A Study of the Treatment of Recurrent Malignant Glioma With rQNestin34.5v.2

Inclusion Criteria:

• Frozen biopsy consistent with glioma by neuropathologist at the time of the firstsurgery in this longitudinal trial. Biopsy confirmation of glioma or infiltrativeglioma at time of surgery will be acceptable, provided the subject has priorpathology confirmation of IDH wild-type glioma. Patients with reactive changes,gliosis or normal brain tissue only, without evidence of glioma at initial studysurgery only will not receive study rQNestin34.5v.2 therapy and will be replaced.Confirmation of glioma at subsequent neurosurgical procedures beyond the initialsurgery 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 withgenetic features consistent with GBM, as confirmed by a neuropathologist or by aprevious local pathology report. IDH wild-type designation may be based on negativeimmunohistochemistry (IDH1 R132H mutation) or next generation sequencing forpatients with grade 4 tumor and by negative next-generation sequencing for thosewith grade 2 or 3 tumors. Patients with negative immunohistochemistry study for IDH1R132H who are identified to have an alternative mutation of IDH1 or 2 are also noteligible.

• Prior history of external beam radiotherapy ≥ 5,000 cGy delivered to the tumor atleast 4 weeks prior to OHRS registration. Participants over the age of 70 with priorhistory of hypofractionated external beam radiotherapy will also be accommodated, inaccordance with NCCN guidelines.

• Prior history of temozolomide chemotherapy provided concurrent with external beamradiotherapy and after as per current standard of care. However, temozolomide is notrequired to have been provided concomitantly or after radiation if the patient hadunmethylated MGMT promoter. At least 23 days must have passed from the last dose oftemozolomide and first dose of rQNestin34.5v.2.

• For use of other investigational drug or other anti-tumor treatment, the followingtime periods must have elapsed from the projected start of scheduled studytreatment: 4 weeks or 5 half-lives (whichever is shorter) from any investigationalagent; 4 weeks from cytotoxic therapy (except 23 days for TMZ; 6 weeks from lastdose for nitrosoureas); 12 weeks from completion of prior radiation therapy; 6 weeksfrom antibodies treatment; 4 weeks or 5 half-lives (whichever is shorter) from otheranti-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 beat least 1.0 cm in diameter and less than or equal to 2 cm in greatest maximaldiameter, as determined by MRI. The initially treated lesion must be located innon-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. Forlesions in dominant or non-dominant lobes, there should be a judgment that thesubject will be able to tolerate multiple injections and biopsies, based onsufficient distance from the enhancing edge and eloquent cortex defined as speech (dominant mid-to posterior temporal lobe, parietal lobe and frontal lobe: Broca'sarea), memory (hippocampus and mesial dominant temporal lobe), or sensorimotorcortex. Subsequent injections (injections at day 15, 30, 60, 90, 120) will not besubject to the limitations of the initially treated lesion detailed above.

• Normal hematological, renal and liver function as defined below before firstinjection: ANC ≥ 1000/mcL, platelets ≥100,000/mcL, PT or PTT <1.5 x institutionalupper limit, Hemoglobin >9.0 g/dL, Total serum bilirubin ≤ 1.5 upper normalinstitutional limits, AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit ofnormal, and Serum creatinine ≤ 1.5 upper normal institutional limits OR Creatinineclearance ≥60 mL/min/1.73 m^2 for participants with creatinine levels aboveinstitutional normal.

• Karnofsky Performance Score ≥70.

• Age ≥ 18 years;

• Ability to understand and the willingness to sign a written informed consentdocument;

• The effects of rQNestin34.5v.2 and cyclophosphamide on the developing human fetusare unknown. For this reason and because cytotoxic & immunomodulating agents as wellas other therapeutic agents used in this trial are known to be teratogenic, women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry and for theduration of study participation including 3 months following the study. Should awoman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately.Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study and for the duration of study participationincluding 3 months following the study. Women of child-bearing potential must have anegative serum pregnancy test within 48 hours of study registration.

• No dexamethasone therapy for at least 14 days prior to the first rQNestin34.5v.2inoculation. Patients who are on physiologic doses of corticosteroids for thetreatment 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 asprogression following initial therapy (i.e., radiation ± chemotherapy). Forparticipants who had prior therapy for a low-grade glioma, the surgical diagnosis ofa high-grade glioma will be considered the first relapse. Residual tumor is definedas 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 fromclinically significant toxic effects of prior therapy (exceptions include but notlimited to alopecia, laboratory values not listed per inclusion criteria, andlymphopenia 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 surgicaltherapy within the past 24 months.

• Known chronic infections with HIV, hepatitis B or C; participants with a history ofresolved Hepatitis A may be included in the trial.

• Participants with active viral, bacterial or fungal infection requiring concurrentantiviral or antibiotics.

• Subjects with active HSV-1 infection on current valacyclovir, acyclovir organciclovir therapy must be off treatment with any of these agents at least 7 daysprior to surgery.

• Active, known, or suspected immunosuppressive disorders, such as acquired orcongenital immune deficiency syndromes and autoimmune diseases.

• Unacceptable anesthesia risk

• Pregnant or lactating females who are breastfeeding.

• Participants who are receiving other investigational agents or immunotherapeuticagents during the period of rQNestin34.5v.2 longitudinal injections.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, significant active hepatic or renal disease, an active infectionrequiring systemic therapy, need for continuous systemic anticoagulation that cannotbe stopped or psychiatric illness/social situations that would limit compliance withstudy requirements.

• Certain tumor sizes and locations are exclusionary: Participants with tumor ≤ 1 cmproximity 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 intothe ventricles regardless of where the tumor is located; Participants whose initialtumor size, location and rate of growth are deemed by the treating neurosurgeons andthe CAC to not be able to tolerate the time period of expected longitudinalinjections with biopsies, which could be as short as 15 days and as long as 120days. This category would include tumors located in: a) dominant and non-dominantlocations close to eloquent cortices (sensorimotor strip, speech and memorycortices), b) deep nuclear structures (caudate, putamen, thalamus), c) closeproximity to corticospinal tracts (based on consensus of Clinical AdvisoryCommittee); Participants with multifocal or multicentric tumors or tumors arising inthe brain stem or spinal cord or diffuse leptomeningeal disease.

• Has received systemic immunosuppressive treatments, aside from systemiccorticosteroids (such as methotrexate, chloroquine, azathioprine, etc.) within sixmonths 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 ofclinically 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 > 3within 6 months of registration.

• Requires systemic anti-coagulation that cannot be halted for each intraoperative andperi-operative biopsy time period.