Diazepam                     | Indinavir            | Nisoldipine   | Sildenafil          |
| Atazanavir                  | Diclofenac                   | Irbesartan           | Nizatidine    | Sirolimus           |
| Atorvastatin                | Dihydroergotamine            | Isoniazid            | Norfloxacin   | Sulconazole         |
| Azelastine                  | Tacrolimus                   |                      |               |                     |
| Diltiazem                   | Isradipine                   | Olanzapine           |               |                     |
| Azithromycin                | Disulfiram                   | Itraconazole         | Omeprazole    | Tamoxifen           |
| Betamethasone               | Docetaxel                    | Ketoconazole         | Orphenadrine  | Telithromycin       |
| Bortezomib                  | Doxorubicin                  | Lansoprazole         | Oxybutynin    | Teniposide          |
| Bromocriptine               | Doxycycline                  | Lidocaine            | Testosterone  |                     |
| Paroxetine                  |                              |                      |               |                     |
| Caffeine                    | Drospirenone                 | Lomustine            | Pentamidine   | Tetracycline        |
| Cerivastatin                | Efavirenz                    | Losartan             | Pergolide     | Ticlopidine         |
| Chloramphenicol             | Enoxacin                     | Lovastatin           | Phencyclidine | Tranylcypromine     |
| Chlorzoxazone               | Entacapone                   | Mefloquine           | Pilocarpine   | Trazodone           |
| Cimetidine                  | Ergotamine                   | Mestranol            | Pimozide      | Troleandomycin      |
| Ciprofloxacin               | Erythromycin                 | Methadone            | Pravastatin   | Valproic acid       |
| Cisapride                   | Ethinyl estradiol            | Methimazole          | Prednisolone  | Venlafaxine         |
| Clarithromycin              | Etoposide                    | Methoxsalen          | Primaquine    | Verapamil           |
| Methylprednisolone          | Vinblastine                  |                      |               |                     |
| Clemastine                  | Felodipine                   | Progesterone         |               |                     |
| Clofazimine                 | Fentanyl                     | Metronidazole        | Propofol      | Vincristine         |
| Clotrimazole                | Fluconazole                  | Miconazole           | Propoxyphene  | Vinorelbine         |
| Clozapine                   | Fluoxetine                   | Midazolam            | Qumdme        | Voriconazole        |
| Fluvastatin                 | Zafirlukast                  |                      |               |                     |
| Cocaine                     | Mifepristone                 | Quinine              |               |                     |
| Conivaptan                  | Fluvoxamine                  | Mirtazapine          | Quinupristin  | Ziprasidone         |
| Cyclophosphamide            | Fosamprenavir                | Mitoxantrone         | Rabeprazole   |                     |
| CYP3A4 Inducers             | Nafcillin                    |                      |               |                     |
| Aminoglutethimide           | Pentobarbital                | Primidone            | Rifapentine   |                     |
| Carbamazepine               | Nevirapine                   | Phenobarbital        | Rifabutin     | St. John's wort (3) |
| Fosphenytoin                | Oxcarbazepine                | Phenytoin            | Rifampin      |                     |
| CYP3A4 Substrates           |                              |                      |               |                     |
| Abuterol                    | Docetaxel                    | Ketoconazole         | Quetiapine    |                     |
| Alfentanil                  | Doxepin                      | Quinidine            |               |                     |
| Lansoprazole                |                              |                      |               |                     |
| Alprazolam                  | Doxorubicin                  | Letrozole            | Rabeprazole   |                     |
| Amlodipine                  | Doxycycline                  | Levomethadyl acetate | Repaglinide   |                     |
| Amprenavir                  | Efavirenz                    | hydrochloride        | Rifabutin     |                     |
| Aprepitant                  | Eletriptan                   | Levonorgestrel       | Rifampin      |                     |
| Anpiprazole                 | Ritonavir                    |                      |               |                     |
| Enalapril                   | Lidocaine                    |                      |               |                     |
| Atazanavir                  | Eplerenone                   | Losartan             | Squinavir     |                     |
| Atorvastatin                | Ergoloid mesylates           | Lovastatin           | Sertraline    |                     |
| Benzphetamine               | Ergonovine                   | Medroxyprogesterone  | Sibutramine   |                     |
