Stereotactic Radiosurgery With Nivolumab and Valproate in Patients With Recurrent Glioblastoma

May 26, 2017 updated by: Benjamin Purow, MD, University of Virginia

A Pilot Study to Evaluate the Feasibility of the Combined Use of Stereotactic Radiosurgery With Nivolumab and Concurrent Valproate in Patients With Recurrent Glioblastoma

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

4

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • University of Virginia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • Gamma Knife Radiosurgery
Drug: Nivolumab
3 mg/kg of nivolumab will be administered through IV infusion every two weeks following stereotactic radiosurgery.
Other Names:
  • 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:
  • Sodium Valproate
  • Valproic Acid
  • Divalproex Sodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
At 3 months following radiosurgery
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.
From the beginning of treatment until no sooner than 30 days following the last study treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From the beginning of treatment until documented disease progression or date of death, assessed up to 48 months.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From the beginning of treatment until documented disease progression or date of death, assessed up to 48 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Virginia

Investigators

  • Principal Investigator: Benjamin Purow, MD, University of Virginia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 24, 2016

Primary Completion (Actual)

February 21, 2017

Study Completion (Actual)

February 21, 2017

Study Registration Dates

First Submitted

December 16, 2015

First Submitted That Met QC Criteria

January 6, 2016

First Posted (Estimate)

January 7, 2016

Study Record Updates

Last Update Posted (Actual)

May 31, 2017

Last Update Submitted That Met QC Criteria

May 26, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 18574
  • CA209-378 (Other Identifier: University of Virginia)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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