Gossypol (AT-101) and Temozolomide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Primary Purpose
Brain and Central Nervous System Tumors
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
R-(-)-gossypol acetic acid
temozolomide
gene expression analysis
mutation analysis
protein expression analysis
laboratory biomarker analysis
pharmacological study
adjuvant therapy
radiation therapy
Sponsored by
![Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins](https://trials-media.s3.amazonaws.com/orgs/sidney-kimmel-comprehensive-cancer-center-at-johns-hopkins.jpeg)
About this trial
This is an interventional treatment trial for Brain and Central Nervous System Tumors focused on measuring adult glioblastoma, adult gliosarcoma, adult giant cell glioblastoma
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
Sites / Locations
- Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
- H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
- Winship Cancer Institute of Emory University
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Josephine Ford Cancer Center at Henry Ford Hospital
- Wake Forest University Comprehensive Cancer Center
- Cleveland Clinic Taussig Cancer Center
- Abramson Cancer Center of the University of Pennsylvania
Outcomes
Primary Outcome Measures
Maximum tolerated dose
Secondary Outcome Measures
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)
Full Information
NCT ID
NCT00390403
First Posted
October 18, 2006
Last Updated
May 1, 2012
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00390403
Brief Title
Gossypol (AT-101) and Temozolomide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2012
Overall Recruitment Status
Completed
Study Start Date
February 2007 (undefined)
Primary Completion Date
June 2009 (Actual)
Study Completion Date
undefined (undefined)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Cancer Institute (NCI)
4. Oversight
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain and Central Nervous System Tumors
Keywords
adult glioblastoma, adult gliosarcoma, adult giant cell glioblastoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Anticipated)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
R-(-)-gossypol acetic acid
Intervention Type
Drug
Intervention Name(s)
temozolomide
Intervention Type
Genetic
Intervention Name(s)
gene expression analysis
Intervention Type
Genetic
Intervention Name(s)
mutation analysis
Intervention Type
Genetic
Intervention Name(s)
protein expression analysis
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Type
Other
Intervention Name(s)
pharmacological study
Intervention Type
Procedure
Intervention Name(s)
adjuvant therapy
Intervention Type
Radiation
Intervention Name(s)
radiation therapy
Primary Outcome Measure Information:
Title
Maximum tolerated dose
Secondary Outcome Measure Information:
Title
Toxicity
Title
Pharmacokinetic profile of gossypol
Title
Therapeutic activity
Title
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Fiveash, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Study Chair
Facility Information:
Facility Name
Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612-9497
Country
United States
Facility Name
Winship Cancer Institute of Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231-2410
Country
United States
Facility Name
Josephine Ford Cancer Center at Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Wake Forest University Comprehensive Cancer Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157-1096
Country
United States
Facility Name
Cleveland Clinic Taussig Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Abramson Cancer Center of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-4283
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Gossypol (AT-101) and Temozolomide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
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