bluuebunny/crossref_metadata_2025 huggingface dataset:
Adverse effects of early bilateral oophorectomy on body composition: Results from a nationally representative sample of United States women.
Authors: Karia Pritesh S , Joshu Corinne , Visvanathan Kala
Published: May 2019

1568

Background: Prior studies suggest that bilateral oophorectomy (BO), a common cancer prevention strategy, may be associated with adiposity. However, the impact of BO on lean mass, a potential marker of healthy aging, and whole-body composition is not known. Declines in lean mass have been linked to physical disability and mortality. We examined the association between BO and total and regional distribution of fat and lean mass in a cross-sectional study. Methods: The study population included women 35-70 years who underwent dual-energy x-ray absorptiometry (DXA) scans at enrollment as part of the National Health and Nutrition Examination Survey 1999-2006 (N = 3,764). Multinomial logistic regression models were used to examine the relationship between prior BO and tertiles of fat and lean mass. Models were adjusted for age, race, education, BMI at age 25, physical activity, smoking, alcohol use, parity, oral contraceptive use and hormone replacement therapy use. Results: Women with prior BO < 45 years (n = 346) had 2.9-times higher odds than women without BO (n = 3,212) of being in the highest compared to the lowest tertile of total fat mass (OR, 2.91; 95% CI, 1.93-4.38) and 2.7-times higher odds of being in the lowest compared to the highest tertile of total lean mass (OR, 2.67; 95% CI, 1.81-3.95). Results were similar when stratified by age at enrollment ( < 45, 45-54, and ≥55). Similarly, among women with normal BMI at enrollment, those with prior BO < 45 years (n = 74) had higher odds of being in the highest tertile of total fat mass (OR, 9.88, 95% CI, 2.21-44.00) and the lowest tertile of total lean mass (OR, 10.09; 95% CI, 2.72-37.46). These differences in body composition were most pronounced in the trunk region. No difference was observed in women with BO ≥45 years compared to women without BO. Conclusions: Women with a history of early BO experience significant changes in body composition, including increased fat mass and decreased lean mass, even while maintaining a normal BMI. If validated in future prospective studies, our results suggest that a comprehensive evaluation of body composition may be warranted in young women who undergo BO.
Racial disparities in cancer survival: A trend analysis based on SEER data (1973-2010).
Authors: Alavi Seyed Navid , Eze Chibuzo , Pandellapalli Poornima
Published: May 2019

1571

Background: African Americans have higher incidence of cancer and lower survival rates compared to other ethnicities. We studied the 5-year relative survival between black and white races for the most common cancers in the United States. Methods: Data was obtained from the SEER database, the largest population-based cancer database including 28% of US population. Data containing 5-year relative survival from the patients who were diagnosed from 1973 to 2010. We included data for cancers of colorectal, lung, prostate, breast and melanoma, the most common cancers in the United States. Results: For colorectal cancer average 5-year relative survival from 1973 to 2010 is 59.9% for whites and 51.5% for blacks. Same results for lung cancer are 14.6% for whites and 12.2% for blacks, for breast cancer is 84.5% for whites and 71.6% for blacks, for prostate cancer is 86.9% for whites and 80.5% for blacks, and for melanoma is 87.9% for whites and 66.4% for blacks. The average black to white 5-year relative survival ratio is 0.86, 0.84, 0.85, 0.92, and 0.76 for cancers of colorectal, lung, breast, prostate, and melanoma, respectively. This ratio has decreased from 0.89 to 0.86 and from 0.87 to 0.81 for colorectal and lung cancer, respectively and for cancers of breast, prostate and melanoma it has increased from 0.85 to 0.87, from 0.88 to 0.89, and from 0.73 to 0.80 respectively. Conclusions: Our analysis shows that for colorectal and lung cancer the survival rate difference between blacks and whites has increased over 4 decades but for cancers of breast, prostate and melanoma this ratio has decreased. Better understating of the factors contributing to racial differences in cancer survival has potential applicability in policymaking for a better and equal health care delivery.
Relationship of liver cancer with LRP1B or TP53 mutation and tumor mutation burden and survival.
Authors: Wang Longrong , Yan Kai , Zhou Jiamin , Zhang Ning , Wang Miao , Song Jia , Zhao Jing , Zhang Yuzi , Cai Shangli , Zhao Yiming , Wang Lu
Published: May 2019

