Phase I/II Adaptive Randomized Trial of Bevacizumab Versus Bevacizumab Plus Vorinostat in Adults With Recurrent Glioblastoma

NCT01266031 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 99991611616-C-N116
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this Phase I portion of this clinical research study is to find the highest tolerable dose of bevacizumab with or without vorinostat, that can be given to patients with malignant gliomas. The safety of these drug combinations will also be studied. The goal of this Phase II part of this clinical research study is to learn if bevacizumab when given with or without vorinostat can help to control malignant gliomas. The safety of these drug combinations will also be studied.

Conditions

Malignant Glioma; Recurrent Glioblastoma

Keywords

Glioblastoma Multiforme

Outcome Measures

Primary Outcomes (2)

• Progression Free Survival (PFS) at 6 Months

  PFS is time measured in months to disease progression as assessed at six months from participant registration. Assessments continue every 8 weeks up to 28 days after last dose (follow-up), anticipated trial length one year. Participants must be assessed at least 4 weeks after surgery to begin treatment in the adaptive randomized Phase 2 portion of the trial. PFS in participants in the surgical arm determined from the date of randomization to the treatment arms and not from the date of registration in the trial. Study outcome measure period ended June 2015.

  Baseline until disease progression or death due to any cause, up to six months

• Maximum Tolerated Dose (MTD) of Oral Vorinostat Used With Bevacizumab

  MTD defined as the dose level at which 1/6 patients experience dose limiting toxicity (DLT), using conventional Phase I design where the MTD was selected using a 3+3 accrual design at each dose level until MTD was determined. Toxicities will be graded according to the Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.

  28 day, cycle 1

Secondary Outcomes (9)

• Time to Progression (TTP)

  3, 6, and 12 months from patient registration

• Overall Survival (OS)

  up to 30 months.

• Effects of Bevacizumab With and Without Vorinostat Upon Biomarkers of Angiogenesis Vascular Endothelial Growth Factor (VEGF), Placental Growth Factor (PIGF), and Basic Fibroblast Growth Factor (bFGF)

  Baseline before treatment, Cycle 1 Day 2, day 15 (pre-infusion and post-infusion), Cycle 2 (pre-infusion)

• Effects of Bevacizumab With and Without Vorinostat Upon Biomarkers of Angiogenesis Stromal Cell-derived Factor α (SDF1α), and Angiopoietin 1 (Ang 1) and 2 (Ang 2) by Enzyme-linked Immunosorbent Assay (ELISA)

  Baseline before treatment, Cycle 1 Day 2, day 15 (pre-infusion and post-infusion), Cycle 2 (pre-infusion)

• Percentage of Patients Rating Their Symptoms to be 7 or Greater on a 0-10 Scale Using the Mean Severity of the MD Anderson Symptom Inventory-Brain Tumor Module (MDSAI-BT) Self Reporting Tool

  Baseline, week 4, week 8, and end of therapy, approximately week 52 (cycle 12)

Study Arms (2)

Bevacizumab

EXPERIMENTAL

10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.

Drug: bevacizumab

Vorinostat and Bevacizumab

EXPERIMENTAL

Vorinostat: 400 mg/day by mouth on days 1 to 7 and days 15 to 21 of a 28 day cycle. Bevacizumab: 10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.

Drug: vorinostat; Drug: bevacizumab

Interventions

vorinostat DRUG

Vorinostat 400mg/day will be administered on day 1 to 7 and day 15 to 21 orally on a 28 day cycle in the arm with combination of vorinostat and bevacizumab. Vorinostat will be administered orally. Vorinostat capsules should not be opened or crushed and must be administered whole.

Also known as: Zolinza

Vorinostat and Bevacizumab

bevacizumab DRUG

Bevacizumab 10mg/kg will be administered on day 1 and 15 intravenously on a 28 day cycle in both arms.

