Intramural Perspective from the Clinical Research Side

1. Intramural Perspective from the Clinical Research Side Andrea B. Apolo, MD Head, Bladder Cancer Section Genitourinary Malignancies Branch Center for Cancer Research National Cancer Institute National Institutes of Health June 23, 2014

2. Outline • My Research • My Story • The Undergraduate Scholarship Program • The Assistant Clinical Investigator program • The Loan Repayment Program • Tenure Track position • Lasker Scholarship Program • U01-grant opportunity

3. My research

4. Urothelial Carcinoma • In the Unites States, over 15,000 deaths are expected to occur in 2014 • Is a chemosensitive disease but response durations are short • No standard 2nd line therapy in the United States • Prognosis for metastatic disease is poor • Median survival for metastatic disease is approximately 12–14 months • We are in desperate need of effective therapies

5. Major Advances in Targeted Therapy in Cancer Advances in tumor biology and cancer genetics have led to the development of effective targeted therapies in oncology over the last decade

6. Presented by: Andrea B. Apolo FDA Approved Drugs for Genitourinary Tumors in the last Seven Years

7. FDA Approved Drugs for Genitourinary Tumors in the last Seven Years Presented by: Andrea B. Apolo

8. Presented by: Andrea B. Apolo FDA Approved Drugs for Genitourinary Tumors in the last Seven Years

9. Presented by: Andrea B. Apolo FDA Approved Drugs for Genitourinary Tumors in the last Seven Years

10. NCI Bladder Cancer Program Muscle Invasive Metastatic Non-muscle Invasive 1st line Neoadjuvant Therapy Adjuvant Therapy Cisplatin-ineligible Cisplatin-eligible MetMab-MVAC HER-2 Vaccine Lenalidomide/Gem/Carbo Lenalidomide/Gem/Cis BCG refractory 2st line and beyond Tri-modality Therapy Metastatic PANVAC and BCG Chemo+xrt RTOG TRC105 MetMab-XRT Cabazitaxel Cabo+PD1+Ipilimumab Cabozantinib Cabo Phase III AMG337 COXEN

12. Presented by: Andrea B. Apolo A phase II study of cabozantinib in patients with advanced refractory urothelial carcinoma (NCT01688999) PI: Apolo • Cabozantinib • An oral agent that inhibits multiple • receptor tyrosine kinases, primarily • targeting MET and VEGFR2 • Has been shown to reduce tumor • growth, metastasis, and angiogenesis There are three study cohorts: Metastatic urothelial carcinoma Bone only metastatic urothelial carcinoma Metastatic rare bladder cancer histology

13. Presented by: Andrea B. Apolo Chest CT scan of a metastatic urothelial cancer patient on single agent cabozantinib September 2012 December 2012

14. Presented by: Andrea B. Apolo NaF PET/CT of two metastatic urothelial cancer patients with bone-only disease on single agent cabozantinib Bone–only patient 1 Bone–only patient 3 post-cabozantinib Baseline Baseline post-cabozantinib

15. Regulatory T cells (Tregs) in bladder cancer patients treated with cabozantinib N=28 Tregs at baseline and after treatment with cabozantinib in CD4+ T-cells Baseline Tregs in CD4+ T-cells p=0.0137 Responders Partial response+ NaF PET improvement Non-Responders Stable disease+ Progressive disease • Percent Treg among CD4+ T-cells • decreased significantly after treatment • with cabozantinib • Cabozantinib has immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining cabozantinib with immunotherapeutic strategies • Patients with lower percent Treg (CD4+CD25hiFoxp3+) in CD4+ T-cells (<3.89% = median value) at baseline had better response compared with those who had higher percent Treg at baseline

16. Presented by: Andrea B. Apolo We are in the beginning of an immunotherapy revolution in oncology 1 • Immune check point therapy has demonstrated significant clinical activity in multiple solid tumors • PD-L1 is highly expressed in patients with urothelial cancer of the bladder 4 2 1 3. Xylinas E et al. Eur J Surg Oncol. 2014 Jan;40(1):121-7 4. Nakanishi J et al. Cancer Immunol Immunother 2007 56(8):1173-82 1. Inman BA, Sebo TJ, Frigola X, et al Cancer. 2007 15;109(8):1499-505 2. Boorjian S A et al. Clin Cancer Res 2008;14:4800-4808

