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

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

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.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Genetic: gene expression analysis; Other: pharmacological study; Radiation: radiation therapy; Drug: temozolomide; Genetic: protein expression analysis; Other: laboratory biomarker analysis; Genetic: mutation analysis; Procedure: adjuvant therapy; Drug: R-(-)-gossypol acetic acid

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Maximum tolerated dose

Secondary Outcome Measures

Outcome Measure
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)

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: John Fiveash, MD, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (ACTUAL): June 1, 2009

Study Registration Dates

• First Submitted: October 18, 2006
• First Submitted That Met QC Criteria: October 18, 2006
• First Posted (ESTIMATE): October 19, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): May 3, 2012
• Last Update Submitted That Met QC Criteria: May 1, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antineoplastic Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Anti-Bacterial Agents; Adjuvants, Immunologic; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Anticarcinogenic Agents; Contraceptive Agents, Male; Spermatocidal Agents; Antispermatogenic Agents; Temozolomide; Acetic Acid; Gossypol; Retinol acetate; Gossypol acetic acid
• Other Study ID Numbers: NABTT-0602 CDR0000507451; U01CA062475 (U.S. NIH Grant/Contract); NABTT-0602