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

Brain and Central Nervous System Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00390403
• Other study ID #: NABTT-0602 CDR0000507451
• Secondary ID: U01CA062475NABTT
• Status: Completed
• Phase: Phase 1
• First received: October 18, 2006
• Last updated: May 1, 2012
• Start date: February 2007

Study information

• Verified date: May 2012
• Source: Sidney Kimmel Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Glioblastoma
• Nervous System Neoplasms

Intervention

Drug:
• R-(-)-gossypol acetic acid

• temozolomide

Genetic:
• gene expression analysis

• mutation analysis

• protein expression analysis

Other:
• laboratory biomarker analysis

• pharmacological study

Procedure:
• adjuvant therapy

Radiation:
• radiation therapy

Locations

Country	Name	City	State
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham	Birmingham	Alabama
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan
United States	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida
United States	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose			Yes
Secondary	Toxicity			Yes
Secondary	Pharmacokinetic profile of gossypol			No
Secondary	Therapeutic activity			No
Secondary	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)			No