| Bisoprolol                  | Ergotamine                   | Mefloquine           | Sildenafil    |                     |
| Bortezomib                  | Erythromycin                 | Mestranol            | Simvastatin   |                     |
| Bosentan                    | Escitalopram                 | Methadone            | Sirolimus     |                     |
| Bromazepam                  | Estradiol                    | Methylergonovine     | Sufentanil    |                     |
| Bromocriptine               | Methysergide                 | Tacrolimus           |               |                     |
| Estrogens, conj., synthetic |                              |                      |               |                     |
| Buprenorphine               | Estrogens, conj., equine     | Miconazole           | Tamoxifen     |                     |
| Buspirone                   | Estrogens, conj., esterified | Midazolam            | Tamsulosin    |                     |  
| Busulfan           | Estrone                | Miglustat      | Telithromycin   |
|--------------------|------------------------|----------------|-----------------|
| Carbamazapine      | Estropipate            | Mirtazapine    | Teniposide      |
| Cerivastatin       | Ethinyl estradiol      | Modafinil      | Terbinafine     |
| Chlordiazepoxide   | Ethosuximide           | Montelukast    | Tetracycline    |
| Chloroquine        | Etoposide              | Moricizine     | Theophylline    |
| Chlorpheniramine   | Felbamate              | Nateglinide    | Tiagabine       |
| Cisapride          | Felodipine             | Nefazodone     | Ticlopidine     |
| Citalopram         | Fentanyl               | Nelfinavir     | Tolterodine     |
| Clarithromycin     | Flurazepam             | Nevirapine     | Toremifene      |
| Clobazam           | Flutamide              | Nicardipine    | Trazodone       |
| Clonazepam         | Fosamprenavir          | Nifedipine     | Triazolam       |
| Trimethoprim       |                        |                |                 |
| Clorazepate        | Fulvestrant            | Nimodipine     |                 |
| Cocaine            | Gefitimib              | Nisoldipine    | Trimipramine    |
| Colchicine         | Halofantrine           | Nitrendipine   | Troleandomycin  |
| Cyclophosphamide   | Haloperidol            | Norethindrone  | Vardenafil      |
| Cyclosporine       | Ifosfamide             | Norgestrel     | Venlafaxine     |
| Dantrolene         | Imatimib               | Ondansetron    | Verapamil       |
| Dapsone            | Indinavir              | Paclitaxel     | Vinblastine     |
| Delavirdine        | Irinotecan             | Pergolide      | Vincristine     |
| Diazepam           | Isosorbide dinitrate   | Phencyclidine  | Vinorelbine     |
| Digitoxin          | Isosorbide mononitrate | Pimozide       | Zolpidem        |
| Dihydroergotamine  | Isradipine             | Pioglitazone   | Zonisamide      |
| Diltiazem          | Itraconazole           | Primaquine     | Zopiclone       |
| Disopyramide       | Ketamine               | Progesterone   |                 |
| CYP2C19 INHIBITORS |                        |                |                 |
| Chloramphenicol    | Indomethacin           | Pantoprazole   |                 |
| Cimetidine         | Ketoconzaole           | Probenicid     |                 |
| Esomeprazole       | Lansoprazole           | Rabeprazole    |                 |
| Felbamate          | Modafinil              | Ticlodipine    |                 |
| Fluoxetine         | Omeprazole             | Topiramate     |                 |
| Fluvoxamine        | Oxcarbazepine          |                |                 |
| CYP2C19 INDUCERS   |                        |                |                 |
| Carbamazepine      |                        |                |                 |
| Norethindrone      |                        |                |                 |
| Prednisone         |                        |                |                 |
| Rifampicin         |                        |                |                 |
| CYP2C19 SUBSTRATES |                        |                |                 |
| Amitriptyline      | Hexobarbital           | Omeprazole     | Teniposide      |
| Carisoprodol       | Imipramine             | Pantoprazole   | R-warfarin      |
| Citalopram         | Indomethacin           | Phenobarbitone |                 |
| Chloramphenicol    | Lansoprazole           | Phenytoin      |                 |
| Clomipramine       | S-mephenytoin          | Primidone      |                 |
| Clopidogrel        | R-mephobarbital        | Progesterone   |                 |
| Cyclophosphamide   | Moclobemide            | Proguanil      |                 |
| N-DeME             | Nelfinavir             | Propanolol     |                 |
| Diazepam           | Nilutamide             | Rabeprazole    |                 |  
Because the lists of these agents are constantly changing, frequently-updated lists available at http://medicine.iupui.edu/clinpharm/ddis/table.asp will be consulted.
untitled h1
appendix c drugs with risk

Obtained from the Arizona Center for Education and Research on Therapeutics (AZCERT)
website http://crediblemeds.org, last revised May 4, 2015.  
