- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00540722
Gossypol in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme
A Phase 2 Study of R-(-)-Gossypol (Ascenta's AT-101) in Recurrent Glioblastoma Multiforme
Study Overview
Status
Conditions
Intervention / Treatment
Detailed 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 06-methylguanine-DNA-methyltransferase (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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
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Alabama
-
Birmingham, Alabama, United States, 35294
- University of Alabama at Birmingham
-
-
Florida
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Tampa, Florida, United States, 33612
- Moffitt Cancer Center
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-
Maryland
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Baltimore, Maryland, United States, 21287
- Johns Hopkins University
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
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Michigan
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Detroit, Michigan, United States, 48202
- Henry Ford Hospital
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North Carolina
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Winston-Salem, North Carolina, United States, 27157
- Wake Forest University Health Sciences
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Ohio
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Cleveland, Ohio, United States, 44195
- Cleveland Clinic Foundation
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- University of Pennsylvania
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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 elapsed 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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (R-(-)-gossypol acetic acid)
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. Laboratory Biomarker Analysis: 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. |
Correlative studies
Given PO
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall Survival
Time Frame: 4.5 years
|
The overall failure rate will be estimated along with 95% confidence intervals.
A median time of survival will be estimated using standard methods.
|
4.5 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percent of Patients With Grade 3 and 4 Adverse Events Related to Treatment
Time Frame: 3 years
|
The proportion of patients with serious or life threatening (grade 3 and 4) toxicities will be estimated using NCI CTCAE
|
3 years
|
Tumor Response Rate
Time Frame: 3 years
|
Complete response Complete disappearance of all tumor on MRI scan, off all glucocorticoids with stable or improving neurological exam minimum of 4 wks Partial response Greater than or equal 50% reduction in tumor size on MRI, on sable or decreasing glucocorticoids with stable or improving neurological exam for a minimum of 4 wks. Progressive disease Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion. Stable disease Clinical status and MRI does not qualify for complete response, partial response or progression |
3 years
|
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
Time Frame: 6 months
|
The probability of 6-month progression-free survival will be estimated using binomial distribution.
|
6 months
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Explore Clinical Outcome (Overall Survival) With Changes of Potential Serum Biomarkers, Baseline Tumor Protein Expression and Gene Methylation Status
Time Frame: 1 month
|
Archived tumor tissue and 1 serum sample pre first dose and 1 sample anytime during week 2 of cycle 1
|
1 month
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: John Fiveash, MD, National Cancer Institute (NCI)
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms, Glandular and Epithelial
- Disease Attributes
- Astrocytoma
- Glioma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Glioblastoma
- Recurrence
- Gliosarcoma
- Physiological Effects of Drugs
- Anti-Infective Agents
- Antineoplastic Agents
- Immunologic Factors
- Protective 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
- Acetic Acid
- Gossypol
- Retinol acetate
- Gossypol acetic acid
Other Study ID Numbers
- NCI-2013-00018
- U01CA062475 (U.S. NIH Grant/Contract)
- 0702
- CDR0000569405
- ABTC-0702
- NABTT 0702
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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