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Ph II SAHA and Bevacizumab for Recurrent Malignant Glioma Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01738646
Recruitment Status : Completed
First Posted : November 30, 2012
Results First Posted : October 29, 2015
Last Update Posted : March 6, 2017
Sponsor:
Collaborators:
Genentech, Inc.
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Duke University

Tracking Information
First Submitted Date  ICMJE November 28, 2012
First Posted Date  ICMJE November 30, 2012
Results First Submitted Date  ICMJE September 30, 2015
Results First Posted Date  ICMJE October 29, 2015
Last Update Posted Date March 6, 2017
Study Start Date  ICMJE January 2013
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 2, 2015)
Six-month Progression-free Survival (PFS6) [ Time Frame: 6 months ]
The percentage of participants alive and progression-free at 6 months after the start of study treatment will be determined. Based on Response Assessment in Neuro-Oncology (RANO) criteria, progression is defined as a ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration not attributable to other causes apart from the tumor; failure to return for evaluation as a result of death or deteriorating condition; or clear progression of non-measurable disease. PFS6 will be calculated from the date study treatment started until the date of progression or death, or the date of last follow-up if participants are alive without progression. Kaplan-Meier methods will be used to estimate survival.
Original Primary Outcome Measures  ICMJE
 (submitted: November 29, 2012)
6-month progression-free survival [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 15, 2016)
  • Radiographic Response [ Time Frame: 3 Years ]
    The percentage of participants with a complete or partial response as determined by modified Response Assessment in Neuro-Oncology (RANO) criteria will be determined. Complete Response (CR) is defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) is defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Tumor assessments are done at baseline and the end of every second cycle (every 8 weeks) thereafter.
  • Percentage of Participants Who Experience Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities. [ Time Frame: 2.7 Years ]
    The percentage of participants who experience grade 3 or greater, treatment-related, non-hematologic toxicities will be calculated.
  • Median Progression-free Survival (PFS) [ Time Frame: 3 Years ]
    Progression-free survival is defined as the time in months from the start of protocol treatment until the date of progression or death if death occurred before progression. If the participant is alive and progression-free, PFS will be censored at the date of last follow-up. Kaplan-Meier methods will be used to estimate progression-free survival.
  • Median Overall Survival (OS) [ Time Frame: 3 Years ]
    Overall survival is defined as the time in months from the start of protocol treatment until the date of death, or the date of last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 29, 2012)
  • Radiographic Response [ Time Frame: 2.5 Years ]
    MRI evaluations for assessment of radiographic response and response will be classified according to the Response Assessment in Neuro-Oncology criteria. Brain MRI will be performed prior to the initiation of every other cycle. Comparisons of objective assessments, excluding progressive disease, are based upon major changes in tumor size on the Gd-MRI scan compared to the baseline scan. Determination of progressive disease is based upon comparison to the previous scan with the smallest measurements.
  • Safety & Tolerability [ Time Frame: 2.5 Years ]
    Grade 3 or greater, treatment related, non-hematologic toxicities.
  • Median progression-free survival [ Time Frame: 2.5 Years ]
  • Overall survival [ Time Frame: 2.5 Years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ph II SAHA and Bevacizumab for Recurrent Malignant Glioma Patients
Official Title  ICMJE Phase II Study of Bevacizumab and Vorinostat for Recurrent WHO Grade IV Malignant Glioma Patients
Brief Summary It has been shown that bevacizumab has significant anti-tumor activity in patients with recurrent glioblastoma multiforme. Vorinostat has modest anti-tumor activity against malignant glioma and can enhance the action of both chemotherapy and anti-angiogenics. Patients will be treated with a combination of bevacizumab and vorinostat.
Detailed Description There is no effective therapy for patients with recurrent glioblastoma multiforme (GBM) hence such patients remain a major unmet need in oncology. The investigators have recently demonstrated that bevacizumab (BV), a humanized monoclonal antibody against vascular endothelial growth factor, has significant anti-tumor activity among recurrent glioblastoma multiforme patients. Vorinostat has modest anti-tumor activity against malignant glioma and can potentiate the action of both chemotherapy and anti-angiogenics. The current study is designed to evaluate the anti-tumor activity of vorinostat when combined with BV among recurrent glioblastoma multiforme patients.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Glioblastoma Multiforme
  • Malignant Glioma
  • Adult Brain Tumor
Intervention  ICMJE
  • Drug: Vorinostat
    Other Name: SAHA
  • Drug: Bevacizumab
    Other Name: Avastin
Study Arms  ICMJE Experimental: Vorinostat & Bevacizumab
Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day.
Interventions:
  • Drug: Vorinostat
  • Drug: Bevacizumab
Publications * Ghiaseddin A, Reardon D, Massey W, Mannerino A, Lipp ES, Herndon JE 2nd, McSherry F, Desjardins A, Randazzo D, Friedman HS, Peters KB. Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma. Oncologist. 2018 Feb;23(2):157-e21. doi: 10.1634/theoncologist.2017-0501. Epub 2017 Nov 13.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 30, 2015)
48
Original Estimated Enrollment  ICMJE
 (submitted: November 29, 2012)
40
Actual Study Completion Date  ICMJE February 2016
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age > 18 years.
  • An interval of at least 4 weeks between prior surgical resection or one week from stereotactic biopsy.
  • An interval of at least 12 weeks from the end of prior radiotherapy unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field, or there is biopsy-proven tumor progression
  • An interval of at least 4 weeks from prior chemotherapy [6 weeks for nitrosoureas, 1 week for daily administered chemotherapy (metronomic dosing)] or investigational agent unless the patient has recovered from all anticipated toxicities associated with that therapy.
  • Eastern Cooperative Oncology Group (ECOG) 0-1.
  • Hematocrit ≥ 29%, hemoglobin ≥ 9, absolute neutrophil ≥1,500 cells/microliter, platelets ≥ 100,000 cells/microliters.
  • Serum creatinine, serum glutamic oxaloacetic transaminase(SGOT) and bilirubin < 1.5 times upper limit of normal.
  • Signed informed consent approved by the Institutional Review Board prior to patient entry.
  • No evidence of hemorrhage on the baseline MRI or CT scan other than those that are stable grade 1.
  • If sexually active, patients will take contraceptive measures for the duration of the treatments. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation, hysterectomy, vasectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD).

