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Rancour-Laferriere, Daniel. "Nadežda Durova Remembers her Parents." Russian Literature 44, no. 4 (November 1998): 457–68. http://dx.doi.org/10.1016/s0304-3479(98)80002-1.
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López, Camila Soares. "“Durtal”, de Paul Valéry: uma tradução." Rónai – Revista de Estudos Clássicos e Tradutórios 7, no. 2 (December 11, 2019): 151–59. http://dx.doi.org/10.34019/2318-3446.2019.v7.25968.
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Neste trabalho, propomos uma tradução do ensaio crítico “Durtal”, de autoria de Paul Valéry e que versa sobre o romance homônimo de J.-K. Huysmans. Originalmente, o texto de Valéry foi publicado em 1898 na revista Mercure de France, petite revue parisiense que circulou nos meios simbolistas e de demais entusiastas da renovação literária. Em um primeiro momento, tecemos considerações acerca dos dois autores, bem como sobre a proximidade de ambos. Por fim, apresentamos a tradução de “Durtal” para língua portuguesa.
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Wojciech, Jernajczyk, and Leszek Jerzy. "EEG SLEEP PATTERN DURTNG INTERFERON TREATMENT." Clinical Neuropharmacology 15 (1992): 276B. http://dx.doi.org/10.1097/00002826-199202001-00533.
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Goldman, Jonathan Wade, Sarina Anne Piha-Paul, Brendan D. Curti, Katrina Pedersen, Todd Michael Bauer, Stefanie L. Groenland, Richard D. Carvajal, et al. "Safety and tolerability of MEDI0562 in combination with durvalumab or tremelimumab in patients with advanced solid tumors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3003. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3003.
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3003 Background: We report safety and tolerability of MEDI0562, a humanized IgG1κ OX40 monoclonal antibody (mAb), in combination with durvalumab (durva; anti-PD-L1 mAb) or tremelimumab (treme; anti-CTLA-4 mAb) in patients (pts) with previously treated advanced solid tumors. Methods: In this phase 1, open-label study (NCT02705482), adult pts received escalating doses of MEDI0562 (2.25, 7.5 or 22.5 mg/kg) every 2 wks (Q2W) in combination with durva (1500 mg/kg) or treme (75 or 225 mg/kg) Q4W, until confirmed disease progression or unacceptable toxicity. Tumor assessments were performed Q8W with immune-related Response Evaluation Criteria in Solid Tumors. Results: In total, 27 and 31 pts received MEDI0562 + durva or treme, across 5 dose combination cohorts (3 + 3 design), with a maximum tolerated dose of 7.5 mg MEDI0652 + 1500 mg durva and maximum administered dose of 10 mg MEDI0562 + 225 mg treme. Median duration of exposure was 12.0 (range 2.0–80.9) and 8.0 (range 2.0–42.0) wks, respectively. Two (22.5 mg MEDI10562 + durva) and 3 (2.25 mg MEDI0652 + 225 mg treme, 22.5 mg MEDI0562 + 75 and 225 mg treme) dose limiting toxicities were observed. For MEDI0562 + durva and MEDI0562 + treme groups respectively, treatment-emergent adverse events (TEAEs) were reported in 96.3% and 100% of pts; most common TEAEs were fatigue (55.6%) and pruritus (45.2%), Gr 3/4 TEAEs occurred in 74.1% and 67.7%; and MEDI0562-related AEs were reported in 20 (74.1%) and 24 (77.4%) pts. Six TEAEs in each group led to MEDI0562 discontinuation (22.2% and 19.4%, respectively), 2 led to death (renal failure [7.5 mg MEDI0562 + durva], multiple organ dysfunction syndrome [22.5 mg MEDI0562 + 225 mg treme]). Three response evaluable pts had PR (11.5% [7.5 and 22.5 mg MEDI0562 + durva, n = 26]). Median overall survival was 17.4 and 11.9 mos for MEDI0562 + durva and MEDI0562 + treme, with stable disease seen in 9 pts from each group, 34.6% vs 29.0%, respectively. Serum exposure of MEDI0562 increased dose proportionally. Post treatment serum antidrug antibody (ADA) was detected in 20 pts from MEDI0562 + durva and MEDI0562 + treme (74.1% and 71.4%, respectively). The impact of ADA on MEDI0562 pharmacokinetics was seen at all doses. Mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased, while mean percentage of OX40+CD4+ memory T cells decreased following the first dose of MEDI0562 + durva or treme. Conclusions: The safety profile of MEDI0562 in combination with durva or treme was similar between groups. Clinical activity was observed with MEDI0562 + durva in pts with advanced solid tumors. Clinical trial information: NCT02705482 .
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Naidoo, Jarushka, Johan F. Vansteenkiste, Corinne Faivre-Finn, Mustafa Özgüroğlu, Shuji Murakami, Rina Hui, Xavier Quantin, et al. "Non-pneumonitis immune-mediated adverse events (imAEs) with durvalumab in patients with unresectable stage III NSCLC (PACIFIC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 9048. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9048.
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9048 Background: The phase 3 PACIFIC trial established durvalumab (durva) after chemoradiotherapy (CRT) as SoC for pts with unresectable stage III NSCLC. We report exploratory analyses to characterize non-pneumonitis (np) imAEs that occurred with durva in PACIFIC. Methods: PACIFIC was a double blind trial of pts without disease progression after platinum-based concurrent CRT (≥2 cycles). Pts were randomized 2:1 to receive durva 10 mg/kg or placebo (pbo) IV q2w for ≤12 months, stratified by age, sex and smoking history. We characterized the time to onset, duration, and management/outcomes of np imAEs and their association with (1) baseline pt/disease factors and (2) AEs (excluding all-cause pneumonitis). Results: Of 709 treated pts, 19% and 11% experienced imAEs and np imAEs of any grade, respectively; proportionally more had np imAEs with durva (71/475; 15%) vs pbo (5/234; 2%). Thyroid disorders (54/475; 11%), rash/dermatitis (9/475; 2%), and diarrhea/colitis (5/475; 1%) were the most common np imAEs with durva; rash/dermatitis had the shortest time to onset (Table). Among durva treated pts with np imAEs, 11% had grade 3/4 np imAEs, 41% had np imAEs that resolved, and none had fatal np imAEs; interventions included endocrine replacement therapy (73%), systemic corticosteroids (34%), high dose corticosteroids (16%), and discontinuation (10%). There were no apparent differences in baseline factors between pts with or without np imAEs. Durva had a broadly manageable safety profile irrespective of the occurrence of np imAEs. However, a higher proportion of durva treated pts with vs without np imAEs experienced all-cause, grade 3/4 events (41% vs 29%); none were fatal (excl. pneumonitis). Conclusions: Np imAEs occurred infrequently in PACIFIC, but were more common with durva vs pbo; thyroid disorders and rash/dermatitis were the most common np imAEs. Of durva treated pts with np imAEs, 11% experienced np imAEs of grade 3/4. Overall, np imAEs were broadly manageable and did not lead to high rates of discontinuation, and no association with baseline factors was seen, suggesting this should not deter use of durva in eligible pts. Clinical trial information: NCT02125461. [Table: see text]
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Planchard, David, Byoung Chul Cho, Jhanelle Elaine Gray, Luis G. Paz-Ares, Mustafa Ozguroglu, Augusto E. Villegas, Davey B. Daniel, et al. "First subsequent treatment after discontinuation of durvalumab in unresectable, stage III NSCLC patients from PACIFIC." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 9054. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.9054.
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9054 Background: In the phase 3 PACIFIC trial of unresectable, stage III NSCLC patients (pts) without progression after concurrent chemoradiotherapy (cCRT), durvalumab (durva) significantly improved PFS and OS with similar safety compared to placebo (pbo). We performed exploratory analyses to characterize first subsequent treatment (Tx) after discontinuation of durva. Methods: Pts with WHO PS 0/1 and any tumor PD-L1 status were randomized (2:1) 1–42 days after ≥2 cycles of platinum-based cCRT to durva 10 mg/kg IV or pbo Q2W up to 12 months, stratified by age, sex and smoking history. Pts were classified by the use or not of first subsequent Tx and category of first systemic Tx (platinum doublet CT [PDCT], single-agent CT [SCT], immunotherapy [IT] or targeted therapy [TT]). Results: As of Mar 22, 2018, 216/476 (45.4%) and 153/237 (64.6%) in the durva and pbo arms, respectively, had a RECIST-based PFS event per BICR (5.7% and 8.4% due to death). 195 (41.0%) and 128 (54.0%) received first subsequent Tx, most of which were systemic Tx (158 [33.2%] and 109 [46.0%]): PDCT (16.4% and 19.0%), SCT (8.6% and 8.4%), IT (4.2% and 13.5%) or TT (3.8% and 5.1%); 7.8% and 8.0% received RT only. Time to first subsequent therapy or death (TFST) was longer with durva vs pbo (HR 0.58; 95% CI 0.47–0.72; median 21.0 vs 10.4 months). Baseline characteristics of pts with or without first subsequent Tx were similar, and similar across durva or pbo arms. Among pts with systemic Tx, baseline characteristics (including pre-cCRT PD-L1 status) were generally similar, except pts on TT, more of whom were EGFR+ (70.0% vs 0–6.6% of other systemic Tx groups) with commonly associated phenotypes (more females, Asians, non-smokers and non-squamous pts). Best overall response to first systemic Tx will be presented. Conclusions: Due to longer PFS and fewer progression events with durva vs pbo, fewer pts on durva required subsequent Tx and, per TFST, much later. With the exception of IT, use of each subsequent Tx was similar between the durva and pbo arms with PDCT the most common. Baseline characteristics were similar for pts with or without first subsequent Tx and pts who received first systemic Tx, except for pts who received TT, as expected due to their molecular profile.
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Sibourg, Eléonore. "Retrouver le temple du sacré : la logique des extrêmes dans le roman de Durtal." Quêtes littéraires, no. 3 (December 30, 2013): 108–15. http://dx.doi.org/10.31743/ql.4611.
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In the late 19th century a reversal of the values linked to the sacred and the profane can be observed. As Religion retreats, Positivism and faith in Progress fill the gap left by the abandoned spiritual belief. A nostalgia for transcendence arises amongst writers. Naturalism turns out to be sterile, but, sill, a belief in God seems to have become impossible. It is in this context that Huysmans writes his novels. The Durtal tetralogy in particular focuses on this theme: desperate, the main character wanders around Catholicism, seeking a sense of the Sacred. He first explores the world of Satanism before the conversion. But even when faith is regained, problems are not solved. In the religious domain itself, Durtal condemns the sacralization of the profane. Henceforth, the Durtal tetralogy manifests itself as a novel of the in-between: from brothel to church, between up-above and down-below, between almighty materialism and bourgeois Catholicism, this misanthropic writer prays for a renewed and primitive form of religious practice in which the individual can access the Sacred again. The quest for the supernatural, through a questioning of contemporary society, becomes a quest for Identity.