| Generic Name            | Brand Names (Partial List)               | Drug Class          | Therapeutic Use      | Risk       | Route     |
|-------------------------|------------------------------------------|---------------------|----------------------|------------|-----------|
| Category                |                                          |                     |                      |            |           |
| Amiodarone              | Cordarone®, Pacerone®,                   | Anti-arrhythmic     | Abnormal heart       | Risk of    | oral,     |
| Nexterone@              | rhythm                                   | TdP                 | injection            |            |           |
| Anagrelide              | Agrylin®, Xagrid®                        | Phosphodiesterase   | Thrombocythemia      | Risk of    | oral      |
| 3 inhibitor             | TdP                                      |                     |                      |            |           |
| Arsenic trioxide        | Trisenox®                                | Anti-cancer         | Cancer (leukemia)    | Risk of    | injection |
| TdP                     |                                          |                     |                      |            |           |
| Astemizole (Removed     | Hismanal®                                | Antihistamine       | Allergic rhinitis    | Risk of    | oral      |
| from US Market)         | TdP                                      |                     |                      |            |           |
| (Removed from US        |                                          |                     |                      |            |           |
| Market)                 |                                          |                     |                      |            |           |
| Azithromycin            | Zithromax®, Zmax®                        | Antibiotic          | Bacterial infection  | Risk of    | oral,     |
| TdP                     | injection                                |                     |                      |            |           |
| Bepridil (Removed from  | Angina Pectoris                          | Risk of             |                      |            |           |
| Vascor®                 | Anti-anginal                             | oral                |                      |            |           |
| TdP                     |                                          |                     |                      |            |           |
| US Market) (Removed     | (heart pain)                             |                     |                      |            |           |
| from US Market)         |                                          |                     |                      |            |           |
| Chloroquine             | Aralen®                                  | Anti-malarial       | Malaria              | Risk of    | oral      |
| TdP                     |                                          |                     |                      |            |           |
| Chlorpromazine          | Thorazine®, Largacti®,                   | Anti-psychotic /    | Schizophrenia,       | Risk of    | oral,     |
| Megaphen®               | Anti-emetic                              | nausea, many others | TdP                  | injection, |           |
| suppository             |                                          |                     |                      |            |           |
| Cilostazol              | Pletal®                                  | Phosphodiesterase   | Intermittent         | Risk of    | oral      |
| 3 inhibitor             | claudication                             | TdP                 |                      |            |           |
| Ciprofloxacin           | Cipro®, Cipro-XR®, Neofloxin® Antibiotic | Bacterial infection | Risk of              | oral,      |           |
| TdP                     | injection                                |                     |                      |            |           |
| Increase GI motility    |                                          |                     |                      |            |           |
| Cisapride (Removed from | Propulsid®                               | GI stimulant        | Risk of              | oral       |           |
| US Market) (Removed     | TdP                                      |                     |                      |            |           |
| from US Market)         |                                          |                     |                      |            |           |
| Citalopram              | Celexa®, Cipramil®                       | Anti-depressant,    | Depression           | Risk of    | oral      |
| TdP                     |                                          |                     |                      |            |           |
| SRI                     |                                          |                     |                      |            |           |
| Clarithromycin          | Biaxing, Prevpace                        | Antibiotic          | Bacterial infection  | Risk of    | oral      |
| TdP                     |                                          |                     |                      |            |           |
| Cocaine                 | Cocaine                                  | Local anesthetic    | Anesthesia (topical) | Risk of    | topical   |
| TdP                     |                                          |                     |                      |            |           |
| Disopyramide            | Norpace®                                 | Anti-arrhythmic     | Abnormal heart       | Risk of    | oral      |
| rhythm                  | TdP                                      |                     |                      |            |           |
| Dofetilide              | Tikosyn®                                 | Anti-arrhythmic     | Abnormal heart       | Risk of    | oral      |
| rhythm                  | TdP                                      |                     |                      |            |           |
| Domperidone  (On non    | Motilium®, Motillium®,                   | Anti-nausea         | Nausea, vomiting     | Risk of    | oral,     |
| TdP                     |                                          |                     |                      |            |           |
| US Market) (On non US   | Motinorm Costi®, Nomit®                  | injection,          |                      |            |           |
| Market)                 | suppository                              |                     |                      |            |           |
untitled h1
ctep #9605

| Clinical Center #14-C-0150    |                                                  |                       |                      |           |           |
|-------------------------------|--------------------------------------------------|-----------------------|----------------------|-----------|-----------|
| Generic Name                  | Brand Names (Partial List)                       | Drug Class            | Therapeutic Use      | Risk      | Route     |
| Category                      |                                                  |                       |                      |           |           |
| Donepezil                     | Aricept®                                         | Cholinesterase        | Dementia             | Risk of   | oral      |
| inhibitor                     | (Alzheimer's Disease)                            | TdP                   |                      |           |           |
| Dronedarone                   | Multaq3                                          | Anti-arrhythmic       | Abnormal heart       | Risk of   | oral      |
| rhythm                        | TdP                                              |                       |                      |           |           |
| Droperidol                    | Inapsine®, Droleptan®, Dridol®, Anti-psychotic / | Anesthesia (adjunct), | Risk of              | injection |           |
| Xomolix®                      | Anti-emetic                                      | nausea                | TdP                  |           |           |
| Erythromycin                  | E.E.S.®, Robimycin®,                             | Antibiotic            | Bacterial infection, | Risk of   | oral,     |
