Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Completed	18 and over	NCI	NABTT-0602 NCT00390403

Objectives

Primary

1. 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.
2. Determine the MTD of gossypol when administered with adjuvant TMZ after standard RT and concurrent TMZ in these patients.

Secondary

1. Assess the toxicity of these treatment regimens.
2. Assess and describe the pharmacokinetics of gossypol.
3. Determine, preliminarily, the therapeutic activities of these regimens.
4. Determine the relationship between these regimens and cellular and molecular features identified in tumor biopsy specimens.

Entry 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)

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

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

Expected Enrollment

A total of 50 patients will be accrued for this study.

Outcomes

Maximum tolerated dose

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)

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.

Trial Contact Information

Trial Lead Organizations

New Approaches to Brain Tumor Therapy

John Fiveash, MD, Protocol chair		Ph: 205-975-0224

Registry Information
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
Trial Start Date		2007-02-22
Trial Completion Date		2009-06-02
Registered in ClinicalTrials.gov		NCT00390403
Date Submitted to PDQ		2006-08-25
Information Last Verified		2008-04-20
NCI Grant/Contract Number		CA062475

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