Tobias Walbert

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).

Palliative and Supportive Care for Glioma Patients

The diagnosis of a brain tumor is a life-changing event for patients and families. High-grade gliomas are incurable and long-term survival remains limited. While low-grade glioma patients have better outcomes, their quality of life is often affected by a variety of symptoms as well. Helping glioma patients improve quality of life at all stages of illness is an important goal for the interdisciplinary care team. There is evidence from advanced lung cancer patients that early involvement of a palliative care team can improve patients quality of life, symptom burden, and even survival and a similar approach benefits glioma patients as well. Patients with high-grade and low-grade glioma often suffer from significant symptom burden. We discuss how validated global symptom assessments and symptom-specific screening tools are useful to identify distressing symptoms. Seizures, fatigue, depression, and anxiety are some of the more common symptoms throughout the disease course and should be managed actively. Patients with glioma also have high symptom burden at the end of life and the majority lose decision-making capacity. Advance care planning conversations early in the disease course are essential to elicit the patients wishes for end of life care and effective communication with surrogate decision makers during all stages of the disease helps ensure that those wishes are respected.

Recurrent high-grade glioma: a diagnostic and therapeutic challenge

The management of recurrent high-grade gliomas with conventional, as well as targeted, therapies is problematic owing to several confounding issues. First, the diagnosis of recurrence using MRI is not straightforward, making the assessment of images in daily routines, as well as in clinical trials, challenging. While chemotherapies with cytotoxic agents have demonstrated initial treatment response, most tumors recur quickly. Second, targeted therapy itself is confounded by the heterogeneous expression of drug targets and nonlinear signaling effects, with functional redundancy and sidestream feedback mechanisms resulting in treatment failure; however, several active agents have been identified, most notably, bevacizumab (an antibody that sequesters VEGF), cilengitide (an inhibitor of integrin αvβ3/5 signaling) and cediranib (an oral tyrosine kinase inhibitor targeting PDGF receptor, c-Kit and all VEGF receptor subtypes). All of these agents have undergone multiple clinical trials and have demonstrated benefits and progression-free survival prolongation in recurrent disease. Given these advances, it is likely that tailored therapies for tumors harboring specific signaling defects will become more efficient and successful in the management of glioblastoma.

Through the patient’s eyes: the value of a comprehensive brain tumor center

Since the founding of the Tumor Section of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) in 1984 much in neurosurgical oncology has changed. More than 40,000 papers have been published on glioma since the arrival of the AANS/CNS Tumor Section. Increasingly, research is focusing on more patient-centered care and quality of life. Preliminary work suggests that a greater emphasis on the patient and caregiver’s experience of disease is crucial. Also, the provision of hope and appropriate information and communication with health care providers helps to lessen anxiety and promote improved quality of life. Lastly, our patients need a mechanism for continued symptom control and psychosocial support throughout their experience of this disease. An excellent venue for providing these facets of neurooncological patient care is the multidisciplinary brain tumor board and symptom management team. Herein, we present the philosophy and practice of the Hermelin Brain Tumor Center at the Henry Ford Health System as one type of approach to caring for the patient with a malignant glioma. The authors are aware of several brain tumor centers that share our philosophy and approach to patient care. Our comments are not meant to be exclusive to our experience and should be interpreted as representative of the growing movement in neurosurgery to provide comprehensive, multidisciplinary, patient-centered care.

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.

Working plan for the use of patient-reported outcome measures in adults with brain tumours: a Response Assessment in Neuro-Oncology (RANO) initiative

The Response Assessment in Neuro-Oncology-Patient-Reported Outcome (RANO-PRO) working group is an international multidisciplinary collaboration that provides guidance on the use of patient-reported outcome (PRO) measures in clinical trials and practice for adult patients with brain tumours. Findings from both PROs and traditional outcome measures, such as survival, and clinical or radiological response, are essential to inform the research community, policy makers, physicians, and patients in the treatment decision-making process. Previous initiatives in oncology have focused on guidelines concerning the collection, analysis, interpretation, and reporting of PRO data. However, we recommend the application of appropriate PRO instruments, with respect to its content and measurement properties (ie, research question, content validity, and other measurement properties), in brain tumour research. PROs should be well defined and reliable to generate high-quality evidence, and our recommendations on the use of specific PRO measures could help to improve the quality of PRO evidence derived from neuro-oncological studies, and might add a new dimension in how the value of therapeutics is assessed in patients with brain tumours. In this Policy Review, we present the RANO-PRO working plan for the use of PROs in adults with brain tumours.

