Phase 2a Study of CAN-2409 With Standard Radiation Therapy for Malignant Glioma

A Phase IIa Study of AdV-tk + Valacyclovir Gene Therapy in Combination With Standard Radiation Therapy for Malignant Gliomas

The purpose of this study was to evaluate the safety and potential efficacy of CAN-2409 (also known / previously described as AdV-tk, GMCI) for malignant gliomas. The approach used an adenoviral vector (disabled virus) engineered to express the Herpes thymidine kinase gene (aglatimagene besadenovec, CAN-2409), followed by an antiherpetic prodrug, valacyclovir. CAN-2409 was injected into the resection bed after standard tumor surgery and valacyclovir pills were taken for 14 days. Standard radiation and chemotherapy were administered which have been shown to work cooperatively with CAN-2409 + prodrug to kill tumor cells. The hypothesis is that this combination therapy can be safely delivered and will lead to improvement in the clinical outcome for patients with newly diagnosed malignant gliomas, including glioblastoma multiforme (WHO grade IV) and anaplastic astrocytomas (WHO grade III).

Patients had resectable or partially resectable malignant glioma and received injection of CAN-2409 into remaining tumor or tumor bed after resection. Pathologic confirmation of malignant glioma must be made prior to CAN-2409 injection; if this was not possible, the injection was not performed and the subject was no longer eligible for the study. The oral prodrug, valacyclovir, started 1-3 days after CAN-2409 injection and continued for 14 days. Standard radiotherapy began on average 7 days after CAN-2409 injection for the up-front course. Patients received temozolomide as per standard of care after completion of prodrug.

Inclusion Criteria:

• Patients must have presumed resectable or partially resectable malignant glioma based on clinical and radiologic evaluation (pathologic confirmation of malignant glioma must be made at the time of surgery if not previously determined). Patients who have previously received CAN-2409 + prodrug on this study may receive an additional CAN-2409 + prodrug course at recurrence if eligibility criteria are still met.
• 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.
• Upfront patients must be planning to undergo standard radiation therapy.
• Patients must be 18 years of age or older.
• Performance status must be KPS ≥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. For re-administration, patients must be re-consented.
• Patients must be able to tolerate MRI scan procedure

Exclusion Criteria:

• Active liver disease including cirrhosis or hepatitis
• 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).
• Other serious co-morbid illness or compromised organ function.
• Patients may not receive chemotherapy until valacyclovir is 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 CAN-2409 injection until tumor progression).