Bendamustine and Radiation Therapy in Treating Patients With Brain Metastases Caused by Solid Tumors

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as bendamustine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Stereotactic radiation therapy may be able to send x-rays directly to the tumor and cause less damage to normal tissue. PURPOSE: This phase I trial is studying the side effects and best dose of bendamustine when given together with radiation therapy in treating patients with brain metastases caused by solid tumors.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the recommended phase II dose of bendamustine hydrochloride when administered in combination with stereotactic radiotherapy for the treatment of patients with 1-4 brain metastases from solid malignancies. Secondary Determine bendamustine hydrochloride pharmacokinetics and correlate this to bendamustine hydrochloride levels in brain metastases, brain margin, arachnoid, cerebral spinal fluid, and plasma acquired at the time of surgery. Assessment of local control of brain metastases. OUTLINE: This is a dose-escalation study of bendamustine hydrochloride. Patients with no potentially resectable lesion(s) receive bendamustine hydrochloride IV over 30 minutes and stereotactic radiotherapy once daily for 5 days. Patients with potentially resectable lesion(s) receive bendamustine hydrochloride IV over 30 minutes on days 1-3 and undergo surgery on day 3. At least 4 weeks after surgery, these patients receive adjuvant bendamustine hydrochloride and stereotactic fractionated radiotherapy as above (in patients with no potentially resectable lesion[s]) Blood samples are collected periodically for pharmacokinetic studies. Cerebrospinal fluid, arachnoid, tumor margin, and tumor samples are also collected during surgery for correlative studies. After completion of study treatment, patients are followed every 3 months for 21 months.

Official Title
-----------------
Phase I Study of Bendamustine and Fractionated Stereotactic Radiotherapy of Patients With 1- 4 Brain Metastases From Solid Malignancies

Conditions
-----------------
Metastatic Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Drug: bendamustine
* Other: laboratory biomarker analysis
* Procedure: Surgical Resection of Brain Metastases
* Radiation: Stereotactic body radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed cancer with 1 to 4 brain metastases imaged by MRI/CT scans not involving thalamus, basal ganglia or brain stem. No cancer originating in central nervous system Candidate for clinically indicated surgery to resect brain lesions. Karnofsky score of at least 60 At least 18 years of age Life expectancy of more than two months Exclusion Criteria: Evidence of leptomeningeal metastases. Need immediate treatment to prevent neurological deterioration. Prior brain radiotherapy or surgery for current brain metastases. Radiosensitive primary tumors such as small cell lung cancer, germ cell tumors, lymphoma, leukemia or multiple myeloma. Absolute neutrophil count (ANC)<1500/mm3 or platelets <50,000/mms. Brain metastasis diameter greater than 5 cm. Not pregnant or nursing More than 3 weeks since prior chemotherapy. No evidence of ischemia on EKG and/or reduced cardiac ejection fraction (i.e., < 50%) on ECHO. No known sensitivity or allergy to bendamustine hydrochloride or mannitol No more than 3 prior cytotoxic chemotherapy regimens No unresolved persistent toxicities for 4 weeks from prior chemotherapy or 6 weeks for nitrosoureas. Calculated creatinine clearance <40 ml/min.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustine and Fractionated stereotactic radiotherapy<br>Bendamustine 40 mg/m2 and will be administered IV on days 1,2,and 3 prior to surgery on each day of SRT (Sterotactic radiation therapy). Laboratory biomarker analysis will be obtained on day 1 or 2 only from patients undergoing surgery on day 3 (i.e. Pharmacokinetic samples will not be collected from patients who begin SRT on day 1). Surgical Resection of Brain Metastases Day 3 (immediately after Bendamustine) Stereotactic fractionated radiation therapy starting at least 4 weeks after surgery (Day 1 if no surgery ); 30 Gy in 5 daily fractions(Mon-Fri). Concurrent Bendamustine is administered on Days of Stereotactic Radiotherapy (Arm 1: 40 mg/m2/ Day; Arm 2: 50 mg/m2/day). | Drug: bendamustine<br>* 40 mg/m2 will be administered IV on days 1,2,and 3 prior to surgery.on each day of SRT.<br>* Other names: Treanda;Other: laboratory biomarker analysis<br>* samples will be obtained on day 1 or 2 only from patients undergoing surgery on day 3 (i.e. PK samples will not be collected from patients who begin SRT on day 1).<br>* Other names: Laboratory Procedure;Procedure: Surgical Resection of Brain Metastases<br>* Surgical Resection of Brain Metastases Day 3 (immediately after Bendamustine)<br>* Other names: surgery;Radiation: Stereotactic body radiation therapy<br>* Starting at least 4 weeks after surgery (Day 1 if no surgery ); 30 Gy in 5 daily fractions(Mon-Fri)<br>* Other names: Stereotactic Fractionated Radiation Therapy;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine recommended dose of Bendamustine when used in combination with Stereotactic Radiotherapy (STR) for treatment of patients with 1-4 brain metastases. |  | up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of bendamustine |  | up to 4 years | 
| Levels of bendamustine hydrochloride in the brain metastases, brain margin, arachnoid, cerebral spinal fluid, and plasma |  | up to 4 years | 
| Local control of brain metastases |  | up to 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
unspecified adult solid tumor, protocol specific, tumors metastatic to brain