Lerapolturev for Glioblastoma

Overseen By Madison Shoaf, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Darell Bigner

Must not be taking: Chemotherapy, Immunotherapy, Bevacizumab, others

Disqualifiers: Pregnancy, Severe heart disease, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

92 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called lerapolturev, a re-engineered poliovirus, for individuals with recurrent glioblastoma, an aggressive brain cancer. The study tests the safety and effectiveness of lerapolturev when administered directly into the tumor and later around the lymph nodes in the head and neck. Participants will be compared to those receiving the standard chemotherapy drug, lomustine. This trial targets adults whose glioblastoma has returned after surgery and who meet specific health criteria, including having a confirmed recurrent tumor and the ability to undergo an MRI. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot have received chemotherapy or certain other treatments within specific time frames before starting the study drug. It's best to discuss your current medications with the study team to understand any potential conflicts.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that lerapolturev, a treatment for glioblastoma, has a good safety record. Previous studies found that patients tolerated lerapolturev well when administered directly into brain tumors, without serious side effects. Another study demonstrated that lerapolturev was safely used for treating recurring glioblastoma in children, indicating its suitability for more advanced trials.

These findings encourage those considering joining a trial with lerapolturev, as they suggest the treatment is generally well-tolerated based on past research. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for glioblastoma?

Researchers are excited about Lerapolturev for glioblastoma because it takes a novel approach by using a virus to attack the cancer. Unlike standard treatments like surgery, radiation, and chemotherapy, Lerapolturev is delivered directly into the tumor through a technique called Convection Enhanced Delivery (CED), which helps it reach areas that other treatments might miss. This method allows the treatment to potentially work more effectively at targeting the cancer cells while minimizing damage to healthy tissue. Additionally, it includes subcutaneous injections to stimulate the immune system, offering a unique two-pronged attack against the tumor.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research shows that lerapolturev, also known as PVSRIPO, may help treat recurrent glioblastoma, a challenging brain cancer. In this trial, some participants will receive lerapolturev. Previous studies have shown that it may lead to longer survival at 24 and 36 months compared to other treatments. Specifically, after two years, 21% of patients were still alive, suggesting that lerapolturev might be more effective for long-term survival. These results offer hope for those considering participation in this trial to try this experimental treatment. ^{1 2 3 6 7}

Who Is on the Research Team?

Madison Shoaf, MD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

Adults over 18 with recurrent high-grade glioblastoma, good performance status (KPS ≥ 70%), and adequate organ function. They must have had prior poliovirus vaccination, be able to undergo MRI scans, and use effective birth control if of childbearing potential. Excluded are pregnant or breastfeeding women, those with severe illnesses like heart disease or uncontrolled diabetes, recent chemotherapy or immunotherapy recipients, and patients on high doses of steroids.

Inclusion Criteria

My brain tumor is a confirmed high-grade glioblastoma.

Able to undergo brain MRI with and without contrast

Patient or partner(s) meets one of the following criteria: Non-childbearing potential (i.e., not sexually active, physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile, or any male who has had a vasectomy). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Postmenopausal for purposes of this study is defined as 1 year without menses.; or Childbearing potential and agrees to use one of the following methods of birth control: approved hormonal contraceptives (e.g. birth control pills, patches, implants, or infusions), an intrauterine device, or a barrier method of contraception (e.g., a condom or diaphragm) used with spermicide

Exclusion Criteria

Patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons or their designate

I am not pregnant or breastfeeding.

