Alice Chu

Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma

Toca 511 and Toca FC show promising results in treating recurrent high-grade glioma, and a specific molecular signature correlates with treatment-related survival. Tag-team attack on glioma Toca FC (extended-release 5-fluorocytosine) and Toca 511 (vocimagene amiretrorepvec) are an investigational therapeutic combination for glioma, consisting of two parts: a prodrug that is inactive on its own and a modified virus that infects the tumor and delivers an enzyme, which then activates the drug and allows it to kill the glioma cells. Cloughesy et al. tested this therapy in 45 human patients with recurrent or progressive high-grade glioma and discovered that the treatment was well tolerated and improved survival compared to an external control group. In addition, the authors identified a gene signature that correlated with response to the treatment, which may help identify the patients most likely to benefit from this approach. Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).

61. Ascending Dose Trials of a Retroviral Replicating Vector (Toca 511) in Patients with Recurrent High-Grade Glioma: Clinical Update, Molecular Analyses, and Proposed Mechanism of Action

We have conducted Phase 1 studies in patients with high grade glioma of a retroviral replicating vector (RRV), Toca 511 (vocimagene amiretrorepvec), based on an amphotropic murine gamma retrovirus encoding an optimized cytosine deaminase. The vector appears highly selective for tumor cells. Infected cells convert the antifungal drug 5-fluorocytosine (5-FC) delivered as an orally available extended-release formulation (Toca FC), into the antineoplastic drug 5-fluorouracil (5-FU). Toca 511 has been delivered by intratumoral injection (NCT01156584), injection into the tumor bed post-resection (NCT01470794), or by IV administration (NCT01985256). In all cases the treatment is well-tolerated. In animal models extensive infection of tumors (close to 100%) leads to control of tumor growth both in xenograft and syngeneic models. Limited access to tumor tissue post Toca 511 treatment in trial subjects, and lack of good markers of human glioblastoma cells in these heterogeneous primary tumors make it difficult to determine the extent of cancer cell infection but there is good evidence of selective tumor infection by PCR, RTPCR and IHC against the CD protein. Clinical data in both the first two trials (intratumoral and resection bed administration with 39 and 43 evaluable subjects respectively) show a favorable safety profile and extended overall survival (OS) compared to historical controls. In the resection study, for example, median OS was 13.6 months compared to 7-8 months in matched historical controls, and the OS at 24 months was 32%. In addition an RNA expression signature in untreated resected tumors that predicts long term survival in trial subjects has been identified from subjects that subsequently underwent tumor bed administration of Toca 511 and Toca FC. This signature does not normally correlate with survival in available public data sets. In immune competent orthotopic animal models, Toca 511 and 5-FC treatment leads to apparent tumor elimination and induction of strong antitumor immune responses by several mechanisms, including local elimination of myeloid derived suppressor cells. Subcutaneous re-implantation of the same tumors did not lead to tumor growth in animals treated up to a year before, whereas tumors did develop in control naive animals. Available data in the human trials are consistent with the immune response playing a significant role in the apparent clinical efficacy. Thus, clinically, treatment with Toca 511 and extended-release 5-FC (Toca FC) appears to selectively destroy tumor cells within the body, while leaving healthy cells unharmed. Toca 511 and Toca FC have been administered to more than 120 high grade glioma subjects in the three studies and, based on results from these trials, a phase 2/3 trial (Toca 5 has recently started recruitment (NCT02414165). The combination of clinical and preclinical data supporting this decision will be reviewed.