bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of the myeloid-derived suppressor cells in advanced breast cancer and comparative analysis with a healthy population cohort.
Authors: Palazón-Carrión Natalia , Jiménez-Cortegana Carlos , Holgado Esther , Jurado Josefina Cruz , Alonso Romero Jose Luis , Sánchez Leon María Luisa , Sanchez Margalet Victor , Nogales Esteban , Moreno Anton Fernando , Quiroga Garcia Vanesa , Andres Raquel , Santisteban Marta , Cortes Javier , Rodríguez-Rodríguez Luz Milva , Soto Gutierrez Asuncion , Cortes Mana Gion , Nieto Garcia A. , Chiesa Massimo , Bezares Susana , De la Cruz-Merino Luis 
Published: May 2019

2543 Background: High levels of myeloid-derived suppressor cells (MDSCs) seem a negative prognostic factor in advanced breast cancer (ABC) patients (pts). Preclinical studies suggest an immunomodulatory effect of some classical anti-tumor agents through alteration of MDSCs homeostasis. We analyzed the association of MDSCs and clinical evolution of ABC pts, taking into account the systemic treatment (tx) modulation of MDSCs levels in pts from two studies (“A”: GEICAM/2015-04 PANGEA-BREAST, NCT03025880 “Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC”, and “B”: PI-0502-2014 “Peripheral blood analyses of immune response induced by 1st line tx of ABC according to clinical guidelines”). Methods: MDSCs (CD33+ CD11b+) levels were determined by flow-cytometry in peripheral blood samples at three time points (basal, at cycles 3 and 6) from: 39 HER2-negative heavily pretreated pts from study “A”, 43 non-pretreated pts (all subtypes) from study “B” and 20 women from a healthy cohort (HC), with no cancer diagnosis. MDSCs levels from the different cohorts were compared and correlated with pts with Clinical Benefit (CB: partial/complete response + disease stabilization) vs pts with Progressive Disease (PD). Results: Tx response was assessed in 33 pts (85%) from study “A” and 39 pts (91%) from study “B”. CB was observed in 11 pts (28%) from study “A” and in 34 (79%) from study “B” while PD was observed in 22 pts (56%) from study “A” and in 5 (12%) from study “B”. Basal MDSCs levels were significantly higher in ABC pts (studies “A”+”B”) than in HC (15.95 vs 0.81 cells/µl, p = 0.009). At cycle 6, MDSCs were considerably lower in pts with CB vs DP (2.90 vs 13.75 cells/µl, p < 0.001). This decrease was more pronounced in study “B” than in study “A” pts (p < 0.001 vs p = 0.074, respectively), probably due to differences in number of events, tumor subtypes and tx between both studies. Conclusions: Our results suggest that ABC pts show alterations in MDSCs and that their decrease along tx may have a positive predictive value, highlighting the importance that immune-competent status may play in the evolution of ABC. MDSCs may represent a target for therapeutic purposes in ABC.
Safety and immunobiological activity of guadecitabine sequenced with ipilimumab in metastatic melanoma patients: The phase Ib NIBIT-M4 study.
