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LTBK-08. TOCA 511 & TOCA FC VERSUS STANDARD OF CARE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

ABSTRACT: Abstract 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. 403 patients were randomized 1:1 to the Toca arm or the SOC arm and stratified by IDH1 status, KPS, and geographic region. Primary endpoint was overall survival (OS), and secondary endpoints were durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. The study used group sequential design including 2 interim analyses and 1 final analysis, and the stratified log-rank test are used for the analysis. RESULTS 271 events were observed for this analysis. Median follow-up was 22.8 months, and the Toca arm missed the primary endpoint (OS) compared to the SOC arm (11.1 months median compared to 12.2 months, HR=1.06, p=0.6154). All secondary endpoints showed no meaningful difference between the arms of the trial. The safety, tolerability and adverse event profile of Toca 511 and Toca FC was as expected for this patient population, with low incidences of Grade 3–4 adverse events. 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 conference.

SUBMITTER: Cloughesy T

PROVIDER: S-EPMC6873620 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil. 5-fluorouracil kills infected cancer cells and surrounding cancer cells, myeloid derived suppressor cells and tumor associated macrophages, thus enabling immune activity against the tumor. In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with rHGG, followed by multiple courses of oral Toca FC. Additional cohorts included combination of the investigational therapy with bevacizumab or lomustine. Objective responses (ORs) are observed in patients with IDH1 wildtype and mutant tumors, including 3 complete responses (CRs) and 2 partial responses with the investigational therapy, and 1 CR with the investigational therapy and bevacizumab. The IDH1-mutant patients treated at 1st recurrence all had CRs and the fact that a CR in rHGG is rare suggests that the investigational treatment may be playing a role. ORs are observed 6–19 months after Toca 511 injection, consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDoR) is 25.2 months. Excluding combination cohorts, mDoR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of durable responses (ORs lasting > 24 weeks) with overall survival. In a 24-patient subgroup who received the recommended Ph2 Toca 511 dose, a durable response rate of 20.8% was observed. Across the Phase 1 program, the safety profile remains favorable. Updated clinical benefit, safety, immune activity, and molecular profiles will be reported.

Project description:Abstract 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. Preclinical evidence demonstrates that the Toca 511 & Toca FC regimen kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to durable antitumor immune responses that can be adoptively transferred to untreated animals. In an ascending dose trial (NCT01470794) in patients with recurrent high grade glioma (rHGG), Toca 511 was injected into the resection cavity walls at the time of resection, and then multiple courses of oral Toca FC were administered. Multiyear durable and complete responses by independent radiology review have been reported. Human immune monitoring results support an immunologic mechanism of action and identify potential biomarkers related to patient outcomes. Measurements included the quantification of peripheral blood and tumor infiltrating leukocyte subsets by flow cytometry, immunohistochemistry, and deconvolution of DNA and RNA sequencing data. In addition, systemic cytokine levels were assessed in peripheral blood serum by multiplex digital ELISA. Univariate comparisons and multivariate models revealed immunologic trends associated with patient outcomes. Pre-treatment tumor infiltrating cell subsets, quantified via deconvolution of RNA sequencing data, were associated with both objective responses and survival. Subsequent exploratory models applied to selected patient data indicate that a combined biomarker using mRNA signatures from multiple leukocyte subsets may predict patient outcomes with high sensitivity and selectivity. In addition, post-treatment serum cytokine time-course results suggest that differences and temporal modulations are associated with both objective response and survival. 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).

Project description:Abstract Toca 511, a clinical-stage retroviral replicating vector (RRV) encoding an optimized yeast cytosine deaminase (CD) prodrug activator gene, in combination with Toca FC (extended-release 5-fluorocytosine (5-FC)), is designed to produce 5-FU which kills cancer cells and immune-suppressive myeloid cells in the tumor microenvironment, leading to anti-cancer immune activation and long term survival. The combination treatment is currently under evaluation in an international Phase 2/3 trial in patients with recurrent high-grade glioma. In the present study, we investigated the feasibility of further applying Toca 511 to brain-metastatic breast cancer, which frequently arises from highly aggressive, treatment-refractory, “triple-negative” (ER(-) PR(-) HER2(-)) disease, and is associated with a dismal prognosis of 4-6 months survival. We first evaluated in vitro replication kinetics of RRV encoding the GFP reporter gene in MDA-MB-231-BR (human) and JC (murine) breast cancer cells. After virus inoculation at either M.O.I. of 0.01 or 0.1, high levels of transduction were achieved within 1-2 weeks as measured by flow cytometric quantitation of GFP fluorescence. Next, we tested in vitro cytotoxicity by MTS assay after 5-FC treatment of MDA-MB-231BR and JC cells transduced with Toca 511. In both Toca 511-transduced breast cancer lines, cell viability was reduced by approximately 70-85% after exposure to 0.1 mM 5-FC and complete cell killing was observed with 1 mM 5-FC within 4-6 days. In survival studies, animals treated with Toca 511 followed by 5-FC prodrug showed statistically significant (231-BR: p<0.0001, JC: p=0.0003) survival benefit compared to the control group. These data provide preclinical validation for a new Phase Ib trial evaluating RRV-mediated immunotherapy in various types of metastatic malignancies, including CNS-metastatic breast cancer (TOCA 6 trial: clinicaltrials.gov NCT02576665), currently recruiting at the University of Miami.