| EMycin®, Erymax®, Ery-Tab®,   | increase GI motility                             | TdP                   | injection            |           |           |
| Eryc Ranbaxy®, Erypar®,       |                                                  |                       |                      |           |           |
| Eryped®, Erythrocin Stearate  |                                                  |                       |                      |           |           |
| Filmtab®, Erythrocot®,        |                                                  |                       |                      |           |           |
| E-Base®, Erythroped®,         |                                                  |                       |                      |           |           |
| losone®, MY-E®,               |                                                  |                       |                      |           |           |
| Pediamycin®, Zineryt®,        |                                                  |                       |                      |           |           |
| Abboticin®, Abboticin-ES®,    |                                                  |                       |                      |           |           |
| Erycin®, PCE Dispertab®,      |                                                  |                       |                      |           |           |
| Stiemycine®, Acnasol®,        |                                                  |                       |                      |           |           |
| Tiloryth®                     |                                                  |                       |                      |           |           |
| Escitalopram                  | Cipralex®, Lexapro®, Nexito®,                    | Anti-depressant,      | Depression (major),  | Risk of   | oral      |
| Anxiset-E® (India), Exodus®   | SRI                                              | anxiety disorders     | TdP                  |           |           |
| (Brazil), Eston (Israel),     |                                                  |                       |                      |           |           |
| Seroplex®, Elicea®, Lexami®,  |                                                  |                       |                      |           |           |
| Lexam®, Entact® (Greece),     |                                                  |                       |                      |           |           |
| Losita® (Bangladesh),         |                                                  |                       |                      |           |           |
| Reposil® (Chile), Animaxen®   |                                                  |                       |                      |           |           |
| (Colombia), Esitalo®          |                                                  |                       |                      |           |           |
| (Australia), Lexamil® (South  |                                                  |                       |                      |           |           |
| Africa)                       |                                                  |                       |                      |           |           |
| Flecainide                    | Tambocor®, Almarytm®,                            | Anti-arrhythmic       | Abnormal heart       | Risk of   | oral      |
| Apocard®, Ecrinal®, Flécaine® | rhythm                                           | TdP                   |                      |           |           |
| Anti-fungal                   |                                                  |                       |                      |           |           |
| Fluconazole                   | Diflucan®, Trican®                               | Fungal infection      | Risk of              | oral,     |           |
| TdP                           | injection                                        |                       |                      |           |           |
| Grepafloxacin  (Off           | Raxar®                                           | Antibiotic            | Bacterial infection  | Risk of   | oral      |
| market worldwide) (Off        | TdP                                              |                       |                      |           |           |
| market worldwide)             |                                                  |                       |                      |           |           |
| Halofantrine                  | Halfan®                                          | Anti-malarial         | Malaria              | Risk of   | oral      |
| TdP                           |                                                  |                       |                      |           |           |
| Haloperidol                   | Hold (US & UK),                                  | Anti-psychotic        | Schizophrenia,       | Risk of   | oral,     |
| Aloperidin®, Bioperidolo®,    | agitation                                        | TdP                   | injection            |           |           |
| Brotopon®, Dozic®,            |                                                  |                       |                      |           |           |
| Duraperidol® (Germany),       |                                                  |                       |                      |           |           |
| Einalon S®, Eukystol®,        |                                                  |                       |                      |           |           |
| Halosten®, Keselan®, Linton®, |                                                  |                       |                      |           |           |
| Peluces®, Serenace®,          |                                                  |                       |                      |           |           |
| Serenase®, Sigaperidol®       |                                                  |                       |                      |           |           |
| Ibutilide                     | Corvert®                                         | Anti-arrhythmic       | Abnormal heart       | Risk of   | injection |
| rhythm                        | TdP                                              |                       |                      |           |           |
| Levo¤oxacin                   | Levaquin®, Tavanic®                              | Antibiotic            | Bacterial infection  | Risk of   | oral,     |
| TdP                           | injection                                        |                       |                      |           |           |
| 84                            |                                                  |                       |                      |           |           |  
| Generic Name              | Brand Names (Partial List)                    | Drug Class          | Therapeutic Use              | Risk    | Route     |
|---------------------------|-----------------------------------------------|---------------------|------------------------------|---------|-----------|
| Category                  |                                               |                     |                              |         |           |
| Levomethadyl (Removed     | Oriaam®                                       | Opiate              | Narcotic dependence          | Risk of | oral      |
| from US Market)           | TdP                                           |                     |                              |         |           |
| (Removed from US          |                                               |                     |                              |         |           |
| Market)                   |                                               |                     |                              |         |           |
| Mesoridazine (Removed     | Serentil®                                     | Anti-psychotic      | Schizophrenia                | Risk of | oral      |
| from US Market)           | TdP                                           |                     |                              |         |           |
| (Removed from US          |                                               |                     |                              |         |           |
| Market)                   |                                               |                     |                              |         |           |
