vocimagene amiretrorepvec/extended release flucytosine (DB107) / Denovo, ApolloBio - LARVOL DELTA

Trial in progress update: A phase 1/2 study of intracranial and intravenous multi-dosing of DB107-RRV (formerly Toca 511) and DB107-FC (5-fluorocytosine) in combination with radiation ± temozolomide (TMZ) in patients with newly diagnosed high-grade gliomas (HGGs) (SNO 2025) - "This enzyme converts DB107-FC into chemotherapeutic agent 5-fluorouracil (5-FU), inducing tumor cell apoptosis. The study is currently enrolling. To date, DB107-RRV multimodal delivery has completed for five patients with histopathologic glioblastoma confirmation, without delays in surgical care. Two mMGMT patients are entering adjuvant therapy, one mMGMT patient is beginning radio/chemotherapy + DB107-FC, and two patients are awaiting MGMT results."

Clinical • Combination therapy • P1/2 data • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Solid Tumor • MGMT

Trial in progress update: A phase 1/2 study of intracranial and intravenous multi-dosing of DB107-RRV (formerly Toca 511) and DB107-FC (5-fluorocytosine) in combination with radiation ± temozolomide (TMZ) in patients with newly diagnosed high-grade gliomas (HGGs) (WFNOS 2025) - "This enzyme converts DB107-FC into chemotherapeutic agent 5-fluorouracil (5-FU), inducing tumor cell apoptosis. The study is currently enrolling. To date, DB107-RRV multimodal delivery has completed for five patients with histopathologic glioblastoma confirmation, without delays in surgical care. Two mMGMT patients are entering adjuvant therapy, one mMGMT patient is beginning radio/chemotherapy + DB107-FC, and two patients are awaiting MGMT results."

Clinical • Combination therapy • P1/2 data • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Solid Tumor • MGMT

Safety, Tumor Homing And Immune Effects Of Systemically Administered Vocimagene Amiretrorepvec In Patients With Advanced Solid Tumors: A Phase 1B Study. (PubMed, Mol Ther) - "Vocimagene amiretrorepvec (Toca 511) is a replicating retroviral vector (RRV) encoding cytosine deaminase that converts 5-fluorocytosine (5-FC) into 5-fluorouracil in the tumor microenvironment. The above results confirm feasibility of systemic administration of Toca 511 in combination with oral Toca FC, successful tumor targeting and tumor and systemic immunomodulation. Further investigation of Toca 511/Toca FC in combination with checkpoint inhibitors and/or targeted agents is warranted."

Journal • P1 data • Immunology • Oncology • Solid Tumor • CD4 • CD8

Anova Announces First Patient Enrolled to Phase 1/2a Study of DB107 for the Treatment of High-Grade Gliomas (Businesswire) - "Anova Enterprises, Inc...has announced enrollment of the first two patients in the highly anticipated study of DB107 for the treatment of brain tumors. The Phase 1/2a clinical trial is a multicenter, open-label study designed to confirm whether treatment DB107, when added to standard-of-care (SOC), provides clinical benefit to patients with newly diagnosed high-grade gliomas (HGG) when compared to historical performance."

Enrollment open • Glioma

DB107-RRV, DB107-FC, and Radiation Therapy with or Without Temozolomide (TMZ) for High Grade Glioma (clinicaltrials.gov) - P1/2 | N=70 | Recruiting | Sponsor: University of California, San Francisco | Trial completion date: Jan 2040 ➔ Jan 2042 | Trial primary completion date: Jan 2040 ➔ Jan 2028

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

DB107-RRV, DB107-FC, and Radiation Therapy with or Without Temozolomide (TMZ) for High Grade Glioma (clinicaltrials.gov) - P1/2 | N=70 | Recruiting | Sponsor: Nicholas Butowski | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Malignant Glioma • Oncology • Solid Tumor • MGMT

