This Phase 2 single arm trial in patients with rGBM will characterize the efficacy, safety,
tolerability and initial efficacy of PVSRIPO intratumoral infusion followed by intravenous
pembrolizumab 14 to 28 days later, and every 3 weeks, thereafter.
Inclusion Criteria:
1. ≥ 18 years of age.
2. Recurrent supratentorial glioblastoma confirmed via prior histology by the site's
neuropathologist or designate.
- Histologically confirmed recurrent glioblastoma within 6 weeks of PVSRIPO
infusion will not require a biopsy to confirm active tumor prior to catheter
placement
- Progression of primary glioblastoma or transformation from a lower grade to a
higher grade is acceptable for recurrence and as for primary glioblastoma, must
be confirmed via prior histology by site pathologist
3. Enhancing lesion ≥1 cm shortest diameter to ≤ 5.5 cm longest diameter in all planes.
4. Before catheter placement based on screening MRI and at the time of catheter placement
via CT prior to infusion, neurosurgical investigator must confirm placement of
infusion catheter within or through the progressive enhancing tumor is feasible and at
a safe distance relative to eloquent brain function, with the tip of the catheter
being placed:
1. Within the enhancing portion or in the vicinity of enhancement of target lesion
(ie, infiltrative disease).
2. ≥ 0.5 cm from ventricles.
3. ≥ 1 cm deep into the brain.
4. ≥ 0.5 cm from corpus callosum.
5. First or second relapse supported by MRI or CT scan; relapse is defined as progression
following initial/prior therapy(ies).
6. Failed previous first line therapy: maximum surgical resection and radiotherapy (RT)
(plus concomitant chemotherapy followed by maintenance chemotherapy if unknown or
methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter). Patients who begin
but do not complete chemotherapy/RT may still be considered for eligibility at the
discretion of Sponsor.
7. Karnofsky Performance Status ≥ 70 at screening and baseline.
8. Undergone prior vaccination against PV and received a boost immunization with
trivalent inactivated poliovirus vaccine (IPOL®) at least 1 week, but less than 6
weeks, prior to administration of PVSRIPO. Note: Patients who are unsure of their
prior vaccination status/who have not been vaccinated must provide proof of
vaccination and/or evidence of anti-PV immunity prior to enrollment, as applicable.
9. Ability to safely discontinue anti-coagulant therapy(ies) prior to biopsy/catheter
placement, as required per site/surgical guidelines.
10. Hemoglobin ≥ 9 g/dL prior to biopsy/catheter placement.
11. Platelet count ≥ 100,000/μL (unsupported); ≥ 125,000/ μL (can be supported via
platelet transfusion) at biopsy/catheter placement.
12. ANC ≥ 1000/μL prior to biopsy/catheter placement.
13. Creatinine ≤ 1.2 x ULN prior to biopsy/catheter placement.
14. Total bilirubin, ALT, AST, ALP ≤ 2.5 x ULN prior to biopsy/catheter placement.
15. PT and aPTT ≤ 1.2 x ULN prior to biopsy/catheter placement.
16. If undetectable ATT IgG at screen, Tdap booster vaccine ≥ 1 week prior to
biopsy/catheter placement.
17. Patients must be willing and able to understand and provide written informed consent.
Exclusion Criteria:
1. Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically
targeting T-cell co-stimulation or checkpoint pathways) ≤ 12 weeks prior to PVSRIPO
infusion (Note: does not apply for patients treated with pembrolizumab under this
protocol who are eligible for PVSRIPO retreatment). Note: patients who had previously
permanently discontinued any anti-PD-1 or PD-L1 therapy due to severe or
life-threatening immune-related AE are excluded.
2. Excluded are:
1. Neoplastic lesions in the brainstem, cerebellum, or spinal cord.
2. Radiological evidence of active/growing multifocal disease: no size increase >
0.5 cm in any direction of any other enhancing non-target lesions present at
baseline confirmed via most recent, prior, consecutive MRIs at least 3 months
apart.
3. Tumors with ≥ 1cm of contrast-enhancing tumor component crossing the midline
(crossing the corpus callosum).
4. Extensive subependymal disease: multiple lesions or lesions covering > 50% of
subependymal space. Tumor touching subependymal space allowed.
5. Extensive leptomeningeal disease: multiple lesions or lesions covering > 50% of
leptomeninges. Tumor touching leptomeninges allowed.
3. Has received systemic immunosuppressive treatments other than systemic corticosteroids
(eg, methotrexate, chloroquine, azathioprine) within six months of PVSRIPO infusion.
4. Requires treatment with high dose systemic corticosteroids, defined as dexamethasone >
4 mg/day or equivalent, within 2 weeks of PVSRIPO infusion.
5. Prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or
therapeutics delivered by local injection or CED, including PVSRIPO (except for
qualifying patients being retreated with PVSRIPO within this trial).
6. Pregnant and/or breast feeding female; patient/female partner of childbearing
potential who is unwilling to utilize protocol-defined acceptable form of
contraception for duration of study.
7. Impending/life-threatening cerebral herniation syndrome, per neurosurgeon/designate.
8. Severe, active co-morbidity, defined as follows:
1. Infection requiring IV treatment/unexplained febrile illness (Tmax >
99.5°F/37.5°C)
2. Known immunosuppressive disease/human immunodeficiency virus infection
3. Known active hepatitis B or C infection via positive viral DNA or RNA,
respectively
4. Unstable or severe intercurrent medical conditions such as severe heart disease
(New York Heart Association Class 3 or 4)
5. Known lung disease with forced expiratory volume in 1st second of expiration <
50%
6. Uncontrolled diabetes mellitus (eg, hemoglobin A1C level > 7.0% with treatment)
7. History of other malignancy requiring active treatment within 2 years of
biopsy/catheter placement with the exception of those with a negligible risk of
metastasis or death (eg, resected cutaneous basal cell carcinoma, or other
cancers with 5-year OS of >90%)
9. Known albumin allergy.
10. Uncontrolled unexplained bleeding and/or hemoptysis within 4 weeks of planned PVSRIPO
infusion.
11. Inability to undergo brain MRI with and without contrast. History of
severe/anaphylactic reaction to gadolinium contrast agent is excluded. Mild allergy
(eg, rash) acceptable with prophylactic acetaminophen and diphenhydramine.
12. History of neurological complications due to PV infection.
13. Not recovered from toxic side effects (alopecia acceptable) and/or no current or prior
tumor treatments within the following timeframe relative to biopsy/catheter placement:
1. Chemotherapy or bevacizumab ≤ 4 weeks (except for nitrosourea (6 weeks) or
metronomic dosed chemotherapy/targeted therapies such as daily temozolomide,
etoposide or cyclophosphamide (1 week)).
2. Tumor treating fields ≤ 7 days.
3. RT of brain ≤ 12 weeks, except for progressive disease outside of the radiation
field or 2 progressive scans at least 4 weeks apart or histopathologic
confirmation.
14. History of agammaglobulinemia.
15. Known hypersensitivity to pembrolizumab, or any components of pembrolizumab.
16. Active autoimmune disease requiring systemic immunomodulatory treatment within the
past 12 months; physiologic replacement therapy (eg, thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)
is not considered a form of systemic treatment.
17. History of other malignancy requiring active treatment within 2 years of
biopsy/catheter placement with the exception of those with a negligible risk of
metastasis or death (eg, resected cutaneous basal cell carcinoma, or other cancers
with 5-year OS of >90%)
