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Stereotactic Radiosurgery With Nivolumab and Valproate in Patients With Recurrent Glioblastoma

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. Identifier: NCT02648633
Recruitment Status : Terminated (The pharmaceutical company (BMS) would no longer provide nivolumab for the study, so the study was terminated early.)
First Posted : January 7, 2016
Last Update Posted : May 31, 2017
Information provided by (Responsible Party):
Benjamin Purow, MD, University of Virginia

Tracking Information
First Submitted Date  ICMJE December 16, 2015
First Posted Date  ICMJE January 7, 2016
Last Update Posted Date May 31, 2017
Actual Study Start Date  ICMJE May 24, 2016
Actual Primary Completion Date February 21, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 6, 2016)
  • Feasibility based on number of subjects who complete 4 doses of nivolumab [ Time Frame: At 3 months following radiosurgery ]
    Feasibility of the radiosurgery and drug combination will be determined based on the number of subjects who complete at least 4 doses of nivolumab.
  • Incidence of adverse events [ Time Frame: From the beginning of treatment until no sooner than 30 days following the last study treatment ]
    Safety will be assessed by imaging of necrosis, incidence and severity of adverse events, changes in laboratory findings, physical examinations, vital signs, and the number of discontinuations due to adverse events.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02648633 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 6, 2016)
Clinical Response Rate [ Time Frame: From the beginning of treatment until documented disease progression or date of death, assessed up to 48 months. ]
Response to therapy will be evaluated by means of RANO criteria.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: January 6, 2016)
Incidence of Pseudoprogressions [ Time Frame: From the beginning of treatment until documented disease progression or date of death, assessed up to 48 months. ]
Pseudoprogression, the transient increase in apparent tumor size, will be documented.
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Stereotactic Radiosurgery With Nivolumab and Valproate in Patients With Recurrent Glioblastoma
Official Title  ICMJE A Pilot Study to Evaluate the Feasibility of the Combined Use of Stereotactic Radiosurgery With Nivolumab and Concurrent Valproate in Patients With Recurrent Glioblastoma
Brief Summary The purpose of this study is to evaluate the safety and feasibility of the immunotherapeutic agent nivolumab given in combination with gamma knife therapy and valproate in patients with recurrent glioblastoma, a common and lethal type of brain cancer.
Detailed Description

Immune checkpoint inhibitors have the potential to treat a wide range of diverse cancers. Of particular interest to researchers is the PD-1 receptor-ligand interaction, a major pathway that many cancers hijack in order to suppress immune control. Anti-PD-1 antibodies such as nivolumab show a strong potential to treat many types of cancers including glioblastoma, the most common and most lethal brain cancer.

This study will examine a means of further focusing immune response on glioblastoma by combining stereotactic "gamma knife" radiosurgery with nivolumab. The rationale behind this intervention is that the radiation therapy will enhance immune response rate by providing additional tumor antigens from dying cells. Additionally, a study from investigators at Johns Hopkins indicates that histone deacetylase (HDAC) inhibitors may boost the anti-cancer efficacy of PD-1 antibodies like nivolumab. Valproate, a class I HDAC inhibitor, will be used concurrently with nivolumab with the goal of enhancing the effects of both the nivolumab and the radiotherapy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Radiation: Stereotactic Radiosurgery
    Subjects will receive a single large dose of radiation to one or more lesions.
    Other Name: Gamma Knife Radiosurgery
  • Drug: Nivolumab
    3 mg/kg of nivolumab will be administered through IV infusion every two weeks following stereotactic radiosurgery.
    Other Name: Opdivo
  • Drug: Valproate
    Subjects will begin regimen of valproate prior to radiosurgery and continue to receive therapy concurrently with nivolumab. Subjects will receive valproate daily with a target serum level of 75-100 μg/ml.
    Other Names:
    • Valproic Acid
    • Sodium Valproate
    • Divalproex Sodium
Study Arms  ICMJE Experimental: Nivolumab & Valproate Following G.K.
Subjects will begin a valproate regimen prior to undergoing stereotactic radiosurgery (gamma knife) on a single lesion. Following the surgery, subjects will receive nivolumab every 2 weeks and daily valproate.
  • Radiation: Stereotactic Radiosurgery
  • Drug: Nivolumab
  • Drug: Valproate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 26, 2017)
Original Estimated Enrollment  ICMJE
 (submitted: January 6, 2016)
Actual Study Completion Date  ICMJE February 21, 2017
Actual Primary Completion Date February 21, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Confirmed malignant, recurrent glioblastoma or gliosarcoma
  • Subject must have adequate organ function
  • Subject must still be able to care for most of his or her personal needs

Exclusion Criteria:

  • Subject is pregnant
  • Subject has extracranial metastatic or leptomeningeal disease
  • Subject has an additional malignancy that is progressing or requires active treatment, exceptions being basal cell and squamous cell carcinomas of the skin, indolent prostate cancer, chronic lymphocytic leukemia, or in situ cervical cancer
  • Subject has received chemotherapy, biological therapy, or had surgery 4 weeks prior to beginning the study
  • Subject has had radiation therapy within 10 weeks prior to entering beginning the study
  • Subject has had prior therapy with bevacizumab
  • Subject has had previous treatment with carmustine wafer except when administered as first-line treatment no less than six months prior to beginning the study
  • Subject requires escalating supraphysiologic doses of corticosteroids greater than 2 mg of dexamethasone or an equivalent
  • Active autoimmune disease requiring systemic treatment within the past 3 months or any syndrome that requires immunosuppressive agents
  • Interstitial lung disease or active, non-infectious pneumonitis
  • Evidence of greater than Grade 1 CNS hemorrhage or greater than Grade 3 venous thromboembolism
  • History of uncontrolled cardiac disease
  • Subject unable or unwilling to have a head contrast enhanced MRI
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 NCT02648633
Other Study ID Numbers  ICMJE 18574
CA209-378 ( Other Identifier: University of Virginia )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Benjamin Purow, MD, University of Virginia
Study Sponsor  ICMJE University of Virginia
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Benjamin Purow, MD University of Virginia
PRS Account University of Virginia
Verification Date May 2017

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