Combination of Sorafenib and Radiation for Brain Metastases and Primary Brain Tumors

Study Overview
=================
Brief Summary
-----------------
Sorafenib™ has the potential to inhibit tumor growth, tumor angiogenesis , and enhance radiation response. This study will test the combination of Sorafenib™ and radiation therapy with or without temozolomide to determine tolerance of the combined treatments. Defining safe dosing of Sorafenib™ in this combination therapy will be achieved.

Detailed Description
-----------------
The current standard of care for patients with brain metastatic malignancies is to receive radiation therapy alone, while the standard of care for patients with high grade primary brain malignancies, astrocytomas, is to receive to receive concurrent temozolomide with radiation therapy. In this phase I study, based on the range of efficacy of kinase inhibitors and its ability to cross the blood-brain barrier we will conduct two parallel studies. The first is to combine sorafenib and radiation therapy for the treatment of patients with brain metastases and the second is to combine sorafenib with temozolomide for primary brain tumors.

Official Title
-----------------
Phase I Study of the Combination of Sorafenib and Radiation Therapy -/+ Temozolomide for the Treatment of Patients With Brain Metastases and Primary Brain Tumors

Conditions
-----------------
Brain Metastases, Primary Brain Tumors

Intervention / Treatment
-----------------
* Drug: Sorafenib
* Drug: Temozolomide
* Radiation: Radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients requiring a minimum 2-week course of radiation therapy Age > or = 18 All tumors of the central nervous system, or metastasis to the central nervous system. Measurable disease preferred but not required for eligibility Histologically or cytologically documented evidence of malignancy (for infratentorial and supratentorial glioma patients only). Radiographic evidence of brain metastasis ECOG performance status of 0 or 1 Life expectancy of > or = 3 months Exclusion Criteria: Patients receiving chemotherapy or other investigational drugs must be discontinued 14 days prior to enrollment. Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. Active clinically serious infection > CTCAE Grade 2

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Brain Metastasis<br>Sorafenib and Radiotherapy | Drug: Sorafenib<br>* Sorafenib 200mg twice daily during XRT and 30 days after. (Sorafenib will be escalated for both cohorts to determine maximum tolerated dose)<br>* Other names: Nexavar;Radiation: Radiotherapy<br>* Radiation Therapy (XRT)<br>* Other names: radiation oncology;|
| Experimental: Cohort 2 - Gliomas<br>Sorafenib and Radiotherapy, plus Temozolomide | Drug: Sorafenib<br>* Sorafenib 200mg twice daily during XRT and 30 days after. (Sorafenib will be escalated for both cohorts to determine maximum tolerated dose)<br>* Other names: Nexavar;Drug: Temozolomide<br>* For Cohort 2 - Gliomas only.<br>* Other names: Temodal;Radiation: Radiotherapy<br>* Radiation Therapy (XRT)<br>* Other names: radiation oncology;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Sorafenib | To determine the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D) of Sorafenib and radiotherapy -/+ temozolomide patients with malignancies of the brain. | 30 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response rate (in those patients with measurable disease) | 30 days post-treatment | 
| Prediction of 1-year Recurrence | Determine if an increase in urinary VEGF and MMP levels, from the end of treatment to a patient's 1-month follow-up examination, is predictive of 1-year recurrence | 1 year post-treatment | 
| Safety and Toxicity of Sorafenib | To evaluate the safety and toxicity profile of Sorafenib in combination with radiation therapy -/+ temozolomide | 30 days post-treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sorafenib, Radiation Therapy, Radiotherapy, Temozolomide, Brain Metastases, Brain Tumors