Asha Das

Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab

Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma.

Corticosteroid Use in Patients with Glioblastoma at First or Second Relapse Treated with Bevacizumab in the BRAIN Study

BACKGROUND Vascular endothelial growth factor inhibitors have corticosteroid-sparing effects in patients with high-grade gliomas. We assessed corticosteroid use in patients with recurrent glioblastoma treated with bevacizumab (BEV) in the BRAIN study (J Clin Oncol 2009;27:4733-4740). METHODS BRAIN was a phase II, multicenter, randomized, noncomparative trial of BEV alone (n = 85) or in combination with irinotecan (CPT-11) (n = 82) in adults with recurrent glioblastoma. Median corticosteroid dose for patients who used corticosteroids at baseline was summarized by treatment arm; the percentage of patients who had sustained (≥50% corticosteroid dose reduction for ≥50% of time on study drug) or complete (discontinuation of corticosteroid for ≥25% of time on study drug) reduction in corticosteroid dose overall and by objective response and progression-free survival was calculated. The incidence of corticosteroid-related adverse events was summarized. RESULTS In each treatment group, 50% of patients were using systemic corticosteroids at baseline. The majority of those experienced a reduction in dose while receiving BEV-based therapy. Thirteen (30.2%) BEV and 20 (46.5%) BEV + CPT-11 patients had a sustained reduction of corticosteroid dose; 7 (16.3%) BEV and 9 (20.9%) BEV + CPT-11 patients had a complete reduction of corticosteroid dose. The majority of patients who had an objective response or progression-free survival >6 months experienced corticosteroid dose reduction. Approximately 64% of patients who used corticosteroids while receiving BEV-based therapy experienced infection. CONCLUSION BEV may have corticosteroid-sparing effects in patients with recurrent glioblastoma. Corticosteroid reduction may positively affect patient health-related quality of life. Given the exploratory nature of the analyses in a noncomparative study, these results should be interpreted cautiously.

Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.

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).

Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC

Background Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results Among 56 patients, durable complete responses were observed. A subgroup was identified based on Toca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

Abstract 5630: 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)

Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to defects in innate and adaptive immune responses found in cancers that support virus replication, and cell division requirements for virus integration into the genome. 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. In preclinical tumor models, as infected cancer cells are killed, diffusible 5-FU also kills nearby susceptible cells, including uninfected cancer cells, and myeloid derived suppressor cells (MDSC) that contribute to immune-suppression in the tumor microenvironment. This action by Toca 511 and Toca FC has been shown in animal models to generate a durable anti-tumor immune response that can be transferred to naive, untreated animals. The Toca 511 and Toca FC immunotherapeutic are proposed to remodel the tumor microenvironment to break tumor tolerance resulting in induction of antitumor activity by the patient9s immune system and durable complete responses. In a phase 1 clinical study for recurrent high grade glioma (NCT01470794), Toca 511 was injected into resection cavity walls at time of resection followed by multiple courses of oral Toca FC. We observed multi-year durable and objective responses; including 5 ongoing complete responses in a group of 23 patients in the higher dose single agent treatment cohorts given approximately the same Toca 511 doses and having the same entry criteria as an ongoing Phase 3 study in recurrent high grade glioma (NCT02414165). Patient tumors at time of resection were analyzed by exome sequencing, RNA sequencing, IHC, and TCR sequencing, before Toca 511 treatment. In this study, we report higher levels of tumor infiltrating T cells by TCR sequencing, before the start of treatment, were significantly associated with responding patients compared to patients whose disease progressed. The significance of this data is supported by the preclinical mechanism of action reported previously. 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. Citation Format: Derek Ostertag, William Accomando, Leah Mitchell, Maria Rodriguez-Aguirre, Daniel Hogan, Oscar Diago, Dawn Gammon, Ali Haghighi, Harry Gruber, Asha Das, Douglas Jolly. 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) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5630.

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.