Authors: Di Giacomo Anna Maria , Covre Alessia , Finotello Francesca , Rieder Dietmar , Sigalotti Luca , Giannarelli Diana , Petitprez Florent , Lacroix Laetitia , Cutaia Ornella , Fazio Carolina , Coral Sandra , Anichini Andrea , Bock Christoph , Lowder James N. , Azab Mohammad , Fridman Wolf-Herman , Sautes-Fridman Catherine , Trajanoski Zlatko , Maio Michele 
Published: May 2019

2549 Background: DNA hypomethylating agents show broad immuno-modulatory activity in neoplastic cells, and may improve the effectiveness of cancer immunotherapies. The phase 1b NIBIT-M4 trial investigated a previously unexplored therapeutic strategy using the next-generation DNA hypomethylating agent guadecitabine sequenced with ipilimumab for the treatment of advanced melanoma. Methods: Patients with unresectable Stage III/IV melanoma received escalating doses of guadecitabine 30, 45 or 60 mg/m2 subcutaneously on Days 1–5 every three weeks, and ipilimumab 3 mg/kg intravenously on Day 1 every three weeks, starting one week after guadecitabine, for four cycles. Primary endpoints were the safety, tolerability and maximum tolerated dose of treatment; secondary endpoints included immune-related disease control and objective response. Genome-wide methylation, RNA sequencing, and immunohistochemistry analyses were performed on tumor samples collected at baseline, W4 and W12. (NCT02608437). Results: 19 patients were treated and evaluable for safety and efficacy. The most common treatment-related adverse events of any grade were myelotoxicity (n = 17; 89%) and immune-related adverse events (n = 12; 63%). Grade 3 or 4 myelotoxicity occurred in 15 (79%) patients. There were no dose limiting toxicities. Rates of immune-related disease control and objective response were 8/19 (42%) and 5/19 (26%), respectively. Exploratory analyses of tumour samples (n = 8) showed that median CpG site methylation at Week 4 (74.5%) and Week 12 (75.5%) was significantly lower (p < 0.05) than at baseline (80.3%), with a median of 2454 (Week 4) and 4131 (Week 12) differentially expressed genes identified compared to baseline; among the 136 pathways significantly modulated by treatment, the most frequently activated were immune-related. Tumour immune contexture analysis (n = 11) demonstrated up-regulation of Human Leukocyte Antigen (HLA) class I molecules on melanoma cells, and an increase in CD8+, PD-1+ T cells and in CD20+ B cells in post-treatment tumour core specimens. Conclusions: Sequential guadecitabine and ipilimumab is safe and tolerable in patients with metastatic melanoma, and has promising immunological and anti-tumour activity. Clinical trial information: NCT02608437.
Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies.
Authors: Uboha Nataliya Volodymyrivna , Milhem Mohammed M. , Kovacs Christina , Amin Alpesh , Magley Andrea , Purkayastha D. Das , Piha-Paul Sarina Anne 
Published: May 2019

2553 Background: Spartalizumab and LAG525 are monoclonal antibodies targeting PD-1 and LAG-3, respectively. Dual blockade of PD-1 and LAG-3 has shown synergistic antitumor activity in preclinical models. Here we describe preliminary efficacy of spartalizumab + LAG525 across seven tumor types. Methods: Phase II, open-label, parallel-cohort study was conducted in pts with solid or hematologic malignances relapsed and/or refractory to standard-of-care therapies. Prior immunotherapy was prohibited. LAG525 (400 mg) and spartalizumab (300 mg) were dosed intravenously every 3 weeks. Primary endpoint was clinical benefit rate at 24 weeks (CBR24), assessed using a Bayesian hierarchical model-based futility analysis. Posterior probability that clinical benefit exceeds historical control (Pr) was estimated to determine futility at interim against prespecified thresholds. Results: As of January 7 2019, 76 pts received spartalizumab + LAG525; 72 pts were eligible for analysis (Table). The Pr cut-off for all arms was > 0.70. Hence, neuroendocrine tumors (NET), small cell lung cancer (SCLC) and diffuse large B-cell lymphoma (DLBCL) cohorts all met the expansion criteria with Pr of 0.971, 0.975 and 0.804 respectively. CBR24 were as follows; NET: 0.86, SCLC: 0.27, DLBCL: 0.43. Prostate, sarcoma and ovarian cohorts did not meet the expansion criterion (Pr > 0.70) but were not declared futile; enrollment was paused pending results of next analysis. Gastroesophageal (GE) cancer cohort was stopped for futility due to Pr (0.071) below the futility threshold. Conclusions: Spartalizumab and LAG525 showed promising activity in NET, SCLC and DLBCL that met expansion criteria. The GE cohort was declared futile. Remaining cohorts are paused pending further analysis. Clinical trial information: NCT03365791. [Table: see text]
Preliminary safety, efficacy, and pharmacokinetics (PK) results of KN046 (bispecific anti-PD-L1/CTLA4) from a first-in-human study in subjects with advanced solid tumors.