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Richardson, Paul G., William Bensinger, Katja C. Weisel, Kevin Boyd, Karthik Ramasamy, Esther Gonzalez, Linda Favre-Kontula, et al. "Durvalumab (DURVA) plus daratumumab (DARA) in patients (pts) with relapsed and refractory multiple myeloma (RRMM)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS8054. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps8054.
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TPS8054 Background: DARA, a monoclonal antibody (mAb) against CD38, is approved for RRMM. Combination treatment (Tx) with DARA + DURVA, a mAb against programmed death ligand-1 (PD-L1), may enhance host anti-MM immunity and response. DARA and PD-L1 mAbs have each demonstrated clinical activity in combination with pomalidomide (POM) + low-dose dexamethasone (LoDEX) in MM. Thus, the phase 2 MEDI4736-MM-003 trial is evaluating DURVA + DARA in RRMM, and, in an exploratory analysis, the addition of POM + LoDEX to DARA + DURVA either upon progressive disease (PD) with DARA + DURVA or as up-front Tx will be assessed. Methods: ≈ 144 pts with RRMM are being enrolled. Pts with measurable MM who received ≥ 3 prior anti-MM Txs, including a protease inhibitor and an immunomodulatory agent, or are double-refractory to these 2 agents will be included. Exclusion criteria include allogeneic stem cell transplant (SCT), autologous SCT ≤ 12 weeks, and prior DARA or other CD38 antibody therapies. Primary endpoints are overall response rate (ORR) and safety. Secondary endpoints are time to response, duration of response, progression-free survival, and pharmacokinetics. The study includes a 3 + 3 safety run-in phase to confirm the tolerability of the recommended phase 2 doses (RP2Ds) of DURVA and DARA. Dose-limiting toxicities will be evaluated during the first Tx cycle. Safety and efficacy will be assessed by a Simon 2-stage design (Table). POM + LoDEX may be added to DARA + DURVA in pts who received ≥ 2 cycles of DARA + DURVA and had confirmed PD. Based on preliminary safety and efficacy, the 4-drug regimen may be explored as up-front Tx. Tx with either the 2- or 4-drug regimens will continue until PD or unacceptable toxicity. Pts treated with POM will be followed for second primary malignancies every 6 mos until the end of the trial. To date, 6 pts have enrolled in the run-in phase. Clinical trial information: NCT02807454. [Table: see text]
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Joshi, Monika, Matthew Kaag, Leonard Tuanquin, Jason Liao, Deepak Kilari, Hamid Emamekhoo, Alexander Sankin, et al. "Phase II clinical study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: Results for primary analyses and survival. BTCRC-GU15-023." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 398. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.398.
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398 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, or locally advanced and unresectable have limited treatment options. DUART investigates if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. We recently reported that the combination was safe, tolerable and disease control rate (DCR) was 92% post durvaRT. Here we present interim efficacy data of our phase II study. Methods: Pts with pure or mixed urothelial bladder cancer (T2-4 N0-2 M0) were enrolled if their tumor was unresectable (35%), were unfit for surgery (50%) and/or cisplatin ineligible (89%). Primary endpoints: a) PFS at 1-yr b) DCR post adjuvant durva; Secondary endpoints: a) CR post durvaRT b) median PFS c) median OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy. Sample size was based on assumption that this regimen would increase 1 yr PFS by 25% compared to RT alone (50% to 75%); we assumed DCR of 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Twenty-six pts (19 males, 7 females) were enrolled, median age 74 yr (51-94). Sixty two percent of pts had >T2 disease, 31% had positive lymph nodes; 62% with unresectable tumor or were unfit for surgery due to comorbidities. At data cut off (9/30/2020) 20/26 pts were evaluable for DCR post adjuvant durva (3 pts with CR post durvaRT, did not get adjuvant therapy; 1 pt withdrew after 3 cycles for adjuvant durva and was on f/u with unconfirmed CR; 2 pts are still on adjuvant durva) and 25/26 for PFS and all 26 pts for OS. Post completion of adjuvant durva, DCR was seen in 70 % (14/20 with 10 CR; 3 PR; 1 SD; 6 PD). One-year probability of PFS was 73% (95% CI 56.4%, 94.4%), median PFS was 18.5 months. One-year OS probability was 83.8% (95% CI 70.4%, 99.7%) with two-year OS probability of 76.8 (95% CI 60.2%, 98%). Median OS has not been reached. We did not observe any correlation between clinical outcome and baseline tumor PD-L1 expression. Conclusions: DurvaRT followed by adjuvant durva demonstrated promising efficacy with 1-year PFS probability of 73%, 1- year OS probability of 83.8% and DCR of 70% in MIBC and locally advanced BC pts with comorbidities. Results will be updated prior to the final presentation. Efficacy was also seen in node (+) pts which led to the design of prospective randomized NCTN study. Induction chemo followed by chemo+durvaRT+ adjuvant durva vs. chemoRT combination is being evaluated in the ongoing EA8185 clinical trial (ECOG-ACRIN/NRG study) for node (+) BC pts. Clinical trial information: NCT02891161.
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Rozgonyi, Nikoletta. "Effect of air pollution on coarse-grained limestone." Epitoanyag - Journal of Silicate Based and Composite Materials 54, no. 2 (2002): 30–36. http://dx.doi.org/10.14382/epitoanyag-jsbcm.2002.6.
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Pápay, Zita, and Ákos Török. "The effect of silica-acid-ester stone consolidants on coarse limestone." Epitoanyag - Journal of Silicate Based and Composite Materials 58, no. 4 (2006): 102–6. http://dx.doi.org/10.14382/epitoanyag-jsbcm.2006.16.
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Harter, Philipp, Mariusz Bidziński, Nicoletta Colombo, Anne Floquet, Maria Jesús Rubio Pérez, Jae-Weon Kim, Stephanie Lheureux, et al. "DUO-O: A randomized phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS5598. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps5598.
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TPS5598 Background: Ovarian cancer (OC) is the leading cause of death from gynecologic cancers in US women. Despite high response rates to first-line treatment, ~70% of patients (pts) relapse within 3 years and then remain largely incurable. First-line treatment needs to be improved to achieve long-term remission in pts and improve the cure rate. The Phase III SOLO1 trial showed a meaningful clinical benefit for olap maintenance therapy in newly diagnosed OC pts with a BRCA mutation (Moore et al N Engl J Med 2018). Preliminary data suggest that combining a PD-L1 inhibitor, anti-angiogenic and PARP inhibitor (triplet therapy) may achieve a synergistic antitumor effect. The DUO-O study (NCT03737643) evaluates the efficacy and safety of treatment combinations involving standard-of-care platinum-based chemotherapy (chemo), VEGF inhibitor bev, anti-PD-L1 antibody durva and PARP inhibitor olap, in women with newly diagnosed advanced OC. Methods: Eligible pts for this double-blind, randomized, Phase III study must have newly diagnosed, advanced, high-grade epithelial OC and either have completed primary surgery or plan to have interval debulking surgery. Depending on their tumor BRCA mutation (tBRCAm) status (determined by central test), pts will join one of two independent cohorts. Pts in the non-tBRCAm cohort (n~906) will be randomized (1:1:1) before cycle 2 to: a) chemo + bev + placebo (for 6 cycles) followed by bev (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets); b) chemo + bev + durva (6 cycles) followed by bev + durva (1120 mg q3w [total 15 months]) + placebo (tablets) maintenance treatment; or c) chemo + bev + durva (6 cycles) followed by bev + durva + olap (300 mg bd tablets [24 months]) maintenance treatment. Pts in the open-label tBRCAm cohort (n~150) will receive 6 cycles of chemo + durva followed by durva + olap maintenance therapy, with optional use of bev. The primary endpoint of progression-free survival will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, overall response rate and duration of response. Enrollment began in January 2019. Clinical trial information: NCT03737643.
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Puriaeva, N. N. "Mythologem with a Snake: Constructing the Myth of Cavalry-Maiden." Izvestia Ural Federal University Journal Series 1. Issues in Education, Science and Culture 26, no. 4 (2020): 27–31. http://dx.doi.org/10.15826/izv1.2020.26.4.066.
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The article is dedicated to a narrative element that can be found in a number of texts featuring Nadezda Durova, we refer to it as an episode with a snake. The article hypothesizes that the episode is a mythologeme that has several meanings. Based on the results of the study, the following conclusions were made regarding the episode with a snake: it refers to an ancient Greek myth of Hercules’s childhood; it appears as an allusion to the biblical legend of the serpentadversary; it acts as an allegorical image of the enemy conquest. Thus, in the studied number of texts featuring Durova the episode with a snake acquires significance of a mythologem, which in the context of her story denotes the initiation of the heroine.
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Bang, Yung-Jue, Talia Golan, Chia-Chi Lin, Laetitia Dahan, Siqing Fu, Victor Moreno, Ravit Geva, et al. "Ramucirumab (Ram) and durvalumab (Durva) treatment of metastatic non-small cell lung cancer (NSCLC), gastric/gastroesophageal junction (G/GEJ) adenocarcinoma, and hepatocellular carcinoma (HCC) following progression on systemic treatment(s)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2528. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2528.
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2528 Background: A Phase 1b study (NCT02572687) was conducted to examine the combined effects of Ram (anti VEGFR2) and Durva (anti PD-L1). Methods: Patients (pts) with previously-treated, advanced NSCLC (Cohort [CH] A), G/GEJ adenocarcinoma (CH B), HCC (CH C), ECOG PS 0-1, and no prior Ram or IO therapy, received Ram (10 mg/kg) + Durva (1125 mg) Q3W (CH A) or Ram (8 mg/kg) + Durva (750 mg) Q2W (CH B, C). Primary objective was to assess safety; efficacy was also examined. PD-L1 expression of tumor cells (TC) +/- immune cells (IC) in pretreatment tumor biopsies were assessed using SP263 immunohistochemistry. “High” PD-L1 is ≥25% TC for NSCLC and ≥25% TC or IC for G/GEJ, HCC. Results: CH A, B and C enrolled pts with ECOG PS 1 (%) of 43, 66, 68; and average of 2, 2, 1 prior regimens, respectively. The most common grade 3/4 treatment-emergent adverse events (AE) are hypertension (HTN) (14.3, 17.2, 17.9%), anemia (3.6, 24.1, 21.4%), and fatigue (10.7, 10.3, 10.7%). Grade 3/4 AEs of special interest ( > 5% total pts) for Ram: HTN, bleeding events (3.6, 10.3, 10.7%), Venous thromboembolic events (0, 10.3, 7.1%); for Durva: increase in lipase (10.7, 3.4, 10.6%) and AST (3.6, 3.4, 17.9 %). Data from CH B,C suggest a trend toward increased efficacy in pts with high PD-L1 expressing tumors. Conclusions: Ram + Durva generated no unexpected toxicities and demonstrated antitumor activity. Results in pts with high PD-L1 HCC and G/GEJ cancer warrant further evaluation. Clinical trial information: NCT02572687. [Table: see text]
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Joshi, Monika, Leonard Tuanquin, Matthew Kaag, Yousef Zakharia, Jason Liao, Suzanne Merrill, Dana Musapatika, et al. "Phase Ib study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with urothelial cancer of the bladder: BTCRC-GU15-023 study." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 455. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.455.
