Gossypol (AT-101) and Temozolomide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as gossypol and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Gossypol may help temozolomide work better by making tumor cells more sensitive to the drug. Gossypol may also make tumor cells more sensitive to radiation therapy. Giving gossypol and temozolomide together with radiation therapy may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of gossypol when given together with temozolomide with or without radiation therapy in treating patients with newly diagnosed glioblastoma multiforme.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the maximum tolerated dose (MTD) of gossypol (AT-101) when administered with radiotherapy (RT) and concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme. Determine the MTD of gossypol when administered with adjuvant TMZ after standard RT and concurrent TMZ in these patients. Secondary Assess the toxicity of these treatment regimens. Assess and describe the pharmacokinetics of gossypol. Determine, preliminarily, the therapeutic activities of these regimens. Determine the relationship between these regimens and cellular and molecular features identified in tumor biopsy specimens. OUTLINE: This is a multicenter, open-label, nonrandomized, dose-escalation study of gossypol. Patients are assigned to 1 of 2 treatment groups. Patients who participate in group I are NOT eligible for group II. Group I: Patients receive oral gossypol and undergo radiotherapy once daily 5 days a week for up to 6 weeks. Patients also receive oral temozolomide once daily for up to 6 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Group II: Patients receive oral temozolomide on days 1-5 and oral gossypol once daily on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-10 patients per treatment group receive escalating doses of gossypol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 6 or 3 of 10 patients experience dose-limiting toxicity. Patients undergo blood collection periodically for pharmacokinetic studies. Tumor tissue samples are examined for biomarkers including, but not limited to, Bcl-2 family protein expression (e.g., Bcl-2, Bcl-xL, MCl-1, Bax, Bak, and BH3 domain), MGMT gene methylation status, and gene expression array. After completion of study treatment, patients are followed every 2 months. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Official Title
-----------------
A Phase I, Open Label Study of AT-101 Plus Radiotherapy and Temozolomide and of AT-101 Plus Adjuvant Temozolomide for Patients With Newly-Diagnosed Glioblastoma Multiforme

Conditions
-----------------
Brain and Central Nervous System Tumors

Intervention / Treatment
-----------------
* Drug: R-(-)-gossypol acetic acid
* Drug: temozolomide
* Genetic: gene expression analysis
* Genetic: mutation analysis
* Genetic: protein expression analysis
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Procedure: adjuvant therapy
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme) Meets 1 of the following criteria: Completed surgery within the past 6 weeks (group I) Received radiotherapy and concomitant temozolomide at least 4 weeks but no more than 7 weeks prior to start of study treatment (group II) Must be on a stable corticosteroid regimen (no increase for 5 days) PATIENT CHARACTERISTICS: Karnofsky performance status 60-100% Hemoglobin ≥ 10 g/dL Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Creatinine ≤1.5 mg/dL Bilirubin ≤ 1.5 mg/dL ALT and AST ≤ 2.5 times upper limit of normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 2 months after completion of study treatment Mini Mental State Exam score ≥ 15 Must be able to swallow and retain oral medication No serious concurrent infection or medical illness that would preclude study participation No other malignancy within the past 5 years, except for curatively treated carcinoma in situ or basal cell carcinoma of the skin No sensory neuropathy ≥ grade 2 No allergies to gossypol No symptomatic hypercalcemia or hypercalcemia > grade 2 No gastrointestinal disease including any of the following: Malabsorption syndrome Disease significantly affecting gastrointestinal function Ulcerative colitis Inflammatory bowel disease Partial or complete small bowel obstruction PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from the immediate postoperative period No prior radiotherapy, chemotherapy, immunotherapy, therapy with biologic agents (including immunotoxins, immunoconjugates, antisense agents, peptide-receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocyte therapy, lymphokine-activated killer cells or gene therapy), or hormonal therapy for this brain tumor (group I) Prior glucocorticoid therapy allowed No prior polifeprosan 20 with carmustine implant (Gliadel wafers) (group I) No prior gossypol No prior radiosurgery or brachytherapy No prior resection of the stomach or small intestine No other concurrent anticancer therapy (i.e., chemotherapeutics or investigational agents) No concurrent cytochrome p450 enzyme-inducing anticonvulsant drugs No concurrent prophylactic filgrastim (G-CSF) No concurrent iron supplements Nutritional supplements containing iron allowed No concurrent intensity-modulated radiotherapy No concurrent electron, particle, implant, or stereotactic radiosurgery boost

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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: R-(-)-gossypol acetic acid|nan|
|Drug: temozolomide|nan|
|Genetic: gene expression analysis|nan|
|Genetic: mutation analysis|nan|
|Genetic: protein expression analysis|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|
|Procedure: adjuvant therapy|nan|
|Radiation: radiation therapy|nan|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity |  |  | 
| Pharmacokinetic profile of gossypol |  |  | 
| Therapeutic activity |  |  | 
| Cellular and molecular outcomes (intratumoral expression levels of biomarkers, including Bcl-2 family protein expression [e.g., Bcl-2, Bcl-xL, MCl-1, Bax, Bak, BH3 domain], MGMT gene methylation status, and gene expression array) |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult glioblastoma, adult gliosarcoma, adult giant cell glioblastoma