17. Presented by: Andrea B. Apolo Phase I combination study with cabozantinib in development in advanced urothelial carcinoma PI: Andrea Apolo Part 1: Cabozantinib + PD-1/PD-L1 inhibitor Part 2: Cabozantinib + PD-1/PD-L1 inhibitor + CTLA-4 inhibitor

18. Clinical Trial using COXEN in patients with advanced urothelial cancer Advanced Urothelial Cancer COXEN Score for each drug of 80+ FDA approved drugs FDA Approved agents ranked in order of predicted potency for patient PI A. Apolo D. Theodorescu

19. My Story

20. NIH Undergraduate Scholarship Program (UGSP) • The undergraduate scholarships are awarded on a competitive basis to students nation-wide who demonstrate a commitment to pursuing research careers offered at NIH. The application period extends from November through the last day of January of each year. • The basic qualification requirements: • A grade point average of 3.3 (on a 4.0 scale) or within the top 5% of your class • Be from a disadvantaged background* • Be enrolled or accepted for enrollment as a full-time student for the at an accredited four year institution • Be a U.S. Citizen, National, or qualified non-citizen

21. NIH UGSP Information at-a-Glance • Scholarships cover tuition and educational expenses of up to $20,000 per academic year • In exchange for each year awarded, UGSP Scholars are required to participate in a 10-week internship during the summer and work for one year in an intramural research laboratory after graduation.

22. Assistant Clinical Investigator (ACI) positions Purpose: To help fill the gap between clinical fellowship and tenure-track level positions Benefits: Provides clinical investigators with advanced mentoring, independent resources, and more time to develop their talents and research accomplishments. Student loan repayment is possible Appointment: 3 years, with two possible 1-year extensions

23. Center for Cancer Research: Clinical Branches Dermatology Developmental Therapeutics Endocrinology Oncology Experimental Immunology Exper. Transplantation & Immunology Genetics Genitourinary Malignancies HIV and AIDS Malignancy HIV Host-Virus Lymphoid Malignancies Neuro-Oncology Pediatric Oncology Radiation Biology Radiation Oncology Surgery Thoracic and Gastrointestinal Oncology Urologic Oncology Vaccine* Women’s Malignancies Molecular Imaging Pathology * Also has basic component

24. The Lasker Clinical Research Scholars Program Total program duration up to 12 years: Intramural Research Program full support (salary and research support) for 5-7 years Opportunity for Extramural financial support (salary and/or research support of $500,000/year) at outside institution for 5 years Candidates – Early stage clinical researchers, with the ability to conduct independent research. These are tenure-track level positions. http://www.nih.gov/science/laskerscholar/

25. Partnerships • A new grant (UO1) offers extramural investigators the chance to collaborate with intramural investigators at the Clinical Center • 10 grants awarded in 2014 • Next round of applications due in 2015

26. All my patients and their families Medical Oncology: H Parnes, B Dahut, G Gulley, R Madan Nursing: C Keen, L Otten, C Boyle Lab Team: J Trepel, Y Tomita, MJ Lee, S Lee D Bottaro, Y Lee, R Costello J Schlom, J Hodge, J Fallon, A Lyon M Dean, D Figg, L Prokunina, L Cao Urology: P Agarwal, A Metwalli, M Linehan Pathology: M Merino, M Raffeld Radiology: P Choyke, K Kurdziel, L Lindenberg, L Folio Statistician: S Steinberg CTEP: J Wright, H Streicher, E Sharon MSKCC: D Bajorin, J Rosenberg, B Bochner H Herr, D Feldman, G Bosl UNC: M Milowsky GUMDROP: G Philips, N Dawson, J Kim, M Schoenberg, J Aragong-Ching Mount Sinai: M Galsky U Colorado: D Theodorescu Jefferson: J Hoffman-Censits BCAN: D Zipursky Quale, V Hoffman Exelixis: A DeCillis, J Frye

27. Thank You!