Authors: Coward Jermaine , Ganju Vinod , Behzadigohar Ramin , Kwong Kenneth , Xu June , Van Hardy , Kong Paul , Yang Fei , Chen Lisa , Guo Kangping , Liu Mei , Zhu Danming , Donato Lara Kristina , Xu Ting , Richardson Gary Edward 
Published: May 2019

2554 Background: KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. KN046 has a wild type IgG1 Fc portion that preserves intact effector functions, such as depletion of Tregs in tumor microenvironments. This first-in-human study evaluated the safety, tolerability, PK and preliminary efficacy of KN046 in subjects with advanced solid tumors. Methods: This traditional “3+3” dose-escalation design study enrolled patients (pts) with advanced unresectable or metastatic solid tumors refractory or intolerant to standard therapies. Previous treatment from PD1 or PD-L1 immune checkpoint inhibitors was allowed. KN046 was administered intravenously Q2W. Dose limit toxicity (DLT) evaluation period is 28 days. The planned dose levels (DL) were 0.3, 1, 3, 5 and 10 mg/kg. Efficacy evaluation was performed by RECIST 1.1 every 8 weeks. Results: As of Dec 13, 2018, 10 pts had been enrolled (0.3 mg/kg, n = 1; 1 mg/kg, n = 3; 3 mg/kg, n = 3; and 5 mg/kg, n = 3). Median duration of treatment was 8 (range: 2-24) weeks. 1 DLT was observed at 5 mg/kg dose (a grade 3 immune-related hepatitis without elevation in total bilirubin; reversible in two weeks). The most common (≥30%) treatment-emergent AEs (TEAE) were Fatigue, Diarrhea, Nausea, Vomiting. Six immune-related TEAEs (Abdominal pain lower, Arthralgia, Hepatic function abnormal, Hyperthyroidism, Nausea and Transaminitis) were observed in 3 pts. One pt with NSCLC from 3 mg/kg cohort had confirmed completed response. Two pts (TNBC and nivolumab refractory RCC) from 1 mg/kg cohort had shown long-term stable disease ( > 12 weeks). Faster clearance of KN046 was observed at lower dose might be due to target-mediated clearance. T1/2 is approximately 7~9 days at doses of 3 mg/kg and above when saturation occurs. Conclusions: Single agent KN046 has an acceptable safety profile and is in line with previously reported safety data from other immune checkpoint inhibitors. Preliminary efficacy results are promising. PK data from initial 4 cohorts support Q2W schedule. The study is currently ongoing at dose level of 5 mg/kg Q2W. Clinical trial information: NCT03529526.
Antitumor activity and safety of MK-1308 (anti-CTLA-4) plus pembrolizumab (pembro) in patients (pts) with non-small cell lung cancer (NSCLC): Updated interim results from a phase I study.
Authors: Perets Ruth , Yoh Kiyotaka , Kim Dong-Wan , Bar Jair , Ahn Myung-Ju , Nagrial Adnan , Satouchi Miyako , Rasco Drew W. , Lee Dae Ho , Spigel David R. , Kotasek Dusan , Gutierrez Martin , Niu Jiaxin , Siddiqi Shabana , Chain Anne , Butts Brent D. , Li Xiaoyun Nicole , Cyrus Jobin , Altura Rachel , Cho Byoung Chul 
Published: May 2019

2558 Background: An ongoing multicenter, open-label, phase 1 study of the anti–CTLA-4 antibody MK-1308 in combination with pembro in advanced solid tumors (NCT03179436) revealed a manageable safety profile and promising efficacy in pts with first-line (1L) advanced NSCLC. Data from a larger sample size and longer follow-up are presented. Methods: In dose escalation (DE), pts with advanced solid tumors received MK-1308 by IV administration at 25, 75, or 200 mg Q3W ×1 cycle then in combination with pembro 200 mg Q3W ×4 cycles followed by pembro monotherapy (up to 35 cycles). In dose confirmation (DC), pts with 1L advanced NSCLC received MK-1308 at 25 or 75 mg—Q3W or Q6W—plus pembro 200 mg Q3W (up to 35 cycles). Safety (all treated pts), efficacy (subset of 1L