Also known as: Avastin

Bevacizumab; Vorinostat and Bevacizumab

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients will be included in the study based on the following criteria.
• Patients must have histologically proven glioblastoma, gliosarcoma or anaplastic glioma to be eligible for the Phase I component of this protocol. Anaplastic gliomas include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant glioma NOS (not otherwise specified). Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made. Only patients with histologically proven or imaging proven recurrent glioblastoma or gliosarcoma will be eligible for the Phase II component. Wafer acceptable if recurrence is confirmed.
• All patients must sign an informed consent indicating their awareness of the investigational nature of this study. Patients must have signed an authorization for the release of their protected health information.
• Patients must be 18 years old or older.
• Patients must have a Karnofsky performance status (KPS) equal or greater than 60
• At the time of registration:
• Patients must have recovered from the toxic effects of prior therapy to \< grade 2 toxicity per CTC version 4 (except deep vein thrombosis )
• days from any investigational agent,
• weeks (28 days) from prior cytotoxic therapy,
• weeks (14 days) from vincristine,
• weeks (42 days) from nitrosoureas,
• weeks (21 days) from procarbazine administration,
• greater than or equal to1 week (7 days) for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count).
• Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study (such as presurgically for obtaining pharmacology data for the agent) will be eligible to enter the study provided they have recovered from the toxic effects of the agent if any. Any questions related to the definition of noncytotoxic agents should be directed to the Study Chair.
• Patients must have adequate bone marrow function (ANC greater than or equal to 1,500/mm3, platelet count of greater than or equal to 100,000/mm3), adequate liver function (SGPT less than or equal to 3 times upper limit normal and alkaline phosphatase less than or equal to 2 times upper limit normal, total bilirubin less than or equal to 1.5mg/dl, Patients with high bilirubin levels related to known diagnosis of benign hyperbilirubinemia (Gilbert s syndrome) will be eligible ., and adequate renal function (BUN less than or equal to 1.5 times institutional normal and Creatinine \< 1.5 mg/dl) prior to registration. These tests must be performed within 14 days prior to registration.

You may not qualify if:

• Inability to comply with protocol or study procedures (for example, an inability to swallow tablets).
• Prior treatment with bevacizumab or Vorinostat.
• Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor properties, will be excluded, unless they are switched to an alternative agent prior to treatment initiation. A 5-day wash out period is required. Patients who have failed prior treatment with other histone deacetylase inhibitors will be excluded.
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent.
• Any condition, including the presence of clinically significant laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. These would include
• Active infection (including persistent fever) including known AIDS or Hepatitis C infection
• Diseases or conditions that obscure toxicity or dangerously alter drug metabolism
• Serious intercurrent medical illness (e.g. symptomatic congestive heart failure).
• Current, recent (within 4 weeks (28 days) of the first infusion of this study, or planned participation in an experimental antitumor drug study (other than the current one).
• Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix or bladder), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.
• Patients with spinal disease (metastasis) and/or leptomeningeal disease will not be allowed in the study.
• Inadequately controlled hypertension (defined as systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg).
• Prior history of hypertensive encephalopathy.
• New York Heart Association (NYHA) Grade II or greater congestive heart failure.
• History of myocardial infarction or unstable angina within 6 months prior to Day 1.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• M.D. Anderson Cancer Center: collaborator
• Genentech, Inc.: collaborator
• Merck Sharp & Dohme LLC: collaborator
• Brain Tumor Trials Collaborative: collaborator
• Ohio State University: collaborator
• Northwestern University Feinberg School of Medicine: collaborator
• UF Health Cancer Center at Orlando Health: collaborator
• Baylor Health Care System: collaborator
• MUSC Hollings Cancer Center: collaborator
• University of Utah Health System: collaborator
• University of Washington: collaborator
• Henry Ford Health System: collaborator
• Columbia University: collaborator
• Rush University Medical Center: collaborator
• Endeavor Health: collaborator
• The Cleveland Clinic: collaborator
• University of North Carolina, Chapel Hill: collaborator
• Washington University School of Medicine: collaborator
• Texas Oncology-Austin: collaborator

Study Sites (1)

Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

MeSH Terms

Conditions

Glioma; Glioblastoma

Interventions

Vorinostat; Bevacizumab

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Mark Gilbert
• Organization: National Cancer Institute

gilbertmr@mail.nih.gov

301-402-6383

Study Officials

• Mark R Gilbert, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 22, 2010
• First Posted: December 24, 2010
• Study Start: July 12, 2011
• Primary Completion: June 30, 2015
• Study Completion: January 31, 2017
• Last Updated: July 31, 2018
• Results First Posted: September 23, 2016

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)