Oncolytic Adenovirus DNX-2401 in Treating Patients With Recurrent High-Grade Glioma
Oncolytic Adenovirus DNX-2401 in Treating Patients With Recurrent High-Grade Glioma
This phase I trial studies best dose and side effects of oncolytic adenovirus DNX-2401 in
 treating patients with high-grade glioma that has come back (recurrent). Oncolytic adenovirus
 DNX-2401 is made from the common cold virus that has been changed in the laboratory to make
 it less likely to cause an infection (such as a cold). The virus is also changed to target
 brain cancer cells and attack them.
PRIMARY OBJECTIVES:

 I. To determine the maximal tolerated dose (MTD) of allogeneic bone marrow-derived human
 mesenchymal stem cells (BM-hMSCs) loaded with the oncolytic adenovirus DNX-2401
 (BM-hMSCs-DNX2401) administered by intra-arterial injection (i.e., transfemoral
 super-selective endovascular intracranial injection) in patients with recurrent glioblastoma
 (GBM), gliosarcoma or wild-type IDH-1 anaplastic astrocytoma.

 II. To determine the local and systemic toxicity of allogeneic BM-hMSCs-DNX2401 administered
 by intra-arterial injection (i.e., transfemoral super-selective endovascular intracranial
 injection) in patients with recurrent GBM, gliosarcoma or wild-type IDH-1 anaplastic
 astrocytoma.

 III. To determine at the molecular and cellular level the capacity of allogeneic
 BM-hMSCs-DNX2401 administered intra-arterially to home to and deliver DNX-2401 to recurrent
 GBM, gliosarcoma or wild-type IDH-1 anaplastic astrocytoma by analyzing post-treatment
 surgical brain tumor specimens for the expression and distribution of adenoviral proteins.

 SECONDARY OBJECTIVES:

 I. To assess shedding of adenovirus into the blood, sputum, and nasopharynx after
 intra-arterial administration of BM-hMSCs-DNX2401 in patients with recurrent GBM, gliosarcoma
 or wild-type IDH-1 anaplastic astrocytoma.

 II. To assess the development of anti-adenovirus antibodies after intra-arterial
 administration of BM-hMSCs-DNX2401 in patients with recurrent GBM, gliosarcoma or wild-type
 IDH-1 anaplastic astrocytoma.

 III. To evaluate immune-mediated cytokine responses after intra-arterial administration of
 BM-hMSCs-DNX2401 in patients with recurrent GBM, gliosarcoma or wild-type IDH-1 anaplastic
 astrocytoma.

 IV. To assess anti-tumoral activity and to determine progression-free survival (PFS) and
 overall survival (OS) after intra-arterial administration of BM-hMSCs-DNX2401 in patients
 with recurrent GBM, gliosarcoma or wild-type IDH-1 anaplastic astrocytoma.

 OUTLINE: This is a dose-escalation study.

 PART I: Patients receive oncolytic adenovirus Ad5-DNX-2401 intra-arterially (IA) over 20-30
 minutes on day 0.

 PART II: Patients receive oncolytic adenovirus Ad5-DNX-2401 as in part I. After 2 weeks,
 patients undergo surgery, then receive oncolytic adenovirus Ad5-DNX-2401 IA over 20-30
 minutes.

 After completion of study treatment, patients in part I are followed up on days 1, 4, 7, and
 14 of month 1, months 1.5, 3, and 4.5, every 2 months up to month 26, month 30, then every 6
 months thereafter. Patients in part II will be followed up on the day after surgery, weeks 1,
 2 and 4, months 2, 2.5, 4, 5.5 and 7, every 2 months until month 19, every 4 months until
 month 32, then every 6 months thereafter.
Inclusion Criteria:

 -  Subjects must be willing and able to provide informed consent, undergo and comply with
 all study assessments and adhere to the protocol schedule

 -  Patients with recurrent malignant GBM or gliosarcoma will be eligible. Patients with
 recurrent anaplastic astrocytoma with wild-type IDH-1 gene will also be eligible if
 there is a significant enhancing mass on magnetic resonance imaging (MRI) because
 their prognosis/behavior is similar to GBM. A pathology report constitutes adequate
 documentation of histology for study inclusion. Subjects with an initial diagnosis of
 a lower grade glioma are eligible if a subsequent biopsy is determined to be GBM and
 there is a significant enhancing mass on MRI

 -  Patients must show unequivocal evidence for tumor recurrence or progression by MRI
 scan after failing prior surgical resection, biopsy, chemotherapy or radiation. A
 baseline MRI must be performed within 24 days prior to registration. Biopsy is
 encouraged at the time of recurrence if it is unclear that there is recurrent tumor.
 However, biopsy is not required if the practicing physician thinks that there is
 adequate radiographic and clinical evidence for recurrence

 -  Patients must be able to undergo endovascular treatment based on Doppler studies
 showing internal carotid artery (ICA) that is less than 50% occluded

 -  For patients undergoing resection for biological endpoints, tumors must be surgically
 resectable at the time of baseline evaluation and craniotomy for tumor resection would
 be part of their standard medical care

 -  Tumors must be > 1.0 cm in diameter with upper limit of 5 cm maximal diameter

 -  Patients must have a Karnofsky performance score >= 70

 -  Patients must have a life expectancy of at least 16 weeks

 -  Absolute granulocyte count >= 1,500 prior to starting therapy

 -  Platelet count of >= 75,000 prior to starting therapy

 -  Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic
 transaminase (SGOT) < 2 times institutional normal ranges prior to starting therapy