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455 Background: There is a significant variation in the treatment of locally advanced unresectable (T2-4 N0-2 M0) or cisplatin-ineligible (non-cis) bladder cancer (BC) patients (pts). The advent of immunotherapy (IO) in non-cis stage IV BC has been promising (response rate [RR] 23%; median survival 16 mo) but we are still in need of novel combinations for locally advanced unresectable BC. Durvalumab (Durva) is a human monoclonal antibody that inhibits the binding of PD-L1 to PD-1 on T-cell receptors. It has shown efficacy in platinum refractory BC with RR of 17%. Radiation (RT) is also effective in BC and can upregulate pro-inflammatory signals allowing for improved antitumor activity of IO. We report the safety data from phase Ib trial of combining RT with Durva (DurvaRT) in locally advanced BC. Methods: Treatment (Rx) naïve or post neoadjuvant chemotherapy pts with T3-4, N0-2, M0 who were either unresectable or unfit for surgery were treated with DurvaRT followed by Durva. Rx naïve locally advanced non-cis pts were also included in the study. DurvaRT: Durva 1500mg D1, D28 plus concurrent RT, 64.8Gy given in 36 fractions over 7weeks starting D1. These patients then started adjuvant Q4 weekly Durva after 4 weeks for 12 months. Primary end point for Ph Ib was safety of combining Durva with RT during 7-weeks period. Results: We enrolled 6 pts on phase Ib. 5/6 pts had completed the DurvaRT phase and none of them had any dose limiting toxicity. The table below summarizes the treatment related adverse events (TRAE). Post DurvaRT 3/4 pts have ongoing ORR; 1 pt. had progression; Rx response evaluation in 2 pts is ongoing. Clinical trial information: NCT02891161. Conclusions: DurvaRT was tolerable in pts with locally advanced unresectable BC, where there is a dearth for good Rx options. No grade 3 immune related AEs were observed during DurvaRT. Further investigation with DurvaRT is ongoing to evaluate the efficacy in this subset of pts (Clinical trial # NCT02891161).[Table: see text]
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Ferrarotto, Renata, Diana Bell, M. Laura Rubin, J. Jack Lee, Jason Michael Johnson, Ryan Goepfert, Jack Phan, et al. "Checkpoint inhibitors assessment in oropharynx cancer (CIAO): Safety and interim results." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 6008. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6008.
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6008 Background: Anti-PD-1/PD-L1 are active in metastatic oropharynx squamous cell carcinoma (OPC). Durvalumab (durva) and tremelimumab (tremi) target respectively PD-L1 and CTLA-4, which in combination may be synergistic. Here we report the safety and interim results of durva vs. durva+tremi prior to surgery in a window of opportunity trial in OPC. Methods: Pts were randomized 1:1 to durva 1500 mg or durva 1500 mg + tremi 75 mg IV Q4W x 2 cycles. The primary objective was to quantify pre- and post-treatment differences in CD8+ tumor infiltrating lymphocytes for the two arms. Secondary objectives included safety, toxicity, ORR by RECIST, fraction of patients undergoing surgery at 8 wks, and percentage viable tumor cells in the surgical specimen. Serial pre- and post-treatment blood and tumor specimens were collected for ongoing correlative analyses. Results: 28 pts enrolled: median age 64y, 27 (96%) male, 19 (68%) newly diagnosed, most (63%) at stage IVA (AJCC 7th Ed), 9 (32%) had locoregional recurrence, 24 (86%) p16 positive, and 22 (79%) had ≤ 10 PPY smoking history. Median follow-up was 7.6 months. The most common AEs were fatigue (36%), leukopenia/lymphopenia (25%), transaminitis (25%), and rash (21%). Grade 3 AEs occurred in 4 (14%) pts: 2 elevated lipase, 1 diarrhea, and 1 hepatitis, all were manageable. There were no grade >3 AEs. ORR was 43%: 50% had SD (including 29% tumor shrinkage in 1 pt). Treatment effect in the surgical specimen was observed in 19 (79%) of 24 evaluable pts; 2 pts had major pathologic response (≤ 10% viable tumor) at the primary site. Efficacy was equivalent in both arms. The 2 pts with PD and 1 pt with SD were switched to chemotherapy after durva +/- tremi before resection; interestingly, each achieved a pCR in the primary. Most pts (57%) didn’t receive radiotherapy after surgery. There was a statistically significant association between ORR and treatment effect (p=0.014). The median percentage of viable tumor in the primary was 37.5% in pts with PR, and 82.5% in SD (p=0.003). Conclusions: Durva +/- tremi prior to surgery was well tolerated in OPC pts. Activity is encouraging with treatment effect seen in 79% of pts. The primary endpoint and complete efficacy data will be presented. Clinical trial information: NCT03144778.
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RYU, Jinhyun. "Les amis de Durtal dans Là-bas de Huysmans." Études de Langue et Littérature Françaises 117 (March 15, 2019): 35–69. http://dx.doi.org/10.18824/ellf.117.02.
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Westin, Shannon Neville, Kathleen N. Moore, Els Van Nieuwenhuysen, Amit M. Oza, Linda R. Mileshkin, Aikou Okamoto, Akiko Suzuki, et al. "DUO-E/GOG-3041/ENGOT-EN10: a randomized phase III trial of first-line carboplatin (carb) and paclitaxel (pac) in combination with durvalumab (durva), followed by maintenance durva with or without olaparib (ola), in patients (pts) with newly diagnosed (nd) advanced or recurrent endometrial cancer (EC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS6108. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps6108.
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TPS6108 Background: There is a high unmet need for advances in EC treatment that provide progression-free survival (PFS) and overall survival (OS) benefits. EC tumors are sensitive to carb/pac (Pectasides et al. Gynecol Oncol 2008). Maintenance therapy with the poly(ADP-ribose) polymerase inhibitor (PARPi) ola (with or without bevacizumab) led to significant PFS benefits in advanced ovarian cancer pts with either nd (SOLO1, Moore et al. NEJM 2018; PAOLA-1, Ray-Coquard et al. NEJM 2019) or recurrent (SOLO2, Pujade-Lauraine et al. Lancet Oncol 2017; Study 19, Friedlander et al. Br J Cancer 2018) platinum-sensitive disease, regardless of BRCA mutation status (PAOLA-1; Study 19), and in BRCA-mutated metastatic pancreatic cancer pts (POLO, Golan et al. NEJM 2019). Molecular features of EC could predict sensitivity to PARPi (de Jonge et al. Clin Cancer Res 2019; Auguste et al. Mod Pathol 2018). PARPi has been shown to prime the immune microenvironment in a preclinical BRCA1 mutant ovarian model (Higuchi et al. Cancer Immunol Res 2015). Clinical trials have demonstrated antitumor activity of the anti-programmed cell death ligand-1 (anti-PD-L1) blocker durva (Antill et al. J Clin Oncol 2019) and anti-programmed cell death-1 (anti-PD-1) antibody therapies (Makker et al. ESMO 2019; Oaknin et al. SGO 2019) in EC pts. The DUO-E trial (EUDRACT 2019-004112-60, D9311C00001, NCT04269200) will investigate whether the addition of durva to carb/pac, followed by durva (with or without ola) maintenance treatment, improves PFS in pts with nd advanced or recurrent EC. Methods: Eligible pts for this multicenter, double-blind, Phase III trial must have nd Stage III/IV or recurrent EC and be naïve to first-line chemotherapy. Pts will be randomized (1:1:1; n=~233 per arm) to: arm A) carb/pac + placebo (pbo) (q3w for six cycles) followed by pbo maintenance treatment; arm B) carb/pac + durva (1120 mg; q3w for six cycles) followed by maintenance treatment with durva (1500 mg q4w) + pbo (tablets bid); or arm C) carb/pac + durva (1120 mg; q3w for six cycles) followed by maintenance treatment with durva (1500 mg q4w) + ola (300 mg bid tablets). Pts received maintenance treatment until disease progression. Primary endpoint: investigator-assessed PFS (RECIST 1.1) of arm B vs. arm A. Key secondary endpoints: PFS of arm C vs. arm A; OS of arm B vs. arm A, and of arm C vs. arm A. Enrollment began in Q1 2020. Clinical trial information: 2019-004112-60.
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Burman, Bharat, Eric Jeffrey Sherman, Anuja Kriplani, Loren S. Michel, Lara Dunn, James Vincent Fetten, Elizabeth Warner, et al. "Radioiodine (RAI) in combination with durvalumab for recurrent/metastatic thyroid cancers." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 6587. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.6587.
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6587 Background: Immune checkpoint blockade (ICB) has limited efficacy for radioiodine-refractory thyroid cancer. The high incidence of autoimmune thyroid disease and ICB-induced hypothyroidism suggests that loss of T cell tolerance to thyroid protein epitopes is common and can be activated by ICB to induce immune responses. We hypothesize that RAI can enhance presentation of thyroid protein immunogens and putative neoantigens in thyroid cancers to amplify the effectiveness of ICB. We studied the safety and efficacy of RAI plus the anti-PD-L1 agent durvalumab (durva) in recurrent/metastatic (R/M) patients (pts). Methods: Pts. had at least one RAI-avid tumor on the most recent RAI scan or one tumor on FDG PET with an SUVmax < 10. RECIST measurable disease was required. Any number of prior therapies was allowed. Pts were treated with durva 1500 mg IV every 4 weeks with recombinant human TSH (rhTSH)-stimulated RAI (100 mCi) administered in Cycle 1. Treatment beyond progression was allowed. The primary objective was to assess safety. Durva related dose limiting toxicities (DLTs) were monitored for 6 weeks after the first dose. Since no durva DLTs were observed in the first 6 pts, per protocol rules the trial accrued 11 pts total. Secondary objectives were assessing best overall response (BOR) per RECIST and progression-free survival (PFS). Results: 11 pts (7 female) were enrolled. Eight had prior drug therapy. No DLTs or > Grade 3 durva related adverse events (AEs) were observed. The most common non-laboratory AEs (regardless of attribution) were cough (7), hypertension (7), pain (6), edema (5), and fatigue/nausea/diarrhea/arthralgia/dry skin/dyspnea/edema (4 each). As of 2/6/20, 2 had partial response, 7 stable disease, and 2 progression of disease as BOR. Six pts had tumor regression. Four pts received treatment for > 6 months. Six are still on treatment. Analyses of research biopsies (bxs) (8 had pre-treatment bxs, 6 had an additional on-treatment bx) will be presented. Conclusions: Durva plus RAI is safe and well tolerated. The preliminary efficacy signal in this small cohort is promising. Understanding how RAI plus PD-L1 targeting impacts the tumor immune microenvironment may guide how RAI should be evaluated in future ICB trials. Clinical trial information: NCT03215095 .