A biomarker-guided phase 2 Study of DB107-RRV (a retroviral replicating vector) combined with DB107-FC (flucytosine extended-release tablets) in patients with recurrent glioblastoma or anaplastic astrocytoma: a clinical protocol. (SNO 2024) - P2/3 | "The first clinically tested replicating retroviral vector DB107-RRV (vocimagene amiretrorepvec, formerly Toca511) was assessed in a randomized Phase 3 study (NCT02414165) to evaluate the intracranial administration of DB107-RRV with subsequent oral administration of DB107-FC (5-fluocytosine extended-release tablets) in patients with recurrent HGG...Key inclusion criteria include presence of the DGM7 biomarker in blood, patient age 18–75 with histologically proven, measurable (MRI) recurrent/progressive HGG, and no radiation therapy for at least 12 weeks without histopathologic/MRI progression confirmation. The primary endpoint of this study will be progression-free survival at 6 months (PFS6) and OS of DB107-RRV+DB107-FC in DGM7+ patients with recurrent/progressive HGG compared to the historical study arm SOC/DGM7+ from NCT02414165."

Biomarker • Clinical • Clinical protocol • P2 data • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

DB107-RRV, DB107-FC, and Radiation Therapy With or Without Temozolomide (TMZ) for High Grade Glioma (clinicaltrials.gov) - P1/2 | N=70 | Not yet recruiting | Sponsor: Nicholas Butowski | Initiation date: Sep 2024 ➔ Dec 2024

Combination therapy • Trial initiation date • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • MGMT

Therapeutic activity of retroviral replicating vector-mediated gene therapy in combination with anti-PD-1 antibody in a murine pancreatic cancer model. (PubMed, Cancer Gene Ther) - "Toca 511, a tumor-selective retroviral replicating vector encoding the yeast cytosine deaminase (yCD) gene, exerts direct antitumor effects through intratumoral prodrug 5-fluorocytosine (5-FC) conversion to active drug 5-fluorouracil by yCD, and has demonstrated therapeutic efficacy in preclinical and clinical trials of various cancers. In an orthotopic tumor and peritoneal dissemination model, the combination therapy resulted in complete regression in both transduced orthotopic tumors and untransduced peritoneal dissemination. Thus, Toca 511/5-FC treatment induced a systemic antitumor immune response, and the combination therapy could be a promising clinical strategy for treating metastatic pancreatic cancer."

Combination therapy • Gene therapy • IO biomarker • Journal • Preclinical • Gastrointestinal Cancer • Gene Therapies • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD8

DB107-RRV, DB107-FC, and Radiation Therapy With or Without Temozolomide (TMZ) for High Grade Glioma (clinicaltrials.gov) - P1/2 | N=70 | Not yet recruiting | Sponsor: Nicholas Butowski

New P1/2 trial • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • MGMT

CIRM Awards $11.8 Million Grant for Clinical Trial in High-Grade Glioma Including Glioblastoma Using DB107, a Novel DGM7 Genetic Biomarker-Guided Gene Therapy (PRNewswire) - "Denovo Biopharma LLC...today announced that the California Institute for Regenerative Medicine (CIRM) has awarded a $11.8M grant for further development of DB107...for high–grade glioma (HGG) including glioblastoma (GBM), a malignant brain cancer. CIRM has awarded the grant to Dr. Noriyuki Kasahara, MD, PhD, at the University of California San Francisco (UCSF) and a group of investigators at California universities to conduct a Phase 1/2 clinical trial studying DB107 in patients with newly–diagnosed HGG....The trial aims to demonstrate improvements in progression–free survival."

