Oncolytic HSV-1716 in Treating Younger Patients With Refractory or Recurrent High Grade Glioma That Can Be Removed By Surgery

PRIMARY OBJECTIVES:

I. To determine whether intratumoral/peritumoral injection of HSV1716 (oncolytic HSV-1716)
is safe in children with recurrent high-grade gliomas amenable to resection.

II. To estimate the maximum tolerated dose (MTD) or a recommended Phase II dose of
intratumoral/peritumoral injection of HSV1716.

III. To describe any dose-limiting toxicities (DLT) of intratumoral/peritumoral injection of
HSV1716 at the doses given to children with high-grade gliomas.

IV. To evaluate changes in tumor enhancement, quantitative magnetic resonance (MR) measures
of tumor perfusion (relative cerebral blood volume [rCBV], transfer coefficient [k^trans],
fractional blood-plasma volume [Vp] and extravascular extracellular space per unit volume
tissue [Ve] values and apparent diffusion coefficient [ADC]) in response to HSV1716
injection.

SECONDARY OBJECTIVES:

I. To measure antiviral immune response in patients with refractory high-grade gliomas
injected with HSV1716.

II. To measure the systemic viremia and viral shedding following intratumoral/peritumoral
administration of HSV1716.

III. To preliminarily describe the antitumor activity of HSV1716 injection within the
confines of a Phase I study.

IV. To evaluate anti-tumor immune cellular and humoral immune responses. V. To evaluate
changes in fluorodeoxyglucose (FDG)- positron emission tomography (PET) uptake in response
to HSV1716 injection.

VI. To evaluate changes in tumor choline values using magnetic resonance (MR) spectroscopy
in response to HSV1716 injection and further delineate from progressive disease versus
pseudo-progression post therapy.

OUTLINE: This is a dose-escalation study.

Patients receive oncolytic HSV-1716 intratumorally (IT) and peritumorally after undergoing
surgical tumor resection. Patients also receive dexamethasone intravenously (IV) prior to
and 6 and 12 hours after surgery.

After completion of study treatment, patients are followed up every 2 months for 1 year,
every 6 months for 4 years, and then annually for 10 years.

Inclusion Criteria:

- Imaging evaluations necessary to establish eligibility for study entry must be done
within three (3) weeks prior to registration; all other evaluations necessary to
establish eligibility for study entry must be done within two (2) weeks prior to
registration; in the event that the patient's condition deteriorates (performance
score < 60) within 48 hours prior to the injection the patient is no longer eligible
to receive HSV1716 injection

- Patients must have a histologically-confirmed primary diagnosis of high-grade glioma
(HGG) (such as glioblastoma multiforme, gliosarcoma, anaplastic oligodendroglioma,
anaplastic ganglioglioma, high grade astrocytoma, not otherwise specified [NOS]) that
is recurrent or refractory to conventional therapy; patients with metastatic disease
are not eligible

- Patients must be those for whom surgical resection is clinically indicated; the
intent of surgical resection may include debulking or attempt to resect as much of
the tumor as safely feasible; if a gross total or near total resection is not
feasible, HSV1716 injection into the wall of the resection cavity, encompassing
residual tumor, is permissible

- Patients must be amenable to receiving 1 dose of HSV1716 intra-operatively with
planned HSV1716 injection sites >= 1 cm from the ventricular system AND meet at
least one of the criteria below based upon pre-surgical magnetic resonance
imaging (MRI):

- Tumor is >= 1 cm from the ventricular system

- Patients whose tumors that are =< 1 cm from the ventricular system are
eligible if there is sufficient space within the tumor cavity and/or
residual tumor to perform the HSV 1716 injections that are >= 1 cm from the
ventricular system

- An intraoperative MRI upon resection will confirm the distance of the planned
injection sites from the ventricular system prior to the HSV1716 injection;
intra-operatively, the neurosurgeon may decide to not inject the HSV1716 or may
revise the sites of HSV1716 injection if injection cannot be guaranteed >= 1 cm
from the ventricular system; patient will removed from the study if there are
not sufficient areas in the tumor cavity to guarantee injection of HSV1716 >= 1
cm from the ventricular system

- Patients must have received prior therapy other than surgery and must have fully
recovered from the acute treatment related toxicities of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study

- Patients must have received their last dose of known myelosuppressive anticancer
chemotherapy at least three (3) weeks prior to study registration treatment or at
least six (6) weeks if nitrosourea

- Investigational/Biologic agent:

