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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00390403
First received: October 18, 2006
Last updated: May 1, 2012
Last verified: May 2012
  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 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

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
Primary Completion Date: June 2009 (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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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
Sidney Kimmel Comprehensive Cancer Center
Investigators
Study Chair: John Fiveash, MD University of Alabama at Birmingham
  More Information

Additional Information:
No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00390403     History of Changes
Other Study ID Numbers: NABTT-0602 CDR0000507451, U01CA062475, NABTT-0602
Study First Received: October 18, 2006
Last Updated: May 1, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
adult glioblastoma
adult gliosarcoma
adult giant cell glioblastoma

Additional relevant MeSH terms:
Glioblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Temozolomide
Gossypol acetic acid
Gossypol
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antineoplastic Agents, Phytogenic
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Spermatocidal Agents
Antispermatogenic Agents

ClinicalTrials.gov processed this record on October 01, 2014