| Methadone                 | Dolophine®, Symoron®,                         | Opiate              | Narcotic dependence,         | Risk of | oral,     |
| Amidone®, Methadose®,     | pain                                          | TdP                 | injection                    |         |           |
| Physeptone®, Heptadon®    |                                               |                     |                              |         |           |
| Avelox®, Avalox®, Avelon® | Bacterial infection                           | Risk of             |                              |         |           |
| Moxifloxacin              | Antibiotic                                    | oral,               |                              |         |           |
| TdP                       | injection                                     |                     |                              |         |           |
| Ondansetron               | Zofran®, Anset®, Ondemet®,                    | Anti-emetic         | Nausea, vomiting             | Risk of | oral,     |
| Zuplenz®, Emetron®,       | TdP                                           | injection           |                              |         |           |
| Ondavell®, Emeset®,       |                                               |                     |                              |         |           |
| Ondisolv®, Setronax®      |                                               |                     |                              |         |           |
| Pentamidine               | Pentam®                                       | Antifungal          | Fungal infection             | Risk of | injection |
| (Pneumocystis             | TdP                                           |                     |                              |         |           |
| pneumonia)                |                                               |                     |                              |         |           |
| Tourette's Disorder       | Risk of                                       |                     |                              |         |           |
| Pimozide                  | Orap®                                         | Anti-psychotic      | oral                         |         |           |
| TdP                       |                                               |                     |                              |         |           |
| Probucol (Removed from    | Lorelco®                                      | Antilipemic         | Hypercholesterolemia Risk of | oral    |           |
| US Market) (Removed       | TdP                                           |                     |                              |         |           |
| from US Market)           | Pronestyl®, Procan®                           | Anti-arrhythmic     | Abnormal heart               | Risk of | injection |
| Procainamide (Oral off    |                                               |                     |                              |         |           |
| US mkt) (Oral off US mkt) | rhythm                                        | TdP                 |                              |         |           |
| Propofol                  | Diprivan®, Propoven®                          | Anesthetic, general | Anesthesia                   | Risk of | injection |
| TdP                       |                                               |                     |                              |         |           |
| Quinidine                 | Quinaglute®, Duraquin®,                       | Anti-arrhythmic     | Abnormal heart               | Risk of | oral,     |
| Quinact®, Quinidex®,      | rhythm                                        | TdP                 | injection                    |         |           |
| Cin-Quin®, Quinora®       |                                               |                     |                              |         |           |
| Sevoflurane               | Ulanes, Sojourns                              | Anesthetic, general | Anesthesia                   | Risk of | inhaled   |
| TdP                       |                                               |                     |                              |         |           |
| Sotalol                   | Betapace®, Sotalex®, Sotacor® Anti-arrhythmic | Abnormal heart      | Risk of                      | oral    |           |
| rhythm                    | TdP                                           |                     |                              |         |           |
| Sparfloxacin (Removed     | Zagam®                                        | Antibiotic          | Bacterial infection          | Risk of | oral      |
| from US Market)           | TdP                                           |                     |                              |         |           |
| (Removed from US          |                                               |                     |                              |         |           |
| Market)                   |                                               |                     |                              |         |           |
| Sulpiride (On non US      | Dogmatil®, Dolmatil®,                         | Anti-psychotic,     | Schizophrenia                | Risk of | oral      |
| Market) (On non US        | Eglonyl®, Espiride®, Modal®,                  | TdP                 |                              |         |           |
| atypical                  |                                               |                     |                              |         |           |
| Market)                   | Sulpor®                                       |                     |                              |         |           |
| Terfenadine (Removed      | Seldane®                                      | Antihistamine       | Allergic rhinitis            | Risk of | oral      |
| from US Market)           | TdP                                           |                     |                              |         |           |
| (Removed from US          |                                               |                     |                              |         |           |
| Market)                   |                                               |                     |                              |         |           |
| Thioridazine              | Mellaril®, Novoridazine®,                     | Anti-psychotic      | Schizophrenia                | Risk of | oral      |
| Thioril®                  | TdP                                           |                     |                              |         |           |
| 85                        |                                               |                     |                              |         |           |  
|  Generic Name   | Brand Names (Partial List)   |  Drug Class    | Therapeutic Use   | Risk    | Route   |
|-----------------|------------------------------|----------------|-------------------|---------|---------|
| Category        |                              |                |                   |         |         |
| Vandetanib      | Caprelsa®                    | Anti-cancer    | Cancer (thyroid)  | Risk of | oral    |
| TdP             |                              |                |                   |         |         |
appendix d 89zr-labeled panitumumab order
ctep #9605

| 89Zr-panitumumab Order Form     |                      |                              |             |     |
|---------------------------------|----------------------|------------------------------|-------------|-----|
| Site                            | Subject / Patient ID | Date of Request * DD MM YYYY |             |     |
| Scheduled 89Zr-Panitumumab Scan | Time                 | Dose Activity                |             |     |
| DD                              | MM                   | YYYY                         | 24 hr clock | mCi |
appendix d 89zr-labeled panitumumab order
1. site section complete and

| *Please place 89Zr-Panitumumab orders 5 business days prior to scheduled scan date and time.  Site Contact Information Site Name: Principal Investigator: Study Coordinator:  NCI Protocol Number:  Shipping Information Account Name: Contact Name: Contact Phone & Email  or Fax: Shipment Address:  2. Leidos Radiopharmacy Section: Confirm receipt of Request Form and fax or e-mail to  Clinical Site 89Zr-Panitumumab Request Form received on ___ ___ ________ by _________________________   DD MM YYYY Print Name 3. Leidos Radiopharmacy Section  Date request received: Leidos Radiopharmacy Shipment Number: Tracking Number: Mode of Transportation: Batch Number: Attachments:  Please affix copy of the syringe label below   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Checked by: Packed by: *Date Shipped:*
