bluuebunny/crossref_metadata_2025 huggingface dataset:
Full enrollment results from an extended phase I, multicenter, open label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed glioblastoma (GBM).
Authors: Mason Warren P. , Kesari Santosh , Stupp Roger , Aregawi Dawit Gebremichael , Piccioni David Eric , Roth Patrick , Desjardins Annick , Reich Steven D. , Casadebaig Marie-Laure , Elias Ileana , Winograd Benjamin , Levin Nancy , Bota Daniela Annenelie
Published: May 2019

2021

Background: Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for GBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma activity was combined with standard TMZ/RT → TMZ in newly diagnosed GBM (NCT02903069), to determine the recommended dose (RD). The primary endpoint of this expanded phase 1 trial was toxicity, with secondary endpoint of OS. Methods: Patients were enrolled in separate cohorts (TMZ/RT+MRZ→TMZ+MRZ, N=15; TMZ/RT→TMZ+MRZ, N=18) in dose-escalation (3+3 design), followed by dose-expansion (N=20) with TMZ/RT+MRZ at RD → TMZ+MRZ at RD. A separate cohort received TMZ/RT→TMZ+MRZ at RD with Tumor Treating Fields (Optune, N=13). MRZ was infused IV (10 min at 0.55, 0.7, 0.8, and 1.0 mg/m2) on Days 1, 8, 15, 29, 36 (42-day TMZ/RT+MRZ cycle) and Days 1, 8, 15 (28-day TMZ+MRZ cycle). Results: 66 patients treated; median age 58 years, 68% male, 50% receiving corticosteroid at baseline, 52% unmethylated MGMT. Dose-limiting toxicities (DLTs) in dose-escalation cohorts: 1 (fatigue) at 0.7 mg/m2 MRZ, 5 (ataxia/diarrhea; ataxia/confusion; myocardial infarction, delirium/ataxia; ataxia/fatigue) in 1.0 mg/m2 cohorts. MRZ demonstrated a steep dose-response with treatment-emergent adverse events (TEAEs)/DLTs predominately CNS AEs (Grade ≥3 TEAEs in 12 of 12 patients at 1.0 mg/m2 vs 22 of 41 patients at ≤0.8 mg/m2); the RD for MRZ was determined to be 0.8 mg/m2. Most common TEAEs (all grades): fatigue, nausea (both 70%), hallucination (54%), vomiting (53%), headache (47%), confusional state (33%), ataxia, constipation, muscular weakness (all 29%). Conclusions: CNS TEAEs were short-lasting, reversible and ameliorated by early dose reductions (29% patients dose-reduced), allowing patients to remain on treatment. For patients receiving MRZ with TMZ/RT→TMZ (N=35), the median OS was 14.8 months (17 deaths, median follow-up 14.3 months), and 7 patients remain active (Cycles 11-23). The MRZ RD + TMZ/Optune combination was tolerated, with 4 of 13 patients treated on this arm remaining active. An international Phase 3 trial (EORTC 1709-BTG/CCTG CE.8, NCT03345095) is ongoing. Clinical trial information: NCT02903069.
DGM1 may serve as a novel genetic biomarker of response to enzastaurin in glioblastoma.
Authors: Butowski Nicholas A. , Shazer Ronald L. , Sun Hong , Han Isabel , Jivani Manoj A. , Luo Wen
Published: May 2019

2023

Background: Despite countless clinical trials being conducted, little has changed over the last decade in the chemotherapies available for glioblastoma (GBM) with survival remaining poor. Meaningful advances in treating this deadly malignancy may rely on precision medicine. We discovered a novel pharmacogenomic biomarker for enzastaurin (enz) in treating lymphoma (lymph). We evaluated if this biomarker can be used to predict enz response in GBM. Methods: Biomarker discovery was performed by a genome-wide screen using DNA extracted from blood samples from a ph 3 enz lymph trial and confirmed in an independent ph 2 enz lymph trial. The biomarker was then evaluated for its predictability in GBM using the archived DNA samples from a prior ph 1/2 enz GBM trial. Results: A novel biomarker, Denovo Genomic Marker 1 (DGM1), a germline polymorphism on chromosome 8, was found to be highly correlated with response to enz in the two lymph trials. Using DNA extracted from blood of pts from the single-arm ph 1/2 study of newly diagnosed GBM receiving enz added to radiation and temozolomide (tmz), we found median OS for DGM1+ pts treated with enz was 18 mon vs 12.8 mon for DGM1- pts, HR (95% CI) 0.68 (0.25, 1.81), p = 0.12. In addition, we found pts in the GBM study receiving a mean daily dose of enz ≥ 245 mg had an OS of 19.8 mon vs 14.9 mon for pts receiving a mean daily dose of < 245 mg [HR (95% CI) 0.55 (0.34, 0.90)]; enz 500 mg/day was used in the lymph studies. Conclusions: These data are supportive of DGM1 as a potentially predictive biomarker for enz response in both lymph and GBM. There is an ongoing biomarker-driven pivotal ph 3 study in lymph at 500 mg/day, and DGM1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM with 500 mg/day of enz in combination with tmz.
Safety and activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrent glioblastoma (GBM).
Authors: Strowd Roy E. , Ellingson Benjamin M. , Wen Patrick Y. , Ahluwalia Manmeet Singh , Piotrowski Anna F. , Desai Arati Suvas , Clarke Jennifer Leigh , Lieberman Frank S. , Desideri Serena , Nabors Louis B. , Ye Xiaobu , Grossman Stuart A.
Published: May 2019

2027

Background: Hypoxia inducible factor 2-alpha (HIF2a) mediates cellular responses to hypoxia and is overexpressed in GBM. PT2385 is an oral HIF2a inhibitor with in vivo activity against GBM. Methods: A two-stage single-arm open-label phase II study of adults with first recurrent GBM following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (CR+PR); secondary outcomes were safety and survival. Exploratory objectives included PK (day 15 Cmin), PD, and pH-weighted amine-CEST MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤1 response. Results: Of the 24 patients, mean age was 61±11 years, median KPS 80, MGMT promoter methylated in 46%. PT2385 was well tolerated. Grade ≥3 drug-related AEs were hypoxia (n = 2), anemia (1), hyperglycemia (1), hyponatremia (2) and lymphopenia (2). No objective radiographic responses were observed; median PFS was 1.8 months (95%CI 1.6-3.1). Drug exposure varied widely (Table) and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, 0.009). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. Baseline acidity correlated significantly with treatment duration (R2= 0.49, p = 0.017). Conclusions: Drug exposure to PT2385 was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic (e.g. hypoxic) lesions on baseline imaging. A second-generation HIF2a inhibitor is being studied. Clinical trial information: NCT03216499. [Table: see text]
Survival outcomes in glioma patients with noncanonical IDH mutations: Beyond diagnostic improvements.
Authors: Franceschi Enrico , De Biase Dario , Pession Annalisa , Tosoni Alicia , Paccapelo Alexandro , Visani Michela , Tallini Giovanni , Argento Chiara Maria , Urbini Benedetta , Bartolini Stefania , Brandes Alba Ariela
Published: May 2019

2028

Background: According to the 2016 WHO classification of Central Nervous System tumors, the assessment of exon 4 mutations in IDH1 or IDH2 genes is an essential step in the characterization of gliomas. The R132H mutation is the most frequent alteration in IDH1 gene, however other non-canonical IDH mutations have been identified. The aim of this study was to evaluate the prognostic role of IDH non-canonical mutations. Methods: We analyzed our institutional data warehouse for all consecutive patients (pts) with newly diagnosed, histologically proven grade II – IV IDH mutant gliomas. IDH sequencing was performed using the 454 GS-Junior next generation sequencer (NGS) (Roche Diagnostic, Mannheim, Germany). All analyses were performed on DNA from formalin fixed and paraffin embedded (FFPE) specimens. Results: The analysis included 493 pts with IDH mutations. We found 279 (56.6%) grade 2, 173 grade 3 (35.1%) gliomas, and 41 (8.3%) IDH mutant glioblastoma. Canonical IDH1 R132H mutation was found in 428 pts (86.8%). The remaining pts showed IDH2 (3.9%) or IDH 1 non-canonical mutations (mainly R132C, R132G, R132S – 9.3%). Median follow-up time was 80.5 months. Pts with non-canonical mutations showed a younger median age (32 vs 39 years, p < 0.001). Other clinical characteristics and treatments were similar across IDH groups. Median survival was 145 months (95%CI: 137.7 - 152.9) and 198.6 (95%CI 155.2– 242.1) in patients with IDH R132H and non-canonical mutations, respectively (p = 0.013). In multivariate analysis grading (p < 0.001), extent of surgery (p < 0.001), 1p19q codeletion (p = 0.003) and presence of non-canonical mutations (p = 0.022) showed a significant role for improved survival. Conclusions: Detecting non-canonical IDH1 mutations is essential for diagnosis and for prognosis in patients with gliomas. Differential enzymatic activity of non-canonical IDH1 mutations, resulting in different levels 2-hydroxyglutaratecould be the reason of improved survival.
Glioblastoma gene expression subtypes and correlation with clinical, molecular and immunohistochemical characteristics in a homogenously treated cohort: GLIOCAT project.
Authors: Pineda Estela , Esteve-Codina Anna , Martinez-Garcia Maria , Alameda Francesc , Carrato Cristina , Arpi Oriol , Aldecoa Iban , Menendez Silvia , Ribalta Teresa , Vidal Sarro Noemi , Berron Sonia Del Barco , Estival Anna , Gallego Oscar , Gil Gil Miguel J. , Mesia Barroso Carlos , Craven Jordi , Villa Salvador , Fuentes Rafel , de la Iglesia Núria , Balana Carmen
Published: May 2019

2029

Background: Glioblastoma (GBM) gene expression subtypes have been described in last years, data in homogeneously treated patients is lacking. Methods: Clinical, molecular and immunohistochemistry (IHC) analysis from patients with newly diagnosed GBM homogeneously treated with standard radiochemotherapy were studied. Samples were classified based on the expression profiles into three different subtypes (classical, mesenchymal, proneural) using Support Vector Machine (SVM), the K-nearest neighbor (K-NN) and the single sample Gene Set Enrichment Analysis (ssGSEA) classification algorithms provided by GlioVis web application. Results: GLIOCAT Project recruited 432 patients from 6 catalan institutions, all of whom received standard first-line treatment (2004 -2015). Best paraffin tissue samples were selected for RNAseq and reliable data were obtained from 124. 82 cases (66%) were classified into the same subtype by all three classification algorithms. SVM and ssGEA algorithms obtain more similar results (87%). No differences in clinical variables were found between the 3 GBM subtypes. Proneural subtype was enriched with IDH1 mutated and G-CIMP positive tumors. Mesenchymal subtype (SVM) was enriched in unmethylated MGMT tumors (p = 0.008), and classical (SVM) in methylated MGMT tumors (p = 0.008). Long survivors ( > 30 months) were rarely classified as mesenchymal (0-7.5%) and were more frequently classified as Proneural (23.1-26.). Clinical (age, resection, KPS) and molecular ( IDH1, MGMT) known prognostic factors were confirmed in this serie. Overall, no differences in prognosis were observed between 3 subtypes, but a trend to worse survival in mesenchymal was observed in K-NN (9.6 vs 15 ). Mesenchymal subtype presented less expression of Olig2 (p < 0.001) and SOX2 (p = 0.003) by IHC, but more YLK-40 expression (p = 0.023, SVM). On the other hand, classical subtype expressed more Nestin (p = 0.004) compared to the other subtypes (K-NN). Conclusions: In our study we have not found correlation between glioblastoma expression subtype and outcome. This large serie provides reproducible data regarding clinical-molecular-immunohistochemistry features of glioblastoma genetic subtypes.
Cancer differentiation analysis technology as a novel technology for cerebral cancer screening.
Authors: Tao Hongmei , Tang Xing , Lin Yue , Yu Chris Chang , Du Xuedong
Published: May 2019

2040

Background: While the current cancer screening methods mostly failed to detect cerebral cancer, a novel, promising technology named cancer differentiation analysis (CDA) technology has been developed to measure novel bio-physical properties to obtain valuable multi-level and multi-parameter information including protein, cellular and molecular level information. Initial results showed that CDA technology is capable of detecting cerebral cancer with a high degree of sensitivity and specificity. Methods: In this study, samples from 78 cerebral cancer patients and 321 healthy individuals were measured. Peripheral blood of each individual was drawn in EDTA tubes. One class of bio-physical property in blood samples was utilized for CDA tests. CDA data were conducted using SPSS, and the results were shown in table. Results: The average CDA values of cerebral cancer and control groups were 52.30 and 33.38 (rel. units) respectively. The results indicated that cerebral cancer could be significantly distinguished from the control (p < 0.001). Area under ROC curve (AUC) was 0.980, and sensitivity and specificity was 92.3% and 96.6% respectively. Conclusions: Initial results showed that CDA technology could effectively distinguish cerebral cancer from healthy individuals. As a novel bio-physical based cancer detection approach with multi-level and multi-parameter expressions, CDA could be a potential candidate for cerebral cancer screening. Results from Statistical Analysis of CDA. [Table: see text]
Health-related quality of life (HRQL) in VERTU: A randomized phase II trial of veliparib (V), radiotherapy (RT), and temozolomide (TMZ) for newly diagnosed MGMT unmethylated (uMGMT) glioblastoma (GBM).
Authors: Sim Hao-Wen , Barnes Elizabeth , Lwin Zarnie , Rosenthal Mark , Wheeler Helen , Koh Eng-Siew , Foote Matthew C. , Fisher Lauren , Leonard Robyn , Hall Merryn , Simes John , Khasraw Mustafa
Published: May 2019

2042

Background: The VERTU trial (ANZCTR #ACTRN12615000407594) compared Arm A (standard of care) = RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2 D1–5) every 28 days for 6 cycles vs Arm B (experimental arm) = RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2 D1–5) + V (40mg PO BID, D1–7) every 28 days for 6 cycles in pts with newly diagnosed centrally determined uMGMT GBM. To ensure that veliparib was not associated with clinical detriment, serial HRQL assessments were performed for comparison as a secondary objective. Methods: Pts completed the EORTC quality of life core questionnaire (QLQ-C30) and brain cancer module (BN20) every 4 weeks (w) (baseline: w0; concurrent: w4,8; adjuvant: w10,14,18,22,26,30). Based on relevance to GBM patients, 5 HRQL scales (global health [GH], physical functioning [PF], social functioning [SF], motor dysfunction [MD] and communication deficit [CD]) were pre-selected for primary analysis. Maximum change from baseline score (clinically relevant deterioration/improvement defined as ≥10-point change) during the progression-free period, and deterioration-free survival (time to deterioration/progression/death) were evaluated. Results: Patient characteristics were well-matched (Arm A: N = 41, median age = 62, male = 68%, ECOG 0 = 66%, macroscopic resection = 88%; Arm B: N = 84, median age = 60, male = 70%, ECOG 0 = 65%, macroscopic resection = 86%). Almost all completed at least one HRQL assessment (98%). HRQL assessments during the progression-free period were completed in 87% (Arm A) and 90% (Arm B) of cases. For Arm A vs B, the proportion of patients who experienced a deterioration in GH (59% vs 64%, p = 0.69), PF (53% vs 53%, p > 0.99), SF (46% vs 53%, p = 0.56), MD (63% vs 58%, p = 0.70) and CD (45% vs 46%, p > 0.99) were similar. Deterioration-free survival was not statistically different for any HRQL item. Conclusions: The addition of veliparib to standard of care for newly diagnosed uMGMT GBM does not appear to compromise HRQL. This would support the primary efficacy analysis of the VERTU trial. Clinical trial information: ACTRN12615000407594.
Pembrolizumab (Pem) in recurrent high-grade glioma (HGG) patients (PTS) with mismatch repair deficiency (MMRd): An observational study.
Authors: Lombardi Giuseppe , Caccese Mario , Simonelli Matteo , Fassan Matteo , Padovan Marta , Persico Pasquale , Bellu Luisa , Dipasquale Angelo , Gardiman Marina Paola , Indraccolo Stefano , Zagonel Vittorina
Published: May 2019

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.
Health-related quality of life (HRQoL) evaluation in the REGOMA trial: A randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients.
Authors: Lombardi Giuseppe , Del Bianco Paola , Brandes Alba Ariela , Eoli Marica , Ruda Roberta , Ibrahim Toni , Lolli Ivan , Pace Andrea , Daniele Bruno , Pasqualetti Francesco , Rizzato Simona , Bergo Eleonora , Caccese Mario , Magni Giovanna , Soffietti Riccardo , De Salvo Gian Luca , Zagonel Vittorina
Published: May 2019

2045

Background: REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in relapsed glioblastoma (GBM) patients (pts) with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point. Methods: HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P = 0.01 (2-sided). Results: Of 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n = 56 REG; n = 58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD = 28.6) vs 7.6 (SD = 16.0); p = 0.0081). The proportion of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p = 0.0146). Conclusions: In the REGOMA trial, HRQoL did not change during REG treatment. Pts treated with REG and LOM reported no significant difference in HRQoL. Clinical trial information: NCT02926222. [Table: see text]
EGFR amplification predicted selective sensitivity to PARP inhibitors with high PARP-DNA trapping potential in human GBM.
Authors: Yung W. K. Alfred , Wu Shaofang , Gao Feng , Zheng Siyuan , Ding Jie , Zhang Chen , Li Xialong , Ezhilarasan Ravesanker , Feng Ningping , De Groot John Frederick , Sulman Erik P. , Heffernan Timothy , Koul Dimpy
Published: May 2019

2047

Background: Poly-ADP-ribose polymerase (PARP) is an enzyme critical for regulating a variety of DNA damage repair mechanisms such as BER/SSBR, and PARP inhibitors have been shown to have single agent activity in breast and ovarian cancer patients with BRCA ½ mutations. However, PARP inhibitor such as veliparib has limited single agent activity in GBM and identifying markers predicting sensitivity is critical to select individuals or certain groups of patients for PARP inhibitor therapy. Methods: Potency and selectivity of PARP inhibitors were analyzed in a panel of glioma stem cells (GSCs) with varying genetic background. In vivo anti-tumor activity was evaluated in xenograft models. Results: In this study, we report that PARP inhibitor, talazoparib, showed strong single-agent cytotoxicity and remarkable selective activity in glioma stem cells (GSCs). This single agent activity was strongly correlated with EGFR amplification. GSCs with EGFR amplification (which occurs in about 45% of GBMs) showed higher oxidative base damage, DNA breaks, and genomic instability than non-amplified GSCs. To sustain the elevated basal oxidative stress, EGFR-amplified GSCs had increased basal expression of DNA repair proteins. As a result of blocked DNA damage repair by talazoparib treatment, DNA damage accumulated and lead to increased PARP-DNA complexes, which was then trapped by talazoparib and resulted in high toxicity. The PARP-DNA trapping function of PARPi is essential as olaparib and veliparib, two PARP inhibitors with weak DNA-PARP trapping potential did not show sensitivity in GSCs. In contrast, Pamiparib, another PARP inhibitor with similar PARP-DNA trapping ability to that of talazoparib, showed selective sensitivity in EGFR-amplified GSC. Conclusions: Our data showed that EGFR amplified GSCs with higher basal DNA damage exhibited therapeutic vulnerability to PARP inhibitors with high PARP-DNA trapping ability, and that EGFR amplification is a potential selection or predictive biomarker for PARP inhibitor therapy in GBM.
Stratified monotherapy approach according to MGMT methylation status in elderly patients with glioblastoma.
Authors: Shirahata Mitsuaki , Adachi Junichi , Kobayashi Keiichi , Yamasaki Fumiyuki , Tamura Kaoru , Suzuki Tomonari , Mishima Kazuhiko , Nagane Motoo , Ichimura Koichi , Nishikawa Ryo
Published: May 2019

2050

Background: The elderly patients with glioblastoma have an extremely poor prognosis. As they often have some degree of age-related vulnerability, it is especially important to minimize a risk of treatment-related adverse events by optimizing treatment intensity for this population. We conducted phaseⅡ clinical trial to investigate the efficacy of stratified monotherapy approach according to O6-methylguanine-DNA methyltransferase (MGMT) methylation status in elderly patients with glioblastoma. Methods: Patients aged 70 years or older with Karnofsky performance status (KPS) of at least 60 were eligible for this study. MGMT methylation status was quantitatively assessed by pyrosequencing based on the average methylation ratio of 16 CpG sites in the MGMT gene promoter. The patients with highly methylated MGMT promoter defined as an average methylation ratio with 30% or higher were treated with temozolomide (TMZ) monotherapy (standard 5/28 regimen), while the others with low or intermediate levels of MGMT promoter methylation were treated with radiation therapy (40Gy/15fr) alone. Results: Between April 2013 and December 2017, 70 patients were enrolled in this study. Median age was 78 years (70-91) and median KPS was 60 (60-100). Of 70 patients, 19 patients with highly methylated MGMT promoter received TMZ monotherapy, while the remaining 51 patients were treated with radiation therapy. Median progression-free survival (PFS) and median overall survival (OS) were 7.5 and 17.4 months in the TMZ group, respectively. Median PFS and median OS were 4.6 and 10.4 months in the radiotherapy group, respectively. Conclusions: For elderly glioblastoma patients with highly methylated MGMT promoter, TMZ monotherapy could be a treatment option. Clinical trial information: UMIN000012172.
Are patients with oligodendroglioma at higher risk for radiation neurotoxicity?
Authors: Ahmad Haroon , Patel Sohil H. , Donahue Joseph , Lopes M. Beatriz , Purow Benjamin , Schiff David , Fadul Camilo E.
Published: May 2019

2061

Background: Symptomatic radiation neurotoxicity (RN), manifesting on MRI as focal necrosis and/or T2 signal abnormality, is a dreaded complication of radiation therapy (RT). While RT is standard of care for anaplastic gliomas, the long-term benefit vs risk profile in low-grade gliomas is not well defined. Patients with oligodendroglioma carry a better overall survival than those with astrocytoma. Anecdotally, they are more prone to experience RN than astrocytomas, as suggested by Acharya et al in 2017. We hypothesized that, independent of grade, oligodendrogliomas have a higher incidence of RN as compared to astrocytomas. Methods: We reviewed the records of 628 patients with WHO grade II and III gliomas from our institution. Study population comprised 326 patients with: standard fractionated RT, pathology confirmation by a neuropathologist, and follow up of at least 2 years after diagnosis. RN was defined as either histologically confirmed by pathology or requiring intervention for clinically presumed RN (bevacizumab or high-dose steroids.) A separate category included patients with dramatic cognitive decline with increased T2 signal abnormality, in the absence or tumor progression. Results: There were 131 patients with oligodendroglioma, based upon 1p/19q co-deletion (105 cases) or histology in the absence of molecular testing (26 cases). The remaining 195 patients had astrocytoma with intact 1p/19q, isocitrate dehydrogenase (IDH) wild-type, or diagnosed histologically absent molecular testing. The incidence of RN were 18.3% and 8.2% for oligodendroglioma and astrocytoma, respectively (p = 0.0063). An additional four patients with oligodendroglioma and two with astrocytoma had significant cognitive deterioration with increased T2 signal abnormality, without tumor progression. Conclusions: The greater than two-fold increase in RN incidence for oligodendrogliomas is significant and suggests patients with oligodendrogliomas may be more at risk to develop RN. Therefore, in patients with oligodendroglioma, the consideration of fractionated RT needs to be weighed against the increased potential for RN. Analysis of baseline imaging and patient characteristics variables that correlate with development of RN are ongoing and will be presented at the meeting.
Retrospective review for outcomes of IDH mutant, 1p/19q co-deleted gliomas based on initial treatment.
Authors: Trevino Christopher Ray , Weathers Shiao-Pei S. , Alfaro-Munoz Kristin , Hallatt Gemma , Wiliford Garret L. , Park Minjeong , Liu Diane D. , Overeen Tim , Mandel Jacob Joseph , De Groot John Frederick
Published: May 2019

2063

Background: Treatment for oligodendroglioma in the molecular era is based on trials that used histologic criteria alone and has evolved over time to include observation and a combination of radiation (RT) and chemotherapy. In particular, treatment for high-risk patients is variable including sequential RT followed by temozolomide (TMZ) or procarbazine, lomustine, and vincristine (PCV) or chemoradiation with TMZ. This is a single institutional review of outcomes of molecular IDH mutant, 1p19q co-deleted oligodendroglioma based on initial treatment. Methods: Using both Palantir Foundry and direct record review, we stratified adult patients with grade II/III gliomas diagnosed from 1997-2017 harboring an IDH mutation and 1p/19q co-deletion based on initial treatment and excluded patients without molecular testing. Overall survival (OS) and progression free survival (PFS) were calculated by Kaplan-Meier analysis. Results: 187 patients were initially managed as: 55 (31%) observation, 16 (9%) RT alone, 51 (29%) chemotherapy alone, 39 (22%) sequential RT and chemotherapy, and 17 (10%) chemoradiation. For all patients, a subtotal (STR) or gross total resection (GTR) was associated with prolonged OS vs biopsy (NR vs 123 mos, p = 0.007). Age < 40 did not correlate with OS (p = 0.87). In the chemotherapy group, although PCV demonstrated improved PFS vs TMZ (157 vs 45 mos, p = 0.004) there was no difference in OS, only 3 patients received PCV. For patients treated sequentially with RT and PCV or TMZ vs chemoradiation, there were no differences in OS (NR vs 140 mos; p = 0.87) or PFS (49 vs 45 mos, p = 0.52), though sequential treatment trended toward prolonged survival. Conclusions: This data supports both STR and GTR as prognostic for overall survival. Despite the prolonged PFS observed with patients treated with PCV alone which did not translate to improved OS, the small PCV sample size limits the strength of this evidence. We did not find significant survival differences between sequential RT and chemotherapy vs concurrent, but interestingly, there was a trend toward improved OS in sequentially treated patients.
Phase II study of durvalumab (MEDI4736) in cancer patients HIV-1-infected.
Authors: González-Cao María , Moran Teresa , Dalmau Judith , Garcia-Corbacho Javier , Bernabé Reyes , Juan Oscar , De Castro Javier , Blanco Remei , Meyerhans Andreas , Blanco Julia , Karachaliou Niki , Brander Christian , Garcia-Prado Julia , Carrillo Jorge , Provencio Mariano , Molina Vila Miguel Angel , Massuti Bartomeu , Clotet Bonaventura , Martinez-Picado Javier , Rosell Rafael ,   Spanish Lung Cancer Group (SLCG)
Published: May 2019

2501

Background: Durvalumab (MEDI4736), a programmed cell death-ligand 1 (PD-L1) blocking antibody, is currently approved for treatment of several cancer types. As HIV-1-infected (HIV+) patients have been excluded from cancer clinical trials, there are no data on the safety of durvalumab in this population. Methods: DURVAST (NCT03094286) is a multicenter, open-label, phase 2 clinical trial evaluating the safety and feasibility of durvalumab treatment at the recommended dose of 1500 mg Q4W in HIV+ cancer patients with solid tumors. Secondary endpoints include analyses of antitumoral activity in terms of objective response rate and duration of response (DOR). An associated translational sub-study includes the assessment of antiviral activity and the interaction of chronic viral infection with anti-cancer response and drug tolerance. Results: Twenty HIV+ individuals with advanced solid tumors were enrolled (Table). All participants maintained their standard-of-care antiretroviral therapy. Basal plasma viremia was undetectable and CD4+ T-cell count was over 200/mm3. There were no durvalumab-related serious adverse events. Only 8 patients (40%) presented drug-related adverse events (all grade 1-2) including diarrhea (15%), rash (15%), nausea (15%) and asthenia (10%). Best response includes: partial response in 5 (25%) (4 NSCLC and 1 anal cancer), stable disease in 4 (20%) (3 NSCLC and 1 melanoma) and progression disease in 11 (55%) patients. At data cut-off, 8 patients (40%) remained on therapy for a median of 10.5 months (range: 6-19 m). Median DOR has not been reached (range 1m to 19 m+). Plasma viremia remained suppressed during the study suggesting no viral reactivation upon durvalumab treatment. Conclusions: DURVAST study demonstrates durvalumab safety in HIV+ cancer patients and suggests an excellent tolerance profile. Understanding how chronic viral infection could contribute to a better tolerance towards immune checkpoint inhibitors will open a new way for the development of safer anti-cancer immunotherapy strategies. Clinical trial information: NCT03094286. [Table: see text]
A phase II, randomized, double-blind, placebo-controlled trial evaluating efficacy and safety of namodenoson (CF102), an A3 adenosine receptor agonist (A3AR), as a second-line treatment in patients with Child-Pugh B (CPB) advanced hepatocellular carcinoma (HCC).
Authors: Stemmer Salomon M. , Manojlovic Nebojsa S. , Marinca Mihai Vasile , Petrov Petar , Cherciu Nelly , Ganea Doina , Ciuleanu Tudor-Eliade , Puscas Ioana Adriana , Beg Muhammad Shaalan , Purcell William T. , Croitoru Adina-Emilia , Ilieva Rumyana Nedyalkova , Natošević Sladjana , Nita Amedeia Lavinir , Kalev Dimitar Nikolaev , Harpaz Zivit , Farbstein Motti , Silverman Michael H. , Fishman Pnina , Llovet Josep M
Published: May 2019

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Background: There is no established primary treatment for patients with advanced HCC and severe liver dysfunction (Child-Pugh B class; CPB), thus this representing a clear unmet need. Namodenoson, an A3AR agonist, showed promising preliminary results in this population in an open label phase 1/2 clinical study (NCT00790218), with median overall survival (OS) of 8.1 months. We present the results of a double blind, randomized phase 2, placebo-controlled study (NCT02128958), assessing the efficacy and safety of namodenoson as a second-line therapy of patients with advanced HCC and CPB class. Methods: Patients were randomized 2:1 to BID namodenoson (25 mg; n = 50) or placebo (n = 28) in 15 centers globally. Primary endpoint was OS and secondary endpoints were safety, progression-free survival (PFS), objective response (OR) and disease control rate (DCR). Assessment of OS and PFS was done by log rank test at a one final analysis when 75 deaths had occurred. Response was assessed by RECIST (local investigator) and mRECIST (central review). Results: The study did not meet the primary end point, with median OS 4.1 months (mo) for namodenoson vs. 4.3 mo for placebo (HR: 0.82). Pre-planned subgroup analysis of Child-Pugh 7 patients (n=56; namodenoson=34, placebo=21) showed median survival 6.8mo vs 4.3 mo [HR: 0.77 (95% CI 0.49-1.40)]. Similarly, for this subgroup of patients PFS was 3.5 mo vs 1.9 (HR=0.87). In terms of objective response, 3/34 patients assessed achieved OR (9%) with namodenoson vs 0% for placebo. Namodenoson was generally well-tolerated, with no treated patients being withdrawn for toxicity and no cases of treatment-related deaths. The most common adverse event (>10%) were anemia, abdominal pain, ascites, nausea, asthenia, fatigue, peripheral edema, and increased AST. Treatment-related grade 3 toxicities accounted for anemia, fatigue and hyponatremia. Conclusions: Namodenoson has demonstrated favorable clinical safety profile in patients with advanced HCC and severe liver dysfunction. Although the primary end-point was not met, the subgroup analysis showed a positive signal of efficacy for OS in patients with Child-Pugh 7. Both safety and efficacy results warrant testing this drug in a phase III trial. Clinical trial information: NCT02128958.
Analysis of early mortality in randomized clinical trials evaluating anti-PD-1/PD-L1 antibodies: A systematic analysis by the United States Food and Drug Administration (FDA).
Authors: Mulkey Flora , By Kunthel , Theoret Marc Robert , Maher Virginia Ellen , Pazdur Richard , Sridhara Rajeshwari
Published: May 2019

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Background: Many studies exhibit what seems to be dis-proportionately higher early mortality (EM) in anti-PD-1/PD-L1 containing arms (IO) when compared to active control arms (AC), resulting in early crossing of the Kaplan-Meier overall survival curves. We examine if EM with the use of IO is specific to certain demographic and disease characteristics. Methods: Data from 16 randomized AC trials submitted to FDA containing 6055 IO and 3604 AC patients in HNSCC, Melanoma, NSCLC, RCC, and Urothelial Carcinoma were evaluated for signs of EM. Study-specific and pooled piecewise hazard ratios (HRs) were used to quantify EM from 0 to 60 and > 60 days. Additionally, HRs up to 60 days were used to assess the extent specific subgroups account for EM. Results: Piecewise HRs comparing OS between IO and AC changed direction, > 1 to < 1 in 11 trials; melanoma (5/6), NSCLC (3/7), HNSCC (1/1), RCC (1/1), and urothelial cancer (1/1). When pooled, NSCLC studies retained this EM pattern, although attenuated, with HR (95% CI) of 1.12 (0.91, 1.38) ≤60 days and 0.66 (0.61, 0.72) after 60 days. This was not observed in the pooled melanoma studies: 0.88 (0.63, 1.24) ≤ 60 days and 0.59 (0.53, 0.67) after 60 days. EM in both arms was associated with poor ECOG performance status (PS), increased LDH, and high tumor burden. Comparing EM patients in the IO and AC arms, a larger proportion were female in the melanoma trials (41% vs. 28%), a smaller proportion had squamous histology in the NSCLC trials (32% vs. 41%), and a larger proportion were PD-L1 negative (56% vs. 36% melanoma; 60% vs. 43% NSCLC). Analysis of the pooled melanoma studies suggests PD-L1 negative melanoma patients with high baseline tumor burden and PS played a role in EM with HR before 60 days of 1.49 (0.75, 2.97). However, these results were not reproducible in NSCLC. Conclusions: Potential risk factors for EM were assessed in individual and pooled trials. While several factors—negative PD-1/PD-L1 status and high ECOG, LDH and tumor burden—seem to play a role in EM, these high-risk subgroups do not fully explain the EM patterns observed in the IO treated patients.
Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1.
Authors: Sarnaik Amod , Khushalani Nikhil I. , Chesney Jason Alan , Kluger Harriet M. , Curti Brendan D. , Lewis Karl D. , Thomas Sajeve Samuel , Whitman Eric D. , Hamid Omid , Lutzky Jose , Pavlick Anna C. , Weber Jeffrey S. , Larkin James M.G. , Barton Debora , Yung Lotus , Suzuki Sam , Fardis Maria , Kirkwood John M.
Published: May 2019

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Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable long-term responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel (LN-144), a centrally manufactured autologous TIL therapy are presented. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of the efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 55) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. Results: In 55 patients with Stage IIIC/IV unresectable melanoma, 3.1 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 24%), high baseline tumor burden (110 mm mean target lesion sum of diameters), ORR was 38% (2 CR, 18 PR, 1 uPR). Of 21 responders, 4 have progressed to date with median follow up of 7.4 months. Overall disease control was 76%. Improved responses in some patients were observed with longer follow up. Most (54) patients progressed on prior anti-PD1 and those with PD-L1 negative status (TPS < 5%) were among responders. Mean cells infused was 28 x109. Median IL-2 doses administered was 6.0. Adverse events resolved to baseline, 2 weeks post TIL infusion, a potentially important benefit of one-time TIL therapy. Conclusions: Lifileucel treatment results in 38% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who received prior anti-PD1 and BRAF/MEK inhibitor if BRAF mutated. Based on these data, a new Cohort 4 in C-144-01 has been initiated to support lifileucel registration. Clinical trial information: NCT02360579.
First-in-human first-in-class phase I trial of murlentamab, an anti-Mullerian-hormone receptor II (AMHRII) monoclonal antibody acting through tumor-associated macrophage (TAM) engagement, as single agent and in combination with carboplatin (C) and paclitaxel (P) in AMHRII-expressing advanced/metastatic gynecological cancer patients (pts).
Authors: Leary Alexandra , Awada Ahmad , Delord Jean-Pierre , Floquet Anne , Ray-Coquard Isabelle Laure , Abdeddaim Cyril , Fabbro Michel , Kalbacher Elsa , Vergote Ignace , Banerjee Susana N. , Frenois François-Xavier , Noël Grégory , Lantz Olivier , Cassard Lydie , Coste Agnès , Villard Marine , Lemee Fanny , Tabah-Fisch Isabelle Marie , Le Tourneau Christophe
Published: May 2019

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Background: Membranous expression of AMHRII is found in ~70% of gynecological tumors. Murlentamab (M) binds with high affinity both AMHRII (at cell membrane) and CD16 (on macrophage, via its low fucose Fc). M reprograms TAMs, restoring their antitumoral functions (phagocytosis) resulting in cytotoxic T cell reactivation. Methods: Pts with advanced/metastatic AMHRII-expressing ovarian, cervical or endometrial cancer with measurable disease and performance status ≤ 1 received M as single agent (SA) in 8 dose escalating and 2 expansion cohorts. Combination with CP was studied in 2 escalating cohorts. Safety, recommended dose determination, antitumor activity, pharmacodynamics (PD) effects (circulating immune cells and tumor microenvironment (TME) from paired biopsies) were assessed. Results: 68 heavily pretreated (median 4 prior lines) pts received M for 0.5 to 11 months (mo) (59 pts M SA and 9 pts M + CP). No dose limiting toxicity was reported. Most common toxicity was G1-2 asthenia (29 %). Eight pts (12%) had G ≥ 3 reversible toxicities (asthenia, nausea/vomiting, anorexia, arthralgia). No antidrug antibody was detected. One partial response (PR) was achieved with M SA in a granulosa pt. In CP combination, 4/9 pts (44%) responded to treatment (1 Complete Response and 3 PRs). Overall, 22/67 (33%) pts were progression-free at 4 mos. Among 17 pts treated ≥ 6 mos, 6/9 (67%) granulosa pts with M SA and 4/5 (80%) endometrium and cervix with CP combination had a longer PFS than under previous regimen. PD blood assessment of 25 pts treated with M SA showed an increase in classical monocytes, and T cells and neutrophils activation. Changes in TME under M will be presented. Conclusions: Murlentamab was very well tolerated, demonstrated immune PD effects and showed hints of antitumor activity. These results together with its innovative immunological mode of action support development of M in AMHRII-expressing cancers, in combination with chemotherapy or other immune oncology drugs. Clinical trial information: NCT02978755.
A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.
Authors: Burris Howard A. , Patel Manish R. , Cho Daniel C. , Clarke Jeffrey Melson , Gutierrez Martin , Zaks Tal Z. , Frederick Joshua , Hopson Kristen , Mody Kinjal , Binanti-Berube Alverina , Robert-Tissot Celine , Goldstein Bree , Breton Ben , Sun Jing , Zhong Shan , Pruitt Scott K. , Keating Karen , Meehan Robert S. , Gainor Justin F.
Published: May 2019

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Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. Methods: A phase I dose escalation study of mRNA-4157 as adjuvant monotherapy in patients with resected solid tumors (melanoma, bladder carcinoma, HPV negative HNSCC, NSCLC, SCLC, MSI-High, or TMB High cancers) and in combination with pembrolizumab in patients with advanced or metastatic cancer is being conducted to evaluate safety. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients may receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection (0.04 – 1 mg). In the combination arm, pembrolizumab (200 mg) is administered for two cycles prior to combination with mRNA-4157; patients may continue pembrolizumab after completion of 9 cycles of combination therapy. Primary end points include safety, tolerability, and recommended phase 2 dose. Results: 33 patients received mRNA-4157; 13 as monotherapy and 20 in combination with pembrolizumab. No DLTs were reported, and treatment related AEs have generally been of low grade and reversible, and no drug related SAEs or AEs ≥ grade 3 have been observed. Of the 13 patients on adjuvant monotherapy (3 melanoma, 8 NSCLC, 2 MSI-High), 12 patients remain disease free on study, median follow-up of 8 months. 20 patients have been treated in combination (1 TMB-high, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high), 12 had progressed on prior CPI, 16 have been restaged and there are 1 CR (on pembrolizumab prior to vaccination), 2 PR, 5 SD for at least 5 combination cycles, 5 PD, 2 iuPD, and 1 patient is non-evaluable for response but remains on study. Neoantigen specific T cell responses have been detected by IFN-γ ELISpot from PBMCs. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT03313778.