Patients with severe, active co-morbidity, defined as follow: Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax > 99.5°F/37.5°C), Patients with known immunosuppressive disease or known human immunodeficiency virus infection, Patients with unstable or severe intercurrent medical conditions such as severe heart disease (New York Heart Association Class 3 or 4), Patients with known lung (forced expiratory volume in the first second of expiration (FEV1) < 50%) disease or uncontrolled diabetes mellitus, Known albumin allergy, History of agammaglobulinemia, Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except for nitrosourea (6 weeks), or metronomic dosed chemotherapy such as daily etoposide or cyclophosphamide (1 week)] prior to starting the study drug unless patients have recovered from side effects of such therapy, Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study drug unless patients have recovered from side effects of such therapy, Patients may not have received treatment with tumor treating fields (e.g., Optune®) ≤ 1 week prior to starting the study drug, Patients may not be less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation, Patients who have not completed all standard of care treatments, including surgical procedure and radiation therapy (Please note: For patients under 65 years old, standard radiation therapy is typically at least 59 Gy in 30 fractions over 6 weeks. For patients 65 years or older, standard RT is often reduced to a minimum 40 Gy in 15 fractions over 3 weeks.), If the MGMT promoter in their tumor is known to be unmethylated, patients are not mandated to have received chemotherapy prior to participating in this trial, If the MGMT promoter in their tumor is known to be methylated or the MGMT promoter methylation status is unknown at time of screening, patients must have received at least one chemotherapy regimen prior to participating in this trial, Patients with neoplastic lesions in the brainstem, cerebellum, or spinal cord; radiological evidence of active (growing) disease (active multifocal disease); extensive subependymal disease (tumor touching subependymal space is allowed); tumor crossing the midline or leptomeningeal disease, Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to the 1st lerapolturev infusion via CED, Patients with worsening steroid myopathy (history of gradual progression of bilateral proximal muscle weakness, and atrophy of proximal muscle groups), Patients with prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin, Patients with active autoimmune disease requiring systemic immunomodulatory treatment within the past 3 months, Patients with known history of hypersensitivity to lomustine, dacarbazine, or any components of lomustine

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stage 1 - Safety Lead-in

Safety of lerapolturev is assessed with two infusions 4 days apart via Convection Enhanced Delivery (CED) in the residual disease of recurrent Glioblastoma patients.

5 weeks

2 visits (in-person)

Stage 2 - Treatment

Randomized phase comparing lerapolturev and lomustine. Lerapolturev is infused twice, 4 days apart, followed by weekly subcutaneous injections for 4 weeks, then every 3 weeks for about a year. Lomustine is taken every 6 weeks for up to 9 cycles.

1 year

Follow-up

Participants are monitored for serious adverse events for 30 days after stopping the study. Medical records are reviewed for life to collect data on subsequent treatments, disease progression, tumor size/volume, and survival.

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Lerapolturev

Trial Overview

The trial is testing the safety and effectiveness of lerapolturev injections into residual brain tumor areas after surgery followed by more injections near lymph nodes in the head and neck area. The study also involves taking lomustine pills as part of the treatment regimen for recurrent glioblastoma.

How Is the Trial Designed?

Group I: Lerapolturev Arm (Stage 2 - Arm 1) Experimental Treatment 1 Intervention

Lerapolturev (intratumoral) will be given by Convection Enhanced Delivery (CED), infused twice, 4 days apart, in the remaining disease of recurrent Glioblastoma (rGBM) subjects following maximal safe resection of their disease recurrence. This will be followed by subcutaneous injections of lerapolturev in the cervical perilymphatic (CPL) area on the same side as their tumor, weekly for 4 weeks and afterward every 3 weeks for about a year.

Group II: Lerapolturev Arm (Stage 1) Experimental Treatment 1 Intervention

Lerapolturev (intratumoral) will be dosed by Convection Enhanced Delivery (CED), infused twice, 4 days apart, in the remaining disease of recurrent Glioblastoma (rGBM) subjects following maximal safe resection of the disease recurrence. To assess treatment response and/or immunologic responses in the brain, a tissue biopsy of the area infused will be recommended 5 weeks (± 1 week) after the 2nd lerapolturev infusion via CED, in the event that changes suggestive of tumor progression are seen on the MRI obtained 4-5 weeks after the 2nd lerapolturev infusion via CED. .

Group III: Lomustone (Stage 2 Arm 2) Active Control 1 Intervention

Following maximal safe resection of their tumor recurrence subjects will receive Lomustine as a single oral dose of 110 mg/m2 every six weeks for up to 9 cycles.

Lerapolturev is already approved in United States for the following indications:

Approved in United States as Lerapolturev for:

• None approved; Orphan Drug Designation for recurrent glioblastoma and advanced melanoma

Who Is Running the Clinical Trial?

Darell Bigner

Lead Sponsor

Trials

8

Recruited

380+

Istari Oncology, Inc.

Industry Sponsor

Trials

13

Recruited

400+

Published Research Related to This Trial

The study found that the poliovirus receptor (CD155) is expressed in various pediatric brain tumors, including pleomorphic xanthoastrocytoma and medulloblastoma, indicating a potential target for poliovirus oncolytic immunotherapy.

The poliovirus-rhinovirus recombinant, PVSRIPO, effectively infected and killed specific cancer cell lines, significantly reducing their proliferation, particularly in pleomorphic xanthoastrocytoma and Group 3 medulloblastoma, suggesting its potential as a novel treatment for these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma. Thompson, EM., Brown, M., Dobrikova, E., et al.[2019]

A novel anti-CD155 antibody was successfully validated for detecting CD155 expression in glioblastoma tissue samples, which is crucial for the development of PVSRIPO oncolytic immunotherapy.