appendix d 89zr-labeled panitumumab order
appendix e - patient study

The study drugs are given over a 28-day period of time called cycles. The 28-day treatment cycle will be repeated as long as you are tolerating the medications and your cancer is either stable or getting better. The chart below shows what will happen to you during cycle 1 and future cycles after you sign the consent form and start the study. Each cycle is numbered. The left-hand column shows the day in the cycle, and the right-hand column tells you what will happen on that day.  
| Day                          | What to do and what will happen to you                                                                                                |                                                                                                             |
|------------------------------|---------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|
| Before  starting  study drug | -                                                                                                                                     | Check in at the Outpatient Clinic                                                                           |
| -                            | Get routine blood tests and electrocardiogram of your heart (EKG)                                                                     |                                                                                                             |
| -                            | Urine tests to check for protein in your urine                                                                                        |                                                                                                             |
| -                            | Pregnancy test for women who are able to become pregnant                                                                              |                                                                                                             |
| -                            | Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider                                    |                                                                                                             |
| -                            | CT or MRI scan will be done                                                                                                           |                                                                                                             |
| -                            | Echocardiogram or MUGA scan will be done to check your heart                                                                          |                                                                                                             |
| -                            | Eye exam                                                                                                                              |                                                                                                             |
| -                            | Blood draws for research will be obtained from some patients                                                                          |                                                                                                             |
| -                            | For patients who agree to undergo 89Zr-panitumumab PET/CT, baseline scans  will be done prior to the start of cycle 1.                |                                                                                                             |
| Cycle 1,                     | -                                                                                                                                     | Get routine blood tests and EKG (does not need to be repeated if done within                                |
| Day 1                        | 3 days before starting treatment)                                                                                                     |                                                                                                             |
| -                            | Urine tests to check for protein in your urine (does not need to be repeated if  done within 3 days before starting treatment)        |                                                                                                             |
| -                            | Receive the first dose of ziv-aflibercept through a vein                                                                              |                                                                                                             |
| -                            | Receive the first dose of ganetespib through a vein; for patients who have  tumor biopsies, this dose of ganetespib will not be given |                                                                                                             |
| Cycle 1,                     | -                                                                                                                                     | An electrocardiogram of your heart will be done approximately 24 hours after                                |
| Day 2                        | receiving ganetespib                                                                                                                  |                                                                                                             |
| Cycle 1,                     | -                                                                                                                                     | For patients who have agreed to undergo tumor biopsies, the first tumor  biopsy will take place on this day |
| Day 7  Cycle 1,              | -                                                                                                                                     | Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider          |
| Day 8                        | -                                                                                                                                     | Blood draws for research will be obtained from some patients. Get routine  blood tests and EKG              |
| -                            | Ganetespib will be given through a vein                                                                                               |                                                                                                             |  
| Clinical Center #14-C-0150 Day What to do and what will happen to you Cycle 1,  - An electrocardiogram of your heart will be done approximately 24 hours after  receiving ganetespib Day 9  Cycle 1,  - Check in at the Outpatient Clinic Day 15  - Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider - Get routine blood tests and EKG  - Urine tests to check for protein in your urine  - Ziv-aflibercept will be given through a vein  - Ganetespib will be given through a vein  - Blood draws for research will be obtained from some patients  Cycle 1,  - An electrocardiogram of your heart will be done approximately 24 hours after  Day 16  receiving ganetespib - For patients who agree to undergo 89Zr-panitumumab PET/CT, post-treatment  scans will be done on this day. If there are scheduling conflicts, scans may be  done during Cycle 2, Day 16.  Cycle 1,  - No drug is given Day 22  Cycle 2,  - Have a history taken of how you feel and undergo a physical examination by a  Day 1  Health Care Provider - Get routine blood tests and EKG  - Urine tests to check for protein in your urine  - Ziv-aflibercept will be given through a vein  - Ganetespib will be given through a vein  Cycle 2,  - For patients who having tumor biopsies, the second tumor biopsy will take  Day 7  place on this day prior to treatment with ganetespib. Cycle 2,  - Check in at the Outpatient Clinic Day 8  - Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider  - Blood draws for research will be obtained from some patients  - Get routine blood tests and EKG  - Ganetespib will be given through a vein  Cycle 2,  - Check in at the Outpatient Clinic Day 15  - Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider - Get routine blood tests and EKG  - Urine tests to check for protein in your urine   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Day                                          | What to do and what will happen to you - Ziv-aflibercept will be given through a vein - Ganetespib will be given through a vein  - Blood draws for research will be obtained from some patients   |                                                                           |
