Phase 1b Study of AdV-tk + Valacyclovir Combined With Radiation Therapy for Malignant Gliomas

Study Overview
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Brief Summary
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This phase I study evaluated a Gene Mediated Cytotoxic Immunotherapy approach for malignant gliomas, including glioblastoma multiforme and anaplastic astrocytoma. The purpose of this study was to assess the safety and feasibility of delivering an experimental approach called GliAtak which uses AdV-tk, an adenoviral vector containing the Herpes Simplex thymidine kinase gene, plus an oral anti-herpetic prodrug, valacyclovir, in combination with standard of care radiation.

Detailed Description
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This study was designed to include patients with newly diagnosed unresectable (Arm A) and resectable (Arm B) malignant glioma. Three dose levels of AdV-tk were evaluated with a fixed dose level of valacyclovir prodrug. AdV-tk was delivered to tumor cells by stereotactic injection into the tumor at the time of biopsy (Arm A) or injection into the tumor bed following resection (Arm B). Oral valacyclovir began 1-3 days after the AdV-tk injection and continued for 14 days. Standard radiation therapy began 3-7 days following the AdV-tk injection to maximize synergy with radiation. Standard temozolomide could be administered after completion of valacyclovir.

Official Title
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A Phase 1b Study of AdV-tk + Valacyclovir Gene Therapy in Combination With Standard Radiation Therapy for Malignant Gliomas

Conditions
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Malignant Glioma, Glioblastoma Multiforme, Anaplastic Astrocytoma

Intervention / Treatment
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* Biological: AdV-tk
* Drug: Valacyclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presumed malignant glioma based on clinical and radiologic evaluation (pathologic confirmation of malignant glioma must be made at the time of stereotactic biopsy or resection prior to AdV-tk injection; if this is not possible, the injection will not be performed and the subject will no longer be eligible for the study). Tumor must be accessible for injection and must not be located in the brainstem, midbrain, contained within the ventricular system, or located in an infratentorial location. Patients must be planning to undergo standard radiation therapy. Patients must be 18 years of age or older. Performance status must be KPS > or equal to 70. Patients must have SGOT (AST) < 3x upper limit of normal. Patients must have serum creatinine < 2mg/dl and calculated creatinine clearance >10ml/min. Patients must have platelets > 100,000/mm3 and WBC > 3000/mm3. Patients of reproductive age must agree to use a medically accepted form of birth control while on the study. Patients must give study specific informed consent prior to enrollment. Patients must be able to tolerate MRI scan procedure Exclusion Criteria: Prior or ongoing liver disease including known cirrhosis, hepatitis B or C infection but not to exclude patients with a distant history of resolved hepatitis A infection. Patients on immunosuppressive drugs (with exception of corticosteroid) Known HIV+ patients. Patients with acute infections (viral, bacterial or fungal infections requiring therapy). Pregnant or breast feeding patients. Female patients of childbearing age must have negative serum or urine pregnancy test within 1 week of beginning therapy. Evidence of metastatic disease or other malignancy (except squamous or basal cell skin cancers). Prior radiation therapy to the brain or prior treatment for brain tumor (except prior biopsy or subtotal resection). Other serious co-morbid illness or compromised organ function. Patients may not receive temozolomide until valacyclovir completed and may not receive other investigational anti-tumor agents within 30 days prior to study entry or during active participation in the study (defined as from study entry until tumor progression).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Arm A for unresectable malignant glioma was closed due to poor accrual. | Biological: AdV-tk<br>* Three different dosing levels of AdV-tk (3x10e10, 1x10e11, 3X10e11) were evaluated. A single injection of AdV-tk at the assigned dose level was administered, followed by 14 days of the oral prodrug valacyclovir. Patients then received standard of care radiation therapy and chemotherapy.<br>Drug: Valacyclovir<br>* The oral prodrug valacyclovir was given beginning 1-3 days following the AdV-tk. Valacyclovir tablets were taken three times a day for a total of 14 days.<br>|
| Experimental: B<br>Arm B for resectable malignant glioma completed the Phase I accrual and long term follow up continues. A follow on study at dose level 3 was opened as a Phase 2a study (see BrTK02). | Biological: AdV-tk<br>* Three different dosing levels of AdV-tk (3x10e10, 1x10e11, 3X10e11) were evaluated. A single injection of AdV-tk at the assigned dose level was administered, followed by 14 days of the oral prodrug valacyclovir. Patients then received standard of care radiation therapy and chemotherapy.<br>Drug: Valacyclovir<br>* The oral prodrug valacyclovir was given beginning 1-3 days following the AdV-tk. Valacyclovir tablets were taken three times a day for a total of 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events |  | Through month 3 and long term follow up for late effects. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival |  | Clinical monitoring, laboratory and radiological imagining and pathological/histological assessments (if performed) | 
| Overall Survival |  | 5 years | 
| Functional Assessment of Cancer Therapy - Brain (FACT-Br) |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Gene therapy, Tumor Vaccine, Cytotoxicity, Radiation