1573

Background: Liver cancer (LC), one of the most common causes of cancer-related deaths, is a serious medical problem due to the limited treatment options available for this disease. Immune checkpoint inhibitors (ICIs) that are proved to be beneficial in the treatment of advanced LC. Similar to observations in other cancers, these ICIs as monotherapy may benefit only a fraction of HCC patients. Tumor mutation burden (TMB) is an important predictor for efficacy of ICIs in several solid tumors. However, the research on exploring the association between TMB and mutant genes with high frequency of liver cancer is limited. Besides, previous research on prognostic factors primarily focus on pathological features, probing the effects of genetic variations are urgently needed to study. Methods: Whole-exome sequencing data of 377 liver tumors from the Cancer Genome Altas (TCGA) and next generation sequencing (NGS) data of 655 liver tumors from Chinese clinical dataset were analyzed to explore the associated between LRP1B or TP53 gene alteration and TMB. TMB was defined as total number of somatic non-synonymous mutations in coding region. Results: In total, 9.3% (35/377) of hepatic tumors in TCGA and 7.8% (51/655) in clinical cohort harboring LRP1B mutation. LRP1B mutation was significantly associated with higher TMB in both TCGA cohort (P = 0.0003) and clinical cohort (P = 0.0005). The frequency of TP53 mutation was 28.1% (106/377) in TCGA cohort, however, TP53 mutation represented a greater rate of 54.5% (357/655) in Chinese clinical cohort. TP53 mutation was also associated with higher TMB in the two cohort (P = 0.0005 for the TCGA cohort and P = 0.0010 for the clinical cohort). In addition, prognosis analysis was performed on patients in TCGA cohort. LRP1B statue resulted in significantly shorter overall survival (OS, median, 20.9 vs 61.7 months; HR, 2.22; P = 0.0012), and a decreasing trend on progression-free survival (PFS) without significant difference (median, 8.7 vs 16.6 months; HR, 1.28; P = 0.2839). TP53 mutation was an independent risk factors affecting both OS (HR 1.58, P = 0.0109) and PFS (HR 1.59, P = 0.0027), respectively. Conclusions: The results indicated that LRP1B or TP53 mutation was a poor prognostic factor in LC, and patients harboring any of these two gene mutations might easily benefit from the immunotherapy.
Second interim and first molecular analysis of the EORTC randomized phase III intergroup CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q codeletion.
Authors: Van Den Bent Martin J. , Erridge Sara , Vogelbaum Michael A. , Nowak Anna K. , Sanson Marc , Brandes Alba Ariela , Wick Wolfgang , Clement Paul M. , Baurain Jean-Francois , Mason Warren P. , Wheeler Helen , Weller Michael , Aldape Kenneth D. , Wesseling Pieter , Kros Johan M. , Tesileanu Mircea , Golfinopoulos Vassilis , Gorlia Thierry , Baumert Brigitta G. , French Pim
Published: May 2019

2000

Background: The 1st interim analysis of the CATNON trial showed benefit from adjuvant (adj) temozolomide (TMZ) on overall survival (OS) but remained inconclusive about concurrent (conc) TMZ. A 2nd interim analysis was planned after 356 events. Methods: The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed non-codeleted anaplastic glioma to either 59.4 Gy radiotherapy (RT) alone; the same RT with concTMZ; the same RT and 12 cycles of adjTMZ or the same RT with both concTMZ and adjTMZ ( doi: 10.1016/S0140-6736(17)31442-3). MGMT promoter methylation ( MGMTmeth) status was re-assessed with the Infinium Methylation EPIC Beadchip using the MGMT_STP27 model. Isocitrate dehydrogenase 1 and 2 ( IDH) mutation (mt) status was assessed with glioma targeted Agilent SureSelect baits sequence using an Illumina HiSeq2500 Rapid PE100. Results: With a median follow-up of 56 months and 356 events, the hazard ratio (HR) for OS adjusted for stratification factors after concTMZ was 0.968 (99.1% CI 0.73, 1.28). 5-year OS was 50.2% with and 52.7% without concTMZ (95% CI [44.4, 55.7] and [46.9, 58.1]). An IDHmt was found in 335 of 480 assessed cases (70%). Median OS was 19 mo (95% CI 16.3, 22.3) in IDHwt tumors and 116 mo (95% CI 82.0, 116.6) in IDHmt tumors. HR for OS after concTMZ in patients with known IDH status. Clinical trial information: NCT00626990. IDHmt was predictive of benefit from adjTMZ ( IDHmt HR: 0.41, 95% CI 0.27, 0.64; IDHwt: HR 1.05, 95% CI 0.73, 1.52; interaction test p = 0.001). In IDHmt patients that received adjTMZ, the HR for OS after concTMZ was 0.71 (95% CI 0.35, 1.42, p=0.32). MGMTmeth was found in 288 of 410 assessed cases (70%), interaction test for concTMZ (p = 0.092) and adjTMZ (p = 0.166) did not reach statistical significance. Conclusions: In the entire study cohort, concTMZ did not increase OS. However, in IDHmt tumors a trend towards benefit of concTMZ is present. AdjTMZ increased OS in IDHmt but not in IDHwt tumors. The ongoing molecular analyses and further follow-up will allow full assessment of efficacy in the molecular subgroups.[Table: see text]
A phase I, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: Results from cohort 1.
Authors: Mellinghoff Ingo K. , Cloughesy Timothy Francis , Wen Patrick Y. , Taylor Jennie Webster , Maher Elizabeth A. , Arrillaga Isabel , Peters Katherine B. , Choi Changho , Ellingson Benjamin M. , Lin Alexander P. , Thakur Sunitha B , Nicolay Brandon , Lu Min , Le Kha , Yin Feng , Tai Feng , Schoenfeld Steven , Steelman Lori , Pandya Shuchi Sumant , Clarke Jennifer Leigh
Published: May 2019

