Stereotactic Radiosurgery With Nivolumab and Valproate in Patients With Recurrent Glioblastoma
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
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.
Study Design
Arms and Interventions
| 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:
Drug: Nivolumab
3 mg/kg of nivolumab will be administered through IV infusion every two weeks following stereotactic radiosurgery.
Other Names:
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:
|
Outcome Measures
Primary Outcome Measures
- Feasibility based on number of subjects who complete 4 doses of nivolumab [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 [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
- Clinical Response Rate [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
- Incidence of Pseudoprogressions [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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Confirmed malignant, recurrent glioblastoma or gliosarcoma
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Subject must have adequate organ function
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Subject must still be able to care for most of his or her personal needs
Exclusion Criteria:
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Subject is pregnant
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Subject has extracranial metastatic or leptomeningeal disease
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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
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Subject has received chemotherapy, biological therapy, or had surgery 4 weeks prior to beginning the study
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Subject has had radiation therapy within 10 weeks prior to entering beginning the study
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Subject has had prior therapy with bevacizumab
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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
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Subject requires escalating supraphysiologic doses of corticosteroids greater than 2 mg of dexamethasone or an equivalent
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Active autoimmune disease requiring systemic treatment within the past 3 months or any syndrome that requires immunosuppressive agents
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Interstitial lung disease or active, non-infectious pneumonitis
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Evidence of greater than Grade 1 CNS hemorrhage or greater than Grade 3 venous thromboembolism
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History of uncontrolled cardiac disease
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Subject unable or unwilling to have a head contrast enhanced MRI
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Virginia | Charlottesville | Virginia | United States | 22908 |
Sponsors and Collaborators
- University of Virginia
Investigators
- Principal Investigator: Benjamin Purow, MD, University of Virginia
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 18574
- CA209-378