Gossypol in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme

Adult Glioblastoma Clinical Trial

Official title:

A Phase 2 Study of R-(-)-Gossypol (Ascenta's AT-101) in Recurrent Glioblastoma Multiforme

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00540722
• Other study ID #: NCI-2013-00018
• Secondary ID: 0702CDR000056940
• Status: Completed
• Phase: Phase 2
• First received: October 5, 2007
• Last updated: December 27, 2016
• Start date: January 2008
• Est. completion date: June 2012

Study information

• Verified date: December 2016
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase II trial is studying how well gossypol works in treating patients with progressive or recurrent glioblastoma multiforme. Gossypol may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Description:

PRIMARY OBJECTIVES:

I. To estimate the overall survival rate associated with AT-101 in treating adult patients with recurrent glioblastoma multiforme.

SECONDARY OBJECTIVES:

I. To assess and estimate the acute and late toxicities. II. Tumor response rate. III. To estimate 6-month progression free survival. IV. To explore associations of the clinical outcome (overall survival) among the changes of potential serum biomarkers, baseline tumor protein expression and gene methylation status.

OUTLINE: This is a multicenter study.

Patients receive oral R-(-)-gossypol once daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo tumor tissue and blood sample collection at baseline and periodically during study for biomarker correlative studies. Archived tumor tissue samples, if available, are analyzed for Bcl-2 family protein expression (e.g., Bcl-2, Bcl-xL, MCl-1, Bax, Bak, and BH3 domain for BH3 members only) and MGMT gene methylation status. Blood samples are analyzed for apoptotic protein levels (Bcl-2) by enzyme-linked immunosorbent assay.

After completion of study therapy, patients are followed every 2 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have histologically confirmed supratentorial glioblastoma multiforme which is progressive or recurrent after radiation therapy ± chemotherapy; patients with previously low grade glioma who progressed after radiotherapy ± chemotherapy and are biopsied and found to have glioblastoma multiforme are eligible

• Patients must have tumor tissue form completed and signed by a pathologist

• Patients must have measurable contrast enhancing progressive or recurrent glioblastoma multiforme by MRI or CT imaging (Within 14 days before starting treatment)

• Patients must have recovered from toxicity of prior therapy; an interval of at least 3 months must have elapsed since the completion of the most recent course of radiation therapy, while at least 3 weeks must have elapsed since the completion of a non-nitrosourea containing chemotherapy regimen, and at least 6 weeks since the completion of a nitrosourea containing chemotherapy regimen; NOTE: For non-cytotoxic, FDA approved agents (i.e. celebrex, thalidomide, etc.) therapy could be started 2 weeks after discontinuing this agent provided the patient has fully recovered from all toxicity associated with the agent; for investigational, non-cytotoxic agents a minimum of 3 weeks must have elasped before the patient will be eligible for this study

• Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)

• Absolute neutrophil count >= 1500/mm^3

• Platelets >= 100,000/mm^3

• Creatinine =< 1.5mg/dl

• Total Bilirubin =< 1.5mg/dl

• Transaminases =< 2.5 times above the upper limits of the institutional norm

• Patients must be able to provide written informed consent

• Women of childbearing potential must have a negative serum pregnancy test; the effects of AT-101 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because Bcl-2 inhibitors have the potential to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for at least one month following the last dose of AT-101; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Patients must have a Mini Mental State Exam score >= 15

Exclusion Criteria:

• Patients with serious concurrent infection or medical illness which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety; (Examples of medical illnesses are [but not limited to] the following: uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements)

• Patients who are pregnant or breast-feeding

• Patients who have received more than two prior treatments

• Patients who have been previously treated with gossypol, or have allergies to gossypol

• Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents); concurrent steroid use is allowed

• Patients with a concurrent malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin; patients with a prior malignancy are ineligible unless they have been free of disease for >= five years

• Patients with = Grade 2 sensory neuropathy based on the NCI CTCAE

• Patients who are taking iron supplements

• Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow pills are excluded

• Patients cannot be receiving cytochrome P450-inducing anticonvulsants (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital, primidone, oxcarbazepine)

• Patients with malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel are excluded; subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded

• Eligibility of patients receiving any other medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of AT-101 will be determined following review of their case by the Principal Investigator

• Patients with symptomatic hypercalcemia that is > Grade 2 (according to CTCAE)

• Requirement for routine use of hematopoietic growth factors (including granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, or interleukin-11) or platelet transfusions to maintain absolute neutrophil counts or platelets counts above the required thresholds for study entry

• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AT-101; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Glioblastoma
• Gliosarcoma
• Recurrent Adult Brain Tumor

Intervention

Drug:
• R-(-)-gossypol acetic acid
Given PO

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Moffitt Cancer Center	Tampa	Florida
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Death, in terms of survival time	The overall failure rate is expressed as hazard of failure per person-year of follow-up (the number of deaths divided by the total exposure time in the study cohort). The overall failure rate will be estimated along with 95% confidence intervals. A median time of survival will be estimated using standard methods.	From time of first day of the treatment to death occurrence, assessed up to 4.5 years	No
Secondary	Incidence of acute and late toxicities	The proportion of patients with serious or life threatening toxicities will be estimated along with 95% confidence intervals. The frequency of different type toxicities will be tabulated by each cycle of the treatment.	Up to 4.5 years	Yes
Secondary	Tumor response rate	The probability of tumor response will be estimated using binomial distribution along with 95% CI.	Up to 4.5 years	No
Secondary	Progression-free survival rate, defined as patient who is alive and disease progression free at the time of 26-week (6 months) from first day of the treatment	The probability of 6-month progression-free survival will be estimated using binomial distribution.	6 months	No