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Joshi, Monika, Se Eun Kim, Abhishek A. Solanki, David Tomoaki Miyamoto, David Degraff, Jennifer Wei Zou, Joshua J. Meeks, et al. "EA8185: Phase 2 study of bladder-sparing chemoradiation (chemoRT) with durvalumab in clinical stage III, node positive urothelial carcinoma (INSPIRE)—An ECOG-ACRIN and NRG Collaboration." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS4590. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps4590.
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TPS4590 Background: Patients [pts] withlymph node positive (LN+), non-metastatic bladder cancer (BC) have a better prognosis than those with metastatic (M1) disease. However, this population is under-represented in advanced bladder trials and ineligible for bladder-sparing trials. Therefore, there have been no larger prospective trials establishing the standard of care in LN+ BC. Given the promise of immunotherapy in advanced BC and potential synergy between immunotherapy and radiation, INSPIRE was designed to determine the role of concurrent and adjuvant durvalumab (durva) in this patient population when treated with induction chemotherapy (IC) followed by concurrent chemoRT. Methods: This is a randomized phase II study that is enrolling BC pts with stage III [N1-2 M0], pure or mixed urothelial cancer. Pts must have received ≥3 cycles of IC [either before or after registration, prior to randomization] without progression. LN+ is defined as radiologically LN ≥1.0 cm in short axis, with or without biopsy prior to IC. As long as pts do not progress on induction chemotherapy, they will be randomized to chemoRT+/- durva using 5 stratification factors (Simon Pocock minimization method) a) IC prior vs. post registration b) cisplatin vs non-cisplatin regimen during RT c) LN size d) response to IC e) extent of TURBT. Pts on the chemoRT+durva arm will get chemotherapy per physician choice + IMRT + 3 x doses of Q3wk durva for 6.5-8 wks, whereas those on the control arm will get chemoRT alone. The primary end point is clinical complete response [CR], defined as no radiologically measurable disease in the LNs and negative cystoscopy and bladder biopsy 8-10 weeks post-chemoRT +/- durva. Pts on the chemoRT + durva arm who have a CR or clinical benefit ( > T0 and ≤T2 in bladder per cystoscopy, biopsy + CR/PR/SD in LN by imaging) will get adjuvant Q4wk durva for 9 doses, while those on the chemoRT arm will undergo observation. Secondary end points include OS, PFS, bladder-intact event-free survival, rate of toxicity and salvage cystectomy. This study is designed to detect an improvement of 25% in clinical CR between both arms (37.5% to 62.5%). A total accrual of 114 pts (in order to enroll 92 evaluable pts) will provide 81% power to detect this difference using a Fisher’s exact test (assuming 10% drop out + anticipating that 20% chemotherapy-naïve pts will progress post IC). We are banking blood and primary tumor tissue pre- and post-chemoRT in both groups. The study was activated in August 2020 and accrual is ongoing. INSPIRE is the first prospective study designed for only LN+ BC and will define both short-term and long-term outcomes for bladder sparing in this patient population and has the potential to define a new treatment strategy for stage III BC. Clinical trial information: NCT04216290.
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Joshi, Monika, Se Eun Kim, Abhishek A. Solanki, David Tomoaki Miyamoto, David Degraff, Jennifer Wei Zou, Joshua J. Meeks, et al. "EA8185: Phase II study of bladder-sparing chemoradiation (chemoRT) with durvalumab in clinical stage III, node-positive urothelial carcinoma (INSPIRE), ECOG-ACRIN/nrg collaboration." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): TPS500. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.tps500.
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TPS500 Background: Patients [pts] withlymph node positive (LN+), non-metastatic bladder cancer (BC) have a better prognosis than those with metastatic (M1) disease. However, this population is under-represented in advanced bladder trials and ineligible for bladder-sparing trials. Therefore, there have been no larger prospective trials establishing the standard of care in LN+ BC. Given the promise of immunotherapy in advanced BC and potential synergy between immunotherapy and radiation, INSPIRE was designed to determine the role of concurrent and adjuvant durvalumab (durva) in this patient population when treated with induction chemotherapy (IC) followed by concurrent chemoRT. Methods: This is a randomized phase II study that is enrolling BC pts with stage III (N1-2 M0), pure or mixed urothelial cancer. Pts must have received ≥3 cycles of IC [either before or after registration, prior to randomization] without progression. LN+ is defined as radiologically LN ≥1.0 cm in short axis, with or without biopsy prior to IC. As long as pts do not progress on induction chemotherapy, they will be randomized to chemoRT+/- durva using 5 stratification factors (Simon Pocock minimization method) a) IC prior vs. post registration b) cisplatin vs non-cisplatin regimen during RT c) LN size d) response to IC e) extent of TURBT. Pts on the chemoRT+durva arm will get chemotherapy per physician choice + IMRT + 3 x doses of Q3wk durva for 6.5-8 wks, whereas those on the control arm will get chemoRT alone. The primary end point is clinical complete response [CR], defined as no radiologically measurable disease in the LNs and negative cystoscopy and bladder biopsy 8-10 weeks post-chemoRT +/- durva. Pts on the chemoRT + durva arm who have a CR or clinical benefit (>T0 and ≤T2 in bladder per cystoscopy, biopsy + CR/PR/SD in LN by imaging) will get adjuvant Q4wk durva for 9 doses, while those on the chemoRT arm will undergo observation. Secondary end points include OS, PFS, bladder-intact event-free survival, rate of toxicity and salvage cystectomy. This study is designed to detect an improvement of 25% in clinical CR between both arms (37.5% to 62.5%). A total accrual of 114 pts (in order to enroll 92 evaluable pts) will provide 81% power to detect this difference using a Fisher’s exact test (assuming 10% drop out + anticipating that 20% chemotherapy-naïve pts will progress post IC). We are banking blood and primary tumor tissue pre- and post-chemoRT in both groups. The study was activated in August 2020 and accrual is ongoing. INSPIRE is the first prospective study designed for only LN+ BC and will define both short-term and long-term outcomes for bladder sparing in this patient population and has the potential to define a new treatment strategy for stage III BC. Clinical trial information: NCT04216290.
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Reardon, David A., Thomas Joseph Kaley, Jorg Dietrich, Jennifer Leigh Clarke, Gavin Dunn, Michael Lim, Timothy Francis Cloughesy, et al. "Phase II study to evaluate safety and efficacy of MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma (new unmeth GBM)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2032. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2032.
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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.
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Smeets, Marc. "La Proie et l'ombre. Durtal et la confusion gastro-sexuelle." Nineteenth Century French Studies 30, no. 1 (2001): 121–30. http://dx.doi.org/10.1353/ncf.2001.0057.
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Mamdani, Hirva, Bryan J. Schneider, Pashtoon Murtaza Kasi, Laith I. Abushahin, Thomas J. Birdas, Kenneth Kesler, Heather Burney, Susan Perkins, and Shadia Ibrahim Jalal. "Durvalumab following multimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Updated survival and early translational results from Big Ten Cancer Research Consortium Study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 4572. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4572.
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4572 Background: Concurrent chemoradiation(CRT) followed by esophagectomy is a standard of care for locally advanced esophageal(LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients(pts) experience disease relapse within the 1st yr after treatment(tx) completion. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown radiation +/- chemotherapy upregulates PD-1/PD-L1 pathway. Methods: We conducted a phase II trial evaluating safety and efficacy of PD-L1 inhibitor durvalumab(durva) in pts with LA-EAC and GEJ adenocarcinoma who had residual disease in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: Initially 24 pts were enrolled, study was expanded to enroll additional 13 pts. Median age: 61yrs (range, 43-73). 31 received carbo/paclitaxel and 6 received cis/5-FU concurrently with RT. 24(64.9%) pts had positive lymph nodes(LN) at the time of surgery following CRT: N3(n = 3,8.1%), N2(n = 10, 27%), N1(n = 11,29.7%).17 pts relapsed: 11 on tx, 6 had late relapses. 3/5 late relapses were locoregional and were re-treated with chemo-RT. Remaining relapses were systemic with lung and LN being the most common sites. 2 of 3 pts who developed grade 3 irAEs are alive and disease free at 17 and 23 mo. RFS/OS:1 yr- 79.2%/95.5%, 2yr-55.5%/67.4%. 20/37 pts have HER-2 status available: 5/6 HER2 positive pts had disease relapse, 1 is undergoing tx. Molecular profiling is available on 8 relapsed pts: all were microsatellite stable with low TMB and PD-L1 < 10% CPS. Mutations in DNA repair genes ( ARID1A, ATM, ATR, CHEK2), and PIK3CA E542K were more prevalent among late relapsing pts. Circulating tumor cells (CTCs) analysis is available for 10/37 pts. 4/5 pts where CTCs increased from C1 to C4 had disease relapse. Molecular profiling of the remaining pts and correlation of PD-L1 expression, TMB, specific genes mutations, CTCs, and Immunoscore with outcomes with durva is being evaluated will be presented at the meeting. Conclusions: Adjuvant durva following trimodality therapy for LA-EAC and GEJ adenocarcinoma improved 1-yr RFS to 79.2% compared to historical rate of 50%.2-yr RFS and OS data are encouraging in this high risk pt population. HER-2 positivity may be associated with lack of benefit from durva. Mutations in DNA repair genes are prevalent in pts with delayed relapse. Rise in CTCs during durva tx may be an early marker of disease relapse. Clinical trial information: NCT02639065 .
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Nowakowski, Grzegorz S., Wolfgang Willenbacher, Richard Greil, Thomas Stauffer Larsen, Krish Patel, Ulrich Jäger, Robert F. Manges, et al. "Safety and efficacy of PD-L1 inhibitor durvalumab with R-CHOP or R2-CHOP in subjects with previously untreated, high-risk DLBCL." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 7520. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.7520.
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7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.
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Gao, Jianjun, Arlene O. Siefker-Radtke, Neema Navai, Matthew T. Campbell, Rebecca Slack Tidwell, Charles Guo, Ashish M. Kamat, et al. "A pilot presurgical study evaluating anti-PD-L1 durvalumab (durva) plus anti-CTLA-4 tremelimumab (treme) in patients (pts) with high-risk muscle-invasive bladder carcinoma (MIBC) who are ineligible for cisplatin-based neoadjuvant chemotherapy (NAC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 4551. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4551.