The study found that CD155 is widely expressed in glioblastoma cells, indicating that these tumors are likely susceptible to infection and destruction by the PVSRIPO virus, supporting its potential as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Validation of an Immunohistochemistry Assay for Detection of CD155, the Poliovirus Receptor, in Malignant Gliomas. Chandramohan, V., Bryant, JD., Piao, H., et al.[2019]

In a study of 12 melanoma patients, those who received anti-PD-1 therapy close to the administration of the intratumoral poliovirus treatment, lerapolturev, showed significantly longer median progression-free survival (PFS) of 2.3 years compared to 1.6 months in others, suggesting that prior anti-PD-1 therapy may enhance the effectiveness of lerapolturev.

Higher levels of CD8+ T cell infiltrates in the tumors of patients with longer PFS indicate that an inflamed tumor microenvironment, possibly from previous treatments, is linked to better immune responses and outcomes after lerapolturev treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma. Beasley, GM., Brown, MC., Farrow, NE., et al.[2023]

The phase 1b trial of lerapolturev, a viral immunotherapy for recurrent pediatric high-grade glioma, demonstrated a safety profile suitable for further testing, with no irreversible grade 4 adverse events reported among the 8 treated patients.

Despite the treatment showing a median overall survival of only 4.1 months, one patient survived for 22 months, indicating potential for longer-term benefits in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant polio-rhinovirus immunotherapy for recurrent paediatric high-grade glioma: a phase 1b trial. Thompson, EM., Landi, D., Brown, MC., et al.[2023]

The study found that administering the oncolytic recombinant poliovirus, PVS-RIPO, intrathecally in rodent models showed no signs of toxicity, indicating it may be a safe treatment option.

PVS-RIPO significantly increased median survival in rats with glioblastoma multiforme neoplastic meningitis, with some rats surviving over 60 days without residual tumors, suggesting its potential efficacy for treating this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus. Ochiai, H., Campbell, SA., Archer, GE., et al.[2016]

In a study involving 939 infants from 67 villages in Bangladesh, the transmission of Sabin 2 poliovirus was found to be higher among household contacts of children who received the monovalent type 2 oral polio vaccine (mOPV2) in villages using bivalent oral polio vaccine (bOPV) and inactivated polio vaccine (IPV), compared to those who received the trivalent oral polio vaccine (tOPV).

However, the overall incidence of Sabin 2 shedding in infants who did not receive mOPV2 did not differ significantly between the bOPV/IPV and tOPV groups, indicating that while household transmission risk increased, the broader community risk remained stable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Community transmission of type 2 poliovirus after cessation of trivalent oral polio vaccine in Bangladesh: an open-label cluster-randomised trial and modelling study. Taniuchi, M., Famulare, M., Zaman, K., et al.[2019]

PVS-RIPO is a genetically engineered poliovirus that selectively targets and kills cancer cells, particularly in the central nervous system, while sparing normal neuronal cells, making it a promising treatment for glioblastoma multiforme.

The virus's unique mechanism allows it to replicate in tumor cells due to a specific translation initiation process, leading to strong anti-tumoral effects observed in animal models, which supports its potential for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme. Goetz, C., Gromeier, M.[2020]

Citations

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clinicaltrials.gov

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NCT01491893 | PVSRIPO for Recurrent Glioblastoma (GBM)

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nejm.org

nejm.org/doi/full/10.1056/NEJMoa1716435

Recurrent Glioblastoma Treated with Recombinant Poliovirus

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We are doing this study to find out how safe and effective it is to give people with recurrent glioblastoma two infusions of an experimental drug called ...

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pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/29943666/

Recurrent Glioblastoma Treated with Recombinant Poliovirus

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This phase II trial compares the safety, side effects and effectiveness of lerapolturev to lomustine in treating patients with glioblastoma (GBM) that has ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT06177964

NCT06177964 | Lerapolturev (PVSRIPO) in GBM

The purpose of this research study is to determine the safety and efficacy of administering two doses of lerapolturev in residual disease (within tumor ...

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Recombinant polio–rhinovirus immunotherapy for recurrent ...

Convection enhanced delivery of lerapolturev is safe enough in the treatment of recurrent paediatric high-grade glioma to proceed to the next phase of trial.