- Biologic or investigational agent (anti-neoplastic): Patient must have recovered
from any acute toxicity potentially related to the agent and received their last
dose of the investigational or biologic agent >= 7 days prior to study
registration

- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which
adverse events are known to occur

- Monoclonal antibody treatment: At least three half-lives must have elapsed prior
to registration; Note: A list of the half-lives of commonly used monoclonal
antibodies is available on the Pediatric Brain Tumor Consortium (PBTC) webpage
under Generic Forms and Templates

- Patients must have had their last fraction of:

- Craniospinal irradiation (> 24 Gray [Gy]) or total body irradiation > 3 months
prior to registration

- Focal irradiation to symptomatic metastatic sites > 4 weeks prior to
registration

- Local palliative external beam radiation therapy (XRT) (small port) >= 4 weeks

- If prior total-body irradiation (TBI), craniospinal XRT or if >= 50% radiation
of pelvis >= 6 months must have elapsed

- If other substantial bone marrow (BM) radiation >= 6 weeks must have elapsed

- Patient must be:

- >= 6 months since allogeneic bone marrow transplant prior to registration

- Stem cell transplant or rescue without TBI: No evidence of active graft vs. host
disease and >= 3 months must have elapsed since transplant

- Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score
(LPS for =< 16 years of age) assessed within two weeks of registration must be >= 60

- Hemoglobin: >= 10 g/dl

- Absolute neutrophil count: >= 1000/mm^3

- Platelets: >= 100,000/mm^3 (transfusion independent defined as not receiving platelet
transfusions within 7 days prior to registration)

- Total bilirubin: < 1.5 x upper limit of institutional normal for age

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): =< 2.5
× institutional upper limit of normal

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age and gender as follows:

- Age 10 to < 13 years: maximum serum creatinine (mg/dL): 1.2 for males and 1.2
for females

- Age 13 to < 16 years: maximum serum creatinine (mg/dL): 1.5 for males and 1.4
for females

- Age >= 16 years: maximum serum creatinine (mg/dL): 1.7 for males and 1.4 for
females

- Albumin >= 2.5 g/dL

- Partial thromboplastin time (PTT) < 1.2 X institutional upper limits of normal

- Patients with neurological deficits should have deficits that are stable for a
minimum of 1 week prior to registration; this is to be documented at baseline

- Patients with central nervous system (CNS) tumors who are receiving dexamethasone
must have been on a stable or decreasing dose of dexamethasone for the 7 days prior
to enrollment

- Growth factors that support platelet or white cell number or function must not have
been administered within the past 7 days; growth factors include: GCSF (filgrastim),
PEG-GCSF (Neulasta), GM-CSF (sargramostim) and erythropoietin

- Documented evidence of negative tests for the presence of hepatitis B surface
antigen, hepatitis C antibody, and human immunodeficiency virus (HIV)1/2 antibodies
within the three months preceding study entry; subjects who do not have such evidence
must undergo appropriate testing prior to virus administration; HIV-positive patients
on combination antiretroviral therapy are ineligible

- Female patients of childbearing potential must have a negative serum or urine
pregnancy test at the time of enrollment

- Ability to understand and the willingness to sign a written informed consent document
according to institutional guidelines

Exclusion Criteria:

- Patients with metastatic disease i.e. leptomeninges, multi-focal lesions in the CNS

- Patients whose tumor lies within 1 cm of the ventricular system

- Patients who are receiving any other investigational agents

- Patients who are currently receiving other anti-cancer agents are excluded from this
trial

- Patients with history of prior HSV encephalitis or encephalitis due to other
etiologies

- There is no available information regarding human fetal or teratogenic toxicities

- Pregnant women are excluded to avoid the risk of systemic intrauterine/neonatal HSV
infection

- Males or females of reproductive potential may not participate unless they have
agreed to use an effective contraceptive method from the time of study entry to a
period of no less than four months post the HSV1716 injection

- Women who participate in this study must agree not to breastfeed from study entry to
a period of no less than four months post the HSV1716 injection

- Subjects whose primary physicians determine that anti-HSV antiviral therapy (such as
acyclovir, ganciclovir, foscarnet, etc.) cannot be safely discontinued from 2 days
prior to the injection to 28 days following the injection are excluded from this
study

- Patients on systemic anticoagulants are excluded from this study

- Patients with any clinically significant unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction),
that would compromise the patient's ability to tolerate protocol therapy or would
likely interfere with the study procedures or results