Project description:Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV), encodes and delivers a functionally optimized yeast cytosine deaminase (CD) gene to tumors. In orthotopic glioma models treated with Toca 511 and 5-fluorocytosine (5-FC) the CD enzyme within infected cells converts 5-FC to 5-fluorouracil (5-FU), resulting in tumor killing. Toca 511, delivered locally either by intratumoral injection or by injection into the resection bed, in combination with subsequent oral extended-release 5-FC (Toca FC), is under clinical investigation in patients with recurrent high-grade glioma (HGG). If feasible, intravenous administration of vectors is less invasive, can easily be repeated if desired, and may be applicable to other tumor types. Here, we present preclinical data that support the development of an intravenous administration protocol. First we show that intravenous administration of Toca 511 in a preclinical model did not lead to widespread or uncontrolled replication of the RVV. No, or low, viral DNA was found in the blood and most of the tissues examined 180 days after Toca 511 administration. We also show that RRV administered intravenously leads to efficient infection and spread of the vector carrying the green fluorescent protein (GFP)-encoding gene (Toca GFP) through tumors in both immune-competent and immune-compromised animal models. However, initial vector localization within the tumor appeared to depend on the mode of administration. Long-term survival was observed in immune-competent mice when Toca 511 was administered intravenously or intracranially in combination with 5-FC treatment, and this combination was well tolerated in the preclinical models. Enhanced survival could also be achieved in animals with preexisting immune response to vector, supporting the potential for repeated administration. On the basis of these and other supporting data, a clinical trial investigating intravenous administration of Toca 511 in patients with recurrent HGG is currently open and enrolling.

Project description:Background:Patients with recurrent glioma after prior radiotherapy have a poor prognosis. Carbon ion beam radiotherapy offers highly conformal dose distributions and more complex biological radiation effects eventually resulting in optimized normal tissue sparing and improved outcome. The aim of this study was to analyze toxicity, local control and overall survival after reirradiation of recurrent high-grade glioma with carbon ion radiotherapy. Methods:Between 10/2015 and 12/2018, 30 patients (median age: 59 years) with recurrent high-grade glioma were reirradiated with carbon ion beams and retrospectively analyzed. Diagnosis of recurrent glioma was based on magnetic resonance imaging. Thirteen patients had repeated resection prior to reirradiation and 24 patients underwent additional chemotherapy. The median initial radiation dose was 60 Gy and the median time interval between the initial and repeated radiotherapy was 10 months. The reirradiation dose was 45 Gy (relative biological effectiveness) applied in 15 fractions. All patients received regular follow-up imaging after reirradiation. Kaplan-Meier estimation, log rank test and Cox regression analysis were used for statistical assessment. Results:Applying common toxicity criteria, there were no grade 5 or 4 adverse events, while 8 patients showed grade 3 adverse events. The median follow-up after reirradiation was 11 months and the median overall survival after diagnosis of recurrent high-grade glioma was 13 months. The 6-, 12- and 24-month overall survival rates after diagnosis of recurrent high-grade glioma were 76%, 50% and 19%, respectively. Upon multivariate Cox regression analysis, a Ki67 score of the initial tumor histology of less than 20% was prognostic. Repeated resection or chemotherapy for the recurrent disease did not result in significantly prolonged survival. Conclusion:Carbon ion reirradiation in recurrent high-grade glioma is safe and feasible. No radiation-associated grade 4 toxicities were documented and treatment was tolerated well.

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LTBK-08. TOCA 511 & TOCA FC VERSUS STANDARD OF CARE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

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