Gossypol in Treating Patients With Progressive or Recurrent Glioblastoma Multiforme

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00540722
First received: October 5, 2007
Last updated: April 8, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Tumor
Drug: R-(-)-gossypol acetic acid
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of R-(-)-Gossypol (Ascenta's AT-101) in Recurrent Glioblastoma Multiforme

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Death, in terms of survival time [ Time Frame: From time of first day of the treatment to death occurrence, assessed up to 4.5 years ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Incidence of acute and late toxicities [ Time Frame: Up to 4.5 years ] [ Designated as safety issue: Yes ]
    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.

  • Tumor response rate [ Time Frame: Up to 4.5 years ] [ Designated as safety issue: No ]
    The probability of tumor response will be estimated using binomial distribution along with 95% CI.

  • 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 ] [ Designated as safety issue: No ]
    The probability of 6-month progression-free survival will be estimated using binomial distribution.


Enrollment: 56
Study Start Date: January 2008
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

Drug: R-(-)-gossypol acetic acid
Given PO
Other Name: AT-101
Other: laboratory biomarker analysis
Correlative studies

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00540722

Locations
United States, Maryland
Adult Brain Tumor Consortium
Baltimore, Maryland, United States, 21231-1000
Sponsors and Collaborators
Investigators
Principal Investigator: John Fiveash National Cancer Institute (NCI)
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00540722     History of Changes
Other Study ID Numbers: NCI-2013-00018, 0702, CDR0000569405, ABTC-0702, NABTT 0702, U01CA062475
Study First Received: October 5, 2007
Last Updated: April 8, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Gossypol
Gossypol acetic acid
Retinol acetate
Adjuvants, Immunologic
Anticarcinogenic Agents
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Antispermatogenic Agents
Contraceptive Agents
Contraceptive Agents, Female
Contraceptive Agents, Male
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Reproductive Control Agents
Spermatocidal Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014