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Suberoylanilide Hydroxamic Acid (SAHA), Bevacizumab, Daily Temozolomide for Recurrent Malignant Gliomas

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ClinicalTrials.gov Identifier: NCT00939991
Recruitment Status : Completed
First Posted : July 15, 2009
Results First Posted : June 24, 2013
Last Update Posted : June 24, 2013
Sponsor:
Collaborators:
Genentech, Inc.
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Katy Peters, Duke University

Tracking Information
First Submitted Date  ICMJE July 14, 2009
First Posted Date  ICMJE July 15, 2009
Results First Submitted Date  ICMJE May 3, 2013
Results First Posted Date  ICMJE June 24, 2013
Last Update Posted Date June 24, 2013
Study Start Date  ICMJE October 2009
Actual Primary Completion Date January 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 3, 2013)
  • Phase I: Determination of the Maximum Tolerated Dose (MTD) [ Time Frame: Cycle 1 (28 days) ]
    The MTD is based upon dose-limiting toxicities (DLTs) experienced during Cycle 1 of treatment. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with at least two patients experiencing DLT at the next higher dose level. Using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, DLTs are defined as: Grade 4 neutropenia lasting greater than 5 days; Grade 3 thrombocytopenia; the occurrence of non-hematologic Grade 3 or greater drug-related adverse events excluding Grade ≥ 3 elevation in alkaline phosphatase, Grade ≥ 3 nausea or vomiting unless occurring despite the use of standard anti-emetics or Grade 3 diarrhea unless occurring despite standard anti-diarrheal therapy; > 14 day delay to re-treat due to failure to resolve drug-related toxicity to re-treatment criteria or pre-treatment baseline.
  • Phase II: 6-month Progression-free Survival (PFS) [ Time Frame: 6 months ]
    Phase II: Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to RANO criteria, or to death due to any cause. Per RANO, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.
Original Primary Outcome Measures  ICMJE
 (submitted: July 14, 2009)
The primary outcome of the phase I component is determination of MTD and DLT while the primary outcome of the phase II component is 6 month progression-free survival. [ Time Frame: 6 months ]
Change History Complete list of historical versions of study NCT00939991 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 3, 2013)
  • Phase II: 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. A confirmation of response was not required. Complete Response (CR) was 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) was 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 were done at baseline, the end of the first cycle (4 weeks), then the end of every second cycle (every 8 weeks) thereafter.
  • Phase II: Median Progression-free Survival (PFS) [ Time Frame: 3 years ]
    Phase II: Time in months from the start of study treatment to the date of first progression according to RANO criteria, or to death due to any cause. Per RANO, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
  • Phase II: Median Overall Survival (OS) [ Time Frame: 3 years ]
    Phase II: Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
  • Phase II: Number of Patients With Grade 2 or Greater, Treatment-related Toxicities [ Time Frame: 3 years ]
    Phase II: Number of patients with grade 2 or greater, treatment-related toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 14, 2009)
  • Radiographic response. [ Time Frame: 6 months ]
  • Median progression free survival and overall survival. The primary measure of safety outcome will include a tabulation of all grade 2 or greater, treatment related toxicities. [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Suberoylanilide Hydroxamic Acid (SAHA), Bevacizumab, Daily Temozolomide for Recurrent Malignant Gliomas
Official Title  ICMJE Phase I/II Study of Bevacizumab Plus Daily Temozolomide and Vorinostat for Recurrent Malignant Glioma Patients
Brief Summary This is a Phase I/II open-label, single-arm study among recurrent malignant glioma patients. Patients will be treated with Vorinostat in combination with Bevacizumab (BV) (10 mg/kg) and Temozolomide (T) (50 mg/m2/day) BV is administered every 2 weeks. Temozolomide will be taken orally once every day. Vorinostat will be taken orally on days 1-7 and 15-21 of each 28-day cycle. In the phase I portion of this study, the dose of Vorinostat will be escalated in successive cohorts of patients to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). In the phase II portion of this study, the dose of Vorinostat will be the MTD determined in the phase I portion. The primary endpoint of the phase II study is 6-month progression-free survival (PFS) for recurrent GBM (Glioblastoma) patients. This study will be conducted at The Preston Robert Tisch Brain Tumor Center at Duke.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Brain Tumor
  • Glioblastoma
Intervention  ICMJE Drug: Vorinostst/Bevacizumab/Temozolomide
Bevacizumab will be administered intravenously at the dose 10 mg/kg every other week. Temozolomide will be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat will be administered daily on days 1-7 and 15-21 of each 28 day cycle. The dose of Vorinostat will be escalated in successive cohorts of patients to determine the MTD of this regimen. Bevacizumab doses may be given by the local oncologists under the direction of the Duke investigators.
Other Names:
  • Bevacizumab (Avastin)
  • Temozolomide (Temodar)
  • Vorinostat (Zolinza)
Study Arms  ICMJE Experimental: 1
Phase I- Bevacizumab will be administered intravenously every other week. Temozolomide will be administered on a continuous daily dosing schedule. Vorinostat will be administered daily on days 1-7 and 15-21 of each 28 day cycle. The dose of Vorinostat will be escalated in successive cohorts of patients to determine the MTD of this regimen.
Intervention: Drug: Vorinostst/Bevacizumab/Temozolomide
Publications * Not Provided

