This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug as a possible
treatment for this diagnosis. "Investigational" means that the intervention is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved rQNestin34.5v.2 as a
treatment for any disease. This is the first time that rQnestin34.5v.2 will be given to
The research drug, rQNestin34.5v.2, is an oncolytic viral vector made from the herpes simplex
virus type 1 (HSV1). The large majority of humans already have regular HSV1 in their nervous
system. Normally, this virus can cause cold sores in areas like the lips, fingers and
genitals in humans by making copies of itself in normal healthy cells. In some cases, HSV1
can cause severe infection of the brain and liver and/or death. However, scientists have
removed or changed parts of the rQNestin virus being used on this study so it can only make
copies of itself in glioma cells and not normal healthy cells.
If it is effective, the rQNestin34.5v.2 drug will spread to a glioma cell, kill it, and then
make a copy of itself and spread again. This should be repeated over and over until all
glioma cells are reached. If rQNestin34.5v.2 moves into a normal brain cell, it should not
grow and make copies, and therefore should not spread to other normal brain cells.
The purpose of this research study is to test if rQnestin34.5v.2 is safe to use in humans,
and if it is effective in treating malignant glioma. This study is also looking for the
highest dose of rQNestin34.5v.2 that can be given safely to people with malignant brain
- At the time of surgery, frozen biopsy confirmation of high grade or malignant glioma
by neuropathologist. Biopsy confirmation of glioma or infiltrative glioma at time of
surgery will be acceptable, provided that subject has prior pathology confirmation of
high-grade glioma. If subject had previous diagnosis of low grade glioma, then the
biopsy must show high grade glioma. To be confirmed at time of surgery, after
registration in OnCore.
- Participants must have prior diagnosis of glioma (astrocytoma, malignant astrocytoma,
oligodendroglioma, anaplastic oligodendroglioma, mixed oligo-astrocytoma), exclusive
of ependymoma, ganglioglioma, pylocytic/pylomyxoid astrocytoma as confirmed by a
neuropathologist or by a previous local pathology report.
- Prior history of external beam radiotherapy ≥ 5,000 cGy delivered to the tumor at
least 4 weeks prior to registration. Participants over the age of 70 with prior
history of hypofractionated external beam radiotherapy will also be accommodated, in
accordance with NCCN guidelines; For participants with diagnosis of oliogodendroglioma
or anaplastic oligodendroglioma, prior history of external beam radiotherapy < 5,000
cGy or no history of radiation are both acceptable
- Prior history of temozolomide chemotherapy provided concurrent to external beam
radiotherapy and after as per current standard of care. However, temozolomide would
not be required to have been provided concomitantly or after radiation if the patient
had unmethylated MGMT promoter or if the patient initially was diagnosed with a low
grade glioma. At least 4 weeks must have passed from the last dose of temozolomide and
first dose of cyclophosphamide and/or rQNestin34.5v.2; 184.108.40.206 For participants with
diagnosis of oliogodendroglioma or anaplastic oligodendroglioma, chemotherapy may have
been administered before, during, or after radiation or not at all.
- If participant was treated with bevacizumab, at least 4 weeks must elapse before
treatment with either agent (Cyclophosphamide or rQNestin34.5v.2);
- Recurrent lesion must be ≥ 1.0 cm in diameter as determined by MRI;
- Normal hematological, renal and liver function as defined below: Leukocytes
≥3,000/mcL; Absolute lymphocyte count > 500/ mcL; Absolute neutrophil count
≥1,500/mcL; platelets ≥100,000/mcL; PT or PTT <1.5 x institutional upper limit;
Hemoglobin >10.0 g/dL; Total serum bilirubin within normal institutional limits;
AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal; Serum creatinine
within normal institutional limits OR Creatinine clearance ≥60 mL/min/1.73 m2 for
participants with creatinine levels above institutional normal;
- Karnofsky Performance Score ≥70.
- Age ≥ 18 years;
- Ability to understand and the willingness to sign a written informed consent document;
- The effects of rQNestin34.5v.2 and cyclophosphamide on the developing human fetus are
unknown. For this reason and because cytotoxic & immunomodulating agents as well as
other therapeutic agents used in this trial are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation including 3 months following the study. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she should inform her treating physician immediately. Men treated or enrolled
on this protocol must also agree to use adequate contraception prior to the study and
for the duration of study participation including 3 months following the study. Women
of child-bearing potential must have a negative serum pregnancy test within 48 hours
of study registration.
- Steroid regimen stable or decreasing for at least 7 days prior to inoculation;
- Ability to undergo MRI scanning with contrast;
- Subjects with any recurrence (first, second, third, etc recurrence) will be able to be
Participants who exhibit any of the following conditions prior to initiating study
treatment will not be eligible for this study:
- Participants with significant renal or liver disease
- Participants with progressive systemic malignancy.
- Known chronic infections with HIV, hepatitis B or C; participants with a history of
resolved Hepatitis A may be included in the trial.
- Participants with active viral, bacterial or fungal infection requiring concurrent
antiviral or antibiotics.
- Subjects with active HSV1 infection on current valacyclovir, acyclovir or ganciclovir
therapy must be off treatment with any of these agents at least 7 days prior to
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cyclophosphamide (only for arm B).
- Active, known, or suspected immunosuppressive disorders, such as acquired or
congenital immune deficiency syndromes and autoimmune diseases
- Unacceptable anesthesia risk
- Serious cardiopulmonary medical condition
- Pregnant or lactating females
- Recurrent glioma where injection in either arm A or B of the biologic agent would
require access and/or considerable spillage into the ventricular system.
- Prior participant in another protocol using an investigational agent or device within
5 half-lives or 4 weeks of the investigational agent, whichever is shorter.
- Known HIV seropositivity.
- Concurrent therapy with drugs active against HSV (acyclovir, valaciclovir,
penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir). Participants must be off
treatment with these agents for at least 7 days prior to surgery.
- Active oral or genital herpes lesions.
- Participants who have had chemotherapy or radiotherapy within 4 weeks prior to
entering the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier.
- Participants who are receiving any other investigational agents. Previous
rQNestin34.5v.2 participants may be re-enrolled if they completed at least the day 56
assessment without DLT.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
- Participants with tumor ≤ 1 cm proximity to the ventricles will be allowed to enroll.
However the study agent (rQNestin34.5v.2) may not be injected in any area that is
within 1 cm of the ventricle regardless of where the tumor is located.