Temodar (Temozolomide), Bevacizumab, Lithium and Radiation for High Grade Glioma

Study Overview
=================
Brief Summary
-----------------
This pilot phase II trial studies how well giving temozolomide, bevacizumab, lithium carbonate, and radiation therapy works in treating patients with newly diagnosed high grade glioma.

Detailed Description
-----------------
Treatment of high grade glioma (HGG) with anti-angiogenic therapy results in clinical improvement and prolonged progression-free survival (PFS). However, mant patients experience diffuse recurrence and treatment failure. This is a phase II trial testing the feasibility of adding lithium carbonate, previously shown to have anti-invasive properties in HGG, to bevacizumab and chemoradiation following surgical resection of HGG.

Official Title
-----------------
Temozolomide, Bevacizumab, Lithium and Radiation Treatment for Newly Diagnosed High Grade Glioma: A Phase II Study

Conditions
-----------------
Brain Cancer

Intervention / Treatment
-----------------
* Drug: Temozolomide
* Drug: Bevacizumab
* Drug: Lithium Carbonate
* Radiation: Radiation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed high grade glioma (WHO Grade III and IV) Brain magnetic resonance imaging (MRI) scan with gadolinium contrast Patient must have normal organ and marrow function as defined below: Absolute neutrophil count >= 1,500/mm^3; Platelet count >=100,000/mm^3; Hemoglobin >= 10g/dL; Blood urea nitrogen and serum creatinine both =< 1.5 times upper limit of normal (ULN); Total bilirubin both =< 1.5 times ULN; SGOT and SGPT both =< 3 times ULN; Alkaline phosphatase =< 2 times ULN. >=18 years of age; Karnofsky Performance Score >= 70; Life expectancy >= 8 weeks; Negative serum or urine beta-hCG pregnancy test at screening for patients of child bearing potential; Men and women with reproductive potential must agree to use an acceptable method of birth control (surgical, hormonal or double barrier, ie, condom and diaphragm) during treatment and for 6 months after completion of treatment; Patient or their legal proxy must provide written informed consent prior to registration on study; Residual measurable disease. Exclusion Criteria: Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study; Prior radiation therapy to the brain; Prior treatment with Chemotherapy or Targeted agent Previous (within last 5 years) or current malignancies at other sites except for adequately treated basal cell or squamous cell skin cancer in situ carcinoma of the cervix; (Uncontrolled High blood pressure >150/100 Common Terminology Criteria Adverse Event 3.0 >= Grade 2 congestive heart failure (CHF); History of myocardial infarction within 6 months; History of stroke within 6 months; Clinically significant peripheral vascular disease; Evidence of bleeding diathesis or coagulopathy; Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the first dose of bevacizumab or anticipation of need for major surgical procedure during the course of the study; Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to study enrollment; Urine protein/Creatinine ratio >= 2.0 at screening; Serious, non-healing wound, ulcer, or bone fracture; Inability to comply with study and/or follow-up procedures; Glioma showing active intratumoral bleeding; Patients on enzyme-inducing anti-epileptic drugs; Known Positive HIV-1, hepatitis B surface antigen, or hepatitis C antibody; Medications like nonsteroidal antiinflammatory drugs, antipsychotics, iodides, and angiotensin-converting enzyme inhibitor, If they are receiving them, they must have been discontinued for 7 days prior to initiating lithium; Any previous cytotoxic drug therapies, excluding corticosteroids and temozolomide concurrent with radiation therapy; Any known genetic cancer-susceptibility syndromes; Acute infection: any active viral, bacterial, or fungal infection that requires specific therapy. Active uncontrolled infection - examples include sexually transmitted disease, herpes, scrofula, malaria, etc.; Fever > 101.5 degrees Fahrenheit; Unstable or severe intercurrent medical conditions such as unstable angina, uncontrolled arrythmias, Crohn's disease, ulcerative colitis, psoriasis, etc.; Implantation of Gliadel wafers at surgery; Patients with organ allografts; and Allergies to reagents used in this study.

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: TBL/RT<br>Cycle 1(One 42-day cycle) Temozolomide 75 mg/m^2 orally (42 consecutive days), beginning the night prior to the first radiation treatment Radiation within 3-5 weeks of surgery Bevacizumab 10mg/kg, IV, starting 29 (+3) days post surgery and every 2 weeks Treatment Cycles 2-7 (28 days per cycle) Temozolomide at a dose of 150 mg/m^2 on Days 1-7 Bevacizumab 10 mg/kg on Day 8 and Day 22 Initiate Lithium carbonate treatment at 300 mg, orally, twice a day; dose increased every 7 days up to 600mg, orally, twice a day, to a serum lithium level of 0.8-1.2 mEq/L. | Drug: Temozolomide<br> <br> * Other names: Temodar;Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Lithium Carbonate<br> <br> * Other names: Lithobid;Radiation: Radiation<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-Free Survival (PFS) | PFS defined as time from date of diagnosis to most recent follow up, disease progression, or death. Disease progress defined as either clinical deterioration or radiographic progressive disease on magnetic resonance imaging (MRI) per updated response assessment in neuro-oncology criteria (Wen, et al). | Up to 50 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival (OS) | OS defined as time from diagnosis to most recent follow up or death. | Up to 50 months | 
| Number of Patients With Grade 3 or 4 Adverse Events | Adverse events evaluated per CTCAE 3 | The whole time while on treatment and 30 days after the treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
brain tumor, brain cancer, glioma