Lerapolturev for Glioblastoma

Overseen By Stevie Threatt

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Darell Bigner

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

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

No Placebo Group

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to determine the safety and efficacy of administering two doses of lerapolturev in residual disease (within tumor margins) after surgery, followed later by repeated injections of lerapolturev in the subcutaneous area (under the skin) around the lymph nodes of the head and neck for adult patients diagnosed with recurrent glioblastoma at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke.

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.

What data supports the effectiveness of the treatment Lerapolturev for Glioblastoma?

Lerapolturev, a modified poliovirus, has shown promise in early trials for treating recurrent glioblastoma, a type of brain cancer, by targeting a specific receptor (CD155) found in these tumors. It has also demonstrated potential in treating other cancers like melanoma by activating the body's immune response against the tumor. ^{1 2 3 4 5}

Is Lerapolturev safe for use in humans?

Lerapolturev, also known as PVSRIPO, has been tested in clinical trials for glioblastoma and other conditions. In a phase 1b trial for pediatric high-grade glioma, its safety was assessed when given directly into the brain, and it has also been tested in melanoma patients. These studies suggest it is generally safe, but as with any treatment, there may be risks involved. ^{1 2 3 4 6}

How is the drug Lerapolturev different from other treatments for glioblastoma?

Lerapolturev is unique because it is a genetically modified virus that specifically targets cancer cells by using the poliovirus receptor, CD155, which is commonly found on glioblastoma cells. This approach allows the virus to infect and kill cancer cells while sparing normal cells, offering a novel way to treat this aggressive brain tumor. ^{1 2 3 5 7}

Research Team

Madison Shoaf, MD

Principal Investigator

Duke University

Eligibility Criteria

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

Able to undergo brain MRI with and without contrast

My brain tumor is a confirmed high-grade glioblastoma.

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

Trial Timeline

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

Treatment Details

Interventions

• Lerapolturev (Virus Therapy)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

Darell Bigner

Lead Sponsor

Trials

8

Recruited

380+

Istari Oncology, Inc.

Industry Sponsor

Trials

13

Recruited

400+

Findings from Research

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]

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]

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 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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Validation of an Immunohistochemistry Assay for Detection of CD155, the Poliovirus Receptor, in Malignant Gliomas. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Recombinant polio-rhinovirus immunotherapy for recurrent paediatric high-grade glioma: a phase 1b trial. [2023]

3. England 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. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus. [2016]

5. England pubmed.ncbi.nlm.nih.gov

Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme. [2020]

6. United States 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. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma. [2019]