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

Condition(s) targeted: Malignant Glioma; Glioblastoma Multiforme; Anaplastic Astrocytoma

Intervention: AdV-tk (Biological); Valacyclovir (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: Advantagene, Inc.

Official(s) and/or principal investigator(s):
E. Antonio Chiocca, MD, PhD, Principal Investigator, Affiliation: The Ohio State University Medical Center

This phase I study evaluates a Gene Mediated Cytotoxic Immunotherapy approach for unresectable malignant gliomas, including glioblastoma multiforme and anaplastic astrocytoma. The study is evaluating an experimental gene therapy treatment which uses AdV-tk, an adenoviral vector containing the Herpes Simplex thymidine kinase gene, plus an oral anti-herpetic prodrug, valacyclovir. This is given in combination with standard of care radiation and optional temozolomide. Only Arm A of this study remains open to accrual; Arm B for resectable malignant glioma completed the phase I evaluation and is now open as a phase 2a study (see BrTK02 study).

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

Study design: Treatment, Open Label, Single Group Assignment, Safety Study

Primary outcome: Safety of the intervention will be evaluated based on laboratory and clinical parameters graded using CTCAEver3.

Secondary outcome:

Tumor Response

Progression-free Survival

Overall Survival

Quality of Life (QOL)

Detailed description: This phase I study involves the use of the biotherapeutic agent, AdV-tk, a replication deficient adenoviral vector containing a Herpes Simplex thymidine kinase gene, plus oral administration of an anti-herpetic prodrug, as an adjuvant to standard of care therapy for the treatment of newly diagnosed, unresectable malignant glioma. Three dose levels of AdV-tk are being evaluated with a fixed dose level of valacyclovir prodrug.

AdV-tk is injected stereotactically directly into the tumor at the time of biopsy, followed 1-3 days later by a 14 day course of the prodrug valacyclovir at a dose of 2 gm TID, with dose modifications made for patients presenting with a baseline creatinine clearance of <50 ml/min. Beginning 3-7 days following the AdV-tk injection, all patients receive standard of care radiation therapy and may receive temozolomide as per standard of care.

Objective tumor response will be measured according to MRI imaging results. Patients will undergo MRI imagining at baseline, 2-4 weeks following the completion of radiation therapy and then every 2-4 months for the first year or until disease progression, whichever occurs first.

Quality of life will be assessed and monitored using the FACT-Br version 4 questionnaire and a mini-mental status exam, both administered at baseline, once during prodrug administration, 2-4 weeks following the completion of radiation therapy, then every 3 months for the first year or until disease progression, whichever occurs first.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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).

The Methodist Hosptial, Houston, Texas 77030, United States; Recruiting
Pamela Z. New, MD, Phone: 713-441-3800, Email: pnew@tmhs.org
Pamela New, MD, Principal Investigator

Starting date: November 2005
Ending date: December 2010
Last updated: April 27, 2009