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14.1.3.2 human studies

In a study of 45 patients in a first in human study of INC280, one DLT, CTCAE Grade 3 AST and alkaline phosphatase increase was reported for a patient at the dose level of 50mg. Forty-four (97.8%) out of 45 patients experienced adverse events (AEs) any grades and regardless of causality. The most common adverse events (≥15%) were peripheral edema (44.4%), nausea (35.6%), fatigue (33.3%), tremor (28.9%), vomiting (24.4%), abdominal pain (22.2%), headache (20.0%), cough (17.8%), abdominal tenderness, constipation, diarrhea, dizziness and musculoskeletal pain (15.6%, respectively). The most frequent AEs suspected to be related to INC280 any CTCAE grade, were nausea (26.7%), tremor (24.4%), fatigue (20.0%), peripheral edema (15.6%), and headache (15.6%). Two patients (4.4%) experienced CTCAE Grade 3 or Grade 4 AEs suspected to be treatment related, which were AST (50mg QD) and hypophosphataemia (150mg QD).  
| Expected Adverse Events are listed in the table below. MedDRA system organ class Preferred Term Blood and Lymphatic Anemia,  System Disorders Neutropenia Ear and Labyrinth Disorders Deafness Gastrointestinal disorders Vomiting  Nausea Diarrhea Abdominal pain Pancreatitis General disorders and administration site conditions Fatigue,  Edema peripheral Asthenia Cellulitis  Pruritus Urticaria   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Expected Adverse Events are listed in the table below.  
| Version Date: February 14, 2022  MedDRA system organ class   | Preferred Term                                                                                                                                                                                                    |
|--------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Infections and infestations                                  | Lung infection                                                                                                                                                                                                    |
| Investigations                                               | Alanine aminotransferase increased Aspartate aminotransferase increased  Gamma-glutamyltransferase increased  Amylase increased  Blood bilirubin increased  Lipase increased Amalyse increased Creatine Increased |
| Metabolism and nutrition                                     | Decreased appetite                                                                                                                                                                                                |
| disorders                                                    | Hyponatremia Dehydration Hypophagia  Hypophosphatemia                                                                                                                                                             |
| Nervous system disorders                                     | Dizziness                                                                                                                                                                                                         |
| Respiratory, thoracic and mediastinal disorders              | Dyspnea, cough                                                                                                                                                                                                    |  
Eleven serious adverse events (SAEs) have been reported in 9 (20%) out of 45 patients. They were deep venous thrombosis, electrocardiogram QT prolonged, failure to thrive (all at 10 mg QD), clavicle fracture (20mg QD), ascites, humerus fracture (both at 200mg QD), constipation, pneumonia, staphylococcal sepsis, hepatic encephalopathy (all at 400mg QD), diarrhea (50mg BID). All SAEs were reported as not related to INC280. 14.1.4 Administration procedures See section 3.2 14.1.5 Incompatibilities The chemical name of INC280 drug substance is 2-fluoro-N-methyl-4-(7-(quinolin-6ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride monohydrate. INC280 has a molecular formula of C23H21Cl2FN6O2 and a molecular weight of 503.35 (salt form on monohydrate basis). INC280 dihydrochloride monohydrate is a slightly hygroscopic light yellow to yellow powder. The solubility of INC280 dihydrochloride at 25°C is approximately 3.47 mg/mL in water; 0.08 mg/mL in pH 6.8 and 0.72 mg/mL in pH 3.0 buffer. Please see section 4 on concomitant medications for managing drug interactions. 14.1.6 Drug compliance and accountability Clinical drug supply must be accounted for and patients will be asked to return all unused study drug and packaging on a regular basis, usually at the time of scheduled clinic visits and at the end of the study or at the time of study drug discontinuation. Drug accountability and subject compliance will be assessed with drug dispensing and return records as described below. All oral self-administered investigational agents will be properly accounted for, handled, and disposed in accordance with existing federal regulations and principles of Good Clinical Practice. CRR SOPs on self-administered investigational agents may be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Documenting+Drug+Accountability+for+ Oral+Investigational+Agents The investigator will maintain accurate records of receipt of all INC280, including dates of receipt. In addition, accurate records will be kept regarding when and how much study treatment is dispensed and used by each subject in the study. Reasons for deviation from the expected dispensing regimen must also be recorded. At the conclusion of the study, and, as appropriate during the course of the study, the Investigator will return all used and unused study drug, packaging, drug labels, and a copy of the completed drug accountability ledger to Novartis. 14.1.7 Disposal and destruction The drug supply will be destroyed at a Novartis facility, Drug Supply group or third party, as appropriate. Study drug destruction at the investigational site will only be permitted if authorized by Novartis in a prior agreement and if permitted by local regulations.
