1. PHASE 1 STUDY OF NILOTINIB GIVEN WITH RADIATION FOR PATIENTS WITH HIGH RISK CHORDOMA (Interim Update) Gregory Cote, Yen-Lin Chen, Thomas DeLaney, David Harmon, Norbert Liebsch, John Mullen, Alex Haynes, Santiago Lozano-Calderon, Joseph Schwab, Kevin Raskin, Karen Bernstein, Francis Hornicek, Edwin Choy CTOS 2014

2. Disclosures I have no conflicts

3. Chordoma Uncommon tumor of the axial skeleton: 200-300 cases per year Believed to arise from the embryonic notochordal remnant Variable clinical course: relatively indolent - locally aggressive 20-30% can develop metastatic disease

4. Management Surgery with or without radiation is the standard of care High local failure rates with radical surgery and conventional radiation dosing <60 Gy local failure rates: 50-100% 1-6 1.Cummings 1983 2.Rich 1985 3.Sundaresan 1990 4.Keisch 1991 5.Bjornsson 1993 6.Fuchs 2005

5. Management Cont. Higher rates of local control with high-dose photon/proton RT (70.2-77.4 Gy) +/- surgical resection 1 Primary chordoma: – Local control at 7 years: 22/23 patients – 1 failure received RT alone Recurrent chordoma: – Local control at 7 years: 3/6 patients High-dose photon/proton without surgery 2 – Median 77.4 Gy – 5-year PFS 79.8% 5 1.Delaney 2014 2.Chen 2013

6. Patients at High Risk for Local Failure Unresectable tumors / radiation therapy alone Prior intra-lesional/unplanned incomplete resection Local recurrence after surgery Can we improve local control for these patients?

7. PDGFR as a Target in Chordoma PDGFR beta highly expressed and phosphorylated 1,4 PDGF alpha and beta receptor and ligand present in skull base chordoma 2 Clinical activity of imatinib 3,4 1.Tamborini 2006 2.Orzan 2007 3.Stacchiotti 2009 4.Stacchiotti 2012 Hypothesis: PDGFR beta inhibition will sensitize chordoma to radiation therapy

8. Nilotinib Synthetic aminopyrimidine Activity against multiple kinases: – BCR-ABL (10-60 nM) – KIT (30-210 nM) – DDR1 (1 nM) – PDGFR beta (57-72 nM) – PDGFR alpha (180 nM) – CSFR1 (45 nM)

9. Phase I study of Nilotinib Given with Radiation for Patients with High Risk Chordoma Tumor resection Nilotinib 1 14 Day Radiation 50.4 Gy 15 56 Nilotinib Microscopic: 18 Gy Gross: 23.4 Gy Nilotinib 1 14 Day Nilotinib 50.4 Gy 15 56 Nilotinib 23.4 Gy Nilotinib

10. Nilotinib with Radiation for High Risk Chordoma Open-label, standard 3+3 dose-escalation 11 patient planned expansion at the MTD

11. Objectives Primary: – To determine the MTD and/or recommended phase 2 dose Secondary – Safety of nilotinib combined with radiation – Overall response rate, local/distant disease control, DFS, OS – Nilotinib/RT effects in chordoma resection samples 11

12. Eligibility High-risk Chordoma – Local recurrence after surgery alone – Prior intralesional/incomplete resection – Unresectable or marginally resectable by advanced local disease Measurable disease, ECOG 0-2, age >18 No prior TKI No prior radiation therapy 12

13. Patients 16 patients consented as of 10/1/14 – 1 patient under active treatment currently Male / Female: 12 / 4 Median age: 60 (range 30-76) Primary tumor with high-risk features: 4 Partial or unplanned resection: 7 Locally recurrent tumor: 5

14. Adverse Events: 5 Patients at Dose Level 1: 200 mg bid DLT’s: Grade 3 Bilirubin Prolonged Grade 2 Nausea and Vomiting 6 Patients at Dose Level -1: 200 mg qd 1 DLT: Prolonged Grade 2 ALT Open for 11 further patient slots (5/11 enrolled to date)

15. Adverse Events Cont. Organ SystemEvent Grade 2 N (%) Grade 3 N (%) HematologicLymphopenia1 (7)3 (20%) Anemia1 (7) MetabolismHypophosphatemia1 (7) RenalCreatinine Increased1 (7) GastrointestinalNausea1 (7) Vomiting1 (7) Hyperbilirubinemia1 (7) ALT increased1 (7) Pancreatitis1 (7) ImmunologicWound Infection1 (7) DermatologicRadiation Dermatitis1 (7) Rash1 (7) NeurologicPain1 (7)

16. Nilotinib with Radiation in High Risk Chordoma 16 Nilotinib/Radiation and Surgery 10 patients Nilotinib/Radiation Only 5 patients 1 Off-study and Unevaluable

17. Response by RECIST

18. Response by RECIST: Nilotinib-Radiation 18 * *off drug (DLT)

19. 19 Sacral Chordoma 77.4 Gy RBE + Nilotinib (IMRT 30.6 Gy, Protons 46.8 GyRBE)

20. Interim Study Conclusions Nilotinib at 200 mg per day + radiation is the MTD and it is reasonably safe Clinical activity unknown at this time – PFS / OS data pending Correlatives pending completion of the study – PDGFR signaling, necrosis rate Neoadjuvant and Phase I studies are feasible in chordoma

21. Acknowledgements MGH Edwin Choy, Thomas DeLaney, Yen-Lin Chen, David Harmon, Norbert Liebsch, John Mullen, Alex Haynes, Santiago Lozano- Calderon, Joseph Schwab, Kevin Raskin, Karen Bernstein, Francis Hornicek Clinical Trials Office Kristina Goodwin, Amy Gisondi, Ashley O’Meara, Eleni Tsiroyannis, David Wells, Barbara Anderson Stephen L. Harris Chordoma Fund 21