2003

Background: AG-120 (ivosidenib [IVO]) is a first-in-class oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) evaluated in 66 glioma patients (pts) in an ongoing phase 1 study. AG-881 (vorasidenib [VOR]) is an oral, potent, brain-penetrant inhibitor of mIDH1/2 evaluated in 52 glioma pts in an ongoing phase 1 study. In an orthotopic glioma model, IVO and VOR reduced 2-hydroxyglutarate (2-HG) by 85% and 98%, respectively, despite different brain:plasma ratios (<0.04 vs 1.33). Methods: Primary endpoint: brain tumor 2-HG concentration with IVO or VOR treatment in mIDH1 low-grade glioma. Pts with recurrent non-enhancing WHO-2016 Grade (Gr) 2 or 3 mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500mg QD, VOR 50mg QD, or no treatment for 4 wks preoperatively in Cohort 1. Post-operatively, pts continued to receive IVO or VOR and control pts were randomized 1:1 to IVO or VOR. Tumors were assessed for mIDH1 status, cellularity, 2-HG, and drug concentration. Treated samples were compared to control pts and mIDH1 and wild type (WT) banked reference (ref) samples. Plasma and CSF 2-HG were assessed. Pts with non-evaluable tissue were replaced. Results: As of 29 Nov 2018, 26 pts (17M, 9F; 25 Gr 2, 1 Gr 3) were randomized preoperatively (IVO 10, VOR 11, control 5), 25 received drug (IVO 12, VOR 13). At the data cut, 19 tumors were analyzed with 16 evaluable. Common (>10%) TEAEs (all grade 1/2): diarrhea (36%), hypocalcemia and constipation (each 20%), anemia, hyperglycemia, pruritus, headache and nausea (each 16%), and hypokalemia and fatigue (each 12%). Mean brain:plasma ratio: 0.16 for IVO, 2.4 for VOR. Tumor 2-HG results are shown in Table. Updated data from Cohort 1 will be presented. Conclusions: In Cohort 1 of this phase 1 perioperative study, IVO and VOR were CNS penetrant and lowered 2-HG compared to untreated samples. Cohort 2 is open and will evaluate IVO 250mg BID and VOR 10mg QD. Brain tumor 2-HG concentration. Clinical trial information: NCT03343197. [Table: see text]
Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma.
Authors: Chiocca E. Antonio , Lukas Rimas Vincas , Rao Ganesh , Barrett John A. , Buck Jill Y. , Demars Nathan , Smith Amy , Miao John , Zhou Qiang (John) , Gelb Arnold Bruce , Cooper Laurence
Published: May 2019

2020

Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate conditionally expressing IL-12 under the control of veledimex (V) acting via the proprietary RheoSwitch Therapeutic System (RTS) gene switch with a therapeutic window. Intratumoral Ad + oral V monotherapy (Phase 1 study, NCT02026271 ) resulted in a new sustained intra-tumor influx of activated cytotoxic T cells, consistent with an immune-mediated anti-tumor effect improving median overall survival (mOS) of subjects with recurrent glioblastoma (rGBM). This correlated with an increased circulating CD8+/FoxP3+ T cell ratio (“cytoindex”), an emerging biomarker for mOS. PD-1 expression on infiltrating T cells at biopsy after Ad+V, supports combining controlled IL-12 with a PD-1 inhibitor to further augment T-cell-mediated anti-tumor effects. The rationale is also supported by increased OS (100% combo vs 63% for Ad+V vs 40% for anti-PD-1) in mice bearing GL-261 glioma. Methods: An ongoing open label, dose-escalation Phase 1 trial (NCT03636477) is evaluating safety and tolerability of local, controlled IL-12 with nivolumab (nivo) in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles, Day 0) plus V (10-20 mg) PO QD x 15 with nivo (1-3mg/kg) IV on Days -7, 15, then Q2W. Results: Safety data revealed a similar profile as Ad +V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with anti-PD-1 reports. ARs were manageable and reversible with no synergistic toxicities. Nivo alone did not alter peripheral IL-12 levels (median baseline (before anti-PD-1) 0.9 pg/mL; Day 0 1 pg/mL) increasing to 5.5 pg/mL on Day 3. Nivo alone increased peripheral T cells (CD3+CD8+ median baseline 23%; Day 0 26%) and Ad+V elevated peripheral CD3+CD8+ to 31% at Day 14. Nivo alone decreased regulatory T cells (FoxP3 baseline 1.5% vs Day 0 0.8%). Ad+V decreased these to 0.3% (Day 14). Combination therapy improved the cytoindex (baseline 15; Day 0 29; Day 14 80). Conclusions: Controlled IL-12 production using Ad + V with nivo is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile, warranting continued investigation in rGBM. Clinical trial information: NCT03636477.
Phase I trial of TG02 plus dose-dense or metronomic temozolomide for recurrent anaplastic astrocytoma and glioblastoma in adults.
Authors: Wu Jing , Yuan Ying , Cordova Christine , Aboud Orwa , Penas-Prado Marta , Theeler Brett James , Bryla Christine , Su Yu-Ting , Grajkowska Ewa , McCoy Ann , Boris Lisa , Siegel Christine , Antony Ramya , Garren Nancy , Lawhon Tracy , Armstrong Terri , Gilbert Mark R.
Published: May 2019

2031

Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.
Phase II study to evaluate safety and efficacy of MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma (new unmeth GBM).
Authors: Reardon David A. , Kaley Thomas Joseph , Dietrich Jorg , Clarke Jennifer Leigh , Dunn Gavin , Lim Michael , Cloughesy Timothy Francis , Gan Hui Kong , Park Andrew J. , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph Rudolph
Published: May 2019