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15 references

1 Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2012. *CA: a cancer journal for* clinicians 62, 10-29, doi:10.3322/caac.20138 (2012).  
2 Singer, E. A., Gupta, G. N. & Srinivasan, R. Targeted therapeutic strategies for the management of renal cell carcinoma. *Current opinion in oncology* 24, 284-290, doi:10.1097/CCO.0b013e328351c646 (2012).  
3 Chung, P., Linehan, W. M. & Bratslavsky, G. in *ASCO Genitourinary Cancers Symposium.* 4 Cohen, H. T. & McGovern, F. J. Renal-cell carcinoma. *The New England journal of* medicine 353, 2477-2490, doi:10.1056/NEJMra043172 (2005).  
5 Sankin, A., Cohen, J., Wang, H., Macchia, R. J. & Karanikolas, N. Rate of renal cell carcinoma subtypes in different races. *International braz j urol : official journal of the* Brazilian Society of Urology 37, 29-32;discussion 33-24 (2011).  
6 Delahunt, B. & Eble, J. N. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 10, 537-544 (1997).
7 Furge, K. A. *et al.* Gene expression profiling in kidney cancer: combining differential expression and chromosomal and pathway analyses. *Clinical genitourinary cancer* 5, 227231, doi:10.3816/CGC.2006.n.041 (2006).  
8 Linehan, W. M., Srinivasan, R. & Schmidt, L. S. The genetic basis of kidney cancer: a metabolic disease. *Nature reviews. Urology* 7, 277-285, doi:10.1038/nrurol.2010.47 (2010).  
9 Singer, E. A., Bratslavsky, G., Linehan, W. M. & Srinivasan, R. Targeted therapies for non-clear renal cell carcinoma. *Targeted oncology* 5, 119-129, doi:10.1007/s11523-0100148-3 (2010).  
10 Schmidt, L. *et al.* Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. *Nature genetics* 16, 68-73, doi:10.1038/ng0597-68 (1997).  
11 Lubensky, I. A. *et al.* Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. *The American journal of pathology* 155, 517-526, doi:10.1016/S0002-9440(10)65147-4 (1999).  
12 Schmidt, L. *et al.* Novel mutations of the MET proto-oncogene in papillary renal carcinomas. *Oncogene* 18, 2343-2350, doi:10.1038/sj.onc.1202547 (1999).
13 Schmidt, L. *et al.* Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. *Cancer research* 58, 1719-1722 (1998).  
14 Schmidt, L. S. *et al.* Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. *The Journal of urology* 172, 1256-1261 (2004).  
15 Duh, F. M. *et al.* Gene structure of the human MET proto-oncogene. *Oncogene* 15, 15831586, doi:10.1038/sj.onc.1201338 (1997).  
16 Cecchi, F., Rabe, D. C. & Bottaro, D. P. Targeting the HGF/Met signaling pathway in cancer therapy. *Expert opinion on therapeutic targets* 16, 553-572, doi:10.1517/14728222.2012.680957 (2012).  
17 Peruzzi, B. & Bottaro, D. P. Targeting the c-Met signaling pathway in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 12, 3657-3660, doi:10.1158/1078-0432.CCR-06-0818 (2006).  
18 Fischer, J. *et al.* Duplication and overexpression of the mutant allele of the MET protooncogene in multiple hereditary papillary renal cell tumours. *Oncogene* 17, 733-739, doi:10.1038/sj.onc.1201983 (1998).  
19 Zhuang, Z. *et al.* Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. *Nature genetics* 20, 66-69, doi:10.1038/1727 (1998).  
20 Balint, I., Szponar, A., Jauch, A. & Kovacs, G. Trisomy 7 and 17 mark papillary renal cell tumours irrespectively of variation of the phenotype. *Journal of clinical pathology* 62, 892895, doi:10.1136/jcp.2009.066423 (2009).  
21 Kovacs, G., Fuzesi, L., Emanual, A. & Kung, H. F. Cytogenetics of papillary renal cell tumors. *Genes, chromosomes & cancer* 3, 249-255 (1991).  
22 Tannir, N. M. *et al.* A phase 2 trial of sunitinib in patients with advanced non-clear cell renal cell carcinoma. *European urology* 62, 1013-1019, doi:10.1016/j.eururo.2012.06.043 (2012).  
