First Recurrence Of Glioblastoma Research Articles

P17.14.B PHASE I TRIAL OF DNX-2401 ONCOLYTIC ADENOVIRUS COMBINED WITH A SHORT COURSE OF DOSE-DENSE TEMOZOLOMIDE FOR RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Oncolytic virotherapy is emerging as a novel therapeutic strategy for glioblastoma (GBM). DNX-2401, an oncolytic adenovirus with selective replication and enhanced infectivity in tumor cells, showed anti-tumor effect in a previous clinical trial for recurrent GBM. The combination of DNX-2401 and Temozolomide (TMZ) has shown a synergistic anti-glioma effect in preclinical models. MATERIAL AND METHODS We conducted a phase I open-label single-center study to investigate the safety and efficacy of this therapeutic combination in patients with first recurrence of GBM. Following tumor biopsy or resection, 3x10e10 viral particles of DNX-2401 were injected intratumorally or into the post-resection cavity, respectively. Approximately 2 weeks after DNX-2401 injection, patients were treated with up to two 28-day cycles of oral 150 mg/m2/day TMZ in a 7 days on/7 days off schedule. RESULTS Thirty-one patients (13 [42%] female, 18 [58%] male) with confirmed recurrent GBM were enrolled and treated with DNX-2401 followed by a median of 1.5 cycles of TMZ (range, 0-2). Median age was 54 years (range, 25-78) and median KPS was 70 (range 70-90). Surgery consisted of biopsy in 14, partial resection in 15 and complete resection in 2 patients. IDH1/2 mutation was confirmed in 1 patient. MGMTP was methylated in 9 and unmethylated in 21 patients (1 patient, unknown). Best response according to RANO criteria was partial response in 1 patient, stable disease in 21 subjects and progressive disease in the remainder. Median PFS was 51 days (95% CI, 43-81). Median OS was 282 days (95% CI 202-344) with 6-month and 12-month OS rates of 72.5 (95% CI 52.4-85.2) and 27.5 % (95% CI 12.4-45.0), respectively. Four patients survived more than 18 months with 2 long-term survivors exceeding 4.5 years. Treatment was generally well tolerated. The safety profile was as expected for subjects treated with TMZ alone. Except one subject who experienced grade 2 brain edema possibly related to DNX-2401, no additional toxicity was considered attributable to DNX-2401. The most frequent reported adverse events were lymphopenia (54.8%), asthenia (48.4%), constipation (41.9%), headache (29%) and pyrexia (22.6%). Ongoing correlative analyses evaluating immune response are ongoing. CONCLUSION Our data suggest that treatment with DNX-2401 followed by a short-course of dose-dense TMZ is feasible, can be safely administered with expected adverse events related to chemotherapy, and appears to render a clinical benefit in a subset of patients with recurrent GBM. Further assessment of this therapeutic approach is warranted.

Texture Analysis of the Apparent Diffusion Coefficient Focused on Contrast-Enhancing Lesions in Predicting Survival for Bevacizumab-Treated Patients with Recurrent Glioblastoma.

Glioblastoma often recurs after treatment. Bevacizumab increases progression-free survival in some patients with recurrent glioblastoma. Identifying pretreatment predictors of survival can help clinical decision making. Magnetic resonance texture analysis (MRTA) quantifies macroscopic tissue heterogeneity indirectly linked to microscopic tissue properties. We investigated the usefulness of MRTA in predicting survival in patients with recurrent glioblastoma treated with bevacizumab. We evaluated retrospective longitudinal data from 33 patients (20 men; mean age 56 ± 13 years) who received bevacizumab on the first recurrence of glioblastoma. Volumes of contrast-enhancing lesions segmented on postcontrast T1-weighted sequences were co-registered on apparent diffusion coefficient maps to extract 107 radiomic features. To assess the performance of textural parameters in predicting progression-free survival and overall survival, we used receiver operating characteristic curves, univariate and multivariate regression analysis, and Kaplan-Meier plots. Longer progression-free survival (>6 months) and overall survival (>1 year) were associated with lower values of major axis length (MAL), a lower maximum 2D diameter row (m2Ddr), and higher skewness values. Longer progression-free survival was also associated with higher kurtosis, and longer overall survival with higher elongation values. The model combining MAL, m2Ddr, and skewness best predicted progression-free survival at 6 months (AUC 0.886, 100% sensitivity, 77.8% specificity, 50% PPV, 100% NPV), and the model combining m2Ddr, elongation, and skewness best predicted overall survival (AUC 0.895, 83.3% sensitivity, 85.2% specificity, 55.6% PPV, 95.8% NPV). Our preliminary analyses suggest that in patients with recurrent glioblastoma pretreatment, MRTA helps to predict survival after bevacizumab treatment.

Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma

Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma. To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma. This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022. Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily). The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life. Among the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects. This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma. ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16.

Safety and anti-tumor activity of lisavanbulin administered as 48-hour infusion in patients with ovarian cancer or recurrent glioblastoma: a phase 2a study

Purpose. Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m2. Results from the Phase 1 dose-escalation portion of the study identifying the RP2D have been previously reported. Here, we present the findings from the Phase 2a portion of this study. Methods. This multi-center, open-label study included patients with ovarian, fallopian-tube, or primary peritoneal cancer that was either platinum-resistant or refractory (11 patients), or with first recurrence of glioblastoma (12 patients). Lisavanbulin was administered as a 48-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. Results. Lisavanbulin was well tolerated in both patient cohorts. Thirteen patients (56.5%) developed 49 adverse events assessed as related to study treatment. The majority were mild or moderate; four were grade 3/4. Sixteen SAEs were reported in nine patients (39.1%), with none considered related to study treatment. No AEs led to permanent treatment discontinuation. Three patients in the ovarian cancer cohort had stable disease with lesion size reductions after two cycles of treatment; in the glioblastoma cohort, one patient showed partial response with a > 90% glioblastoma area reduction as best response, and one patient had stable disease after eight cycles of treatment. Conclusion. This study demonstrated a favorable safety and tolerability profile of 48-hour continuous IV infusion of lisavanbulin in patients with solid extracranial tumors or glioblastoma. Clinicaltrials.gov registration: NCT02895360.

ALA-RDT in GBM: Protocol of the Phase I/II dose escalation trial of radiodynamic therapy with 5-Aminolevulinic acid in patients with first recurrence of glioblastoma

ALA-RDT in GBM: Protocol of the Phase I/II dose escalation trial of radiodynamic therapy with 5-Aminolevulinic acid in patients with first recurrence of glioblastoma

EPID-10. SEIZURE CONTROL BY BEVACIZUMAB IN GLIOBLASTOMA PATIENTS

Abstract Seizures are a frequent symptom in patients with glioblastoma and bear a relevant impact on quality of life. Likewise, anti-epileptic treatment may affect patients’ well-being due to side effects. Here, we assessed whether owing to relieve from edema and intracranial pressure, treatment with bevacizumab for recurrent glioblastoma might contribute to seizure control.We retrospectively analyzed clinical data of adult patients with glioblastoma who were treated with bevacizumab versus a non-bevacizumab-containing regimen for first recurrence of glioblastoma in the Canton of Zurich between 2010 and 2014 and assessed occurrence and dynamics of seizures before and after first recurrence. Categorical and continuous variables were compared by the Chi-square and the Mann-Whitney U test, respectively. Associations of clinical parameters and seizures were analyzed by binary logistic regression.We identified 55 patients with glioblastoma who had received bevacizumab and 61 patients that received a non-bevacizumab-containing regimen at first recurrence. Seizures were noted in 42 of 111 patients (37.8%) during the 12 weeks preceding tumor recurrence. In the non-bevacizumab group, 23 patients (39.0%) still suffered from seizures 3 months after recurrence whereas only 4 patients (7.7%) in the bevacizumab group experienced seizures (p < 0.001). Multivariable binary logistic regression analyses, including sex, age, performance status, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and first-line treatment confirmed bevacizumab to be inversely associated with seizures in the 12 weeks after first recurrence (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06-0.94, p = 0.009).Bevacizumab may contribute to a reduction in seizure frequency in patients with recurrent glioblastoma.

P11.63.B Thrombocytopenia limits the feasibility of salvage lomustine chemotherapy in recurrent glioblastoma: a secondary analysis of EORTC 26101

Abstract Background Chemotherapies used for the treatment of primary brain tumors frequently induce hematological toxicity. Thrombocytopenia represents the main cause of stopping chemotherapy for toxicity. Here we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine chemotherapy at first recurrence of glioblastoma. Methods We performed a retrospective analysis of thrombocytopenia at first recurrence of glioblastoma, its consequences for treatment delivery, and associations with outcome in the phase II and III parts of EORTC 26101, a randomized trial designed to define the role of lomustine versus bevacizumab versus their combination in glioblastoma patients at first relapse. Results 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients of group 1 and 187 patients of group 2 experiencing at least one episode of thrombocytopenia, 36 patients in group 1 and 93 in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. Patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated glioblastoma treated with lomustine alone experienced more interference with study treatment than patients with tumors without MGMT promoter methylation. On adjusted analysis accounting for major prognostic factors, treatment modification by thrombocytopenia was a positive prognostic factor for overall survival, and this effect was entirely driven by patients with tumors without MGMT promoter methylation only. Conversely, thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumors, suggesting a link to insufficient lomustine exposure. Conclusion Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine salvage chemotherapy in patients with recurrent glioblastoma. Its association with survival suggests that mitigating thrombocytopenia to allow enhanced drug exposure in patients with MGMT promoter methylated tumors might improve outcome.

Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study

BackgroundAn open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma.MethodsPatients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%.ResultsOf the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27–66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4–17.7) and 1.5 (1.4–1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3–4 and 2.0% for Grade 5; most adverse events resolved and were manageable.ConclusionsThe 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types.Clinical Trial RegistrationJapicCTI-152967.

Evaluation of GM-CSF and AS01B adjuvants in a phase I/IIa trial of a therapeutic CMV vaccine (VBI-1901) against recurrent glioblastoma (GBM).

2047 Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. Methods: We enrolled a total of 20 patients with KPS at least 70 and first recurrence of GBM into 2 arms of the Phase IIa extension of gB/pp65 enveloped virus-like particles (eVLPs) adjuvanted with either GM-CSF given intradermally or with AS01B given intramuscularly (NCT03382977). Patients were vaccinated with VBI-1901 every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks. Results: 10 patients (6 women, 4 men) with a median age of 58 (33-67 yrs) were enrolled into the GM-CSF arm and 10 patients (3 women, 7 men) with a median age of 65 (40-67) enrolled into the AS01B arm. Disease control rates of 40% and 50% were observed in the GM-CSF and AS01B arms, respectively, with 2 sustained PRs in the GM-CSF arm. The 6-month OS rate for the GM-CSF arm is 80% and is estimated to be comparable for the AS01B arm. CMV-specific CD4+ effector memory T cells may correlate with tumor responses in both arms of the study, with AS01B boosting higher frequencies of these cells regardless of baseline CD4/CD8 ratio. Conclusions: These encouraging results from both arms of the trial justify further clinical evaluation in a randomized, controlled trial expected to begin later in 2021. Clinical trial information: NCT03382977.

Treatment options for progression or recurrence of glioblastoma: a network meta-analysis.

Treatment options for progression or recurrence of glioblastoma: a network meta-analysis.

CTIM-10. PHASE II STUDY OF PEMBROLIZUMAB PLUS SurVaxM FOR GLIOBLASTOMA AT FIRST RECURRENCE

Abstract BACKGROUND Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 2 (PD-L2). Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. It acts in concert with the mitotic spindle apparatus to regulate cell division and localizes to the spindle microtubule organizing center (MTOC) during the G2/M phase of cell cycle progression. Survivin has also been shown to modulate the function of a number of terminal effector cell death proteases (caspases) leading to an inhibition of apoptosis. METHODS This is a Phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of 10 patients who have failed prior anti-PD1 therapy. The ongoing study is a phase II clinical study with a 10 patient, toxicity run-in. All patients will receive the study drug combination consisting of SurVaxM and pembrolizumab with no randomization, stratification or dose escalation. RESULTS So far ten patients have been enrolled on the study as safety run in. Primary endpoint is Progression free survival at 6 months. Safety and tolerability of Pembrolizumab and SurVaxM, Response rates of Pembrolizumab and SurVaxM determined using RANO criteria are secondary endpoints. Additional secondary endpoints include Overall survival and Progression Free survival Exploratory endpoints include Cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. CONCLUSION This is an ongoing clinical trial.

Abstract CT231: Clinical study of the safety and tolerability of laser interstitial thermal therapy and avelumab for recurrent glioblastoma

Abstract Background: Glioblastoma (GBM) is a fatal disease with no standard care for disease progression and as other cancers is known to evade the immune system. Avelumab is a human IgG1 antibody that binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7-1. Consequently, the suppressive effect on T cell function is inhibited and anti-tumor CD8+ T cells cytotoxicity is restored.Laser Interstitial Thermal Therapy (LITT) is a minimally invasive technique that allows the delivery of light energy causing disruption of the blood-brain barrier and hyperthermia of a brain lesion, initiating a cascade of events leading to coagulative necrosis and potentially triggering immunogenic death of cancer cells. It is hypothesized that avelumab combined with MRI-guided LITT has acceptable safety, tolerability and will generate robust immunomodulation and clinical activity to treat brain cancer. Methods: This phase 1 study is enrolling adult patients with first recurrence of GBM. The study follows a 3+3 design exploring safety and tolerability in part A, Avelumab alone and part B, Avelumab combined with LITT (NCT03341806). Objective response will be determined by iRANO criteria and secondary objectives include PFS and OS. Avelumab is administered intravenously within a week of LITT and every two weeks thereafter until disease progression or intolerable toxicity. Tissue immune biomarkers, signature of plasma analytes, and circulating cellular signature profiling are assessed. Part A and B completed enrollment with no serious infusion or immune-related adverse events. The study will proceed with an expansion cohort on January 2020. A Simon minimax two-stage design will be used for efficacy. The first stage consists of the 6 subjects evaluable from the safety cohorts in Part 1B together with the first 8 subjects in the expansion cohort (total of 14 subjects). Citation Format: Adilia Hormigo, John Mandeli, Saadi Ghatan, Constantinos Hadjipanayis, Raymond Yong, Seunghee Kim-Schulze, Sacha Gnjatic. Clinical study of the safety and tolerability of laser interstitial thermal therapy and avelumab for recurrent glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT231.

Phase II study of pembrolizumab plus SurVaxM for glioblastoma at first recurrence.

TPS2581 Background: Glioblastoma is the most common primary malignant brain tumor with median survival of approximately 15-16 months. Following first recurrence, progression free survival at six months ~15%. There is no therapy in recurrent glioblastoma associated with any survival benefit and there is an urgent need for better therapeutic options. Immunotherapy is one promising option for patients with cancer. This is being explored in glioblastoma and a number of forms of active specific vaccination and immune checkpoint based approaches have been devised and are being investigated in glioblastoma. Methods: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor. Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. SurVaxM is a 15 amino acid antigenic peptide that targets surviving capable of binding several human MHC class I molecules. Primary Objective is to assess clinical activity of Pembrolizumab and SurVaxM in patients with recurrent glioblastoma using progression free survival at 6 months (PFS-6) as determined using RANO criteria. Secondary Objective(s) includes safety and tolerability of combination, response rates, progression free survival and overall survival. Exploratory Objective include measuring cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. This is a phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of glioblastoma patients who have failed prior anti-PD1 therapy. This clinical trial will enroll 41 patients with glioblastoma at first recurrence (bevacizumab naïve) in arm 1.This will include a 6-patient toxicity/safety run-in. There will an exploratory cohort of 10 patients who have failed prior PD1 blockade for a total of 51 patients in 2 arms. Key inclusion criteria include diagnosis of glioblastoma, Age ≥18 years old, Previous first line treatment with at least radiotherapy with or without temozolomide and Documented first recurrence of GBM and Karnofsky performance status of 70 and normal organ function. Key exclusion criteria include more than one recurrence of GBM, presence of extracranial metastatic or leptomeningeal disease, patients with > 1 cm midline shift on imaging. Patients must not require > 10 mg daily of prednisone equivalent. Clinical trial information: NCT04013672 .

OptimalTTF-1: Enhancing tumor treating fields therapy with skull remodeling surgery. A clinical phase I trial in adult recurrent glioblastoma

BackgroundPreclinical studies suggest that skull remodeling surgery (SR-surgery) increases the dose of tumor treating fields (TTFields) in glioblastoma (GBM) and prevents wasteful current shunting through the skin. SR-surgery introduces minor skull defects to focus the cancer-inhibiting currents toward the tumor and increase the treatment dose. This study aimed to test the safety and feasibility of this concept in a phase I setting.MethodsFifteen adult patients with the first recurrence of GBM were treated with personalized SR-surgery, TTFields, and physician’s choice oncological therapy. The primary endpoint was toxicity and secondary endpoints included standard efficacy outcomes.ResultsSR-surgery resulted in a mean skull defect area of 10.6 cm2 producing a median TTFields enhancement of 32% (range 25–59%). The median TTFields treatment duration was 6.8 months and the median compliance rate 90%. Patients received either bevacizumab, bevacizumab/irinotecan, or temozolomide rechallenge. We observed 71 adverse events (AEs) of grades 1 (52%), 2 (35%), and 3 (13%). There were no grade 4 or 5 AEs or intervention-related serious AEs. Six patients experienced minor TTFields-induced skin rash. The median progression-free survival (PFS) was 4.6 months and the PFS rate at 6 months was 36%. The median overall survival (OS) was 15.5 months and the OS rate at 12 months was 55%.ConclusionsTTFields therapy combined with SR-surgery and medical oncological treatment is safe and nontoxic and holds the potential to improve the outcome for GBM patients through focal dose enhancement in the tumor.

Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma.

The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here, we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n = 260) or bevacizumab without or with irinotecan (n = 84) for first recurrence of glioblastoma. Outcome was stratified for O6-methylguanine DNA methyltransferase (MGMT) status and crossover to bevacizumab or alkylators at further progression. Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agents at first recurrence was longer than with bevacizumab (11.1 versus 7.4months, p < 0.001). The use of alkylators was associated with longer PRS-1 for patients with a methylated versus unmethylated MGMT promoter (p = 0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in patients receiving alkylating chemotherapy compared to bevacizumab for patients with methylated (p < 0.001) or unmethylated MGMT promoter (p = 0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p = 0.002). This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of MGMT promoter methylation.

ATIM-07. EFFICACY AND SAFETY OF NIVOLUMAB IN PATIENTS WITH FIRST RECURRENCE OF GLIOBLASTOMA: A MULTICENTER, OPEN-LABEL, NON-COMPARATIVE STUDY (ONO-4538-19)

Abstract BACKGROUND The anti-programmed cell death protein 1 (PD-1) immune checkpoint antibody, nivolumab, may be beneficial in patients with recurrent glioblastoma. OBJECTIVE This open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma. METHODS Patients with a first recurrence of histologically confirmed World Health Organization (WHO) Grade IV glioma, after treatment with temozolomide plus radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression based on Response Assessment in Neuro-Oncology (RANO) criteria or development of toxicity. The primary endpoint was 1-year overall survival rate (1y-OS) assessed using a Bayesian approach. The prespecified efficacy criteria were that the Bayesian posterior mean 1y-OS with nivolumab would be 49%, and the Bayesian posterior probability threshold for exceeding the 1y-OS of bevacizumab (34.5%) from the Japanese Phase II study (JO22506) would be 93%. RESULTS Of the 50 patients enrolled, 44 (93.5%) had recurrent malignant glioma (glioblastoma and gliosarcoma), 26 (59.1%) had measurable disease, and 4 (9.1%) received corticosteroids at baseline. The posterior mean (90% Bayesian credible intervals) 1y-OS with nivolumab was 54.35% (42.27–66.21), and the observed posterior probability of exceeding the 1y-OS of bevacizumab (34.5%, JO22506) was 99.7%. The median (90% confidence interval) overall and progression-free survival (PFS) was 13.09 months (10.38, 17.68) and 1.45 months (1.41, 1.54), respectively. One partial response was observed (objective response rate [ORR] 1/26 evaluable patients [3.8%]). The grade 3–5 treatment-related adverse event rate was 16.0%; most adverse events resolved and were manageable. CONCLUSION The 1y-OS with nivolumab monotherapy in Japanese patients was higher than that in the bevacizumab group in the JO22506 study. However, PFS and ORR were not improved compared with JO22506. The safety profile of nivolumab was consistent with that observed in other tumor types.

OS1.6 Peripheral blood immune profiles at first recurrence of IDH wild type glioblastoma after standard chemoradiotherapy predict overall survival: secondary analyses of the phase II DIRECTOR trial

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) wildtype glioblastoma is associated with distinctive peripheral blood immune cell profiles that evolve under first line chemoirradiation with temozolomide. Whether peripheral blood immune cell profiles at recurrence are associated with survival of IDH wildtype glioblastoma has not been studied in detail. PATIENTS AND METHODS Peripheral blood mononuclear cells (PBMC) of 21 healthy donors and of 52 clinically well-annotated patients with IDH wildtype glioblastoma were analyzed by 11-color flow cytometry at 1st recurrence after standard chemoirradiation with temozolomide and at 2nd recurrence after dose-intensified temozolomide re-challenge. Patients were treated within the randomized phase II trial DIRECTOR, which explored the efficacy of dose-intensified temozolomide at first recurrence of glioblastoma. Patients were classified based on unsupervised analyses of PBMC profiles at 1stand 2ndrecurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors. RESULTS At 1strecurrence, two patient clusters were identified which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase (MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vsCD4low 2.1 vs 2.4 months, p=0.19), whereas post-recurrence overall survival was longer among the CD4highcluster (12.7 vs 8.7 months, p= 0.004). At 2nd recurrence, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Unsupervised segregation of patients by CD4+ subpopulations yielded two clusters characterized by the abundance of memory T-cell fractions and higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p=0.004). The reported prognostic associations were retained in multivariate Cox models controlling for established prognostic factors. CONCLUSION We conclude that temozolomide-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.

P14.108 Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma

Abstract BACKGROUND The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status PATIENTS AND METHODS We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n=260) or bevacizumab without or with irinotecan (n=84) for first recurrence of glioblastoma. Outcome was stratified for MGMT status and cross-over to bevacizumab or alkylators at further tumor progression. RESULTS Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agent chemotherapy at first recurrence was longer than for patients receiving bevacizumab (11.1 versus 7.4 months, p&lt;0.001). The use of alkylating agents was associated with longer PRS-1 for patients with a methylated versus an unmethylated MGMT promoter (p=0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in the group receiving alkylating chemotherapy compared to bevacizumab for patients with a methylated (p&lt;0.001) or unmethylated MGMT promoter (p=0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p=0.002). CONCLUSION This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of a methylated MGMT promoter.

Impact of stereotactic radiosurgery on first recurrence of glioblastoma

Background and Aim: The benefit of stereotactic radiosurgery (SRS) in recurrent glioblastoma multiforme (GBM) remains unclear, partly due to disease heterogeneity. Subventricular zone (SVZ) invasion is a prognostic factor for primary GBM, but whether SVZ involvement is also prognostic in recurrent GBM treated with SRS is unknown. Here, we aimed to determine prognostic factors after first GBM recurrence. Materials and Methods: Thirty-nine consecutive patients with a first recurrence of glioblastoma treated at the Gamma Knife Center, Warsaw, Poland and the Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland, between 2012 and 2016 were retrospectively reviewed. Magnetic resonance images were reviewed according to SVZ invasion by primary tumors and at the time of recurrence. Outcomes were evaluated using univariable and multivariable analyses. The study protocol was approved by the Ludwik Rydygier Collegium Medicum of Nicolas Copernicus University Institutional Review Board (approved No. KB 494/2018) on June 19, 2018. Results: SRS was the only prognostic factor for overall survival after recurrence in multivariable analysis. The median overall survival after the first recurrence was 18 months in the SRS group versus 6.5 months in the non-SRS group (P = 0.02). Survival after the first recurrence treated with SRS was shorter when recurrences were localized to the SVZ. Conclusion: SRS appears to be an effective salvage modality for small recurrent GBMs. Although SVZ-positive tumors have a worse prognosis, these tumors may benefit from SRS.

Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial

Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O 6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.