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4551 Background: In MIBC pts, especially in those with high risk features including lymphovascular invasion, hydronephrosis, T3b disease, or variant histology, cisplatin-based NAC followed by cystectomy improves overall survival as compared with cystectomy alone. However, it is estimated that over 50% of pts with MIBC are ineligible for cisplatin-containing therapy. Therefore, we propose this pre-surgical trial with durva + treme for this population of pts. Methods: This is a single-arm, pre-surgical clinical trial with durva + treme in pts with localized, high-risk MIBC (cT2-T4a) who are ineligible for cisplatin-based NAC due to decreased renal function, neuropathy, hearing loss, or heart failure; or refuse cisplatin-based NAC (NCT02812420). Each patient receives durva (1500 mg) plus treme (75 mg) on weeks 1 and 5. Pts then undergo surgery at week 9-11. Pre- and post-treatment blood and tumor samples are collected for correlative biological analyses. Results: Twenty eight of 35 pts have been enrolled on this trial. Twenty-one pts have completed cystectomy as of 11/16/19. Of these 21 pts, 9 (43%) had pathologically complete response (pCR) and two (10%) had pathologic T1N0 (pT1) disease (≤pT1N0 rate = 52%). Fourteen of 21 (67%) had down-staging of disease. Of note, 10 of these 21 pts had 3-D mass (T3) on exam under anesthesia or clinical T4a disease; 5 of these 10 pts (50%) had pCR and one (10%) had pT1 disease (≤pT1N0 rate = 60%). Only 5 of 28 (17%) pts developed grade 3 immune related toxicity including hepatitis and amylase/lipase elevation, and two (7%) resulted in surgery delay for > 30 days. Immune profiling with CyTOF analysis of baseline peripheral blood indicates that pts with pCR have significantly lower frequency of a Th2 subset as compared to pts with up-staging of disease. In addition, gene expression profiling analysis of baseline tumor tissues demonstrates a significantly less immunosuppressive microenvironment in pts with pCR as compared to pts with up-staging of disease. Conclusions: Our data indicate that durva plus treme is an effective and safe neoadjuvant therapy for pts with MIBC ineligible for cisplatin-based therapy. Therefore, neoadjuvant therapy with durva + treme and a number of potential biomarkers warrant testing in a larger phase 3 trial. Clinical trial information: NCT 02812420.
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Hong, Theodore S., Lipika Goyal, Aparna Raj Parikh, Beow Y. Yeap, Christine A. Ulysse, Lorraine C. Drapek, Jill N. Allen, et al. "A pilot study of durvalumab/tremelimumab (durva/treme) and radiation (XRT) for metastatic biliary tract cancer (mBTC): Preliminary safety and efficacy." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 547. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.547.
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547 Background: Metastatic biliary tract cancer (mBTC) is a lethal malignancy with median 5 year OS of less than 10%. Immunotherapy, particularly single agent anti-PD-1/PD-L1, has limited efficacy in mBTC with ORR~9-15%. Recently presented data shows responses in metastatic MSS pancreatic or colon cancer with combination anti-PD-1/CTLA-4 and radiation (XRT) to produce systemic response (abscopal effect) (Parikh A, GI ASCO 2019, ASCO 2019.). We evaluate safety and efficacy of dual PD-1/CTLA-4 inhibition with XRT in MSS mBTC. Methods: 15 of a planned 15 mBTC patients were enrolled. Eligible pts had histologically-confirmed mBTC, ECOG-PS 0/1, and must have progressed on at least one line of previous therapy or refused standard therapy. Safety cohort of 6 pts of durva 1500 mg/treme 75 mg q4w was enrolled. If > 2 DLTs, patients were enrolled subsequently to dose level -1 (durva 1125 mg/ treme 75 mg q4w). 3 fractions of 8 Gy of radiation at C2D1 every other day to a single metastatic site. Durva/treme continued for 4 cycles, followed by 4 cycles of maintenance durva until progressive disease, discontinuation or withdrawal. Endpoints include disease control rate (DCR (SD+PR+CR)), PFS and OS and safety. Radiological evaluations were done q2 mo. Results: 15 mBTC pts enrolled and evaluable from May 2018 to March 2019. Median age 63 years (range 48-75), 47% male. DLTs occurred in 3 patients during the safety run-in. One patient experienced DLT at dose level -1 and subsequent expansion. 3 patients did NOT reach radiation therapy. DCR was 27% with a 13% PR and 7% CR. Of those who reached radiation, DCR was 33% with a 17% PR and 8% CR. At time of analysis, median PFS was 54 days for ITT mBTC. Duration of response for 4 patients with DCR was 26, 52, 122, 254+ days. Treatment-related adverse events were reported in 12/15 patients (80%). Grade ≥3 toxicities were seen in 9/15 pts (60%) with lymphopenia (5 grade 3) and elevated LFTs (2 grade 4 and 4 grade 2) being the main adverse events. All patients with disease control were not MSI. Conclusions: Combination of durva/treme XRT is feasible and shows preliminary activity in metastatic BTC. An expansion cohort is being planned to confirm activity. Clinical trial information: NCT03482102.
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Patel, Manish R., Todd Michael Bauer, Antonio Jimeno, Ding Wang, Patricia LoRusso, Khanh Tu Do, Salomon M. Stemmer, et al. "A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3092. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3092.
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3092 Background: mRNA-2752 is a novel mRNA-based therapeutic agent encoding OX40L T cell co-stimulator, IL-23 and IL-36γ pro-inflammatory cytokines. Here we present findings from a first-in-human study of iTu mRNA-2752 in solid tumor patients as monotherapy or in combination with durvalumab (durva). At the time of presentation, data will encompass the monotherapy escalation MTD/RDE along with the supporting translational work, and the available data in combination. Methods: iTu mRNA-2752 was administered every 2 weeks for up to 7 doses as monotherapy or in combination with durva in patients with advanced solid malignancy or lymphoma. Biomarker analyses include measurement of IL-23, IL-36γ and pro-inflammatory cytokine proteins in pre- and post-treatment tumor biopsies and plasma. PD-L1 immunohistochemistry was used to further characterize baseline status and changes to the TME with treatment. Results: As of 20 December 2019, 23 solid tumor patients have been treated either with mRNA-2752 alone (n = 14) or in combination (n = 9) and has been well tolerated with no dose limiting toxicities or related grade 3/4 toxicities. Of the 17 patients evaluated per RECIST and iRECIST, 1 had a PR (iRECIST), 6 had SD, and 10 had PD. The patient with a PR (52% tumor reduction) received 0.5 mg mRNA-2752 with durva, and had aPD-1/L1 naïve squamous-cell bladder carcinoma. Tumor shrinkage was observed in an additional 5 patients in injected and/or uninjected lesions in both monotherapy and combination. Preliminary biomarker data showed increased IL-23 and IL-36γ protein expression after 6-24 hours, and increased levels of downstream cytokines IL-22 and IL-6, respectively. Pro-inflammatory cytokines (e.g. IFN-γ, TNF-α) were also significantly increased at 1 day and 1-week post-treatment. Significant increases in PD-L1 expression predominantly in tumor-associated immune cells were observed after first dose and persisted up to 29 days after treatment. Conclusions: iTu mRNA-2752 given as monotherapy and in combination with durva is tolerable at all dose levels studied, and administration can be associated with tumor shrinkage. Analyses of tumor and plasma biomarkers suggest a sustained immunomodulatory effect of treatment that includes elevated IFN-γ, TNF-α, and PD-L1 levels. These data support the ongoing testing of the mRNA-2752/durva combination in the dose escalation part of the study. Clinical trial information: NCT03739931 .
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Cathomas, Richard, Sacha Rothschild, Stefanie Hayoz, Martin Spahn, Julian Schardt, Roland Seiler, Andreas Erdmann, et al. "Safety and efficacy of perioperative cisplatin/gemcitabine (cis/gem) and durvalumab (durva) for operable muscle-invasive urothelial carcinoma (MIUC): SAKK 06/17." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 430. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.430.
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430 Background: The combination of cisplatin-based chemotherapy with immune checkpoint inhibitors is extensively investigated in urothelial carcinoma. Using this combination in the neoadjuvant setting for patients (pts) with MIUC might improve pathological response rate (PaR: <ypT2N0) but carries the risk of increased perioperative morbidity. Methods: SAKK 06/17 is an open-label single arm phase II trial for pts with operable MIUC cT2-T4a cN0-1. Treatment consists of 4 cycles of neoadjuvant cis/gem q3w in combination with 4 cycles durva 1500mg q3w followed by resection. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival (EFS) at 2 years. 58 pts are needed based on type I error of 10% and a power of 80% for H1 EFS at 2 years ≥ 65% compared to H0 EFS at 2 years ≤ 50%. We report the secondary endoints PaR, pathological complete remission (pCR: ypT0 N0), and safety on the full analysis set (FAS, received at least one dose of durva). Results: 61 pts were included between 7/18 and 9/19 at 12 sites. The FAS consists of 58 pts (79% male, median age 67.5 yrs) with bladder cancer (95%) or upper urinary tract/urethral cancer (5%). Clinical T2, T3, T4 stage were present at diagnosis in 69%, 21%, 10%, respectively, and 17% had cN1. 95% of pts received all 4 doses of neoadjuvant durva, 81% all 4 cycles of cis/gem and 17% switched to carboplatin. In total grade 3 and 4 adverse events (AE) during neoadjuvant treatment occurred in 48% and 27%, respectively. AEs related to durva were G3 in 7 pts (12%) and G4 in one patient (2%). Resection was performed in 53 pts (91%; 51 radical cystectomy, 2 nephroureterectomy), 4 pts refused surgery and one patient was irresectable due to a frozen pelvis. R0 resection was achieved in 52 pts (98%), one had R1. Postoperative complications included Clavien-Dindo III in 13 pts (24%) and IV in 5 pts (9%). PaR was found in 60% (95% CI 46.0%-73.5%) with 18 pts achieving pCR (34%; 95% CI 21.5%-48.3%) and 14 patients (26%) ypT1/ypTis. Conclusions: The first FAS results for neoadjuvant durvalumab in combination with cis/gem for operable MIUC confirm elevated pathological response rates and demonstrate acceptable safety. Postoperative morbidity is relevant but not exceeding the expected frequency or severity. Clinical trial information: NCT03406650.
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Togatorop, Togu Parulian, and Umi Murtini. "Pengaruh Ketepatan Waktu Publikasi t aporan Keuangan tcrhadap Cumulative Abnormal Return (Car) Perusahaan Go Publik di Indonesia." Jurnal Riset Manajemen dan Bisnis 5, no. 1 (June 1, 2010): 52. http://dx.doi.org/10.21460/jrmb.2010.51.221.