23 Molina, A. M. *et al.* Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma. *Investigational new drugs* 30, 335-340, doi:10.1007/s10637-0109491-6 (2012).  
24 Lee, J. L. *et al.* Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. *Ann Oncol* 23, 2108-2114, doi:10.1093/annonc/mdr586 (2012).  
25 Hudes, G. *et al.* Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.  
The New England journal of medicine 356, 2271-2281, doi:10.1056/NEJMoa066838 (2007).  
26 Dutcher, J. P. *et al.* Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. *Medical oncology* 26, 202-209, doi:10.1007/s12032-009-9177-0 (2009).  
27 Choueiri, T. K. *et al.* Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26, 127-131, doi:10.1200/JCO.2007.13.3223 (2008).  
28 A, R., S, O. & DR, F. First-line sunitinib in type I and papillary renal cell carcinoma
(PRCC): SUPAP, a phase II study of the French Genito-Urinary Group (GETUG) and the Group of Early Phase trials (GEP). *Ann Oncol* 23, Abstr 797PD (2012).  
29 Gordon, M. S. *et al.* Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27, 5788-5793, doi:10.1200/JCO.2008.18.8821 (2009).  
30 Choueiri, T. K. *et al.* Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. *Journal of clinical oncology :* official journal of the American Society of Clinical Oncology 31, 181-186, doi:10.1200/JCO.2012.43.3383 (2013).  
31 Srinivasan, R. et al. in *ASCO Genitourinary Cancers Symposium.* 32 Choueiri, T. et al. in *ASCO Genitourinary Cancers Symposium.* 33 Dharmawardana, P. G., Giubellino, A. & Bottaro, D. P. Hereditary papillary renal carcinoma type I. *Current molecular medicine* 4, 855-868 (2004).  
34 Zhu, M. *et al.* Exposure-response (E-R) analysis of rilotumumab (R, AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30, suppl abstract 2535 (2012).  
35 Spigel, D. R. *et al.* The MetLUNG study: A randomized, double-blind, phase III study of onartuzumab (MetMAb) plus erlotinib versus placebo plus erlotinib in patients with advanced, MET-positive non-small cell lung cancer (NSCLC). *Journal of clinical* oncology : official journal of the American Society of Clinical Oncology 30, suppl abstract TPS7616 (2012).  
36 Bottaro, D. P. *et al.* Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. *Science* 251, 802-804 (1991).  
37 Rubin, J. S. & Bottaro, D. P. *Nature UCSD Signaling Gateway: Molecule Pages. A*
comprehensive review of HGF biology, 2011., <http://www.signalinggateway.org/molecule/query?afcsid=A004032> (
38 Athauda, G. *et al.* c-Met ectodomain shedding rate correlates with malignant potential.  
Clinical cancer research : an official journal of the American Association for Cancer Research 12, 4154-4162, doi:10.1158/1078-0432.CCR-06-0250 (2006).  
39 Bottaro, D. P., Athauda, G., Giubellino, A. & Burgess, T. US Provisional Patent Application No. 60/734,993 (November 8, 2005) and US Provisional Patent Application No. 60/780,626 (March 9, 2006): Methods for Diagnosing and Monitoring the Progression of Cancer.  
40 Cecchi, F. *et al.* Shed MET (sMET), VEGFA, and sVEGFR2 are markers of foretinib treatment in metastatic gastric cancer patients *Mol Cancer Ther* 8, Abstract B210, doi: 10.1158/1535-7163.TARG-09-B210 (2009).  
41 Russo, A. L. *et al.* Urine analysis and protein networking identify met as a marker of metastatic prostate cancer. *Clinical cancer research : an official journal of the American* Association for Cancer Research 15, 4292-4298, doi:10.1158/1078-0432.CCR-09-0599 (2009).  
42 Eisenhauer, E. A. *et al.* New response evaluation criteria in solid tumours: revised RECIST
guideline (version 1.1). *Eur J Cancer* 45, 228-247, doi:10.1016/j.ejca.2008.10.026 (2009).
43 Scher, H. I. *et al.* Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. *Journal of clinical oncology : official journal of the* American Society of Clinical Oncology 26, 1148-1159, doi:10.1200/JCO.2007.12.4487 (2008).  
44 Rustin, G. J. *et al.* Re: New guidelines to evaluate the response to treatment in solid tumors
(ovarian cancer). *J Natl Cancer Inst* 96, 487-488, doi:10.1093/jnci/djh081 (2004).
