LUMINOS-101: Lerapolturev (PVSRIPO) and Pembrolizumab in Patients With Recurrent Glioblastoma

Inclusion Criteria:

1. ≥ 18 years of age.

2. Recurrent supratentorial glioblastoma (GBM) confirmed via prior histology by thesite's neuropathologist or designate.

• Histologically confirmed recurrent glioblastoma (rGBM) within 6 weeks ofLerapolturev infusion will not require a biopsy to confirm active tumor priorto catheter placement

• Progression of primary glioblastoma or transformation from a lower grade to ahigher grade is acceptable for recurrence and as for primary glioblastoma, mustbe 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 catheterplacement via CT prior to infusion, neurosurgical investigator must confirmplacement of infusion catheter within or through the progressive enhancing tumor isfeasible and at a safe distance relative to eloquent brain function, with the tip ofthe catheter being placed:

5. Within the enhancing portion or in the vicinity of enhancement of target lesion (ie, infiltrative disease).

6. ≥ 0.5 cm from ventricles.

7. ≥ 1 cm deep into the brain.

8. ≥ 0.5 cm from corpus callosum.

9. First or second relapse supported by MRI or CT scan; relapse is defined asprogression following initial/prior therapy(ies).

10. Failed previous first line therapy: maximum surgical resection and radiotherapy (RT) (plus concomitant chemotherapy followed by maintenance chemotherapy if unknown ormethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter). Patients whobegin but do not complete chemotherapy/RT may still be considered for eligibility atthe discretion of Sponsor.

11. Karnofsky Performance Status ≥ 70 at screening and baseline.

12. Undergone prior vaccination against PV and received a boost immunization withtrivalent inactivated poliovirus vaccine (IPOL®) at least 1 week, but less than 6weeks, prior to administration of Lerapolturev. Note: Patients who are unsure oftheir prior vaccination status/who have not been vaccinated must provide proof ofvaccination and/or evidence of anti-PV immunity prior to enrollment, as applicable.

13. Ability to safely discontinue anti-coagulant therapy(ies) prior to biopsy/catheterplacement, as required per site/surgical guidelines.

14. Hemoglobin ≥ 9 g/dL prior to biopsy/catheter placement.

15. Platelet count ≥ 100,000/μL (unsupported); ≥ 125,000/ μL (can be supported viaplatelet transfusion) at biopsy/catheter placement.

16. Absolute Neutrophil Count (ANC) ≥ 1000/μL prior to biopsy/catheter placement.

17. Creatinine ≤ 1.2 x Upper Limit of Normal (ULN) prior to biopsy/catheter placement.

18. Total bilirubin, Alanine aminotransferase (ALT), aspartate aminotransferase (AST),alkaline phosphatase (ALP) ≤ 2.5 x ULN prior to biopsy/catheter placement.

19. Prothrombin time (PT) and activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x ULNprior to biopsy/catheter placement.

20. If undetectable antitetanus toxin (ATT) Immunoglobulin G (IgG) at screen, Tdapbooster vaccine ≥ 1 week prior to biopsy/catheter placement.

21. Patients must be willing and able to understand and provide written informedconsent.

Exclusion Criteria:

1. Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, oranti- CTLA-4 antibody (including ipilimumab or any other antibody or drugspecifically targeting T-cell co-stimulation or checkpoint pathways) ≤ 12 weeksprior to lerapolturev infusion (Note: does not apply for patients treated withpembrolizumab under this protocol who are eligible for lerapolturev retreatment).Note: patients who had previously permanently discontinued any anti-PD-1 or PD-L1therapy due to severe or life-threatening immune-related adverse events areexcluded.

2. Excluded are:

3. Neoplastic lesions in the brainstem, cerebellum, or spinal cord.

4. Radiological evidence of active/growing multifocal disease: no size increase > 0.5 cm in any direction of any other enhancing non-target lesions present atbaseline confirmed via most recent, prior, consecutive MRIs at least 3 monthsapart.

5. Tumors with ≥ 1cm of contrast-enhancing tumor component crossing the midline (crossing the corpus callosum).

6. Extensive subependymal disease: multiple lesions or lesions covering > 50% ofsubependymal space. Tumor touching subependymal space allowed.

7. Extensive leptomeningeal disease: multiple lesions or lesions covering > 50% ofleptomeninges. Tumor touching leptomeninges allowed.

8. Has received systemic immunosuppressive treatments other than systemiccorticosteroids (eg, methotrexate, chloroquine, azathioprine) within six months ofLerapolturev infusion.

9. Requires treatment with high dose systemic corticosteroids, defined as dexamethasone > 4 mg/day or equivalent, within 2 weeks of Lerapolturev infusion.

10. Prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgeryor therapeutics delivered by local injection or CED, including Lerapolturev (exceptfor qualifying patients being retreated with Lerapolturev within this trial).

11. Pregnant and/or breast feeding female; patient/female partner of childbearingpotential who is unwilling to utilize protocol-defined acceptable form ofcontraception for duration of study.

12. Impending/life-threatening cerebral herniation syndrome, per neurosurgeon/designate.

13. Severe, active co-morbidity, defined as follows:

14. Infection requiring IV treatment/unexplained febrile illness (Tmax > 99.5°F/37.5°C)

15. Known immunosuppressive disease/human immunodeficiency virus infection

16. Known active hepatitis B or C infection via positive viral DNA or RNA,respectively

17. Unstable or severe intercurrent medical conditions such as severe heart disease (New York Heart Association Class 3 or 4)

18. Known lung disease with forced expiratory volume in 1st second of expiration < 50%

19. Uncontrolled diabetes mellitus (eg, hemoglobin A1C level > 7.0% with treatment)

20. History of other malignancy requiring active treatment within 2 years ofbiopsy/catheter placement with the exception of those with a negligible risk ofmetastasis or death (eg, resected cutaneous basal cell carcinoma, or othercancers with 5-year overall survival (OS) of >90%)

21. Known albumin allergy.

22. Uncontrolled unexplained bleeding and/or hemoptysis within 4 weeks of plannedlerapolturev infusion.

23. Inability to undergo brain MRI with and without contrast. History ofsevere/anaphylactic reaction to gadolinium contrast agent is excluded. Mild allergy (eg, rash) acceptable with prophylactic acetaminophen and diphenhydramine.

24. History of neurological complications due to PV infection.

25. Not recovered from toxic side effects (alopecia acceptable) and/or no current orprior tumor treatments within the following timeframe relative to biopsy/catheterplacement:

26. Chemotherapy or bevacizumab ≤ 4 weeks (except for nitrosourea (6 weeks) ormetronomic dosed chemotherapy/targeted therapies such as daily temozolomide,etoposide or cyclophosphamide (1 week)).

27. Tumor treating fields ≤ 7 days.

28. RT of brain ≤ 12 weeks, except for progressive disease outside of the radiationfield or 2 progressive scans at least 4 weeks apart or histopathologicconfirmation.

29. History of agammaglobulinemia.

30. Known hypersensitivity to pembrolizumab, or any components of pembrolizumab.

31. Active autoimmune disease requiring systemic immunomodulatory treatment within thepast 12 months; physiologic replacement therapy (eg, thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered a form of systemic treatment.

32. History of other malignancy requiring active treatment within 2 years ofbiopsy/catheter placement with the exception of those with a negligible risk ofmetastasis or death (eg, resected cutaneous basal cell carcinoma, or other cancerswith 5-year OS of >90%)