|----------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|
| Cycle 2,                                     | -                                                                                                                                                                                                 | For patients who agree to undergo 89Zr-panitumumab PET/CT, post-treatment |
| Day 16                                       | scans not performed during cycle 1, day 16 can have scans rescheduled to this  day.                                                                                                               |                                                                           |
| Cycle 2,                                     | -                                                                                                                                                                                                 | No drug is given                                                          |
| Day 22  Cycle 3,  Day 1 and  15, and  onward | -                                                                                                                                                                                                 | Check in at the Outpatient Clinic                                         |
| -                                            | Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider                                                                                                |                                                                           |
| -                                            | Get routine blood tests and EKG                                                                                                                                                                   |                                                                           |
| -                                            | Urine tests to check for protein in your urine                                                                                                                                                    |                                                                           |
| -                                            | CT scan to determine how your tumor is responding to the treatment will be  done every 8 weeks (every 2 cycles)                                                                                   |                                                                           |
| -                                            | Ziv-aflibercept will be given through a vein                                                                                                                                                      |                                                                           |
| -                                            | Ganetespib will be given through a vein                                                                                                                                                           |                                                                           |
| -                                            | Blood draws for research will be obtained from some patients on day 1 of  every cycle                                                                                                             |                                                                           |
| Cycle 3,  Day 8, and  onward                 | -                                                                                                                                                                                                 | Check in at the Outpatient Clinic                                         |
| -                                            | Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider                                                                                                |                                                                           |
| -                                            | Get routine blood tests and EKG                                                                                                                                                                   |                                                                           |
| -                                            | Ganetespib will be given through a vein                                                                                                                                                           |                                                                           |
appendix f expansion phase pd
appendix e - patient study

| Date:                                                                                                              | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 1                                        |                        |
|--------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|------------------------|
| CTEP Protocol P9605                                                                                                | Page 102-12798 for Sample Pick-up  Lab phone: 301-451-1169                             | Research Nurse:        |
| Dose level:                                                                                                        | Phone:                                                                                 |                        |
| Patient ID:                                                                                                        | Lead AI/PI:   Phone:                                                                   |                        |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION Day Time Instructions Ideal Time Actual Time | Record comments (i.e., if collection missed),  and sign each time you collect a sample |                        |
| Day 1                                                                                                              | Prior to drug                                                                          | PD 400 2x 4 mL K3 EDTA |
| administration                                                                                                     | Label tube: sample number, date and time                                               |                        |  
| Date:                                                                                                              | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 8                                        |                        |
|--------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|------------------------|
| CTEP Protocol P9605                                                                                                | Page 102-12798 for Sample Pick-up  Lab phone: 301-451-1169                             | Research Nurse:        |
| Dose level:                                                                                                        | Phone:                                                                                 |                        |
| Patient ID:                                                                                                        | Lead AI/PI:   Phone:                                                                   |                        |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION Day Time Instructions Ideal Time Actual Time | Record comments (i.e., if collection missed),  and sign each time you collect a sample |                        |
| Day 8                                                                                                              | Prior to drug                                                                          | PD 401 2x 4 mL K3 EDTA |