 -  Bilirubin < 2 times institutional normal ranges prior to starting therapy

 -  Creatinine < 2.0 times institutional normal prior to starting therapy

 -  Prothrombin time (PT), partial thromboplastin time (PTT), and thrombin time within
 institutional normal limits after correction of nutritional deficiencies that may
 contribute to prolonged PT/PTT

 -  Subjects who have received the following chemotherapies must have completed them
 within the following time periods prior to baseline/day 0 of hMSC-DNX2401 delivery
 with recovery from any drug-related toxic effects to grade 1, or less, severity: 4
 weeks from cytotoxic agents (3 weeks from procarbazine or temozolomide, 2 weeks from
 vincristine), 6 weeks from nitrosoureas (lomustine [CCNU], carmustine [BCNU]), 4 weeks
 from any investigational agent, 1 week from non-cytotoxic agents

 -  Patients must be 8 weeks from radiotherapy to minimize the potential for MRI changes
 related to radiation necrosis that might be misdiagnosed as progression of disease, or
 4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is outside
 the primary radiation field (beyond 80% isodose line). However, if a biopsy is
 undertaken prior to these times and this biopsy documents histological evidence for
 recurrent disease, then patients will be eligible regardless of the time after
 radiation

 -  Patients must be willing to forego other cytotoxic and non-cytotoxic drug or radiation
 therapy against the tumor while enrolled in the study

 -  Women of childbearing potential must have a negative urine pregnancy test documented
 within 7 days prior to study initiation

 -  Subjects and their partners must be willing to use effective birth control during the
 study and for up to 6 months following administration of hMSC-DNX2401. Birth control
 that is acceptable to use in this study:

 -  Using twice the normal protection of birth control (i.e., double-barrier) by
 using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal
 jelly or foam. A spermicidal jelly or foam must be used in addition to a barrier
 method (e.g., condom or diaphragm)

 -  Birth control pills ("The Pill")

 -  Depot or injectable birth control

 -  IUD (intrauterine device)

 -  Birth control patch (e.g., Ortho Evra)

 -  NuvaRing

 -  Surgical sterilization (i.e., tubal ligation or hysterectomy for women or
 vasectomy for men)

 Exclusion Criteria:

 -  Histology other than astrocytoma grade IV (GBM or gliosarcoma), although astrocytoma
 grade III that is IDH-1 wild-type will be included

 -  Tumor foci detected below the tentorium or beyond the cranial vault

 -  Tumor within the posterior fossa

 -  Tumor with leptomeningeal spread

 -  Difficulty in obtaining vascular access for percutaneous procedure

 -  Ipsilateral carotid stenosis (> 50%, by Doppler studies)

 -  Thrombophilias or primary hematological diseases

 -  Transfusions or medications (G-CSF) to treat pancytopenia or other hematological
 conditions < 28 days prior to baseline/day 0/hMSC-DNX2401 administration

 -  Biologic/immunotherapy within 2 weeks of baseline

 -  Clinical or laboratory evidence of inflammatory and/or autoimmune disorders

 -  Any contraindication for undergoing MRI such as: individuals with pacemakers,
 epicardial pacer wires, infusion pumps, surgical and/or aneurysm clips, shrapnel,
 metal prosthesis, implants with potential magnetic properties, metallic bodies in the
 eyes, etc. In addition, subjects must present with tumor that is evaluable by MRI

 -  Pregnant or nursing females

 -  Evidence of active uncontrolled infection or unstable or severe intercurrent medical
 conditions. All subjects must be afebrile at baseline (i.e., < 38.0 degrees Celsius
 [C])

 -  Any medical condition that precludes surgery or endovascular treatment

 -  Alcoholism (dependency), alcohol or substance abuse within twelve (12) months prior to
 screening that has caused health consequences

 -  Immunocompromised subjects or those with autoimmune conditions, active hepatitis
 (liver function tests > 2x normal) or human immunodeficiency virus (HIV)
 seropositivity

 -  Evidence of bleeding diathesis or use of anticoagulant medication or any medication
 that may increase the risk of bleeding that cannot be stopped prior to surgery. If the
 medication can be discontinued prior to DNX-2401 injection then the subject may be
 eligible following consultation with the study chair. Low weight heparin and Lovenox
 (enoxaparin) administered on a temporary limited basis for post procedure deep venous
 thrombosis (DVT) prophylaxis is permitted

 -  History or current diagnosis of any medical or psychological condition that in the
 investigator's opinion, might interfere with the subject's ability to participate or
 inability to obtain informed consent because of psychiatric or complicating medical
 problems

 -  Encephalitis, multiple sclerosis or other central nervous system (CNS) infection or
 primary CNS disease that would interfere with subject evaluation

 -  Subjects with known Li-Fraumeni syndrome or with a known germ line deficit in the
 retinoblastoma gene or its related pathways

 -  Subjects with significant systemic or major illnesses including but not limited to:
 congestive heart failure, ischemic heart disease, cerebrovascular disease (history of
 strokes or transient ischemic attacks [TIAs] in large vessel or small vessel
 distribution), kidney disease or renal failure, active liver disease, organ
 transplantation, or significant psychiatric disorder

 -  Enrollment in a concomitant therapeutic clinical study

 -  Any condition that prevents compliance with the protocol or adherence to therapy