45 Bubley, G. J. *et al.* Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. *Journal of clinical oncology : official journal of the American* Society of Clinical Oncology 17, 3461-3467, doi:10.1200/JCO.1999.17.11.3461 (1999).  
46 Vergote, I. *et al.* Re: new guidelines to evaluate the response to treatment in solid tumors
[ovarian cancer]. Gynecologic Cancer Intergroup. *J Natl Cancer Inst* 92, 1534-1535, doi:10.1093/jnci/92.18.1534 (2000).
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16 appendices

| 16.1                                                                                                   | APPENDIX A: PERFORMANCE STATUS CRITERIA                                                                                |             |                                                                    |           |                                 |                                   |                                 |
|--------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|-------------|--------------------------------------------------------------------|-----------|---------------------------------|-----------------------------------|---------------------------------|
| ECOG Performance Status Scale                                                                          | Karnofsky Performance Scale                                                                                            |             |                                                                    |           |                                 |                                   |                                 |
| Grade                                                                                                  | Descriptions                                                                                                           | Percent     | Description                                                        |           |                                 |                                   |                                 |
| 100                                                                                                    | Normal,                                                                                                                | no          | complaints,                                                        | no        |                                 |                                   |                                 |
| evidence of disease.                                                                                   |                                                                                                                        |             |                                                                    |           |                                 |                                   |                                 |
| Normal activity. Fully active, able                                                                    |                                                                                                                        |             |                                                                    |           |                                 |                                   |                                 |
| 0                                                                                                      | to                                                                                                                     | carry       | on                                                                 | all       | pre-disease                     | Able to carry on normal activity; |                                 |
| performance without restriction.                                                                       | 90                                                                                                                     | minor       | signs                                                              | or        | symptoms                        | of                                |                                 |
| disease.                                                                                               |                                                                                                                        |             |                                                                    |           |                                 |                                   |                                 |
| Symptoms,                                                                                              | but                                                                                                                    | ambulatory. |                                                                    |           |                                 |                                   |                                 |
| Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or | Cares for self, unable to carry on                                                                                     |             |                                                                    |           |                                 |                                   |                                 |
| sedentary                                                                                              | nature                                                                                                                 | (e.g.,      | light                                                              | 70        | normal activity or to do active |                                   |                                 |
| housework, office work).                                                                               | work.                                                                                                                  |             |                                                                    |           |                                 |                                   |                                 |
| 80                                                                                                     | Normal activity with effort; some  signs or symptoms of disease.                                                       |             |                                                                    |           |                                 |                                   |                                 |
| 1                                                                                                      | Requires occasional assistance,                                                                                        |             |                                                                    |           |                                 |                                   |                                 |
| In                                                                                                     | bed                                                                                                                    | <50%        | of                                                                 | the       | time.                           | 60                                | but is able to care for most of |
| Ambulatory and capable of all                                                                          | his/her needs.                                                                                                         |             |                                                                    |           |                                 |                                   |                                 |
| 2                                                                                                      | self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                  | 50          | Requires considerable assistance  and frequent medical care.       |           |                                 |                                   |                                 |
| 40                                                                                                     | Disabled, requires special care  and assistance.                                                                       |             |                                                                    |           |                                 |                                   |                                 |
| 3                                                                                                      | In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours. | 30          | Severely disabled, hospitalization  indicated. Death not imminent. |           |                                 |                                   |                                 |
| 20                                                                                                     | Very                                                                                                                   | sick,       | hospitalization                                                    |           |                                 |                                   |                                 |
| indicated. Death not imminent.                                                                         |                                                                                                                        |             |                                                                    |           |                                 |                                   |                                 |
| 4                                                                                                      | 100%                                                                                                                   | bedridden.  | Completely                                                         |           |                                 |                                   |                                 |
| disabled.                                                                                              | Cannot carry on any                                                                                                    |             |                                                                    |           |                                 |                                   |                                 |
| self-care. Totally confined to bed  or chair.                                                          | 10                                                                                                                     | Moribund,   | fatal                                                              | processes |                                 |                                   |                                 |
| progressing rapidly.                                                                                   |                                                                                                                        |             |                                                                    |           |                                 |                                   |                                 |
| 5                                                                                                      | Dead.                                                                                                                  | 0           | Dead.                                                              |           |                                 |                                   |                                 |
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16.2 appendix b patient's pill/

Today's date ________________________________ Cycle__________ Week_________ Dose_________ Patient Name_____________________________ Patient Study ID ___________________________________
(*initials acceptable)*
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instructions to the patient

1. Complete one form for each 1 week period (1 cycle = 4 weeks) 2. You will take your medication in the morning and evening. You should not eat anything 2 hours prior to or after the medication; drink a full glass of water with the medication and 2 hours after you take the medication. If you miss the intended time to take your INC 280 by 4 hours or more, do not take that dose. 3. Record the date, the number of pills you took, and when you took them. Also record that you have fasted. 4. If you have any comments or **notice any side effects**, please record them in the Comments column. 3. Please bring your pill bottle and this form to your physician when you go for your next appointment.  