| administration*                                                                                                    | Label tube: sample number, date and time                                               |                        |
| *No drugs administered on Day 7; Ganetespib administered on Day 8                                                  |                                                                                        |                        |  
| Date:                                                                                                              | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 1 DAY 15                                       |                                                                  |
|--------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|------------------------------------------------------------------|
| CTEP Protocol P9605                                                                                                | Page 102-12798 for Sample Pick-up  Lab phone: 301-451-1169                             | Research Nurse:                                                  |
| Dose level:                                                                                                        | Phone:                                                                                 |                                                                  |
| Patient ID:                                                                                                        | Lead AI/PI:   Phone:                                                                   |                                                                  |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION Day Time Instructions Ideal Time Actual Time | Record comments (i.e., if collection missed),  and sign each time you collect a sample |                                                                  |
| Day 15                                                                                                             | Completion time of Ziv-aflibercept and Ganetespib IV administration:                   |                                                                  |
| 4 hr after                                                                                                         |                                                                                        |                                                                  |
| Day 15                                                                                                             | completion of drug  administration                                                     | PD 402 2x 4 mL K3 EDTA Label tube: sample number, date and  time |  
| Date:                                                                                                              | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 2 DAY 8                                        |                 |
|--------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|-----------------|
| CTEP Protocol P9605                                                                                                | Page 102-12798 for Sample Pick-up  Lab phone: 301-451-1169                             | Research Nurse: |
| Dose level:                                                                                                        | Phone:                                                                                 |                 |
| Patient ID:                                                                                                        | Lead AI/PI:  Phone:                                                                    |                 |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION Day Time Instructions Ideal Time Actual Time | Record comments (i.e., if collection missed),  and sign each time you collect a sample |                 |
| PD 403 2x 4 mL K3 EDTA Label tube: sample number, date and  time                                                   |                                                                                        |                 |
| Day 8                                                                                                              | Prior to drug  administration*                                                         |                 |  
*No drugs administered on Day 7; Ganetespib administered on Day 8  
| Date:                                                                                                              | PD BLOOD SAMPLE COLLECTION SHEET: CYCLE 2 DAY 15                                       |                                                                  |
|--------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|------------------------------------------------------------------|
| CTEP Protocol P9605                                                                                                | Page 102-12798 for Sample Pick-up  Lab phone: 301-451-1169                             | Research Nurse:                                                  |
| Dose level:                                                                                                        | Phone:                                                                                 |                                                                  |
| Patient ID:                                                                                                        | Lead AI/PI:   Phone:                                                                   |                                                                  |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION Day Time Instructions Ideal Time Actual Time | Record comments (i.e., if collection missed),  and sign each time you collect a sample |                                                                  |
| Day 15                                                                                                             | Completion time of Ziv-aflibercept and Ganetespib IV administration:                   |                                                                  |
| 4 hr after                                                                                                         |                                                                                        |                                                                  |
| Day 15                                                                                                             | completion of drug  administration                                                     | PD 404 2x 4 mL K3 EDTA Label tube: sample number, date and  time |  
| Date:                                                                                                              | PD BLOOD SAMPLE COLLECTION SHEET: DAY 1 EACH CYCLE/PER PI                              |                 |
|--------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|-----------------|
| CTEP Protocol P9605                                                                                                | Page 102-12798 for Sample Pick-up  Lab phone: 301-451-1169                             | Research Nurse: |
| Dose level:                                                                                                        | Phone:                                                                                 |                 |
| Patient ID:                                                                                                        | Lead AI/PI:   Phone:                                                                   |                 |
| PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION Day Time Instructions Ideal Time Actual Time | Record comments (i.e., if collection missed),  and sign each time you collect a sample |                 |
| PD 40X 2x 4 mL K3 EDTA Label tube: sample number, date and  time                                                   |                                                                                        |                 |
| Day                                                                                                                | Before drug  administration                                                            |                 |