*   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: May 3, 2013)
48
Original Estimated Enrollment  ICMJE
 (submitted: July 14, 2009)
52
Actual Study Completion Date  ICMJE April 2013
Actual Primary Completion Date January 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically confirmed diagnosis of malignant glioma and radiographic evidence of recurrence or disease progression (defined as either a greater than 25% increase in the largest bidimensional product of enhancement or a new enhancing lesion) following prior therapy. In addition, the following must be met:

Phase I specific

  • WHO grade 3 or 4 malignant glioma Phase II specific
  • WHO grade 4 malignant glioma
  • No more than 2 prior episodes of disease progression

Common to both Phase I and Phase II

  • Age * 18 years
  • KPS (Karnofsky Performance Scale) ≥ 70%
  • 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 are progressive changes on MRI on at least two consecutive MRI scans at least four weeks apart, or there is biopsy-proven tumor progression
  • An interval of at least 4 weeks from prior chemotherapy (6 weeks for nitrosoureas) or investigational agent unless the patient has recovered from all anticipated toxicities associated with that therapy
  • Hematocrit ≥ 29%, ANC ≥ 1,000 cells/*l, platelets ≥ 100,000 cells/*l
  • Serum creatinine < 1.5 times upper limit of normal, serum SGOT < 2.5 times upper limit of normal and bilirubin < 2.0 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:

  • 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
  • Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids
  • Active infection requiring intravenous antibiotics
  • Progression on prior bevacizumab or daily temozolomide
  • Grade 3 or greater toxicity related to prior bevacizumab or daily temozolomide therapy
  • Requires therapeutic anti-coagulation with warfarin
  • Life expectancy of <12 weeks
  • Active malignancy other than basal or squamous cell skin ca or carcinoma in situ of cervix within 5 years
  • Subject recruitment and compensation - subjects will be recruited for this study as follows:

    • Upon determination that a subject's tumor histology and/or radiographic findings are compatible with the eligibility criteria of this protocol, the clinical study will be briefly explained to the subject by the subject's physician, who will be a physician at the Brain Tumor Center at Duke.
    • If the subject indicates interest in study participation, subject education sheets and the informed consent document will be provided to the subject as these provide the most comprehensive explanation of the study in lay terms.
    • If the subject shows continued interest, the PI or designee will thoroughly explain the required elements of the consent form and all aspects of the study to the subject including inclusion/exclusion criteria, risks, benefits, and alternatives to study participation.
    • Subjects will not be paid to take part in this research study.

The list of subjects pre-screened will be kept in an Excel spreadsheet in the study coordinator's office. The PC (personal computer) is on the DUHS (Duke University Health System) network protected by a user ID (identifier) and password and the office is locked when it is unoccupied. All screened subjects who are not enrolled in the study will have all identifiers destroyed immediately.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (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 NCT00939991
Other Study ID Numbers  ICMJE Pro00016446
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Katy Peters, Duke University
Study Sponsor  ICMJE Katy Peters
Collaborators  ICMJE
  • Genentech, Inc.
  • Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Katherine Peters, MD Duke University
PRS Account Duke University
Verification Date May 2013

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