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This research is aimed at evaluating the effect of on-time publication of financial rryorts to Bapepam on the cttmulative abnormal return. The ianples were-the manufacture companies listed in BEI (Indonesia Stock ExchongQ and their respecfive profits durtuS 2004-2007. The result of the auluation prwes that on-time publication of financial reports has an influence on the cumulative abnormal return.Keywords : on-time, c'tnnalative abnormal return
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Giannatempo, Patrizia, Andrea Franza, Laura Marandino, Daniele Raggi, Giuseppina Calareso, Alessandra Alessi, Maurizio Colecchia, et al. "Clinical safety and activity of cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) after platinum chemotherapy (ARCADIA): Preliminary results from a nonrandomized, open-label, phase 2 trial." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e16529-e16529. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e16529.
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e16529 Background: Combining anti-VEGFR drugs with checkpoint inhibitors have shown synergistic effect in pts with UC. ARCADIA is a phase 2 trial evaluating the safety and efficacy of combination of CABO, a multikinase inhibitor, with the anti-PDL1 DURVA in pts with platinum-refractory advanced UC or variant histology (NCT03824691). Herein we report the preliminary results. Methods: Pts received CABO 40 mg daily, orally, in combination with DURVA 1500 mg, intravenously, every 28 days, until disease progression or unacceptable toxicity. Key inclusion criteria were: ECOG-PS 0-1, UC or variant histology, failure of 1 or 2 platinum-based regimen for metastatic disease, non-measurable disease was permitted. Response was evaluated by RECIST criteria v.1.1 every 2 cycles by CT and 18FDG PET/CT scans. The primary endpoint of the study was overall survival (OS). Other endpoints included safety, objective response-rate (ORR), duration of response, progression-free survival (PFS). PD-L1 expression was assessed by Ventana SP142 assay. Next-generation sequencing tests (FoundationOne) on pre-therapy tumor samples were performed. Results: From September 2019 to February 2021, 26 pts were enrolled with a median follow-up of 5 mo. Median age was 64 yrs (range 44-74), 69% were male, and 23% had ECOG PS 1. 8 pts presented variant histology. Five pts (19%) had received 2 prior systemic anticancer therapies. In pts evaluable for efficacy analyses, 3 (11.5%) complete responses (CR) and 6 (23.1%) partial responses (PR) were observed. The ORR and DCR were 34.6% and 57.7% respectively. Treatment-related AEs (TRAEs) occurred in 17 pts (65%), including 2 (8%) grade 3 TRAEs, within the first 2 cycles. 7 pts (27%) discontinued CABO due to toxicity, no interruption of DURVA was observed. The most common AEs by any grade were transaminase increase (35.7%), asthenia (27%), diarrhea (27%), and hypertension (15%). Conclusions: Combination of CABO and DURVA demonstrated promising preliminary activity and a manageable safety profile in pts with advanced UC and variant histology. More mature results according to biomarkers and histology will be presented. Clinical trial information: NCT03824691.
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Bedi, Tarini. "“Network not Paperwork”: Political Parties, the Malkin, and Political Matronage in Western India." Politics & Gender 12, no. 01 (March 2016): 107–42. http://dx.doi.org/10.1017/s1743923x15000549.
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I heard Durva, a fearless leader in the Indian political party,Shiv Sena(Shivaji's Army) repeat this poetic refrain in many of her public speeches. She invariably received rousing applause and breathless admiration from the audiences she addressed. Many junior party workers and female constituents who listened in awe at the large women's rallies she organized around the elections began to repeat this in their own lives and in their political campaigns; and Durva's leadership style and the words uttered by her sharp but poetic and charismatic tongue traveled across the district helping the political careers and the self-confidence of many junior political hopefuls. It also brought hordes of new political constituents into the party's fold. Many of her constituents at these events, admitted me that “[Durva] is themalkin[landlady)] of us all.”
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Monge B., M. Cecilia, Changqing Xie, Seth M. Steinberg, Suzanne Fioraventi, Melissa Walker, Donna Mabry-Hrones, Bradford J. Wood, David E. Kleiner, and Tim F. Greten. "A phase I/II study of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 117. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.117.
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117 Background: The benefit of immune checkpoint inhibition is limited to the small percentage of advanced colorectal cancer (CRC) patients whose tumors present mismatch repair (MMR) gene abnormalities; immunotherapy has not shown benefit in patients with MMR proficient CRC. Oncolytic immunotherapy represents a unique therapeutic platform. This phase I trial tests the safety of the combination of pexastimogene devacirepvec (Pexa-Vec) plus durvalumab (durva) in patients with locally advanced or metastatic CRC. Methods: Eligible patients with advanced proficient mixed match repair (pMMR) CRC received intravenous infusion of Pexa-Vec at dose level 3 x 108 plaque forming units (pfu) (DL1) or at 109 pfu (DL2) every 2 weeks for 4 doses and durva 1500 mg every 28 days. Response was assessed with CT every 8 weeks. Adverse events were recorded and managed. The primary endpoint included safety, tolerability and feasibility of this combination therapy. Samples of tumor and peripheral blood were collected for assessment of immune parameters. Results: Sixteen patients (6 males and 10 females) enrolled with a median age of 52.1 years (range 39-69) from Dec, 2017 to Oct, 2018. Four patients were treated with Pexa-Vec at DL1 and durva;twelve patients were treated with Pexa-Vec at DL2 and durva.The most common treatment related adverse events (TRAE) included fever 15/16 (94 %), hypotension 12/16 (75 %), chills 12/16 (75%), fatigue 8/16 (50%), sinus tachycardia 7/16 (44%) and rash 6/16 (38%). Grade 3/4 TRAEs were reported in 8/16 (50%)patients; the most common were fever 7/16 (44 %), lymphopenia 2/16 (13%), neutropenia 1/16 (6%) and anemia 1/16 (6%). 14 patients were evaluable for response analysis; one patient 1/14 (7 %) achieved a confirmed partial response (lasting 7.1 months) and continues to receive treatment, while 13 patients had progressive disease. The median progression free survival (PFS) was 2.2 months (95% CI: 2.2-2.3 months) and the median overall survival (OS) was 7.5 months (CI: 4.9-10.1 months). Conclusions: Combination therapy of Pexa-Vec with durva ICI issafe, well tolerated and demonstrates possible activity in patients with advanced pMMR CRC. Clinical trial information: NCT03206073.
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Saeed, Anwaar, Milind Phadnis, Robin Park, Weijing Sun, Raed Moh'd Taiseer Al-Rajabi, Joaquina Celebre Baranda, Stephen K. Williamson, et al. "Cabozantinib (cabo) combined with durvalumab (durva) in gastroesophageal (GE) cancer and other gastrointestinal (GI) malignancies: Preliminary phase Ib CAMILLA study results." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 4563. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4563.
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4563 Background: Cabo targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-L1 inhibitors like durva. We conducted a phase Ib GI basket trial to evaluate the safety & efficacy of this regimen in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), & hepatocellular carcinoma (HCC). Methods: Patients received cabo and durva in 3+3 dose escalation then expansion to determine the dose limiting toxicity (DLT), Recommended Phase 2 Dose (RP2D), ORR, PFS & OS. Cabo was dosed at 20mg QD, 40mg QD, and 60mg QD in the first, second, and third cohorts respectively. Durva was dosed at 1500mg IV Q4W in all cohorts. DLT window was 28 days. Scans were obtained every 8 wks. Treatment beyond progression was allowed. Results: 23 Pts (16 M, 7 F), median age 60 yrs (range 33-79) were currently enrolled. 12 in the dose escalation cohort with cabo 20mg (6 pts), or 40mg (3 pts), or 60mg (3 pts). 11 pts enrolled in the dose expansion cohort with cabo 60mg. 8 pts had GEA, 13 pts had CRC, and 2 pts had HCC. Median number of prior chemotherapies was 3 (range 1-3). 3 pts were not evaluable for DLT due to missing ≥30% of DLT window doses, not related to DLT. No DLTs were observed. Drug-related Grade (G) 1&2 AEs included fatigue (83%), abnormal LFTs (39%), anorexia (26%), diarrhea (26%), nausea (13%), & hand foot syndrome (13%). One pt each developed drug related G3 hypertension, hyperthyroidism, thrombocytopenia, & thromboembolic event, all occurring outside the DLT window. 19 pts were evaluable for response: 4 PR (2 GEA & 2 CRC), 12 SD, 3 PD; ORR 21%; clinical benefit rate 84%; median time to PD 16 wks (range 8-40+). Conclusions: RP2D was determined to be Cabo 60mg QD and Durva 1500mg Q4W. Enrollment to phase I dose expansion is ongoing. RP2D may be adjusted based on additional experience & long-term tolerability. Early efficacy data was encouraging. This is an investigator-initiated trial funded by Exelixis & Astrazeneca. Clinical trial information: NCT03539822 .
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ADAMS, BEVERLY. "The ‘Durty Spirit’ at Hertford: A Falling out of Friends." Journal of Ecclesiastical History 52, no. 4 (October 2001): 647–74. http://dx.doi.org/10.1017/s0022046901005930.
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In 1660 the Quaker movement was confronted with a new political situation. In response, the leadership constructed a centralised system of bureaucracy designed to maintain solidarity in the face of persecution. Not all Friends, however, reacted positively to the changes, especially the new arrangements for women's meetings and the conduct of weddings. By the 1670s the movement was split by the Wilkinson–Story controversy, an internal dispute reflected in Quaker meetings throughout the country. This article examines the friction between Friends in Hertford and the claims made by some members of the meeting that George Fox was stifling individual spiritual freedom, the touchstone of Quaker doctrine.
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Lonial, Sagar, Albert Oriol, Maria-Victoria Mateos, Paula Rodriguez-Otero, Nizar J. Bahlis, William Bensinger, Kimmo Porkka, et al. "A phase 1/2 study of durvalumab (DURVA) in combination with lenalidomide (LEN) with or without dexamethasone (DEX) in patients (pts) with newly diagnosed multiple myeloma (NDMM)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS8055. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps8055.
