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

Sponsored by:	Advantagene, Inc.
Information provided by:	Advantagene, Inc.
ClinicalTrials.gov Identifier:	NCT00751270

Purpose

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).

Condition	Intervention	Phase
Malignant Glioma Glioblastoma Multiforme Anaplastic Astrocytoma	Biological: AdV-tk Drug: Valacyclovir	Phase I

MedlinePlus related topics: Cancer Radiation Therapy

Drug Information available for: Valaciclovir Valacyclovir hydrochloride

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Open Label, Single Group Assignment, Safety Study
Official Title:	A Phase 1b Study of AdV-tk + Valacyclovir Gene Therapy in Combination With Standard Radiation Therapy for Malignant Gliomas

Further study details as provided by Advantagene, Inc.:

Primary Outcome Measures:

Safety of the intervention will be evaluated based on laboratory and clinical parameters graded using CTCAEver3. [ Time Frame: Through month 3 and long term follow up for late effects. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Tumor Response [ Time Frame: MRI imaging and pathological/histological response if available ] [ Designated as safety issue: No ]
Progression-free Survival [ Time Frame: Clinical monitoring, laboratory and radiological imagining and pathological/histological assessments (if performed) ] [ Designated as safety issue: No ]
Overall Survival [ Time Frame: Clinical monitoring, laboratory and radiological imagining and pathological/histological assessments (if performed) ] [ Designated as safety issue: No ]
Quality of Life (QOL) [ Time Frame: Periodic completion of FACT-Br QOL questionaire ] [ Designated as safety issue: No ]

Estimated Enrollment:	12
Study Start Date:	November 2005
Estimated Study Completion Date:	December 2010
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A: Experimental Only Arm A for unresectable malignant glioma is open to enrollment. AdV-tk is injected into the tumor at the time of biopsy, followed by 14 days of oral valacyclovir.	Biological: AdV-tk Three different dosing levels of AdV-tk (3x10e10, 1x10e11, 3X10e11) will be evaluated. A single injection of AdV-tk at the assigned dose level will be administered, followed by 14 days of the oral prodrug valacyclovir. Patients will then receive standard of care radiation therapy and chemotherapy. Drug: Valacyclovir The oral prodrug Valacyclovir (2 grams three times a day) will be given beginning 1-3 days following the AdV-tk. Valacyclovir tablets will be taken three times a day for a total of 14 days.

Arms

Assigned Interventions

A: Experimental

Only Arm A for unresectable malignant glioma is open to enrollment. AdV-tk is injected into the tumor at the time of biopsy, followed by 14 days of oral valacyclovir.

Biological: AdV-tk

Three different dosing levels of AdV-tk (3x10e10, 1x10e11, 3X10e11) will be evaluated. A single injection of AdV-tk at the assigned dose level will be administered, followed by 14 days of the oral prodrug valacyclovir. Patients will then receive standard of care radiation therapy and chemotherapy.

Drug: Valacyclovir

The oral prodrug Valacyclovir (2 grams three times a day) will be given beginning 1-3 days following the AdV-tk. Valacyclovir tablets will be taken three times a day for a total of 14 days.

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00751270

Locations

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

Sponsors and Collaborators

Advantagene, Inc.

Investigators

Principal Investigator:

E. Antonio Chiocca, MD, PhD

The Ohio State University Medical Center

More Information

No publications provided

Responsible Party:	Advantagene, Inc. ( Laura Aguilar, MD, PhD )
Study ID Numbers:	BrTK01, 5R44CA107745
Study First Received:	September 9, 2008
Last Updated:	April 27, 2009
ClinicalTrials.gov Identifier:	NCT00751270 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Advantagene, Inc.:

Immunotherapy
Gene therapy
Tumor Vaccine
Cytotoxicity
Radiation

Study placed in the following topic categories:

Valacyclovir
Neuroectodermal Tumors
Glioblastoma
Astrocytoma
Neoplasms, Germ Cell and Embryonal

Neuroepithelioma
Glioblastoma Multiforme
Glioma
Antiviral Agents
Neoplasms, Glandular and Epithelial

Additional relevant MeSH terms:

Glioblastoma
Anti-Infective Agents
Neoplasms by Histologic Type
Astrocytoma
Neoplasms, Nerve Tissue
Antiviral Agents
Pharmacologic Actions
Valacyclovir

Neuroectodermal Tumors
Neoplasms
Therapeutic Uses
Neoplasms, Germ Cell and Embryonal
Glioma
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on May 07, 2009