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Stereotactic Radiosurgery With Nivolumab and Valproate in Patients With Recurrent Glioblastoma

Primary Purpose

Glioblastoma

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Stereotactic Radiosurgery

Nivolumab

Valproate

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring Brain Cancer, Immunotherapy, Nivolumab, Radiosurgery, Gamma Knife

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of Virginia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Nivolumab & Valproate Following G.K.

Arm Description

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.

Outcomes

Primary Outcome Measures

Feasibility based on number of subjects who complete 4 doses of nivolumab

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

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

Clinical Response Rate

Response to therapy will be evaluated by means of RANO criteria.

Full Information

NCT ID

NCT02648633

First Posted

December 16, 2015

Last Updated

May 26, 2017

Sponsor

University of Virginia

1. Study Identification

Unique Protocol Identification Number

NCT02648633

Brief Title

Stereotactic Radiosurgery With Nivolumab and Valproate in Patients With Recurrent Glioblastoma

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2017

Overall Recruitment Status

Terminated

Why Stopped

The pharmaceutical company (BMS) would no longer provide nivolumab for the study, so the study was terminated early.

Study Start Date

May 24, 2016 (Actual)

Primary Completion Date

February 21, 2017 (Actual)

Study Completion Date

February 21, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Virginia

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioblastoma

Keywords

Brain Cancer, Immunotherapy, Nivolumab, Radiosurgery, Gamma Knife

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

4 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Nivolumab & Valproate Following G.K.

Arm Type

Experimental

Arm Description

Intervention Type

Radiation

Intervention Name(s)

Stereotactic Radiosurgery

Other Intervention Name(s)

Gamma Knife Radiosurgery

Intervention Description

Subjects will receive a single large dose of radiation to one or more lesions.

Intervention Type

Drug

Intervention Name(s)

Nivolumab

Other Intervention Name(s)

Opdivo

Intervention Description

3 mg/kg of nivolumab will be administered through IV infusion every two weeks following stereotactic radiosurgery.

Intervention Type

Drug

Intervention Name(s)

Valproate

Other Intervention Name(s)

Valproic Acid, Sodium Valproate, Divalproex Sodium

Intervention Description

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.

Primary Outcome Measure Information:

Title

Feasibility based on number of subjects who complete 4 doses of nivolumab

Description

Feasibility of the radiosurgery and drug combination will be determined based on the number of subjects who complete at least 4 doses of nivolumab.

Time Frame

At 3 months following radiosurgery

Title

Incidence of adverse events

Description

Time Frame

From the beginning of treatment until no sooner than 30 days following the last study treatment

Secondary Outcome Measure Information:

Title

Clinical Response Rate

Description

Response to therapy will be evaluated by means of RANO criteria.

Time Frame

From the beginning of treatment until documented disease progression or date of death, assessed up to 48 months.

Other Pre-specified Outcome Measures:

Title

Incidence of Pseudoprogressions

Description

Pseudoprogression, the transient increase in apparent tumor size, will be documented.

Time Frame

From the beginning of treatment until documented disease progression or date of death, assessed up to 48 months.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Benjamin Purow, MD

Organizational Affiliation

University of Virginia

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Virginia

City

Charlottesville

State/Province

Virginia

ZIP/Postal Code

22908

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Stereotactic Radiosurgery With Nivolumab and Valproate in Patients With Recurrent Glioblastoma

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