lerapolturev (PVS-RIPO) / Istari Oncology - LARVOL DELTA

Randomized phase 2 clinical trial of repeated intratumoral and cervical perilymphatic injections (CPLIs) of lerapolturev vs. lomustine in recurrent glioblastoma (rGBM): safety lead-in results (SNO 2025) - P1, P2 | "Repeated lerapolturev CED infusions into residual non-enhancing disease post-resection shows an acceptable toxicity profile. Safety and efficacy will be updated."

Clinical • P2 data • Brain Cancer • Cervical Cancer • CNS Disorders • Cognitive Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor • CD8

Randomized phase 2 clinical trial of repeated intratumoral and cervical perilymphatic injections (CPLIs) of lerapolturev vs. lomustine in recurrent glioblastoma (rGBM): safety lead-in results (SNO 2025) - P1, P2 | "Repeated lerapolturev CED infusions into residual non-enhancing disease post-resection shows an acceptable toxicity profile. Safety and efficacy will be updated."

Clinical • P2 data • Brain Cancer • Cervical Cancer • CNS Disorders • Cognitive Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor • CD8

Randomized phase 2 clinical trial of repeated intratumoral and cervical perilymphatic injections (CPLIs) of lerapolturev vs. lomustine in recurrent glioblastoma (rGBM): safety lead-in results (WFNOS 2025) - P1, P2 | "Repeated lerapolturev CED infusions into residual non-enhancing disease post-resection shows an acceptable toxicity profile. Safety and efficacy will be updated."

Clinical • P2 data • Cervical Cancer • CNS Disorders • Cognitive Disorders • Glioblastoma • Oncology • Solid Tumor • CD8

Randomized phase 2 clinical trial of repeated intratumoral and cervical perilymphatic injections (CPLIs) of lerapolturev vs. lomustine in recurrent glioblastoma (rGBM): safety lead-in results (WFNOS 2025) - P1, P2 | "Repeated lerapolturev CED infusions into residual non-enhancing disease post-resection shows an acceptable toxicity profile. Safety and efficacy will be updated."

Clinical • P2 data • Brain Cancer • Cervical Cancer • CNS Disorders • Cognitive Disorders • Glioblastoma • Glioma • Solid Tumor • CD8

Administration of Intralesional Oncolytic Virus Injections by Advanced Practice Providers (JADPRO 2025) - "T-VEC, the first FDA-approved OV therapy (a modified herpes simplex virus type-1 (HSV-1), is the first FDA-approved for the treatment of advanced melanoma. PVSRIPO (a modified poliovirus) and also a genetically modified HSV-1, is currently under investigation in a phase 3 clinical trial and early phase clinical trials, respectively, both showing promise, alone and in combination with nivolumab, in patients with advanced melanoma and other progression on prior anti-PD-1 therapy...If not currently in practice, cancer centers should expand the role of APPs to include administration of intralesional injections, which may help increase patient access to effective therapies Standardized training would support safe, effective implementation of OV therapies across cancer centers. Consider an institutional champion for OVs to help facilitate OV implementation and overcome institutional barriers."

Metastases • Oncolytic virus • Head and Neck Cancer • Herpes Simplex • Melanoma • Solid Tumor

The effect of oncolytic virotherapy on pediatric brain tumor- a systematic review. (PubMed, Childs Nerv Syst) - "OVT appears safe and feasible in pediatric brain tumors, with signals of clinical benefit in selected patients. Larger, controlled trials are needed to clarify its survival impact and define optimal therapeutic strategies."

Journal • Review • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Ependymoma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Pain • Pediatrics • Solid Tumor

LUMINOS-102: Lerapolturev With or Without Immune Checkpoint Blockade in Advanced PD-1 Refractory Melanoma (clinicaltrials.gov) - P2 | N=27 | Completed | Sponsor: Istari Oncology, Inc. | Active, not recruiting ➔ Completed | N=56 ➔ 27

Checkpoint inhibition • Enrollment change • IO biomarker • Trial completion • Cutaneous Melanoma • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • BRAF • PD-L1

Lerapolturev in Recurrent Malignant Glioma (clinicaltrials.gov) - P2 | N=121 | Completed | Sponsor: Istari Oncology, Inc. | Active, not recruiting ➔ Completed

