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
Disclosures
• I have no conflicts
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
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 19832. Rich 19853. Sundaresan 19904. Keisch 19915. Bjornsson 19936. Fuchs 2005
Management Cont.
• Higher rates of local control with high-dose photon/proton RT (70.2-77.4 Gy) +/- surgical resection1
• 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 surgery2
– Median 77.4 Gy
– 5-year PFS 79.8%
5
1. Delaney 20142. Chen 2013
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?
PDGFR as a Target in Chordoma
• PDGFR beta highly expressed and phosphorylated1,4
• PDGF alpha and beta receptor and ligand present in skull base chordoma2
• Clinical activity of imatinib3,4
1. Tamborini 20062. Orzan 20073. Stacchiotti 20094. Stacchiotti 2012
Hypothesis: PDGFR beta inhibition will sensitize chordoma to radiation therapy
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)
Phase I study of Nilotinib Given with Radiation for Patients with High Risk Chordoma
Tumor resection
Nilotinib
1 14Day
Radiation
50.4 Gy
15 56
Nilotinib
Microscopic: 18 Gy Gross: 23.4 Gy
Nilotinib
1 14Day
Nilotinib
50.4 Gy
15 56
Nilotinib
23.4 Gy
Nilotinib
Nilotinib with Radiation for High Risk Chordoma
Open-label, standard 3+3 dose-escalation
11 patient planned expansion at the MTD
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
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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
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
Adverse Events:
5 Patients at Dose Level 1: 200 mg bid
DLT’s:Grade 3 BilirubinProlonged 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)
Adverse Events Cont.
Organ System Event Grade 2N (%)
Grade 3N (%)
Hematologic Lymphopenia 1 (7) 3 (20%)Anemia 1 (7)
Metabolism Hypophosphatemia 1 (7)
Renal Creatinine Increased 1 (7)
Gastrointestinal Nausea 1 (7)Vomiting 1 (7)Hyperbilirubinemia 1 (7)ALT increased 1 (7)Pancreatitis 1 (7)
Immunologic Wound Infection 1 (7)
Dermatologic Radiation Dermatitis 1 (7)Rash 1 (7)
Neurologic Pain 1 (7)
Nilotinib with Radiation in High Risk Chordoma
16
Nilotinib/Radiation and Surgery10 patients
Nilotinib/Radiation Only5 patients
1 Off-study and Unevaluable
Response by RECIST
1 2 3 4 5 6 7 8 9 10 11 12 13 14
-15
-10
-5
0
5
10
15
Nilotinib-Radiation Day 57 (prior to surgery)
Response by RECIST: Nilotinib-Radiation
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1 2 3 4
-25
-20
-15
-10
-5
0
5
10
15
20
Best Response
1
2
3
4
0 5 10 15 20 25 30 35 40
Duration of Response
Months
*
*off drug (DLT)
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Sacral Chordoma 77.4 Gy RBE + Nilotinib (IMRT 30.6 Gy, Protons 46.8 GyRBE)
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
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
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