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TPS8055 Background: LEN + DEX (Rd) is approved for pts with newly diagnosed MM, including those who are transplant non-eligible (TNE). DURVA is a monoclonal antibody to programmed death ligand 1 (PD-L1) that blocks PD-L1 binding to programmed death-1 (PD-1). Preclinical studies showed anti-MM immune responses with PD-1/PD-L1 blockade that were enhanced with LEN (Görgün et al, 2015). Here, we present a phase 1/2, multicenter, open-label trial in progress (MEDI4736-MM-002) designed to evaluate DURVA in combination with LEN ± DEX in a target population of pts who are TNE and/or with high-risk NDMM. Methods: Enrollment of up to 138 pts from the US, Canada, and Europe is planned to determine the recommended dose of DURVA (primary endpoint) with LEN ± DEX for the treatment (Tx) of NDMM. Key secondary endpoints include safety, response outcomes, pharmacokinetics, progression-free survival, and overall survival. Pts with previously untreated MM with ≥ 1 of the following will be included: 1 of the CRAB criteria or clonal bone marrow plasma cells ≥ 60% and an Eastern Cooperative Oncology Group performance status of ≤ 2. Pts with a history of primary immunodeficiency will be excluded. Each independent cohort (A, B, C) will enroll 6 pts in parallel in the dose-finding phase (Table). Dose-limiting toxicities will be evaluated during the first cycle of Tx. The optimal regimen will be determined from the dose-finding phase and a parallel dose-expansion phase of up to 40 pts per cohort. Tx will continue until progressive disease or unacceptable toxicity. To date, 15 pts have enrolled. Clinical trial information: NCT02685826. [Table: see text]
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Brar, Gagandeep, Changqing Xie, Charalampos S. Floudas, M. Pia Morelli, Suzanne Fioravanti, Melissa Walker, Donna Mabry-Hrones, Jennifer C. Jones, and Tim F. Greten. "Immune checkpoint inhibition (ICI) in combination with SBRT in patients with advanced pancreatic adenocarcinoma (aPDAC)." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 192. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.192.
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192 Background: Chemotherapy in aPDAC has resulted in only modest improvements in outcome. The effectiveness of ICI monotherapy is also limited in PDAC, suggesting an immunogenic inert tumor microenvironment. SBRT is safe and effective in locally advanced PDAC and exhibits enhanced antitumor immunity. We hypothesize that ICI plus SBRT will improves immunomodulatory effects of ICI in patients with aPDAC resulting in a greater clinical benefit. Methods: Eligible patients with aPDAC were enrolled to four different treatment cohorts. Cohort 1: Durvalumab (Durva) 1500 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 2: SBRT 5 fractions x 5Gy followed by Durva. Cohort 3: Durva + Tremelimumab (Treme) 75 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 4: SBRT 5 fractions x 5Gy followed by Durva + Treme. This was continued until unacceptable toxicity or progression of disease. A biopsy was performed at baseline and pre-cycle 2 of treatment for exploratory correlative analysis. The primary objective was to evaluate the safety and feasibility of combining ICI and SBRT to enhance the efficacy of ICI. Results: 51 patients with aPDAC were enrolled and 31 patients were evaluable for the efficacy. The most commonly TRAEs were lymphopenia. Grade 3-4 AEs were lymphopenia and anemia. No dose limiting toxicities were seen. Out of total 31 evaluable patients, 1 patient achieved a confirmed partial response seen in Cohort 1 and 2 patients in Cohort 4, and 7 stable disease across the 4 treatment arms. Median PFS and OS was 1.7 months (95% CI 0.7-2.8 months) and 3.4 months (95% CI 0.9-11.4 months) in cohort 1; 2.6 months (95% CI 2.1-4.7 months) and 9.1 months (95% CI 3.4-18.7 months)in cohort 2; 1.6 months (95% CI 0.5-4.0 months) and 3.0 months (95% CI 0.7-6.6 months) in cohort 3; and 3.2 months (95% CI 1.5-16.5months) and 6.4 months (95% CI 1.5-17.6 months) in cohort 4. Conclusions: The combination of ICI and SBRT is safe and well tolerated in patients with aPDAC. The overall response rate of 9.6% including 2 patients who achieved a durable partial response lasting over 12 months, suggests meaningful clinical activity. This signifies that ICI and SBRT is a potential new treatment for aPDAC. Clinical trial information: NCT02311361.
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Joshi, Monika, Leonard Tuanquin, Matthew Kaag, Deepak Kilari, Sheldon L. Holder, Hamid Emamekhoo, Alexander Sankin, et al. "Concurrent durvalumab and radiation therapy followed by adjuvant durvalumab in patients with locally advanced urothelial cancer of bladder (DUART): Btcrc-GU15-023." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 513. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.513.
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513 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, unresectable have limited treatment options. In this study, we investigate if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. Our results from phase (ph) Ib suggested that the combination was safe. Here we present the response rate post durvaRT and updated treatment related adverse events (TRAEs) amongst our evaluable pts in ph II. Methods: This is a single arm ph Ib-II study for T2-4 N0-2 M0 pts. The ph II primary endpoints a) PFS rate at 1 yr b) disease control rate (DCR); secondary endpoints were a) CR post durvaRT b) PFS c) OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy post durvaRT. We anticipated that durvaRT followed by durva would increase PFS at 1 yr from 50% to 75% when compared to RT; we assumed DCR of about 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Total N = 26 patients (male 19; female 7, median age 74yr). At the time of data cut off, 21/26 pts were evaluable for response post durvaRT. Post completion of durvaRT time point, clinical CR was seen in 15/21 pts (71.4%); PR 1/21 pts (4.7%); SD 4/21 (19%); PD 1/21 (4.7%). DCR was seen in 20/21 pts (95%) post durvaRT. Median follow up from D1 to last follow up was 6.1 mos. Grade ≥ 3 TRAE amongst 26 pts: anemia (1/26), lipase/amylase (1/26), immune nephritis (1/26), dyspnea (gr 4, copd/immune), fatigue (1/26), lymphopenia (6/26). Other TRAEs: Fatigue was the most common TRAE (16/26); UTI (5/26); cystitis (3/26). No fatal TRAEs were observed. Conclusions: DurvaRT demonstrated promising efficacy with clinical CR of 71.4% and DCR of 95% in unresectable, cisplatin ineligible locally advanced BC. It was generally well tolerated. Ph II study has completed accrual and longer-term results will further our understanding of this regimen’s efficacy in locally advanced BC. Clinical trial information: NCT02891161.
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Forde, Patrick M., Zhuoxin Sun, Valsamo Anagnostou, Hedy L. Kindler, William T. Purcell, Bernardo H. L. Goulart, Arkadiusz Z. Dudek, Hossein Borghaei, Julie R. Brahmer, and Suresh S. Ramalingam. "PrE0505: Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (MPM)—A PrECOG LLC study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 9003. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9003.
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9003 Background: First-line CP was FDA-approved in 2004 for unresectable MPM. Given the role of inflammation in MPM and promising responses to PD-1 pathway blockade in pretreated MPM, we conducted a phase 2 single arm study of the anti-PD-L1 antibody, durvalumab (durva), combined with CP for patients (pts) with untreated MPM of any subtype. Methods: Eligible pts were treatment-naïve with surgically unresectable MPM. Primary endpoint was overall survival (OS); pts received up to 6 cycles of durva-CP, followed by maintenance durva up to 1 year. Carboplatin was permitted for pts with baseline hearing or renal impairment. The first 15 pts were monitored for dose-limiting toxicities (DLTs). Secondary endpoints included toxicity, objective response by modified RECIST, progression-free survival (PFS), and correlative analyses. With a sample size of 55 patients and 32 events, the study had 90% power to detect a 58% improvement in median OS from 12 months (m) (historical control) to 19 m with durva-CP. Results: PrE0505 enrolled 55 patients at 15 US-based sites between 06/2017 and 06/2018. Histologic subtypes were epithelioid (75%), biphasic (11%), sarcomatoid (13%), and desmoplastic (2%). There were no DLTs during the run-in period. As of January 2020 the median follow up is 20.6 m and 29 deaths have occurred. The median OS at the time of report is 21.1 m. The 12 m OS rate was 70% with a 2 sided 95% confidence interval (56%, 81%) and two-sided 80% CI (62%, 78%). Analyses for the secondary endpoints were ongoing at abstract submission. Exome sequencing, TCR sequencing and dual PD-L1/CD8 staining have been completed on baseline tumors from at least 45 of the 55 patients enrolled as well as RNA sequencing for those with adequate tissue. Initial results show that tumors harbored an average tumor mutation burden of 22 somatic sequence alterations and varying levels of aneuploidy were detected. Conclusions: The combination of chemotherapy with durvalumab delivered a promising median OS for previously untreated pts with unresectable MPM. Full results from the study along with the extensive correlative analyses performed will be reported. The phase 3 PrE0506/DREAM3R trial evaluating CP-durvalumab versus CP alone will commence enrollment in the United States and Australia in 2020. Clinical trial information: NCT02899195.
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Pouessel, D., A. Mervoyer, D. Larrieu-Ciron, B. Cabarrou, M. Robert, J. Frenel, P. Olivier, M. Mounier, and E. Cohen-Jonathan Moyal. "OS4.4 Hypofractionated stereotactic radiotherapy and anti-PDL1 Durvalumab combination in recurrent glioblastoma: Results of the phase I part of the phase I/II STERIMGLI trial." Neuro-Oncology 21, Supplement_3 (August 2019): iii10—iii11. http://dx.doi.org/10.1093/neuonc/noz126.034.
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Abstract BACKGROUND Glioblastoma (GBM) remains a lethal disease with inevitable local relapse and no standard treatment. Re-irradiation by hypofractionated stereotactic radiotherapy (hFSRT) is an option of treatment with tolerable safety, but needs improvement in term of efficacy. Radiotherapy (RT) causes immunogenic tumor cell death but also induces PDL1 and PD1 expression on tumors and immune cells, potentially evoking resistance to RT. Pre-clinical studies combining hFSRT with an anti-PD-1 antibody in GBM have shown increased efficacy of the combination. Clinical studies also show encouraging results when checkpoint inhibitors have been combined with high dose RT. We hypothesized that combining the anti PD-L1 Durvalumab (Durva) with hFSRT will be an effective regimen for patients with recurrent GBM. We designed a phase I/II clinical trial studying the combination of hFSRT with Durva for recurrent GBM≤35 mm diameter. Results of the phase I are presented. MATERIAL AND METHODS Patients were included from February 2017 to October 2017. A standard 3 + 3 de-escalation design was used. Patients were treated by hFSRT 24 Gy, 8 Gy/fraction at 80% isodose, every other day, combined with Durva infusion 1500mg first dose (Level 1) or 750 mg (Level -1) delivered on the last hFSRT day followed by 1500 mg Durva infusion every four weeks until relapse. The schema was defined as safe if one patient or less among 6 presents a dose limiting toxicity (DLT). Brain MRI was performed before RT and then every 8 weeks until relapse. Tumor assessment was performed according to RANO criteria. RESULTS Among the 6 patients (3 methylated MGMT, 3 unmethylated MGMT; all wild type IDH) included at the level 1, all completed the hFSRT course, only one had a DLT which was an immune related grade 3 vestibular neuritis. At the time of analysis (24/01/19), all the patients had a local tumor progression, 4 were still alive. Local progression free interval (LPFI) ranges from 2.1 to 8.1 months. Interestingly the 2 patients who presented a pseudo-progression had a prolonged LPFI (5.7 and 8.1 months) compared to the other patients. All the patients except these 2 patients had a lymphopenia at inclusion. PDL-1 expression varied from 0 to 70% in the primary tumor. CONCLUSION Combining three 8 Gy fractions of hFSRT with 1500 mg Durvalumab on the 3rd fraction hFSRT and every 4 weeks for recurrent GBM is well tolerated justifying exploration of its efficacy in the phase II which is currently in interim analysis
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Semenov, A. V., P. A. Krutitskii, and I. A. Devyatov. "Microscopic theory of phase slip in a narrow durty superconducting strip." JETP Letters 92, no. 11 (December 2010): 762–66. http://dx.doi.org/10.1134/s0021364010230098.