Financing • New P1/2 trial • CNS Tumor • Glioblastoma • Solid Tumor

DB107-Retroviral Replicating Vector (RRV) Combined With DB107-Flucytosine (FC) in Patients With Recurrent Glioblastoma or Anaplastic Astrocytoma (clinicaltrials.gov) - P2 | N=33 | Recruiting | Sponsor: Ashish Shah | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

A Biomarker-Guided Phase 2 Study of DB107-Retroviral Replicating Vector (RRV) Combined With DB107-Flucytosine (FC) Extended-Release Tablets (clinicaltrials.gov) - P2 | N=33 | Not yet recruiting | Sponsor: Ashish Shah

Biomarker • New P2 trial • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

United States Food and Drug Administration (FDA) Authorizes Phase 2 Study of DB107 In Promising Turn-Around of Targeted Treatment to Treat Newly Diagnosed High Grade Glioma (Businesswire) - "Anova today announced the FDA authorization of an IND for a Phase II clinical trial under it's management to re-assess a targeted treatment in light of newly discovered pharmacogenomic predictor data in patients with newly diagnosed high-grade glioma.....The Phase 2 study of DB107 will investigate the impact of giving multiple doses of DB107 both directly at time of surgery and intravenously (IV)."

IND • New P2 trial • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor

Therapeutic Efficacy of Retroviral Replicating Vector Toca 511 (vocimagene amiretrorepvec) -Mediated Prodrug Activator Gene Therapy for Lung Cancer (ASGCT 2023) - "Prodrug activator gene therapy with Toca 511 (vocimagene amiretrorepvec), an RRV encoding yeast cytosine deaminase (yCD), which converts the prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU) within Toca 511-infected cells, has been shown to achieve significantly enhanced survival benefit in a variety of preclinical tumor models. As compared with their respective control groups, the Toca 511/5-FC treatment group showed significant reductions in mean signal intensity in both A549 (p=0.0147) and Ex-3LL (p=0.0326) models. Thus, RRV can serve as highly efficient vehicles for gene delivery to LC, and these in vitro and in vivo data indicated the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies."

Clinical • Gene therapy • Brain Cancer • CNS Tumor • Gene Therapies • Glioma • Immune Modulation • Infectious Disease • Lung Cancer • Oncology • Solid Tumor

Toca 511/5-FC Treatment Has the Potential to Increase the Therapeutic Efficacy of Anti-PD-1 Antibody in an Immunocompetent Murine Pancreatic Cancer Model (ASGCT 2023) - "Toca 511 exerts direct anti-tumor effects through yCD-mediated intratumoral conversion of the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU). These data showed that CD8+ or CD4+ T-cell-dependent anti-tumor immune responses were important for the therapeutic efficacy of Toca 511/5-FC treatment and combination therapy. These results indicate that Toca 511/5-FC treatment has the potential to increase the therapeutic efficacy of immune checkpoint inhibitors and the combination therapy may be a promising clinical treatment strategy for PDAC."

Preclinical • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Gene Therapies • Glioma • Hepatology • Immune Modulation • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8

Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma (SNO 2019) - P2/3; "BACKGROUND Toca 511 (vocimagene amiretrorepvec) is a cancer-selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5-fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. Three Ph1 studies in patients with recurrent high grade glioma have demonstrated a tolerable safety profile and encouraging efficacy.METHODS Toca 5 is a multi-national, randomized, open-label Ph3 trial (NCT02414165) of Toca 511 & Toca FC versus standard of care (SOC) options that comprises Investigator’s choice of single agent chemotherapy (lomustine, temozolomide) or bevacizumab in patients who have undergone resection for first or second recurrence of glioblastoma or anaplastic astrocytoma...Pre-planned subgroup analyses showed compelling OS improvement in patients with secondary recurrence, and favorable trends in IDH1 mutant and AA population. Detailed data will be presented at the time of the confere

Clinical • Late-breaking abstract • IDH1

IMMUNOLOGIC TRENDS ASSOCIATED WITH PATIENT OUTCOMES IN A PHASE 1 CLINICAL TRIAL OF TOCA 511 AND TOCA FC IN RECURRENT HIGH GRADE GLIOMA (SNO 2018) - P1, P2/3; "Toca 511 (vocimagene amiretrorepvec) is a cancer selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5- fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. These results support an immune-related mechanism of action for the Toca 511 & Toca FC regimen. Potentially predictive and/or prognostic biomarkers of patient outcomes will be evaluated in the ongoing randomized Phase 3 Toca 5 trial in patients with rHGG (NCT02414165)."

