Nilotinib With Radiation for High Risk Chordoma

Study Overview
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Brief Summary
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The study drug, Nilotinib, is believed to slow down tumor growth by regulating a gene involved in cellular growth of chordoma cells. During this research study, subjects will also receive radiation therapy which is considered a standard treatment for advanced chordomas. It is hoped by adding nilotinib, the benefits of radiation therapy can be enhanced without adding significant toxicities. The purpose of this research study is to determine the safety of nilotinib when used in combination with radiation therapy, and the highest dose of nilotinib that can be given safely with radiation therapy.

Detailed Description
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Nilotinib will be taken orally daily in two cycles of 28 days each. Two weeks after taking nilotinib, subjects will begin radiation therapy. Radiation therapy will continue every weekday until Day 56 of the study. If it is determined that the subject's tumor cannot be removed by surgery, an additional 3 weeks of radiation therapy will be applied after Day 56 of the study. During study visits subjects will have physical exams, routine blood tests, urine and blood clotting tests, and EKGs. Subjects will also have tumor assessment by chest CT and MRI or CT of the tumor at screening, on approximately Day 56 of the study, then every 6 months for one year and then annually thereafter if ther is no disease progression.

Official Title
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Phase I Study of Nilotinib Given With Radiation For Patients With High Risk Chordoma

Conditions
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Chordoma

Intervention / Treatment
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* Drug: Nilotinib
* Radiation: Radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed chordoma Considered to have high risk disease Measurable disease Life expectancy > 3 months Adequate organ function Able to swallow oral capsules Exclusion Criteria: Previous treatment with any other tyrosine kinase inhibitor Previous treatment with radiotherapy to the primary or recurrent chordomas Impaired cardiac function Currently receiving treatment with strong CYP3A4 inhibitors Requires anticoagulation with coumadin Impaired GI function or GI disease that may significantly alter the absorption of study drug Acute or chronic pancreatic disease Known cytopathologically confirmed CNS infiltration Another primary malignant disease which requires systemic treatment Acute or chronic liver disease or severe renal disease considered unrelated to the cancer History of significant congenital or acquired bleeding disorder unrelated to cancer Major surgery within 4 weeks prior to Day 1 of the study or who have not recovered from prior surgery Treatment with other investigational agents within 30 days of Day 1 History of non-compliance to medical regimens Pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib/XRT<br>Nilotinib is administered 400mg PO BID for 2 weeks and then administered concurrently with daily radiation therapy until completion of radiation therapy. Participants can then undergo surgery if clinically possible. After either surgery or definitive radiation, participants have the option to continue on nilotinib therapy. | Drug: Nilotinib<br>* Orally, daily 200 - 400 mg BID<br>* Other names: Tasigna;Radiation: Radiation therapy<br>* External beam radiation will be delivered at 1.8 Gy per day, 5 days per week (excluding holidays)for a total of 28 fractions over a 6 weeks period.<br>* Other names: External beam radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the dose limiting toxicities (DLTs) for participants when treated above the maximum tolerated dose (MTD). | A DLT will be defined as any of the following events occurring during days 1-56 of study according to CTCAE version 4.0. MTD is then determined by identifying a dose cohort demonstrating > or = 30% rate of DLTs, which are defined as: Any Grade ≥ 3 nonhematologic toxicity except alopecia, nausea, or vomiting not otherwise controlled by maximual supportive care. Grade 4 neutropenia (ANC < 500/µL) lasting > 5 days, Grade 3 thrombocytopenia lasting > 7 days, or Grade 4 thrombocytopenia Failure to resume treatment delays within a defined period of time. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events | Adverse event profile, as determined by CTC AE version 4.0, will be determined for patients treated with nilotinib and radiation therapy. Adverse events analyses will include: Detailed examination of adverse events Laboratory test results Vital signs or other physical findings Frequency and extent of dose modification The assessment of adverse events will be based mainly on the frequency of adverse events, particularly adverse events leading to discontinuation of treatment and on the number of significant laboratory abnormalities. | 2 years | 
| Survival | To obtain preliminary data regarding local control, distant control, disease-free survival, and overall survival with this regimen | 2 years | 
| PDGFR signaling | To determine if nilotinib decreases PDGFR signaling in chordoma tumor samples in treated patients | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High Risk Chordoma