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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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A Phase IIa 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, High Grade Glioma

Intervention / Treatment
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* Biological: CAN-2409
* Drug: Valacyclovir
* Drug: Temozolomide
* Radiation: Radiation therapy


Participation Criteria
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Eligibility Criteria
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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).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>This study is an extension of evaluation of the surgical resection arm, Arm B, from a phase Ib study in which dose escalation on arm B was completed. | Biological: CAN-2409<br>* Single dose of 3x10e11 vector particles of CAN-2409 delivered to the tumor bed after resection on day 0.<br>Drug: Valacyclovir<br>* Single course of valacyclovir at dose of 2 grams orally three times per day for 14 days starting on day 1-3<br>* Other names: Valtrex;Drug: Temozolomide<br>* Concomitant TMZ will be administered orally once a day at a dose of 75 mg/m2 starting the next day after completing prodrug and continued for 6 weeks. Adjuvant TMZ will be administered days 1 to 5 of a 28-day cycle for 6 cycles with 150 mg/m2 administered for cycle 1, and 150 to 200 mg/m2 administered for cycles 2 to 6. Adjuvant treatment will start 1 month following completing RT.<br>Radiation: Radiation therapy<br>* Radiation will be administered to up-front patients as per standard of care for the patient. It will start 3-7 days after CAN-2409 injection, preferably closer to 3 days. It will consist of standard external field radiation, limited to the area of tumor and brain adjacent to tumor, fractionated at doses of 200cGy per day for approximately 6 weeks to a total of 5500-6000 cGy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of patients with treatment related adverse events |  | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Cytotoxicity, Tumor vaccine, CAN-2409, AdV-tk, Candel Therapeutics, Inc.