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%

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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

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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

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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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