2032

Background: Durvalumab (durva), a human IgG1 monoclonal Ab against PD-L1, is FDA-approved for selected patients with bladder and non-small cell lung cancers. PD-L1 is expressed by some GBM tumors, while GBM infiltrating T lymphocytes often express PD-1. Radiation induced cell death releases tumor antigens and could potentiate anti-PD-(L)1 therapy. Methods: This ongoing Phase 2 open-label study (NCT02336165) evaluates the safety and efficacy of durva (10 mg/kg every 2 weeks) in 5 GBM cohorts. Results are presented for Cohort A, which evaluates durva + standard radiotherapy (RT, 60 Gy over 30 fractions) followed by durva monotherapy in patients with new unmeth GBM after maximum safe resection. The primary efficacy endpoint for Cohort A is overall survival at 12 months (OS12); secondary endpoints include safety/tolerability, tumor response rate, and progression-free survival (PFS). Historical benchmarks of median OS and OS12 for patients with new unmeth GBM following standard therapy are 12.7 months and 50%, respectively (EORTC 26981-22981/NCIC CE.3). Results: Median follow-up of 40 enrolled patients is 24.5 months (data cutoff = 05 Nov 2018). Baseline characteristics: male, 70%; median age, 57.0 [22 to 77] years; ECOG PS0, 60.0%; ECOG PS1, 40.0%; measurable disease, 80.0%; and dexamethasone use, 32.5%. Treatment-related adverse events with maximum CTCAE grade ≥ 3 occurred in 14 (35.0%) patients; the most common were asymptomatic increased lipase (n = 6) and increased amylase (n = 2). Twenty-four of 40 patients were alive at 12 months (Kaplan-Meier for OS12, 60.0% [90% CI: 46.1, 71.4]). Median OS was 15.1 (95% CI: 12.0, 18.4) months. As of 05 Nov 2018, 8 (20%) patients remain alive, with ongoing survival ranging from 15.7 to 34.9 months. Tumor immunocorrelative and systemic studies are pending. Conclusions: This is the first study report of anti-PD-L1 for new GBM. Durva was well tolerated when combined with RT and seemed to have efficacy among patients with new unmeth GBM. Further studies may be warranted. Clinical trial information: NCT02336165.
A TITE-CRM phase I/II study of disulfiram and copper with concurrent radiation therapy and temozolomide for newly diagnosed glioblastoma.
Authors: Huang Jiayi , DeWees Todd , Campian Jian Li , Chheda Milan G , Ansstas George , Tsien Christina , Zipfel Gregory J. , Dunn Gavin P. , Ippolito Jospeh E , Cairncross J. Gregory , Easaw Jacob C. , Rubin Josh , Kim Albert H
Published: May 2019

2033

Background: Disulfiram (DSF) has shown promising activity against glioblastoma in preclinical studies and is more effective when combined with copper (Cu). Our previous phase I study established the maximum tolerated dose (MTD) of DSF when combined with adjuvant temozolomide (TMZ). This phase I/II study aims to establish the MTD when disulfiram and copper are combined with concurrent radiation therapy (RT) and TMZ for newly diagnosed glioblastoma and to explore preliminary efficacy. Methods: Eligible patients were treated with standard RT and TMZ plus escalating doses of DSF (250 mg - 375 mg PO QD) and Cu (2 mg PO TID), followed by adjuvant TMZ plus DSF (500 mg/day) and Cu. The time-to-event continual reassessment method (TITE-CRM) was used to continuously estimate the probability of dose-limiting toxicity (DLT) and to assign patients to doses with an estimated DLT probability of approximately 20% with a margin of 5%. Tumor mutations were evaluated with next-generation sequencing for all patients. Results: Eighteen glioblastoma patients were treated with the study therapy: 8 with DSF of 250 mg/day and 10 with 375 mg/day. Three DLTs were observed: 1 with 250 mg/day (grade 2 urinary incontinence and ataxia), and 2 with 375 mg/day (both grade 3 elevated liver enzymes). DSF had an estimated DLT probability of 10% (95% CI: 3-29%) at 250 mg/day, and 21% (95% CI: 7-42%) at 375 mg/day. After a median follow-up of 12.3 months, 1-year progression-free survival (PFS) was 57%, and 1-year overall survival (OS) was 69%. There was no significant difference in PFS/OS when stratified by DSF doses, surgical extent, or MGMT methylation status. However, glioblastomas with IDH1 (n = 6), BRAF (n = 2), or NF1 (n = 1) mutations had significantly better PFS and OS than those without the mutations: 1-year PFS: 100% vs 22%, respectively, p = 0.001; 1-year OS: 100% vs 42%, respectively, p = 0.006. Conclusions: The MTD of DSF with RT/TMZ/Cu for glioblastoma is 375 mg/day, and the recommended phase II dose is 250 mg/day. Although confirmation with larger sample size is needed, the combination demonstrates promising preliminary efficacy for the subset of glioblastoma with IDH1, BRAF, and NF1 mutations. Clinical trial information: NCT02715609.
Correlation of systemic and local inflammation with survival prognosis in glioma patients.
Authors: Mir Seyed Nazari Pegah , Ay Cihan , Marosi Christine , Moik Florian , Riedl Julia , Ricken Gerda , Hainfellner Johannes A. , Preusser Matthias , Pabinger Ingrid , Berghoff Anna Sophie
Published: May 2019

2052

Background: Immune modulating therapies have been a long withstanding treatment approach in glioma. However, gliomas are characterized by a particular absence of tumor infiltrating lymphocytes in the local tumor microenvironment. We aimed to gain insight on the distinct patterns of inflammation associated with survival prognosis in glioma. Methods: Patients were recruited at time of glioma diagnosis or progression in the prospective observational Vienna Cancer and Thrombosis Study (CATS). A single blood draw was performed at study inclusion. PD-L1 expression in the tumor tissue was investigated via immunohistochemistry. Optimal cut-off according to ROC curve was used to assess cut off values for survival analysis. Results: 193 patients with glioma (75.6% glioblastoma (WHO grade IV), 19.7% anaplastic glioma (WHO grade III), and 4.7% diffuse glioma (WHO grade II)) were included. 40/193 (20.7%) glioma had an IDH1 mutation. Membranous PDL1 expression in the tumor tissue was observed in 20/193 (10.4%) patients. 1/20 patient presented with PD-L1 expression and IDH1 mutation ( p = 0.082). PD-L1 significantly correlated with increased monocyte count (median: 0.657 vs. 0.450 [G/L], p = 0.008), higher C-reactive protein (CRP) (0.43 vs. 0.1 [mg/dL], p = 0.005) and higher fibrinogen (379 vs. 303 [mg/dL], p = 0.001). Presence of IDH1 mutation significantly correlated with increased platelet count (303 vs. 232 [G/L], p = 0.001) and lower Neutrophil/Lymphocyte (N/L) ratio (3.34 vs. 5.13, p = 0.016). Higher lymphocyte count ( > 1.484 [G/L], log-rank: p = 0.011), higher platelet count ( > 245.5 [G/L], p = 0.0001), as well as decreased N/L ratio ( < 5.13, p = 0.001) were significantly associated with increased survival prognosis. Conclusions: PD-L1 expression in tumor tissue was associated with markers of systemic inflammation in glioma patients. Systemic inflammation markers furthermore predicted improved survival. Immune modulating therapy approaches might be a promising approach in subgroups of glioma associated with increased baseline interaction of immune system and glioma.
Carbon ion reirradiaton for patients with malignant gliomas: Toxicity and first results of the prospective dose-escalation phase I/II CINDERELLA trial.
Authors: Combs Stephanie E , Bernhardt Denise , Adeberg Sebastian , Herfarth Klaus K , Unterberg Andreas , Wick Wolfgang , Debus Juergen , Rieken Stefan
Published: May 2019

2059

Background: The prospective phase I/II CINDERELLA trial investigates toxicity and effectiveness of a dose escalated reirradiation with carbon ions in patients with recurrent gliomas. Methods: Following a dose escalating protocol, 52 patients with WHO°II-IV gliomas were irradiated with carbon ions with doses of 3 Gy (RBE) in 10 – 16 fractions in 7 dose leels. Median age was 42 years (range: 28 - 69) with 19 female and 33 male participants. Forty-one patients were diagnosed with WHO°III/IV gliomas and 11 patients with WHO°II gliomas. At the time of reirradiation, all patients showed contrast-enhancing recurrences. MRI-based treatment planning encompassed the contrast enhancing lesion (GTV) with additional safety margins of 5 mm (CTV) and 3 mm (PTV). Clinical follow-up visits including contrast-enhanced MRI were scheduled every two months. We used RANO-criteria for diagnosis of progression. Survival rates were analyzed with Kaplan-Meier estimator. Relevant prognostic factors were determined with log rank-test, and toxicity was classified according to CTCAE v4.0. Results: Median time between first irradiation and reirradiation was 9 months (range: 7 – 228). PTV size was 12 – 310 ml. During follow-up ≥°3 toxicities were not observed. Follow-up MRI suggested radiation necrosis in 4 patients. Median overall survival was 352 days and was not influenced by age, gender or radiation dose. A significant trend for improved survival rates was seen in patients with small target volumes (480 days [PTV < 75ml] vs. 322 days [PTV > 75ml], p = 0.06) and initial low grade histology (497 days [WHO °II] vs. 322 days [WHO°III/IV], p = 0.069). During follow-up, 45 patients had local progression, while clinical deterioration was not seen. Median local progression-free survival was 138 days. Twenty-eight patients received chemo-/immunotherapy after reirradiation. Of those, 14 patients were treated with bevacizumab. Progression after reirradiation did not influence overall survival significantly. Conclusions: Carbon ion re-irradiation with 10-16 fractions of 3 Gy for patients with recurrent gliomas is safe; no dose limiting toxicities were observed. Median overall survival with approximately one year is high in comparison to other treatment options. It remains unclear if RANO-criteria is securing the diagnosis of therapy failure after carbon ion reirradiation. Further randomized controlled trials must be awaited to evaluate the effectiveness of reirradiation of carbon ions compared to other treatment options. Clinical trial information: NCT01166308.
Stereotactic radiosurgery for resected brain metastases: Does the surgical corridor need to be treated?
Authors: Shi Siyu , Jaoude Joseph Abi , Sandhu Navjot , Wang Elyn , Schofield Kirsten , Jin Michael C. , Zhang Carrie , Liu Elisa , Pollom Erqi L. , Soltys Scott G.
Published: May 2019

2068

Background: Post-operative stereotactic radiosurgery (SRS) is the standard of care for resected brain metastases, but SRS techniques are not standardized. Although expert consensus guidelines recommend that the surgical corridor leading to the resection cavity be included in the SRS plan, this statement is not based on data. We analyzed the patterns of failure and toxicity with post-resection SRS, with the hypothesis that the corridor needs not be targeted with SRS. Methods: In this IRB-approved retrospective review, from 428 lesions treated from 2005-2018 with post-resection SRS, 58 lesions (57 patients) had evaluable data and a ‘deep’ tumor with a surgical corridor defined as ≥ 1.0 cm from the surface pre-operatively. SRS targeted the surgical corridor, defined as the surgical tract uninvolved by tumor on pre-operative imaging, in 33(57%). Brain failure was defined as local (LF) if within the surgical cavity involved with tumor pre-resection, corridor (CF) if within the surgical tract leading to the surgical cavity, distant (DF) if a new parenchymal tumor, or leptomeningeal (LMD) for new nodular/classical leptomeningeal enhancement. The cumulative incidences of failure and adverse radiation effect (ARE) were analyzed with death and whole brain radiation therapy as competing risks. Results: The median follow-up was 14 months. Not targeting surgical corridor was associated with prior SRS/resection for other brain metastases (23% vs. 0%, p=0.01), deeper tumors (median 2.1 cm vs. 1.4 cm, p<0.01), and systemic treatment within 3 months (p =0.01), but not other factors (p>0.10). The 12-month failure rates, if surgical corridor was not treated vs. treated, respectively, were: CF 8% (1-24%) vs. 0% (p=0.12), LF 4% (0-17%) vs. 13% (4-27%) (p=0.32), LMD 40% (19-61%) vs. 10% (2-23%) (p=0.03), DF 65% (43-81%) vs. 35% (19-52%) (p=0.02), and ARE 8% (1-22%) vs. 13% (4-28%) (p=0.35). After adjusting for systemic treatment, differences were not statistically significant (p>0.05). Conclusions: Omitting the surgical corridor in post-operative SRS for resected brain metastases was not associated with statistically significant differences in recurrences or adverse radiation effect. Surgical corridor does not need to be included in all post-resection SRS.
A phase II study of pembrolizumab for HPV-associated papilloma patients with laryngeal, tracheal, and/or pulmonary involvement.
Authors: Pai Sara I. , Friedman Aaron D , Franco Ramon , Muniappan Ashok , Park Jong Chul , Campbell Nicholas Paul , Krantz Seth B. , Song Phillip C , Bove Michiel , Carroll Thomas L , Faquin William C , O'Neill Anne M. , Wirth Lori J.
Published: May 2019

2502

Background: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 & 11. RRP proliferates in the respiratory tract impacting breathing, swallowing, and voice and carries a 1-4% risk of malignant transformation. There is no curative therapy for RRP. Given the tolerized host immune response against HPV, in part through upregulation of the PD1:PDL1 axis, the safety and efficacy of pembrolizumab (pembro) as a novel treatment for this benign tumor patient (pt) population was evaluated in a phase II clinical trial. Methods: RRP pts > 12 years of age were treated with pembro 200mg every 3 weeks. Adjuvant surgical debridement of RRP was permitted for airway obstruction but not dysphonia. Primary endpoints were best overall response (ORR) (measured by endoscopic lesional burden) and safety. Greater than 5 pts with disease in response out of 21 (assuming > 1 of first n = 11 with disease in response) provided 86% power to distinguish between a 15% and a 38% ORR (one-sided 8% binomial test). Serial biopsies (up to 8 biopsies/patient over the 24 months of treatment) to identify biomarkers of response and mechanisms of immune resistance (PD-L1 expression, mutations in HLA class I antigen presentation machinery, and tumor mutational burden) are underway. Results: Accrual is complete (n = 21 pts accrued between May 2016 and Jan 2019). Median age (range) was 45 (19-68), 57% (12/21) were male and 67% (14/21) were white. As of February 1, 2019, ORR is 43% (9/21) (.95 two-stage CI: 22%-66%) (4 of 11 with juvenile-onset RRP and 5 of 10 with adult-onset RRP disease responded). No complete responses have been observed. Fatigue was the most frequent treatment related adverse event (TRAEs); Grade 3 TRAEs included uveitis and hypophysitis, both were reversible upon pembro discontinuation. The frequency of surgical interventions was reduced in all pts undergoing surgery for airway palliation prior to study entry. Conclusions: Pembro reduces the need for routine surgical interventions based on the response rates being achieved. Further study of pembro +/- other agents is warranted to achieve and sustain complete responses in this population. Clinical trial information: NCT02632344.
Results from a first-in-man, open label, safety and tolerability trial of CAN04 (nidanilimab), a fully humanized monoclonal antibody against the novel antitumor target, IL1RAP, in patients with solid tumor malignancies.
Authors: Awada Ahmad , Eskens Ferry , Robbrecht Debbie , Lassen Ulrik Niels , Soerensen Morten Mau , Steeghs Neeltje , Jungels Christiane , Aftimos Philippe Georges , Fretland Signe Øien , Thorsson Lars , Guren Tormod Kyrre
Published: May 2019

2504

Background: Interleukin 1 receptor Accessory protein, IL1RAP, is expressed in several solid tumors, both on cancer cells and tumor-associated inflammatory cells. CAN04 is a first-in-class fully humanized monoclonal antibody targeting IL1RAP blocking IL-1 alpha and beta signaling and triggering antibody dependent cellular cytotoxicity. Methods: The primary objective was to assess safety and tolerability of weekly CAN04 in order to define the Recommended Phase 2 Dose (RP2D). Patients (pts) with relapsed or refractory non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), breast or colorectal cancer were included using a 3+3 dose escalation design. Key eligibility criteria were ECOG ≤1, normal organ function and no bleeding disorder/coagulopathy. Tumor responses were evaluated according to irRC every 8 weeks. PK and biomarkers were analyzed in serum. Results: 22 pts were enrolled across 5 cohorts (1-10 mg/kg). Demography: mean age 62 yrs (39-81); gender 14 M and 8 F; median number of prior lines of therapy 3 (range 1-11). AEs occurred mainly following the first dose and the most common AEs were: infusion related reaction (IRR) (41%), pyrexia (27%), fatigue (23%), chills (23%) and nausea (23%). AE grade 3 or 4: one IRR, one neutropenia/leukopenia and one hypokalemia, all of them grade 3. Serum CRP and IL-6 were reduced after two weeks of treatment. There were linear increases of AUC and Cmax (1-10 mg/kg) and CAN04 exposure at 10mg/kg was above levels associated with signs of efficacy in preclinical models. In pts receiving at least one dose of CAN04, 9/20 (45%) had SD by irRC (7/20 had SD by RECIST 1.1) at 8 weeks follow up. Two pts, one with NSCLC and one with PDAC, had SD for 6 and 4 months (latter still on therapy). Conclusions: CAN04 demonstrated a manageable safety profile and a RP2D of 10 mg/kg has been established. The dose expansion phase of the trial will evaluate CAN04 as monotherapy as well as in combination with relevant chemotherapy regimens in NSCLC and PDAC in separate arms. Clinical trial information: NCT03267316.
Ipilimumab versus placebo after complete resection of stage III melanoma: Long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial.
Authors: Eggermont Alexander M. M. , Chiarion-Sileni Vanna , Grob Jean Jacques , Dummer Reinhard , Wolchok Jedd D. , Schmidt Henrik , Hamid Omid , Robert Caroline , Ascierto Paolo Antonio , Richards Jon M. , Lebbe Celeste , Ferraresi Virginia , Smylie Michael , Weber Jeffrey S. , Maio Michele , Hosein Fareeda , de Pril Veerle , Kicinski Michal , Suciu Stefan , Testori Alessandro
Published: May 2019

2512

Background: Since 2015, ipilimumab (Ipi) is an approved treatment for stage III melanoma based on a significantly (P=0.0013) prolonged recurrence-free survival (RFS) (Eggermont et al, Lancet Oncology, 2015). At a median follow-up of 5.3 years, RFS (HR=0.76) and distant metastasis-free survival (DMFS) (HR=0.76), assessed by an IRC, and overall survival (OS) (HR=0.72) were prolonged in the Ipi group as compared to the placebo (Pbo) group (Eggermont et al, NEJM, 2016), despite a 53.3% (Ipi) vs 4.6% (Pbo) treatment discontinuation rate due to adverse events. Methods: In this randomized double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. Here, we report the comparison between the Ipi and Pbo groups regarding the long-term efficacy outcomes using the local investigator assessments. Results: Overall, 20%/44%/36% of pts had AJCC-7 stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. Median follow-up was 6.9 yrs. The RFS, DMFS and OS benefit observed in the Ipi group was long-lasting (almost 10% difference at 7 years) and consistent across subgroups: no significant predictive factors could be detected. Conclusions: In this phase III trial, Ipi, administered at 10 mg/kg, as adjuvant therapy provided, at a 6.9 yr median follow-up, a sustained improvement in the RFS, DMFS, and OS long-term results in patients with high-risk stage III melanoma. Clinical trial information: NCT00636168. [Table: see text]
Prognostic and predictive value of an immune-related adverse event among stage III melanoma patients included in the EORTC 1325/KEYNOTE-054 pembrolizumab versus placebo trial.
Authors: Eggermont Alexander M. M. , Kicinski Michal , Blank Christian U. , Mandalà Mario , Long Georgina V. , Atkinson Victoria , Dalle Stéphane , Haydon Andrew Mark , Lichinitser Mikhail , Khattak Muhammad , Carlino Matteo S. , Sandhu Shahneen Kaur , Puig Susana , Ascierto Paolo Antonio , Krepler Clemens , Ibrahim Nageatte , Marreaud Sandrine , Van Akkooi Alexander Christopher Jonathan , Robert Caroline , Suciu Stefan
Published: May 2019

2517

Background: Several studies suggested that patients (pts) with an immune-related adverse event (irAE) during immunotherapy have better outcomes than those without. It remains uncertain whether these observations can be explained by guarantee-time bias or the role of irAE as an indicator of drug activity. Here, we investigated the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 trial that compared pembrolizumab and placebo in high-risk stage III melanoma pts. Methods: Eligible pts included adults with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (lymph node metastasis > 1 mm), IIIB or IIIC (without in-transit metastasis) and with no active autoimmune disease that required systemic treatment in past 2 years. We used a Cox model adjusted for sex, age, and stage with a time-varying covariate taking a value zero before the irAE onset and a value one afterwards to estimate the association between the occurrence of irAEs and RFS. Results: Consistent with the main analysis in the ITT population (n = 1019, Eggermont et al, NEJM, 2018), RFS was longer in the pembrolizumab than in the placebo arm (HR = 0.56, 98.4% CI: 0.43-074) among pts who started the treatment (n = 1011). The incidence of irAE on study was 37.3% in the pembrolizumab (n = 509) and 9.0% in the placebo arm (n = 502) and, in each treatment group, it was similar in males and females. The occurrence of an irAE was significantly associated with a longer RFS in the pembrolizumab arm (HR = 0.61, 95% CI: 0.39-0.95, P = 0.03). This was true for both males and females. However, in the placebo arm, no association was observed (HR = 1.39, 95% CI: 0.83-2.32, P = 0.21). Compared to the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater (P = 0.028) after an onset of an irAE (HR = 0.37, 95% CI: 0.24-0.57) than without/before an irAE (HR = 0.61, 95% CI: 0.49-0.77). Conclusions: In the EORTC 1325/KEYNOTE-054 study conducted in high-risk stage III melanoma pts, the occurrence of an irAE was strongly associated with a longer RFS in those treated with pembrolizumab, but not with placebo. Clinical trial information: NCT02362594.
Phase I study of OKT3 x hu3F8 bispecific antibody (GD2Bi) armed T cells (GD2BATs) in GD2-positive tumors.
Authors: Yankelevich Maxim , Modak Shakeel , Chu Roland , Lee Daniel W. , Thakur Archana , Cheung Nai-Kong V. , Lum Lawrence G.
Published: May 2019

2533

Background: With the proven success of anti-GD2 monoclonal antibodies in eradicating minimal residual disease in neuroblastoma (NB), exploiting antibody based anti-GD2 in T cell mediated strategies has potential to combat higher disease burden and improve patient outcome. We hypothesized that arming of ex vivo expanded and activated, autologous, blood derived T cells (ATC) with chemically heteroconjugated GD2Bi should redirect them to target NB. In vitro, ATC coated (armed) with 50 ng/106 cells of GD2Bi exhibited specific killing of NB and osteosarcoma (OS) cell lines. Methods: In this phase I study (NCT02173093), patients with GD2-positive tumors received 8, biweekly infusions of GD2BATs + daily low-dose IL-2 and biweekly granulocyte-macrophage colony stimulating factor (GM-CSF). The study followed the standard 3+3 design with dose levels of 40, 80, and 160 x 106 GD2BATs/kg/infusion. Results: Twelve patients (NB = 7, OS = 3, Desmoplastic Small Round Cell Tumor = 2) were enrolled from 11/2013 to 12/2017 and 9 completed therapy. Adequate ATCs could not be grown in one patient and two patients did not complete 8 infusions because of rapid disease progression. Infusions were given in outpatient settings. All patients developed a mild, dose-independent and manageable form of cytokine release syndrome with grades 2-3 fevers/chills, headaches and occasional hypotension for up to 48 hours after infusion. No patients developed significant pain. Maximum tolerated dose was not reached. Evidence of activity was seen in several patients including one patient with OS who had a PET response, one patient with NB who had complete bone marrow response (this patient had remained progression free for 2.5 years after completion of infusions), and another NB patient who had a minor response on MIBG scan. Four patients with NB are currently alive after additional therapies at 12, 14, 18, and 47 months post BAT infusions. Conclusions: Autologous T cells from heavily pretreated patients could be expanded ex vivo to large numbers, armed with GD2Bi, cryopreserved and thawed for safe IV administration up to total dose of 1.28x109/kg. Ongoing phase II arm of the trial will focus on evaluation of clinical activity of GD2BATs in patients with NB. Clinical trial information: NCT02173093.
Phase 1 trial of anti-CD19 chimeric antigen receptor T (CAR-T) cells with tumor necrosis alfa receptor superfamily 19 (TNFRSF19) transmembrane domain.
Authors: Caimi Paolo Fabrizio , Reese Jane , Otegbeye Folashade , Schneider Dina , Chamoun Kamal , Boughan Kirsten M , Cooper Brenda W. , Galloway Erin , Gallogly Molly , Kruger Winfried , Worden Andrew , Kadan Michael , Malek Ehsan , Metheny Leland L. , Tomlinson Benjamin K. , Sekaly Rafick-Pierre , Wald David , Orentas Rimas , Dropulic Boro , De Lima Marcos J.G.
Published: May 2019

2539

Background: AntiCD19 CAR-T cells have shown encouraging anti-lymphoma activity. Decreasing the time from apheresis to CAR-T infusion can make this therapy available to pts with rapid progression. We present the interim results of a phase I clinical trial using on-site CAR-T manufacture. Methods: Adult pts with r/r CD19+ B cell lymphomas who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc,LTG1563) encoding an antiCD19 binding motif, CD8 linker and TNFRSF19 transmembrane region, and 4-lBB/CD3z domains. GMP-compliant manufacture was done using CliniMACS Prodigy, in a 12-day culture. Dose levels were 0.5, 1 and 2 x 106 CAR-T cells/kg. Lymphodepletion was done with cyclophosphamide (60mg/kg x 1) and fludarabine (25mg/m2/d x 3). Results: 7 pts (4 women, 3 men) were enrolled. Median age was 60y [range 43-69]. Diagnoses were DLBCL (n = 3) PMBCL, follicular lymphoma (FL), transformed FL, and transformed lymphoplasmacytic lymphoma; with a median of 4 previous treatments. Six pts had symptomatic refractory disease. CAR-T cell product manufacture was successful in all pts. Mean transduction rate was 44% [range 29-57]. CAR-T cell doses were 0.5 x 106/kg (n = 3) and 1 x 106/kg (n = 4). Median apheresis to infusion time was 13 days [range 13–20], 5 products were infused fresh. CAR-T persistence based on vector sequence, peaked in peripheral blood MNCs between days 14-21. Five pts are evaluable for safety. CRS grade 1 - 2 (Lee) occurred in 4 pts; with 3 requiring treatment. Grade 4 CRES (CARTOX-10) occurred in 1 pt, with resolution after corticosteroids; considered a DLT as it lasted more than 72 hours. No treatment-related mortality has occurred. 4/5 evaluable pts have achieved complete response. One pt did not respond and died. After a median follow up 3 months, all responding pts are alive and 1 relapsed 6 mo after treatment. Conclusions: Second generation antiCD19 CAR-T cells with TNFRS19 transmembrane domain have clinical activity against refractory NHL. Short manufacture time achieved by local CAR-T cell manufacture with the CliniMACS Prodigy enables treatment of a very high risk NHL population. Clinical trial information: NCT03434769.