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

Sponsored by:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00390403

Purpose

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.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	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	Phase I

MedlinePlus related topics: Cancer Radiation Therapy

Drug Information available for: Acetic acid Temozolomide

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label
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

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Maximum tolerated dose [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Toxicity [ Designated as safety issue: Yes ]
Pharmacokinetic profile of gossypol [ Designated as safety issue: No ]
Therapeutic activity [ Designated as safety issue: No ]
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) [ Designated as safety issue: No ]

Estimated Enrollment:	50
Study Start Date:	February 2007
Estimated Primary Completion Date:	March 2008 (Final data collection date for primary outcome measure)

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00390403

Locations

United States, Alabama
Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
Birmingham, Alabama, United States, 35294
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, United States, 33612-9497
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
United States, Michigan
Josephine Ford Cancer Center at Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, North Carolina
Wake Forest University Comprehensive Cancer Center
Winston-Salem, North Carolina, United States, 27157-1096
United States, Ohio
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104-4283

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Study Chair:

John Fiveash, MD

Lurleen Wallace Comprehensive Cancer at University of Alabama-Birmingham

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Study ID Numbers:	CDR0000507451, NABTT-0602
Study First Received:	October 18, 2006
Last Updated:	February 6, 2009
ClinicalTrials.gov Identifier:	NCT00390403 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

adult glioblastoma
adult gliosarcoma
adult giant cell glioblastoma

Study placed in the following topic categories:

Glioblastoma
Astrocytoma
Contraceptive Agents
Contraceptive Agents, Female
Adjuvants, Immunologic
Central Nervous System Neoplasms
Contraceptive Agents, Male
Temozolomide
Gossypol acetic acid
Gossypol
Neuroectodermal Tumors

Neoplasms, Germ Cell and Embryonal
Retinol acetate
Neuroepithelioma
Antineoplastic Agents, Alkylating
Glioma
Glioblastoma Multiforme
Gliosarcoma
Alkylating Agents
Antineoplastic Agents, Phytogenic
Nervous System Neoplasms
Neoplasms, Glandular and Epithelial

Additional relevant MeSH terms:

Glioblastoma
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptive Agents
Neoplasms, Nerve Tissue
Physiological Effects of Drugs
Contraceptive Agents, Female
Central Nervous System Neoplasms
Reproductive Control Agents
Contraceptive Agents, Male
Gossypol
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Therapeutic Uses
Antispermatogenic Agents

Glioma
Alkylating Agents
Nervous System Neoplasms
Neoplasms by Histologic Type
Astrocytoma
Nervous System Diseases
Gossypol acetic acid
Temozolomide
Pharmacologic Actions
Neuroectodermal Tumors
Neoplasms
Antineoplastic Agents, Alkylating
Neoplasms, Neuroepithelial
Spermatocidal Agents
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on May 07, 2009