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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

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.

Condition or disease Intervention/treatment Phase
Glioblastoma Radiation: Stereotactic Radiosurgery Drug: Nivolumab Drug: Valproate Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study to Evaluate the Feasibility of the Combined Use of Stereotactic Radiosurgery With Nivolumab and Concurrent Valproate in Patients With Recurrent Glioblastoma
Actual Study Start Date : May 24, 2016
Actual Primary Completion Date : February 21, 2017
Actual Study Completion Date : February 21, 2017

Arm Intervention/treatment
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
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

Primary Outcome Measures :
  1. 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.

  2. 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.

Secondary Outcome Measures :
  1. 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.

Other Outcome Measures:
  1. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02648633

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United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
University of Virginia
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Principal Investigator: Benjamin Purow, MD University of Virginia
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Responsible Party: Benjamin Purow, MD, Professor of Neurology, University of Virginia Identifier: NCT02648633    
Other Study ID Numbers: 18574
CA209-378 ( Other Identifier: University of Virginia )
First Posted: January 7, 2016    Key Record Dates
Last Update Posted: May 31, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Benjamin Purow, MD, University of Virginia:
Brain Cancer
Gamma Knife
Additional relevant MeSH terms:
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Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Valproic Acid
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs