Recurrent High-grade Glioma Research Articles

Patterns of Failure After Stereotactic Radiosurgery for Recurrent High-Grade Glioma: A Single Institution Experience of 10 Years.

Stereotactic radiosurgery (SRS) is a treatment modality that is frequently used as salvage therapy for small nodular recurrent high-grade gliomas (HGG). Due to the infiltrative nature of HGG, it is unclear if this highly focused technique provides a durable local control benefit. To determine how demographic or clinical factors influence the pattern of failure following SRS for recurrent high-grade gliomas. We retrospectively reviewed clinical, radiographic, and follow-up information for 47 consecutive patients receiving SRS for recurrent HGG at our institution between June 2006 and July 2016. All patients initially presented with an HGG (WHO grade III and IV). Following SRS for recurrence, all patients experienced treatment failure, and we evaluated patterns of local, regional, and distant failure in relation to the SRS 50% isodose line. Most patients with recurrent HGG developed "in-field" treatment failure following SRS (n=40; 85%). Higher SRS doses were associated with longer time to failure (hazards ratio=0.80 per 1 Gy increase; 95% confidence interval 0.67-0.96; P=.016). There was a statistically significant increase in distant versus in-field failure among older patients (P=.035). This effect was independent of bevacizumab use (odds ratio=0.54, P=1.0). Based on our experience, the majority of treatment failures after SRS for recurrent HGG were "in-field." Older patients, however, presented with more distant failures. Our results indicate that higher SRS doses delivered to a larger area as fractioned or unfractioned regimen may prolong time to failure, especially in the older population.

ADC quantification to classify patients candidate to receive bevacizumab treatment for recurrent glioblastoma.

Background Recurrent high-grade gliomas progressing after surgery and temozolomide plus radiation therapy have traditionally been treated using antiangiogenic drugs as the first-line therapy. Since the phase 3 EORTC 26101 trial showed no significant benefit of administering antiangiogenic drugs, the need to identify a biomarker to classify subgroups of potential responders has increased. Purpose To investigate the feasibility of using apparent diffusion coefficient as a predictor of the response of recurrent high-grade gliomas to bevacizumab or classifier for patients showing better response. Material and Methods This retrospective study analyzed magnetic resonance images obtained from 39 patients at the time of high-grade glioma progression who were treated using bevacizumab. The apparent diffusion coefficient maps were quantified and modelled as a mixture of Gaussian functions. The correlation of their descriptors and the time to second progression was studied. Log-rank tests were performed to determine the power of these descriptors as the classifiers for patients exhibiting better survival. Results None of the descriptors showed correlation with time to second progression (r < 0.35) but several of them stratified subgroups showing a better time to second progression passing log-rank tests ( P < 0.02). Conclusion Apparent diffusion coefficient cannot be used to predict the time to second progression of recurrent high-grade gliomas treated with bevacizumab, but it can stratify groups with better time to second progression distributions.

Treatment Decision-making in Patients With Recurrent High-grade Glioma

Treatment Decision-making in Patients With Recurrent High-grade Glioma

Abstract 5029: OT-101/Chemotherapy- A novel mechanism of action (MOA) in glioblastoma immunization therapy