| 3.                                                               | Please bring your pill bottle and this form to your physician when you go for your next appointment. Time Fasted  Fasted Taken Before After SIDE EFFECTS/COMMENTS   | Init   |    |       |
|------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------|----|-------|
| Date                                                             | Day #                                                                                                                                                               | #      | of | pills |
| taken                                                            |                                                                                                                                                                     |        |    |       |
| #1  #1  # 2  # 2  # 3  #3  # 4  # 4  # 5  # 5  # 6  # 6  #7  # 7 |                                                                                                                                                                     |        |    |       |  
Patient's Signature: _____________________________________________ Date: ______________________________________  
Physician's Office will complete this section:  
| 1.                                                                     | Date patient started protocol treatment________________   | Date patient was removed from study   |       |        |    |       |       |      |
|------------------------------------------------------------------------|-----------------------------------------------------------|---------------------------------------|-------|--------|----|-------|-------|------|
| _____________________ 2. Patient's planned                             | daily                                                     | dose________________________          | Total | number | of | pills | taken | this |
| week_____________________ Physician/Nurse/Data                         | Manager's                                                 | Signature                             |       |        |    |       |       |      |
| ______________________________________________________________________ |                                                           |                                       |       |        |    |       |       |      |
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16.3 appendix c instruction sheet

You have been prescribed the medication INC 280. INC 280 is believed to work by blocking MET, a protein in your body which if altered can promote tumor formation and spread. You should take the INC 280 the same time twice a day, at least 8 hours apart. You should fast for 2 hours before and 2 hours after taking INC 280. You should take a full glass of water (8 OZ) with INC 280 and another full glass of water 2 hours after taking INC 280. If necessary, you can take ginger ale, apple juice, or cranberry juice in addition to water during the fasting period. Document the time you take the medication on your diary. If you forget to take your medication at the usual time, you can take it within 4 hours, then resume your usual schedule the next day. If you vomit a dose of INC280, do NOT take another. Bring your medication and your diary with you to every doctor's visit. ALWAYS check with your medical team before beginning any new medication. There are few important points to remember: - NO grapefruit juice or Seville orange juice while on INC 280. Avoid for 7 days prior to the first dose - NO herbal supplements or teas while on INC 280 until you speak with your medical team. - If you are of reproductive age, you MUST use birth control. - Report any unplanned surgery or wounds IMMEDIATELY to your medical team so your INC 280 can be adjusted accordingly. - You MUST wear sunscreen (SPF> 45) when outside. - If you develop a skin rash, notify your medical team immediately so we can begin medication to prevent the rash from worsening. - You cannot take long acting proton pump inhibitors while on INC 280 because they will affect the absorption of the medication. Examples of these would be Prilosec (omeprasole); Protonix (pantoprazol); Prevacid (lansoprazol). Medications to Treat Common Side Effects: When you begin INC 280, the medical team will give you medications for nausea, diarrhea, and constipation. Please notify the medical team if any of these are occurring, document in your diary, and begin the appropriate medication listed below. Please be sure to have a working thermometer at home so you can check your temperature when instructed to do so. For Nausea: - Prochlorperazine / Ondansetron: Take as directed. For Diarrhea: - Loperamide 2mg tablets to be taken for diarrhea, as directed. - Diet: BRAT diet - bananas, rice, applesauce, toast - can be helpful For Constipation: - Docusate 100mg - take 1-2 initially for constipation, then 1 a day as needed If questions or problems during the week please contact: Erin Purcell RN research nurse; 240-858-3933 OR erin.purcell@nih.gov. After 5pm or on weekends call the NIH page operator: 301-496-1211 and ask to speak with Urologic Oncology fellow. In case of an emergency, go to your nearest hospital emergency department.