Clinical • P1 data • Brain Cancer • Oncology • Solid Tumor

Enhanced efficacy and combinability of low dose toca 511 and 5-FC with metronomic chemotherapy in preclinical models (SITC 2018) - P2/3; "Toca 511 spreads and stably delivers optimized yeast cytosine deaminase (CD) that converts subsequent Toca FC (an investigational, extended-release version of 5-fluorocytosine [5-FC]) into 5-fluorouracil (5-FU). Conclusions These data demonstrate that Toca 511 and 5-FC therapy can be combined with metronomic chemotherapeutics like cyclophosphamide to enhance efficacy in preclinical models when the percent of Toca 511-infected tumor cells is manipulated to be submaximal. Data from this study will inform future clinical development of Toca 511 & Toca FC in combination with other therapies."

Preclinical • Brain Cancer • Oncology • Solid Tumor

The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose (AACR 2019) - P2/3; "These results demonstrate that (1) survival correlates with the transduction levels of Toca 511 when combined with temozolomide in the Tu-2449 orthotopic glioma model and (2) that this combination may support anti-tumor immune memory. These studies along with prior work support evaluation of the combination of Toca 511/5-FC with temozolomide in patients with newly diagnosed GBM (NRG-BN006)."

Preclinical

Immune profile of tumor microenvironment helps predict response in patients treated with an investigational immunotherapeutic consisting of a retroviral replicating vector (Toca 511) and an extended-release formulation of 5-fluorocytosine (Toca FC) (AACR 2018) - P1,P2/3; "Toca 511 spreads through cancer cells, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug Toca FC (investigational, extended-release 5-fluorocytosine) into 5-fluorouracil (5-FU), a canonical chemotherapeutic. Additionally, we plan to report on T cell, B cell, and myeloid populations in the tumor as measured by IHC and RNA sequencing and their relationship to clinical response. Data reported here will provide mechanistic context to the immunotherapeutic mode of action proposed to account for durable responses seen in treatment of brain tumors with Toca 511 and Toca FC."

Biomarker • Clinical • Tumor microenvironment • Solid Tumor

Glioblastoma treatment slowly moves towards change: novel druggable targets and translational horizons in 2022. (PubMed, Expert Opin Drug Discov) - "Nevertheless, stimulating insights for future research and drug development come from innovative treatment strategies for GBM, such as multi-specific "off-the-shelf" CAR-T therapy, oncolytic viral therapy and autologous dendritic cell vaccination. Disappointing results from targeted therapies-clinical trials are mainly due to complex interferences between signaling pathways and biological processes leading to drug resistance: hence, it is imperative in the future to develop combinatorial approaches and multimodal therapies, such as dual block of PI3K and MAPK signaling or PI3K/MTOR inhibition, to improve therapeutic benefit and survival."

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

Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer. (PubMed, Cancers (Basel)) - "Toca 511 (vocimagene amiretrorepvec), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies."

Journal • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Gastrointestinal Disorder • Gene Therapies • Glioma • Lung Cancer • Oncology • Solid Tumor

Durable complete responses observed in IDH1 mutated high grade glioma at first recurrence undergoing treatment with Toca 511 and Toca FC. (ASCO 2017) - P1; "Additional cohorts included combination of Toca 511 & Toca FC with bevacizumab or lomustine. There may be an association between ORs and IDH1 mutation with Toca 511 & Toca FC treatment. Updated clinical benefit, molecular profiles and tumor mutational load are reported."

Biomarker • Clinical • Biosimilar

[PREPRINT] Retroviral Replicating Vector Toca 511 (vocimagene amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer (Preprints) - “In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer….Toca 511 (vocimagene amiretrorepvec)…showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies.”

Preclinical • Preprint • Lung Cancer • Oncology