Trial completion • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor

Pre-treatment innate inflammation associates with survival after polio virotherapy and can be modulated to sensitize gliomas to in situ vaccination. (SNO 2024) - "We previously demonstrated that a recombinant poliovirus (PVSRIPO) functions by inducing MDA5-dependent, type I interferon (IFN) dominant innate inflammation in myeloid cells to provoke durable and functional antitumor T cell responses in mice...Notably, peripheral vaccination induced intratumoral neutrophil and CD4+ T cell inflammation, and increased MHC-class II expression on myeloid cells. These data imply a role for pre-treatment systemic innate immune training in the antitumor efficacy of virotherapy and indicate that modulating either systemic innate inflammation and/or the inflammatory status of bone marrow myeloid progenitors may sensitize gliomas to virotherapy."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Inflammation • Oncology • Solid Tumor • CD4 • CXCL10 • IFIH1 • IL1B

Pre-treatment innate inflammation associates with survival after polio virotherapy and can be modulated to sensitize gliomas to in situ vaccination. (SNO 2024) - "We previously demonstrated that a recombinant poliovirus (PVSRIPO) functions by inducing MDA5-dependent, type I interferon (IFN) dominant innate inflammation in myeloid cells to provoke durable and functional antitumor T cell responses in mice...Notably, peripheral vaccination induced intratumoral neutrophil and CD4+ T cell inflammation, and increased MHC-class II expression on myeloid cells. These data imply a role for pre-treatment systemic innate immune training in the antitumor efficacy of virotherapy and indicate that modulating either systemic innate inflammation and/or the inflammatory status of bone marrow myeloid progenitors may sensitize gliomas to virotherapy."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Inflammation • Oncology • Solid Tumor • CD4 • CXCL10 • IFIH1 • IL1B

LUMINOS-103: A Basket Trial of Safety & Efficacy of Lerapolturev With or Without Checkpoint Inhibitors (clinicaltrials.gov) - P1/2 | N=4 | Terminated | Sponsor: Istari Oncology, Inc. | N=15 ➔ 4 | Trial completion date: May 2025 ➔ Jun 2024 | Recruiting ➔ Terminated | Trial primary completion date: May 2025 ➔ Apr 2024; business decision

Checkpoint inhibition • Combination therapy • Enrollment change • Metastases • Pan tumor • Trial completion date • Trial primary completion date • Trial termination • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Thyroid Gland Papillary Carcinoma

LUMINOS-102: Lerapolturev With or Without Immune Checkpoint Blockade in Advanced PD-1 Refractory Melanoma (clinicaltrials.gov) - P2 | N=56 | Active, not recruiting | Sponsor: Istari Oncology, Inc. | Trial primary completion date: Jun 2024 ➔ Oct 2024

Checkpoint block • Checkpoint inhibition • IO biomarker • Metastases • Trial primary completion date • Cutaneous Melanoma • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • BRAF • CD8 • PD-L1

LUMINOS-101: Lerapolturev (PVSRIPO) and Pembrolizumab in Patients with Recurrent Glioblastoma (clinicaltrials.gov) - P2 | N=25 | Completed | Sponsor: Istari Oncology, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Mar 2024 ➔ Jun 2024 | Trial primary completion date: Mar 2024 ➔ Jun 2024

Checkpoint inhibition • IO biomarker • Trial completion • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Repeated convection-enhanced delivery (CED) infusion of a Polio/Rhinovirus Recombinant (lerapolturev; LERA) in recurrent glioblastoma (rGBM) patients, followed by cervical perilymphatic injections of LERA (LERA-CPLI) (EANO 2024) - "Background: Phase 1 and 2 clinical trials of a single intratumoral injection of LERA (previously PVSRIPO) via CED into enhancing disease of rGBM has been shown safe and prolonged survival was observed in a subgroup of patients...Material and Eligibility includes adult patients with a solitary supratentorial rGBM amenable to resection followed by CED infusion of LERA; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS>70%... Repeated CED infusions of LERA followed by LERA-CPLI in three pilot rGBM patients has been shown safe and feasible. Updates on the formal trial proposed to enroll up to 86 patients will be provided."

Clinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

PVSRIPO for Patients With Unresectable Melanoma (clinicaltrials.gov) - P1 | N=12 | Terminated | Sponsor: Istari Oncology, Inc. | Completed ➔ Terminated; Study closed to enrollment due to business decision prior to enrolling Cohort 4

Trial termination • Melanoma • Oncology • Solid Tumor • BRAF • CD4 • CD8 • PD-1 • PVR

Lerapolturev (PVSRIPO) in GBM (clinicaltrials.gov) - P2 | N=92 | Recruiting | Sponsor: Darell Bigner | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Cervical Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Lerapolturev (PVSRIPO) in GBM (clinicaltrials.gov) - P2 | N=92 | Not yet recruiting | Sponsor: Darell Bigner | Initiation date: Apr 2024 ➔ Jul 2024

Trial initiation date • Brain Cancer • Cervical Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Focus on current and emerging treatment options for glioma: A comprehensive review. (PubMed, World J Clin Oncol) - "This review places a particular focus on immunotherapies, discussing promising agents such as Zotiraciclib and Lerapolturev...Exploration of immunotherapy extends to Pembrolizumab, Nivolumab, and Entrectinib, revealing the challenges and variabilities in patient responses. Despite promising preclinical data, the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment, emphasizing the critical need to understand resistance mechanisms...In addition to advancements in cancer vaccine development, this review highlights the evolving landscape of LGG treatment, emphasizing a shift toward personalized and targeted therapies. Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Pediatrics • Solid Tumor

Phase 1b Study PVSRIPO for Recurrent Malignant Glioma in Children (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Istari Oncology, Inc. | Active, not recruiting ➔ Completed | Phase classification: P1b ➔ P1 | N=12 ➔ 8

Enrollment change • Phase classification • Trial completion • Anaplastic Oligoastrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Embryonal Tumor • Ependymoma • Glioblastoma • Glioma • Gliosarcoma • Medulloblastoma • Oligodendroglioma • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor • NF1

LUMINOS-102: Lerapolturev With or Without Immune Checkpoint Blockade in Advanced PD-1 Refractory Melanoma (clinicaltrials.gov) - P2 | N=56 | Active, not recruiting | Sponsor: Istari Oncology, Inc. | Trial completion date: Oct 2023 ➔ Oct 2024 | Trial primary completion date: Oct 2023 ➔ Jun 2024

Checkpoint block • Checkpoint inhibition • IO biomarker • Metastases • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • BRAF • CD8 • PD-L1

Lerapolturev (PVSRIPO) in GBM (clinicaltrials.gov) - P2 | N=92 | Not yet recruiting | Sponsor: Darell Bigner | Initiation date: Dec 2023 ➔ Apr 2024

Trial initiation date • Brain Cancer • Cervical Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Examining Bioactivity of PVSRIPO in Invasive Breast Cancer (clinicaltrials.gov) - P1 | N=5 | Completed | Sponsor: Istari Oncology, Inc. | Recruiting ➔ Completed

Trial completion • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

The safety and accuracy of intratumoral catheter placement to infuse viral immunotherapies in children with malignant brain tumors: a multi-institutional study. (PubMed, J Neurosurg Pediatr) - P1, P1b | "Although instances of minor hemorrhage were encountered, they were clinically asymptomatic. One of 49 catheters required intervention for a CSF leak. Congruent with previous studies in the literature, the stereotactic placement of catheters in these pediatric tumor patients was accurate with approximately 95% of catheters having been adequately placed."

Clinical • Journal • Brain Cancer • CNS Tumor • Glioma • Hematological Disorders • Infectious Disease • Oncology • Pediatrics • Solid Tumor

Lerapolturev (PVSRIPO) in GBM (clinicaltrials.gov) - P2 | N=92 | Not yet recruiting | Sponsor: Darell Bigner

New P2 trial • Brain Cancer • Cervical Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

PVSRIPO in Recurrent Malignant Glioma (clinicaltrials.gov) - P2 | N=122 | Active, not recruiting | Sponsor: Istari Oncology, Inc. | Trial completion date: Dec 2023 ➔ Mar 2024 | Trial primary completion date: Aug 2023 ➔ Mar 2024

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor