Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase IIa Study of AdV-tk + Valacyclovir Gene Therapy in Combination With Standard Radiation Therapy for Malignant Gliomas
Brief Summary: 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).


Options:
A: Inclusion criteria: Diagnosis: newly diagnosed glioblastoma in elderly patients

1. Signed informed consent
2. Age \> 65 years
3. Newly diagnosed supratentorial glioblastoma
4. Eligible for first infusion of bevacizumab \> 28 and \> 49 days after surgery for glioblastoma
5. Karnofsky performance score 60 or more
6. Paraffin-embedded tissue for central pathology review
7. Stable or decreasing corticosteroid dose within 5 days prior to enrolment
8. Adequate haematological function:
9. Adequate liver function
10. Adequate renal function

Exclusion criteria:

1. Karnofsky performance score 50 or less
2. Evidence of recent hemorrhage on postoperative brain MRI
3. Tumor with infiltration of retina, optic nerve, optic chiasm or brainstem
4. Any prior chemotherapy including carmustine-containing wafers (Gliadel®) or immunotherapy for glioblastoma or lower grade astrocytomas
5. Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field
6. Inadequately controlled hypertension
7. History of hypertensive crisis or hypertensive encephalopathy
8. New York Heart Association (NYHA) grade II or higher congestive heart failure
9. Myocardial infarction or unstable angina within 6 months prior to enrolment
10. Stroke or transitory ischemic attack within 6 months prior to enrolment
11. Other significant vascular disease within 6 months prior to enrolment
12. History of = grade 2 haemoptysis within 1 month prior to enrolment
13. Bleeding diathesis or coagulopathy in the absence of therapeutic anticoagulation
14. Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury within 28 days prior to first dose of bevacizumab
15. Core biopsy (excluding intracranial biopsy) or other minor surgical procedure within 7 days prior to first dose of bevacizumab
16. Abdominal fistula or gastrointestinal perforation within 6 months prior to enrolment
17. Intracranial abscess within 6 months prior to enrolment
18. Serious non-healing wound, active ulcer or untreated bone fracture
19. Pregnancy or lactation
20. Fertile women \< 2 years after last menstruation and men unwilling or unable to use effective means of contraception
21. Active malignancy that may interfere with the study treatment at the investigator?s and PI discretion
B: 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).
C: DISEASE CHARACTERISTICS:

* Histologically confirmed low-grade glioma, including any of the following types:

  * Astrocytoma (gemistocytic, fibrillary, or protoplasmatic)
  * Oligoastrocytoma
  * Oligodendroglioma
* WHO grade II disease
* Supratentorial tumor location only
* RTOG neurological function 0-3
* Not a candidate for surgical treatment alone
* Requires treatment, as determined by ≥ 1 of the following criteria:

  * Age ≥ 40 years
  * Radiologically-proven progressive lesion
  * New or worsening neurological symptoms other than seizures only (e.g., focal deficits, signs of increased intracranial pressure, or mental deficits)
  * Intractable seizures, defined by both of the following criteria:

    * Experiences persistent seizures that interfere with everyday life activities except driving a car
    * Failed 3 anti-epileptic drug regimens, including ≥ 1 combination regimen
* Tumor material (paraffin-embedded) or histopathologic slides available

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* WHO 0-2

Life expectancy

* Not specified

Hematopoietic

* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3

Hepatic

* No chronic hepatitis B or C infection
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* AST or ALT ≤ 2.5 times ULN
* Alkaline phosphatase ≤ 2.5 times ULN

Renal

* Creatinine ≤ 1.5 times ULN

Other

* Not pregnant or nursing
* Fertile patients must use effective contraception during and for 6 months after completion of study treatment
* No known HIV positivity
* No other serious medical condition
* No other prior or concurrent malignancy except surgically cured carcinoma in situ of the cervix or nonmelanoma skin cancer
* No psychological, familial, sociological, or geographical condition that would preclude study participation
* No medical condition that would preclude receiving oral medication (e.g., frequent vomiting or partial bowel obstruction)

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No concurrent growth factors for elevating absolute neutrophil counts for the purpose of temozolomide administration
* No concurrent epoetin alfa
* No concurrent immunotherapy or biologic therapy

Chemotherapy

* No prior chemotherapy
* No other concurrent chemotherapy, including adjuvant chemotherapy for patients randomized to undergo radiotherapy

Endocrine therapy

* Not specified

Radiotherapy

* No prior radiotherapy to the brain
* No concurrent integrated boost with intensity-modulated radiotherapy

Surgery

* Recovered from prior surgery
* No concurrent surgical tumor debulking

Other

* No prior randomization to this study
* No other concurrent investigational drugs
* No concurrent regular use of agents known to be radiosensitizers or radioprotectors (e.g., cyclooxygenase-2 inhibitors, thalidomide, or amifostine) during study radiotherapy

  * Occasional use of nonsteroidal anti-inflammatory drugs for pain allowed
D: Inclusion Criteria:

1. Patients with primary intracranial tumours such as low-grade glioma, meningioma, craniopharyngiomas, ependymomas and other benign tumours considered for radical focal radiotherapy.
2. Tumours measuring upto 7 cms on maximum dimension on the CT/MRI.
3. Age 3 to 25 years.
4. NPS of 0-3.
5. Informed consent from patients or parents as appropriate.
6. Long-term follow up expected

Exclusion Criteria:

1. Previous radiotherapy.
2. Planned adjuvant chemotherapy.
3. Expected median survival of less than two years.
4. Patient not cooperative for planning and execution of SCRT.

Answer: B