Abstract Background: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization which is countered by overexpression of TGF-β2. OT-101 is a TGF-β2-specific Phosphorothioate Antisense. Here we report the results of a randomized Phase 2b clinical trial (NCT00431561) comparing the safety and efficacy of OT-101 versus temozolomide (TMZ) in adult patients with WHO grade III/IV high-grade glioma. We took advantage of the known xenogenization activity of alkylating agent such TMZ to explore the impact of xenogenization on survival on treatment with OT-101. Methods: This is a phase 2b, multi-national, multi-center, open-label, active-controlled, randomized parallel group dose-finding study to evaluate the efficacy and safety of OT-101 in adult patients with recurrent high-grade glioma, administered intratumorally as continuous high-flow microperfusion over a 7-day period every other week. Results: A total of 134 patients, 89 patients in the OT-101 test group and 45 patients in the temozolomide (TMZ) group. OT-101 was superior to TMZ in doubling the number of pts in the good survival group, 64 of 97 pts (66%); whereas, only 14 of 45 pts (31%) treated with TMZ did (p=0.0001). mOSOT-101TMZSubseq. TMZSubseq. TMZ (or other alkylating agent)Prev. TMZNoYesNoYesNo4.2mos (N=14)26.2mos (N=30)5.6mos (N=8)13.2mos (N=9)Yes4.8mos (N=19)29.5mos (N=34)6.6mos (N=14)36.6 mos (N=14) There were two cases of neutropenia in the 90 pts treated with OT-101 versus 8, 10, and 8 pts with leukopenia, neutropenia, and thrombocytopenia, respectively, among 45 pts treated with TMZ (2% vs. 56%, p<0.0001). Conclusions: Improved survival was achieved by repeated exposure to TMZ/alkylating agent. This was further enhanced by OT-101 and consistent with the proposed MOA of OT-101/Chemo as reactivation of immunity during TGF-β suppression and subsequent xenogenization by TMZ. Citation Format: Larn Hwang, David Nam, Fatih Uckun, Vuong Trieu. OT-101/Chemotherapy- A novel mechanism of action (MOA) in glioblastoma immunization therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5029.

Abstract 4771: The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose

Abstract Background: Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized yeast cytosine deaminase (CD) gene to tumors. Within infected cells, CD converts 5-fluorocytosine (5-FC) to the anti-cancer drug 5-fluorouracil (5-FU). The combination of Toca 511 with oral extended release 5-FC (Toca FC), is currently being evaluated in a randomized phase III clinical trial for recurrent high grade glioma (glioblastoma (GBM) and anaplastic astrocytoma) (NCT02414165, Toca 5). Temozolomide (TMZ), in combination with radiation therapy, is the standard of care used for first-line chemotherapy treatment of patients with GBM, the most common and aggressive form of primary brain cancer. Previously, we have shown that: (1) Toca 511/5-FC treatment provides durable response in a syngeneic murine glioma model and supports anti-tumor immune memory; (2) The combination of TMZ and Toca 511/5-FC had synergistic efficacy in a TMZ-sensitive human glioma nude mouse model; (3) TMZ did not inhibit the efficacy of Toca 511/5-FC in a TMZ resistant murine glioma syngeneic model; (4) Toca 511/5-FC caused significant radiosensitization in a radioresistant murine glioma model. Results: To assess the interaction of TMZ with escalating doses of Toca 511 (as defined by percent of tumor transduction by RRV), an orthotopic TMZ-resistant murine glioma model, Tu-2449, was utilized. These results show that moderate levels of tumor transduction of Toca 511 (30% - 50%) with 5-FC treatment prolongs survival in the presence of TMZ compared with lower transduction rates (10%). Additionally, mice treated with Toca 511/5-FC and TMZ are being tested for the establishment of anti-tumor immune memory. Conclusion: These results demonstrate that (1) survival correlates with the transduction levels of Toca 511 when combined with temozolomide in the Tu-2449 orthotopic glioma model and (2) that this combination may support anti-tumor immune memory. These studies along with prior work support evaluation of the combination of Toca 511/5-FC with temozolomide in patients with newly diagnosed GBM (NRG-BN006). Citation Format: Maria E. Rodriguez-Aguirre, Sophie Viaud, Daniel Mendoza, Tiffany Montellano, Derek G. Ostertag, Harry Gruber, Douglas Jolly, Cornelia Bentley. The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4771.

Bevacizumab reduces toxicity of reirradiation in recurrent high-grade glioma

PurposeThe role of bevacizumab (BEV) in the setting of reirradiation (reRT) of malignant glioma recurrences is poorly defined. At our institution, reRT plus BEV was routinely used until its disapproval for glioma treatment by the European Medical Agency. Accordingly, reRT was applied without the addition of BEV since 2017. Here we present for the first time outcome and toxicity profiles of reRT plus BEV and reRT alone for malignant glioma recurrences. Patients and methodsAll adult patients consecutively undergoing reRT of a recurrent malignant glioma (37 anaplastic astrocytoma, WHO III; 124 glioblastoma, WHO IV) between 2007 and 2017 were included. In one group of patients, BEV (10 mg/kg bodyweight) was applied concomitantly on days 1 and 15 of reRT. Radiation toxicity referred to clinically significant toxicities of proven symptomatic radionecrosis (RN) and symptomatic oedema (SE) requiring steroid treatment for more than six weeks after reRT. Post-recurrence survival (PRS) and freedom from RN/SE were estimated with the Kaplan–Meier method. Prognostic factors were obtained from proportional hazards models. ResultsBEV plus reRT was applied in 124 and reRT alone in 37 patients. Both groups were comparable in terms of their patient-, tumour-, and RT/reRT-related variables. PRS was independent from the applied reRT protocols. RN/SE was less frequently seen after reRT plus BEV absolutely (27/124 (21.8%) vs. 14/37 (37.8%) patients; p = 0.025) and over time (1-year RN/SE rate: 23.9% vs. 54.1%; p = 0.013). The unadjusted and adjusted hazard ratio for RN/SE was doubled in case of reRT alone. Absence of BEV remained the only risk factor for RN/SE in multivariate models (p = 0.026). ConclusionConcomitant BEV effectively reduces treatment toxicity of reRT and should be reconsidered in future reRT protocols.

18F-Fluciclovine PET/CT in Suspected Residual or Recurrent High-Grade Glioma.

To retrospectively investigate the uptake of F-fluciclovine on PET/CT in patients with suspected recurrent high-grade glioma (HGG). Twenty-one patients were included. The standard of truth was histopathologic interpretation if available. When histopathology was not available or rebiopsy did not show signs of malignancy, clinical follow-up including MRI and clinical outcome was considered the standard of truth. All 21 patients met the reference standard of either histopathologic proof of HGG recurrence (n = 10) or disease progression clinically and with tumor growth corresponding to the primary tumor sites on follow-up MRI (n = 11). Median time from PET/CT to death was 5 months (range, 1-20 months). Median time from primary diagnosis to death was 14.5 months (range, 6 to >400). Average SUVmax of the lesions was 8.3 ± 5.3 (SD) and 0.34 ± 0.13 for normal brain tissue. Median lesion-to-background ratio was 21.6 (range, 3.1-84.4). In 4 patients, F-fluciclovine PET/CT detected small satellite tumors that had not been reported on MR. The uptake of F-fluciclovine in clinically and/or histopathologically confirmed recurrent HGG is high compared with the uptake reported for other amino acid PET tracers. Because of the high tumor uptake and thus high tracer contrast, small satellite tumors with a diameter below usual reported PET spatial resolution and not reported on MRI were detected in 4 patients. As no patients with confirmed treatment-related changes were included, we cannot as of yet ascertain the ability of F-fluciclovine PET to discriminate between recurrent HGG and treatment-related changes, for example, pseudoprogression and radionecrosis.

Pembrolizumab (Pem) in recurrent high-grade glioma (HGG) patients (PTS) with mismatch repair deficiency (MMRd): An observational study.

2043 Background: Pem, an immune checkpoint inhibitor, demonstrated to be active in various neoplasms with MMRd. No data exists about its efficacy in MMRd glioma PTS. Methods: MMRd HGG relapsed after receiving RT and CT were treated with Pem. MMR status was analyzed by immunohistochemistry, including the MLH1, MSH2, MSH6, and PMS2 markers. MMRd was defined as presence of a weak (wMMRd) or absent (aMMRd) signal for at least one MMR protein. Other inclusion criteria were: ECOG PS 0-2, histologically confirmed glioma, dexamethasone ≤4 mg. Pem was administrated at 200 mg every 3 weeks until disease progression or unacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeks according to the RANO criteria. OS and PFS were evaluated by Kaplan-Meier curves. Results: among 167 glioma PTS, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, all PTS had microsatellite stability. Tumor histologies included 5 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2 deficiency was found in 6 cases , MSH6 deficiency in 9 cases, PMS2 and MLH1 deficiency in 2 cases. Median number of prior lines of chemotherapy was 1 (range 1-5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showed progressive disease (PD). PTS with anaplastic gliomas showed a statistically significant association with SD (p=0.03, OR=3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6 (deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1-13.8), PFS 2.4 ms (95% CI 1.8-2.9). OS was 2.8 ms and 5.6 ms (p=0.9), PFS was 1.8 ms and 3.1 ms (p=0.5) in PTS with wMMRd and aMMRd, respectively. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6-10.2) and 1.8 ms (95% CI 0.2-3.4), p=0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p=0.04), respectively. Grade ≥3 adverse events were reported in 8% of PTS. Conclusions: a subgroup of recurrent MMRd HGG might benefit from Pem, especially anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. The enrollment and analyses for identifying additional molecular predictive factors are ongoing.

Phase 1/2a study of once daily oral BAL101553, a novel tumor checkpoint controller (TCC), in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.

2025 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule shown in rodents to penetrate the brain (brain/plasma ratio around unity), with promising antitumor activity in orthotopic preclinical GBM models as monotherapy or in combination with radiotherapy (RT) with or without temozolomide. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients, with an MTD of 16 mg/d and DLTs of G4 hyponatremia and G2 hallucinations (Lopez 2018, JCO 36, 2018, suppl. A2530). Subsequently the study was expanded by including a separate cohort of patients with progressive or recurrent GBM or high-grade glioma (Ingles Garces 2017, JCO 35, 2018, suppl. TPS2601). Methods: Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, received once-daily oral BAL101553 (28-day cycles) in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events were assessed by CTCAE v4.03 grade (G), and tumor response by RANO every two cycles. Pharmacokinetics (PK) were evaluated on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 23 pts (13M/10F; median age 50 y), median (min–max) number of prior regimens = 2 (1–5), received doses of 8, 15, 20, 25 or 30 mg oral BAL101553 once daily. One DLT of reversible G2 depression and fatigue occurred at 20 mg. Both mean Cmax and AUC increased with dose between 8 and 30 mg. The PK exposure in GBM patients was lower than for solid tumor patients, in particular at 20 and 25 mg. At 25 mg/d (n = 3), one patient with IDH-mutated GBM had a partial response (63% area reduction per RANO) and continues on study > 8 months, and another patient had stable disease for 5 months. At 15–20 mg/d, stable disease was observed in 3/10 patients. Conclusions: The current data in patients with GBM or high-grade glioma suggest that BAL101553 is well tolerated at dose levels above the MTD established in patients with advanced solid tumors, and shows indications of clinical activity. Clinical trial information: 02490800.

Efficacy of re-irradiation with carbon ions (RiCi) in patients with recurrent high-grade glioma (rHGG) compared to the standard re-irradiation with photons (RiP): The reference multicenter cohort of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).

2057 Background: Local recurrence after surgery and radio(chemo)therapy remains a major obstacle in curative treatment of patients with HGG. Eradication of radioresistant glioma subpopulations (hypoxic- and stem cell like cells) together with formation of an antiangiogenic and immuno-permissive glioma niche are among beneficial radiobiological effects recently attributed to carbon ion irradiation in preclinical models. The impact of this novel therapy in management of rHGG patients remains elusive. Methods: 197 patients with rHGG (grade III: 71, IV: 126) received RiCi between Nov 2009 and Feb 2018 at HIT with a median dose of 42GyRBE in 14 fractions. In DKTK-ROG multicenter cohort n:565 rHGG patients (grade III: 63, IV: 479) underwent RiP between 1997-2016 with a median dose of 36 Gy in 14 fractions. Median follow up was 34.2 months (M) for RiCi and 7.1 M for RiP (DKTK) cohort. All three prognostic scores validated in DKTK-ROG cohort were evaluated and re-irradiation risk score (RRRS) considering initial grade, Karnofsky Performance Score and age at re-irradiation was utilized for stratification and matched comparisons. Results: Median PFS was 5.08 [4.26-5.87] M (grade III: 6.79, grade IV: 3.64) after RiCi, data was not available for RiP. Median OS was 10.52 [9.28-12.66] M (grade III: 28.2, grade IV: 8.53) after RiCi compared to 7.93 [7.15-8.79] M (grade III: 10.89, grade IV: 7.93) after RiP. Among the three prognostic scores evaluated, RRRS most robustly correlated with OS. RiCi was associated with HR of 0.52 ([0.49-0.72], p = 0.0000002), and HR 0.66 ([0.51-0.85], p = 0.001) for RRRS matched analysis. Conclusions: Carbon ions demonstrated activity in rHGG. This effect is most prominent in grade III while grade IV patients may further benefit from innovative multimodal strategies. Based on these encouraging results prospective randomized trials utilizing RRRS for stratification are recommended.

Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.

e13526 Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.

The effect of everolimus on CNS penetration and efficacy of dasatinib in the treatment of PDGFRA-driven glioma.

e13508 Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. The CNS penetration of PDGFRA inhibitors, such as dasatinib, is limited by the tumor-efflux protein P-glycoprotein (P-gp). We hypothesized that co-treatment with everolimus, which has been shown to block P-gp, will increase CNS penetration and efficacy of dasatinib in in vitro and in vivo models as well as in human PDGFRA-driven glioma. Methods: Tumors were generated in mice using an intra-uterine electroporation (IUE) model [introduction of TP53, PDGFRA and H3K27M mutations in pre-natal cortex]. Dose response, synergism studies, P-GP inhibition and pharmacodynamics/pharmacokinetic studies were then performed on in vitro and in vivo models employing this IUE system. A phase 2 trial employing dasatinib and everolimus was established for children with HGG and diffuse intrinsic pontine glioma (DIPG) that contain PDGFRA alterations (NCT03352427). Paired CSF/plasma samples (before and after addition of everolimus) were collected from enrolled patients. Results: Dasatinib effectively treated mouse HGG cells with an IC50 of 100 nM. Dose-dependent reduction in PDGFRA and pPDGFRA was found. P-gp inhibitor assay confirmed that everolimus strongly blocks P-gp activity at 1 uM (p = 0.0028 vs untreated). Mice treated with dasatinib and everolimus had extended survival as compared to control. Two-hour exposure to everolimus resulted in sub-IC50 dasatinib concentration in cortex (23 nM) and tumor (65 nM). 24-hour exposure to everolimus resulted in greater cortex (235 nM) and tumor (509 nM) concentrations. Two trial patients, recurrent HGG ( PDGFRA-amplified) and recurrent DIPG ( PDGFRA D842V) respectively, survived 6 months and 9 months (ongoing) after progression, which compares very favorably to historical controls. A paired CSF sample from the PDGFRA-amplified patient showed a 50% increase in CSF dasatinib level after addition of everolimus. Conclusions: Dasatinib treatment of PDGFRA-driven HGG is improved with everolimus blockade of P-gp and represents a novel route for improving CNS penetration and efficacy of therapies for HGG. Clinical trial information: NCT03352427.

Phase I study of procaspase activating compound -1 (PAC-1) in combination with temozolomide (TMZ) for the treatment of recurrent malignant glioma.

TPS3164 Background: The caspase family of cysteine proteases play key roles in the initiation and execution of apoptosis. The activation of procaspase-3 to caspase-3 is critical in both the intrinsic and extrinsic apoptotic cascades. Procaspase-3 levels are elevated in many cancers, including glioblastoma (GBM). As a result, caspase-3 levels are abnormally low in these tumors; thus they avoid apoptosis. PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. PAC-1 has activity against a wide range of cancer cell lines, and in animal models of cancer. PAC-1 crosses the blood brain barrier and has been shown to synergize with TMZ in both canine malignant glioma and meningioma that arise spontaneously. Methods: This Phase I dose escalation study uses a modified- Fibonacci 3+3 design to determine the MTD of PAC-1 when combined with TMZ in patients with recurrent malignant gliomas: anaplastic astrocytoma (AA) and GBM (open to enrollment). Here, we focus on component 2 of the study. Primary objectives: to establish MTD of PAC-1 when combined with a fixed dose of TMZ, tolerability, and toxicity using CTCAE v.4. Secondary and correlative objectives: pharmacokinetics, pharmacodynamics, preliminary anti-tumor activity correlation with procaspase-3 expression in tumor tissue, radiographic response using the Response Assessment in Neuro-Oncology (RANO) criteria, and neurocognitive function using a validated test battery. Inclusion criteria: diagnosis of recurrent high grade glioma (AA or GBM), ECOG PS 0-2, adequate organ function. Exclusion criteria: received prior cytotoxic therapy in the last 3-6 weeks (duration based on prior therapy) or uncontrolled chronic illness. Administration and design, Component 2: PAC-1, orally administered, is dosed at 375-650 mg daily (up to 3 dose levels) on days 1-21 of each 28-day cycle. A fixed dose of TMZ, (150 mg/m2), is administered orally, days 8 -12 of each cycle. The study is currently enrolling patients for Component 2. Clinical trial information: NCT02355535.

Hyperprogressive disease in patients with recurrent high grade gliomas treated with immune checkpoint inhibitors or other therapies.

e13575 Background: Hyperprogressive disease (HPD) has been described in solid tumor patients treated with immune checkpoint inhibitors (ICI). HPD is defined as a ≥2-fold increase in tumor growth rate (TGR) following initiation of ICI. HPD has not been explored in patients with high grade gliomas (HGG) on ICI or standard cytotoxic regimens. In advanced cancer patients receiving ICI, MDM2/4 amplification or EGFR alterations, both found in HGG, correlated with HPD. We compared the rate of HPD in recurrent HGG patients receiving ICIs to those treated with non-immunotherapy agents. Methods: Patients with HGG on ICIs for 1st or 2nd recurrence were compared to a control group receiving other therapies at 1st recurrence. Patients with prior or concurrent bevacizumab or anti-VEGFR were excluded due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment. Results: 49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients treated with ICIs and 20/22 patients in the control group had complete imaging and were eligible for analysis. In the ICI group, 60% were men (15/25) and 88% (22/25) had a diagnosis of GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of GBM. 30% (6/20) were 65 years or older at diagnosis in the control group compared to 28% (7/25) in the ICI group. In total, 7/25 patients met criteria for HPD in the ICI group (28%) compared to 4/20 patients in the control group (20%). 10/25 patients (5/7 with HPD) in the ICI group and 8/20 patients (2/4 with HPD) in the control group had next generation sequencing of their tumors. EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in the HPD group (71% HPD vs. 33.3% no HPD). Conclusions: HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies. While the numbers are small, PTEN mutations may be associated with HPD in patients with HGG. In contrast to other solid tumors, EGFR alterations and MDM2/4 amplifications were not associated with HPD in HGG.

High-grade gliomas (HGGs) and immunotherapeutic early-phase clinical trials (ieCTs): A single-center experience.

e13512 Background: Patients with HGGs have historically been excluded from ieCTs due to unavailability of serial bioptic sampling, frequent need of corticosteroids, concerns on activity of immunotherapy in central nervous system, and rapid clinical deterioration. Methods: We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2018. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for age, line of treatment, MGMT methylation and IDH mutational status, was selected for comparison. Clinical parameters including use of steroids, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein, were correlated with survival through an univariate analysis. Results: 5 among 21 ieCTs allowed inclusion of HGG patients. 20 patients were enrolled in our experimental cohort (EC); 17 (85%) glioblastoma, 3 (15%) anaplastic astrocytoma. Median age was 53 years (range 30-71); 12 patients (60%) were men, 8 (40%) women; 13 pts (65%) required steroid therapy, with a median dexamethasone dose of 2 mg (range 1-6). The median number of prior systemic therapies was 1 (range 1-2). 11 patients (55%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 9 (45%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 45% (1 CR + 2 PR + 6 SD) and 30% (1 RP +5 SD), in EC and CC, respectively. 4 patients (20%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 22 months PFS-6 and OS-6 were 53% and 11% (p < .0001), 80% and 42% (p < 0.0001) in EC and CC, respectively. In our small series, none of clinical factors resulted prognostic. Conclusions: Survival outcomes of our HGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical selection factors remains crucial.

NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance.

Glioma Cancer Stem-Like Cells (GSCs) are a small subset of CD133+ cells with self-renewal properties and capable of initiating new tumors contributing to Glioma progression, maintenance, hierarchy, and complexity. GSCs are highly resistant to chemo and radiotherapy. These cells are believed to be responsible for tumor relapses and patients' fatal outcome after developing a recurrent Glioblastoma (GBM) or High Grade Glioma (HGG). GSCs are cells under replicative stress with high demands on NAD+ supply to repair DNA, maintain self-renewal capacity and to induce tumor plasticity. NAD+ feeds Poly-ADP polymerases (PARP) and NAD+-dependent deacetylases (SIRTUINS) contributing to GSC phenotype. This energetic core axis is mainly controlled by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT), an important oncogene contributing to tumor dedifferentiation. Targeting GSCs depicts a new frontier in Glioma therapy; hence NAMPT could represent a key regulator for GSCs maintenance. Its inhibition may attenuate GSCs properties by decreasing NAD+ supply, consequently contributing to a better outcome together with current therapies for Glioma control.

Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas

Efficacy of Nivolumab for Recurrent IDH Mutated High-Grade Gliomas

Recurrent Agressive Brain Radionecrosis or High-Grade Glioma: How to Treat?

Recurrent Agressive Brain Radionecrosis or High-Grade Glioma: How to Treat?

Reirradiation of recurrent high-grade glioma and development of prognostic scores for progression and survival.

Optimal techniques and patient selection for salvage reirradiation of high-grade glioma (HGG) are unclear. In this study, we identify prognostic factors for freedom from progression (FFP) and overall survival (OS) after reirradiation, risk factors for high-grade toxicity, and validate clinical prognostic scores. A total of 116 patients evaluated between 2000 and 2018 received reirradiation for HGG (99 WHO grade IV, 17 WHO grade III). Median time to first progression after initial therapy was 10.6 months. Salvage therapies before reirradiation included surgery (31%) and systemic therapy (41%). Sixty-five patients (56%) received single-fraction stereotactic radiosurgery (SRS) as reirradiation. The median biologically effective dose (BED) was 47.25 Gy, and the median planning target volume (PTV) was 4.8 cc for SRS and 95.0 cc for non-SRS treatments. Systemic therapy was given concurrently to 52% and adjuvantly to 74% of patients. Median FFP was 4.9 months, and median OS was 11.0 months. Significant multivariable prognostic factors for FFP were performance status, time to initial progression, and BED; for OS they were age, time to initial progression, and PTV volume at recurrence. High-grade toxicity was correlated to PTV size at recurrence. Three-level prognostic scores were generated for FFP and OS, with cross-validated receiver operating characteristic area under the curve (AUC) of 0.640 and 0.687, respectively. Clinical variables at the time of reirradiation for HGG can be used to prognosticate FFP and OS.

The Long-Term Progression Free Survival After the Combination of Radiotherapy with Concurrent Chemotherapy of Nimotuzumab And Temozolomide Followed Adjuvant Temozolomide In Recurrent Anaplastic Astrocytoma

The management of recurrent high-grade gliomas is highly challenging, and treatment outcome remains invariably poor. High-grade gliomas (HGGs) are highly malignant tumor, which complete surgical resection of all microscopic extensions cannot be always achieved. All high-grade gliomas nearly recur and survival following disease progression is doomed to be approximately 6 months for GBMs and 10 months for anaplastic gliomas. Therapy options for recurrent HGGs are limited and may include surgery, re-irradiation, chemotherapy and targeted therapy. We present a case of a 33-year-old male with recurrent anaplastic astrocytoma after initial surgery. The patient underwent the treatment of radiation therapy with concurrent chemotherapy of nimotuzumab and oral temozolomide for 6 weeks followed by six cycles of adjuvant temozolomide for tumor local recurrences, and the patient still do not relapse with a long-term progression free survival lasting seven years. The median survival in patients with recurrent anaplastic astrocytoma is usually 10 months after recurrence, and this unique case illustrates that comprehensive therapy can achieve long-term survival in select situations. We recommend that the treatment of each recurrent patient should be based on each clinical situation and aspire for quality of life and improved longevity.