Cerebral edema induced by laser interstitial thermal therapy and radiotherapy in close succession in patients with brain tumor: CEREBRAL EDEMA AFTER LITT FOR BRAIN TUMORS

Laser interstitial thermal therapy (LITT) is an image‐guided technique that uses high temperature to ablate pathological tissue. Brain tumor patients undergoing LITT may also undergo radiation therapy (RT) either before or after LITT. Both procedures have been reported to increase cerebral edema and thereby the two treatments in close succession may worsen existing edema that can be difficult to control. The purpose of our study was to determine the frequency of increased and/or symptomatic cerebral edema after combined LITT and RT, the radiographic and clinical signs of this cerebral edema, and the treatment required.

Correction: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma [J Transl Med., 16, (2018) (142)] DOI: 10.1186/s12967-018-1507-6

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

Abstract CT100: Tumor treating fields (TTFields) on health-related quality of life (HRQoL) in ndGBM: An exploratory analysis of the EF-14 phase III trial

TTFields are a novel treatment modality based on home-use medical device which continuously delivers alternating electric fields to the region of the tumor. These fields selectively interfere with a number of cellular processes during the mitotic cycle, such as the assembly of the mitotic spindle, leading to apoptosis. In the EF-14 phase III study in newly diagnosed glioblastoma, TTFields added to maintenance temozolomide led to a significant increase in overall survival, as well as in the 5-year survival rate compared to patients treated with temozolomide alone. It was previously reported that the addition of TTFields to maintenance temozolomide did not negatively impact nine prespecified HRQoL scales except for an expected increase in itchy skin, and in addition resulted in a significant delay in the increase of HRQoL pain assessment. Here we present an exploratory analysis of the remaining EORTC QLQ C-30 and BN-20 HRQoL scales. Methods HRQoL was a predefined secondary endpoint in the EF-14 study, measured by collecting the EORTC QLQ-C30 and BN20 questionnaires at baseline and every 3 months thereafter. HRQoL was assessed for the remaining HRQoL scales except for the prespecified and previously reported nine preselected scales: global health, physical, cognitive, role, social and emotional functioning, itchy skin, pain, and leg weakness. Mean changes from baseline scores were evaluated, as well as significant changes in scores over time (>10 points) using a repeated measures test. Moreover, deterioration-free survival and time to deterioration in HRQoL were assessed for each scale, as well as the percentage of patients with stable/improved HRQoL compared to baseline. Results No statistically or clinically significant decline in any of the exploratory HRQoL scales was seen in the repeated measures analysis or in time to deterioration. A significantly larger proportion of patients treated with TTFields compared to control patients reported stable/improved bladder control (63.6% Vs. 46.8%, p=0.001) and diarrhea (60.6% vs. 43.7%, p=0.001) compared to baseline. The deterioration-free survival for diarrhea, future uncertainty and headaches was significantly delayed in TTFields/temozolomide treated patients compared to those treated with temozolomide alone (HR 0.68, 0.71 and 0.67, respectively, p Conclusions The delay in deterioration free survival and increase in percentage of patients with stable/improved HRQoL in several of the additional HRQoL scales may be attributed in part to the longer progression-free survival observed in TTFields/temozolomide treated patients on the EF-14 trial. No negative impact of HRQoL was seen in any of the exploratory analysis. These results further support the addition of TTFields to standard therapy in newly diagnosed glioblastoma patients. Citation Format: Tobias Walbert, Gitit Lavy-Shahaf, Steven A Toms, Santosh Kesari. Tumor treating fields (TTFields) on health-related quality of life (HRQoL) in ndGBM: An exploratory analysis of the EF-14 phase III trial [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 CT100.