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Wahl, Martin. "Bücher: Architektur in Deutschland '03: Deutscher Architekturpreis 2003. By W. Durth." Bautechnik 82, no. 3 (March 2005): 189–90. http://dx.doi.org/10.1002/bate.200590071.
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Al-Bassam, Abdulaziz M., Hussein S. Awad, and Jomaah A. Al-Alawi. "Durov Plot: A Computer Program for Processing and Plotting Hydrochemical Data." Ground Water 35, no. 2 (March 1997): 362–67. http://dx.doi.org/10.1111/j.1745-6584.1997.tb00094.x.
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Vrančić, Frano. "O braćenje na katoličanstvo u Durtalovom romanu J.-K. Huysmansa." Crkva u svijetu 55, no. 1 (March 19, 2020): 79–103. http://dx.doi.org/10.34075/cs.55.1.8.
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Cilj članka je istražiti temu Huysmansova vjerskog obraćenja u onome što književni kritičari obično nazivaju Durtalovim romanom. Autor rada ponajprije promatra originalnost tog pomalo zaboravljenog književnika s kraja XIX. i početka XX. stoljeća, kao i utjecaj ideje dekadencije na njegovo pisanje. Zatim će pokušati pokazati, naslanjajući se na djela stručnjaka za Huysmansovo djelo, zašto se piščev književni i duhovni smjer mijenja te kako se povratak katoličkoj vjeri očituje u „Durtalovu ciklusu“ (Le cycle de Durtal), tetralogiji koja na scenu dovodi isti glavni lik, Durtala, kroz kojeg autor romana „Tamo“ (Là-Bas) pripovijeda o etapama vlastitog puta u Damask.
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Podryabinkina, Anastasiya G. "What Did Jozef Boguslavsky Say About Sergei Durov and Fedor Dostoevsky in Siberian Diary?" Неизвестный Достоевский 7, no. 1 (March 2020): 51–68. http://dx.doi.org/10.15393/j10.art.2020.4421.
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The article examines the chapter <i>Sergei Durov and Fyodor Dostoevsky</i> from the <i>Siberian Diary</i> of the Polish revolutionary Jozef Boguslavsky, who was confined in the Omsk prison at the same time as F. M. Dostoevsky. The <i>Siberian Diary</i> was included in <i>Polacy z Wilna i ze Żmudzi na zesłaniu. Pamiętniki Józefa Bogusławskiego i księdza Mateusza Wejta</i> (<i>Poles from Vilnius and Zemaitija in exile. The Memoirs of Jozef Boguslavsky and priest Mateusz Veit</i>). Some fragments of this book and other Polish sources were translated into Russian for the first time by the author of the article, including the recollections about Sergey Durov and Fyodor Dostoevsky. The interrelation between the <i>Siberian Diary</i> by Y. Boguslavsky, <i>Notes from a Dead House</i> by F. M. Dostoevsky, and S. Tokazhevsky’s <i>Seven Years of Hard Labor</i> and <i>The Convicts</i> is also analyzed in the paper.
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Mickael, Heymann. "119 RELEASE OF CATECHOLAMINES DURTNG THE DIFFERENT PHASES OF BIRTH SIMULATION IN THE FETAL LAMB." Pediatric Research 28, no. 3 (September 1990): 297. http://dx.doi.org/10.1203/00006450-199009000-00143.
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Moldovan, Ana, Maria-Alexandra Hoaghia, Anamaria Iulia Török, Marius Roman, Ionut Cornel Mirea, Reka Barabas, Valer Micle, and Oana Cadar. "Spatial Variation of Water Chemistry in Aries River Catchment Western Romania." Applied Sciences 11, no. 14 (July 17, 2021): 6592. http://dx.doi.org/10.3390/app11146592.
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This study aims to investigate the quality and vulnerability of surface water (Aries River catchment) in order to identify the impact of past mining activities. For this purpose, the pollution and water quality indices, Piper and Durov plots, as well vulnerability modeling maps were used. The obtained results indicate that the water samples were contaminated with As, Fe, Mn, Pb and have relatively high concentrations of SO42−, HCO3−, TDS, Ca, K, Mg and high values for the electrical conductivity. Possible sources of the high content of chemicals could be the natural processes or the inputs of the mine drainage. Generally, according to the pollution indices, which were correlated to high concentrations of heavy metals, especially with Pb, Fe and Mn, the water samples were characterized by heavy metals pollution. The water quality index classified the studied water samples into five different classes of quality, namely: unsuitable for drinking, poor, medium, good and excellent quality. Similarly, medium, high and very high vulnerability classes were observed. The Durov and Piper plots classified the waters into Mg-HCO3− and Ca-Cl− types. The past and present mining activities clearly change the water chemistry and alter the quality of the Aries River, with the water requiring specific treatments before use.
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Savage, Glenn C., and Anna Hickey-Moody. "Global flows as gendered cultural pedagogies: learning gangsta in the ‘Durty South’." Critical Studies in Education 51, no. 3 (September 14, 2010): 277–93. http://dx.doi.org/10.1080/17508487.2010.508808.
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Mamdani, Hirva, Bryan J. Schneider, Laith I. Abushahin, Thomas J. Birdas, Kenneth Kesler, Ahran Lee, Heather Burney, Susan Perkins, and Shadia Ibrahim Jalal. "Safety and efficacy of durvalumab following trimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Early efficacy results from Big Ten Cancer Research Consortium study." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 5. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.5.
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5 Background: The standard of care for locally advanced esophageal adenocarcinoma(LA-EAC) is concurrent chemoradiation (CRT) followed by esophagectomy. Approximately 30% of patients (pts) achieve complete pathologic response (pCR) with this approach. The risk of relapse in the remaining 70% of pts is high, with 1-yr relapse free survival (RFS) of 50%. No adjuvant therapies have been shown to improve survival. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown upregulation of PD-1 pathway with radiation +/- chemotherapy. Methods: We conducted a phase II study evaluating safety and efficacy of durvalumab (durva), a monoclonal antibody against PD-L1, in pts with LA-EAC and GE junction (GEJ) adenocarcinoma who do not achieve pCR after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1 yr after surgery. Primary objective was 1-yr RFS. Secondary objectives were incidence and severity of treatment related adverse events (AEs). Results: Twenty-four pts were enrolled from Apr 2016 to Jan 2018 (median age: 60yrs (range, 43-74)). Fourteen pts had GEJ adenocarcinoma and 10 had distal EAC. Eighteen received carboplatin/paclitaxel and six received cisplatin/5-FU concurrently with 50-50.4Gy radiation. Nineteen pts (79%) had positive lymph nodes at the time of surgery after neoadjuvant CRT, including three (12.5%) with N3, nine (37.5%) with N2, and seven (29%) with N1 disease. Among N0 pts, two had T3N0, one had T2N0, and two had T1N0 disease. At median follow-up of 11.7 mo (range 1.7-23.9 mo), seven pts (29%) have relapsed (five alive, two died); 17(67%) are disease free (six on treatment, seven completed treatment, three off-treatment); 1-yr and projected 26 mo RFS are 78.6% and 62.9%, respectively. Five pts (20.8%) developed grade 3 AEs: diarrhea (n = 1), hepatitis (n = 1), encephalopathy (n = 1), hyperglycemia (n = 1), hypoglycemia (n = 1). Most common grade 1 and 2 AEs were fatigue (33.3%), nausea (25.0%), and cough (20.8%). Conclusions: Adjuvant durva in pts with residual disease following trimodality therapy for EAC and GEJ adenocarcinoma is safe and feasible with 1-yr RFS of 78.6% compared to historical rate of 50%. Clinical trial information: NCT02639065.
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Cathomas, Richard, Ulf Petrausch, Stefanie Hayoz, Martina Schneider, Julian Andreas Schardt, Roland Seiler, Andreas Erdmann, et al. "Perioperative chemoimmunotherapy with durvalumab (Durva) in combination with cisplatin/gemcitabine (Cis/Gem) for operable muscle-invasive urothelial carcinoma (MIUC): Preplanned interim analysis of a single-arm phase II trial (SAKK 06/17)." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 499. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.499.
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499 Background: Cisplatin-based neoadjuvant chemotherapy followed by surgery is the standard of care for patients (pts) with MIUC but relapse rates remain high. Immune checkpoint inhibitors have demonstrated efficacy in advanced urothelial carcinoma (UC). We hypothesize that the integration of the PD-L1 inhibitor durvalumab into perioperative management of MIUC improves outcome. Methods: SAKK 06/17 is an open label single arm phase II study including 61 pts. Operable MIUC cT2-T4a cN0-1 pts without contraindication for Cis were eligible. Four cycles of preoperative Cis/Gem q3w are administered in combination with 4 cycles Durva 1500mg q3w starting at cycle 2. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival at 2 years. We report a preplanned interim analysis of the secondary endpoints safety, pathological complete remission ypT0 N0 (pCR,) and pathological response rate (PaR, defined as ≤ypT1N0) on the first 30 resected pts. Results: Among 34 eligible pts (27M, 7F; median age 70, range 41-81 years) included from 07/18 – 02/19, 33 pts (97%) had primary bladder cancer and 1 pt had upper tract UC. Clinical T2, T3, T4 and TxN1 stage were present at diagnosis in 68%, 18%, 15% and 15%, respectively. Four cycles of chemo-immunotherapy were completed per protocol in 34 pts (100%). No tumor progression was noted at preoperative restaging. AE related to Durvalumab were G3 in 5 pts (15%) and G4 in 3 pts (9%). Surgery was performed as planned in 30 pts (88%), 3 pts refused surgery and 1 pt had a frozen pelvis. Operation technique was open in 20 pts (67%) and laparoscopic/robot-assisted in 10 pts (33%). Postoperative complications included Clavien-Dindo III in 6 pts (20%) and IV in 2 pts (7%) with infections being most common (5 pts, 17%). pCR was found in 9 pts (30%) and additional 6 pts (20%) had ypT1/ypTis for a PaR of 50%. Conclusions: The combination of Cis/Gem and Durva as neoadjuvant treatment for MIUC is feasible with manageable toxicities and pCR and PaR rates in the expected range. The rate of postoperative complications warrants further close follow up. Clinical trial information: 2017-003565-10.