Exclusion Criteria:

Disease-specific exclusions

  • More than 2 prior episodes of disease progression
  • Prior therapy with histone deacetylase inhibitors; valproic acid is not permitted and patients previously treated with valproic acid must be off valproic acid for at least 30 days prior to initiation of study medication
  • Prior bevacizumab therapy
  • Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids
  • Active infection requiring intravenous antibiotics
  • Severe hepatic insufficiency, active viral hepatitis or HIV infection
  • Requires therapeutic anti-coagulation with warfarin

General medical exclusions

Subjects meeting the following criteria are ineligible for study entry:

  • Inability to comply with study and/or follow-up procedures

Bevacizumab-specific exclusions

  • Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
  • Any prior history of hypertensive crisis or hypertensive encephalopathy
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)
  • History of myocardial infarction or unstable angina within 6 months prior to study enrollment
  • History of stroke or transient ischemic attack within 6 months prior to study enrollment
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
  • Symptomatic peripheral vascular disease
  • Evidence of bleeding diathesis or coagulopathy
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
  • Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
  • Serious, non-healing wound, ulcer, or bone fracture
  • Proteinuria at screening as demonstrated by either:

    • Urine protein:creatinine (UPC) ratio >= 1.0 at screening OR
    • Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
  • Known hypersensitivity to any component of bevacizumab
  • Pregnant (positive pregnancy test) or lactating. Refuse the use of effective means of contraception (men and women) in subjects of child-bearing potential
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 120 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01738646
Other Study ID Numbers  ICMJE Pro00024983
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Duke University
Study Sponsor  ICMJE Duke University
Collaborators  ICMJE
  • Genentech, Inc.
  • Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Katherine Peters, MD, PhD Duke University
PRS Account Duke University
Verification Date November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP