bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

2503 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

2516 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.