Inclusion Criteria:
- - Frozen biopsy consistent with glioma by neuropathologist at the time of the first
surgery in this longitudinal trial.
Biopsy confirmation of glioma or infiltrative
glioma at time of surgery will be acceptable, provided the subject has prior pathology
confirmation of IDH wild-type glioma. Patients with reactive changes, gliosis or
normal brain tissue only, without evidence of glioma at initial study surgery only
will not receive study rQNestin34.5v.2 therapy and will be replaced. Confirmation of
glioma at subsequent neurosurgical procedures beyond the initial surgery will not be
required.
- - Participants must have prior diagnosis of IDH wild-type glial tumor including GBM,
grade 3 anaplastic astrocytoma or oligodendroglioma or or grade 2 astrocytoma with
genetic features consistent with GBM, as confirmed by a neuropathologist or by a
previous local pathology report.
IDH wild-type designation may be based on negative
immunohistochemistry (IDH1 R132H mutation) or next generation sequencing for patients
with grade 4 tumor and by negative next-generation sequencing for those with grade 2
or 3 tumors. Patients with negative immunohistochemistry study for IDH1 R132H who are
identified to have an alternative mutation of IDH1 or 2 are also not eligible.
- - Prior history of external beam radiotherapy ≥ 5,000 cGy delivered to the tumor at
least 4 weeks prior to OHRS registration.
Participants over the age of 70 with prior
history of hypofractionated external beam radiotherapy will also be accommodated, in
accordance with NCCN guidelines.
- - Prior history of temozolomide chemotherapy provided concurrent with external beam
radiotherapy and after as per current standard of care.
However, temozolomide is not
required to have been provided concomitantly or after radiation if the patient had
unmethylated MGMT promoter. At least 23 days must have passed from the last dose of
temozolomide and first dose of rQNestin34.5v.2.
- - For use of other investigational drug or other anti-tumor treatment, the following
time periods must have elapsed from the projected start of scheduled study treatment:
4 weeks or 5 half-lives (whichever is shorter) from any investigational agent; 4 weeks
from cytotoxic therapy (except 23 days for TMZ; 6 weeks from last dose for
nitrosoureas); 12 weeks from completion of prior radiation therapy; 6 weeks from
antibodies treatment; 4 weeks or 5 half-lives (whichever is shorter) from other
anti-tumor therapies; 1 day from NOVO-TTF (Optune®) or prior cancer vaccine therapy.
- - The initial recurrent or residual gadolinium-enhancing lesion to be treated must be at
least 1.0 cm in diameter and less than or equal to 2 cm in greatest maximal diameter,
as determined by MRI.
The initially treated lesion must be located in non-eloquent
cortex, defined as non-dominant temporal, frontal, or occipital lobe. If located in
the dominant cortex, the lesion must be in the occipital lobe. For lesions in dominant
or non-dominant lobes, there should be a judgment that the subject will be able to
tolerate multiple injections and biopsies, based on sufficient distance from the
enhancing edge and eloquent cortex defined as speech (dominant mid-to posterior
temporal lobe, parietal lobe and frontal lobe: Broca's area), memory (hippocampus and
mesial dominant temporal lobe), or sensorimotor cortex. Subsequent injections
(injections at day 15, 30, 60, 90, 120) will not be subject to the limitations of the
initially treated lesion detailed above.
- - Normal hematological, renal and liver function as defined below before first
injection: ANC ≥ 1000/mcL, platelets ≥100,000/mcL, PT or PTT <1.5 x institutional
upper limit, Hemoglobin >9.0 g/dL, Total serum bilirubin ≤ 1.5 upper normal
institutional limits, AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal,
and Serum creatinine ≤ 1.5 upper normal institutional limits OR Creatinine clearance
≥60 mL/min/1.73 m^2 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.
- - No dexamethasone therapy for at least 14 days prior to the first rQNestin34.5v.
2
inoculation. Patients who are on physiologic doses of corticosteroids for the
treatment of adrenal insufficiency will be allowed to enroll.
- - Ability to undergo MRI scanning with contrast;
- Have residual tumor or be at first or second relapse.
Note: Relapse is defined as
progression following initial therapy (i.e., radiation ± chemotherapy). For
participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a
high-grade glioma will be considered the first relapse. Residual tumor is defined as
contrast-enhancing tumor that is present after the initial surgery, radiation, and
chemotherapy.
- - Participants must have recovered to grade 0 or 1 or pre-treatment baseline from
clinically significant toxic effects of prior therapy (exceptions include but not
limited to alopecia, laboratory values not listed per inclusion criteria, and
lymphopenia which is common after therapy with temozolomide).
Exclusion Criteria:
Participants who exhibit any of the following conditions prior to initiating study
treatment will not be eligible for this study:
- - Prior systemic malignancy requiring or expected to require more than surgical therapy
within the past 24 months.
- - 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 HSV-1 infection on current valacyclovir, acyclovir or ganciclovir
therapy must be off treatment with any of these agents at least 7 days prior to
surgery.
- - Active, known, or suspected immunosuppressive disorders, such as acquired or
congenital immune deficiency syndromes and autoimmune diseases.
- - Unacceptable anesthesia risk.
- - Pregnant or lactating females who are breastfeeding.
- - Participants who are receiving other investigational agents or immunotherapeutic
agents during the period of rQNestin34.5v.
2 longitudinal injections.
- - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, significant active hepatic or renal disease, an active infection requiring
systemic therapy, need for continuous systemic anticoagulation that cannot be stopped
or psychiatric illness/social situations that would limit compliance with study
requirements.
- - Certain tumor sizes and locations are exclusionary: 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 could lead to spillage into the
ventricles regardless of where the tumor is located; Participants whose initial tumor
size, location and rate of growth are deemed by the treating neurosurgeons and the CAC
to not be able to tolerate the time period of expected longitudinal injections with
biopsies, which could be as short as 15 days and as long as 120 days. This category
would include tumors located in: a) dominant and non-dominant locations close to
eloquent cortices (sensorimotor strip, speech and memory cortices), b) deep nuclear
structures (caudate, putamen, thalamus), c) close proximity to corticospinal tracts
(based on consensus of Clinical Advisory Committee); Participants with multifocal or
multicentric tumors or tumors arising in the brain stem or spinal cord or diffuse
leptomeningeal disease.
- - Has received systemic immunosuppressive treatments, aside from systemic
corticosteroids (such as methotrexate, chloroquine, azathioprine, etc.) within six
months of registration.
- - Has received anti-VEGF or anti-VEGFR targeted agents (e.g. bevacizumab, cediranib,
aflibercept, vandetanib, XL-184, sunitinib, etc.)
- Has history of known coagulopathy that increases risk of bleeding or a history of
clinically significant hemorrhage within 12 months of registration.
- - Has a known history of active TB (Bacillus Tuberculosis).
- - Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3
within 6 months of registration.
- - Requires systemic anti-coagulation that cannot be halted for each intraoperative and
peri-operative biopsy time period.