NSCLC pts), pharmacokinetics (PK, all treated pts), and PD-L1 tumor expression (subset of 1L NSCLC pts) were analyzed. Results: 213 pts were treated (DE, n=39; DC, n=174). All pts were included in the safety analyses (median follow-up, 8 months); 113 pts from DC were included in the efficacy analyses (median follow-up, 8 months). PK showed a dose-dependent increase in MK-1308 exposure. Neither target dose-limiting toxicity (≥10%) nor maximum tolerated dose were reached for MK-1308 plus pembro; however, toxicity increased with increasing MK-1308 dose and shorter dosing intervals. Treatment-related adverse events grade ≥3 occurred at the lowest rates at 25 mg Q3W in DE (0%) and 25 mg Q6W in DC (25%) and at the highest rates at 200 mg Q3W in DE (75%) and 75 mg Q3W in DC (50%). Efficacy was observed at all MK-1308 dose levels and intervals: confirmed ORR per RECIST 1.1 by central review in 1L advanced NSCLC was 39% at 25 mg Q3W, 33% at 25 mg Q6W, 22% at 75 mg Q6W, and 25% at 75 mg Q3W; 6-month PFS and OS rates are 67% and 89% for the 25 mg Q6W arm. There was a 25% ORR in PD-L1–negative 1L advanced NSCLC pts. Conclusions: MK-1308 plus pembro was generally well tolerated with no unexpected toxicity and conferred encouraging antitumor activity in 1L advanced NSCLC pts. Efficacy, safety, and PK data suggest that 25 mg given Q6W is the recommended phase 2 dose for MK-1308 in combination with pembro. Clinical trial information: NCT03179436.
IOLite: Multipart, phase 1b, dose-finding study of the PD-1 inhibitor dostarlimab in combination with the PARP inhibitor niraparib ± bevacizumab (bev), or with platinum-based chemotherapy ± bev for advanced cancer.
Authors: Gabrail Nashat Y. , Bessudo Alberto , Hamilton Erika Paige , Sachdev Jasgit C. , Patel Manish R. , Rodon Ahnert Jordi , Evilevitch Lena , Duncan Meghan , Guo Wei , Lu Sharon , Dezube Bruce Jeffrey , Yap Timothy A 
Published: May 2019

2560 Background: Novel combinations of drugs may overcome resistance in patients (pts) with solid tumors who had progressed on standard therapy. Methods: IOLite (NCT03307785) is a multicenter, open label, multipart study to determine dosing and evaluate safety and efficacy of dostarlimab in combination with approved therapies in pts with advanced solid tumors. Pts were enrolled in each part based on tumor histology, prior treatment (tx) history, and physician preference. Primary endpoint is dose-limiting toxicities (DLTs) deemed as tx-related per investigator, and safety and tolerability of the combination. Tumor responses were assessed per RECIST v1.1. Results: Parts A-D (see Table) are fully enrolled. One complete response was reported in part B (endometrial); confirmed partial responses in part A (ovarian, small cell lung [SCLC], gastrointestinal stromal [GIST]); part B (breast [2], bladder, SCLC); part C (prostate, fallopian tube), and part D (endometrial, non-SCLC). Stable disease was reported in part A (colorectal, prostate [2], breast, GIST, gastric); part B (SCLC, squamous cell, head and neck, prostate); part C (pancreatic, ovarian, GIST, breast [2], liver, endometrial); part D (ovarian, head & neck, cholangiocarcinoma). At data cutoff, 24 pts remain on treatment. PK’s of dostarlimab and niraparib (nir) were not altered by any of the combination agents tested. Conclusions: Dostarlimab is well tolerated in combination with nir ± bev, or carbo-pac ± bev. Preliminary efficacy data show responses in various histologies. No new safety signals were identified. Clinical trial information: NCT03307785. [Table: see text]
Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors.
Authors: Patel Manish R. , Falchook Gerald Steven , Wang Judy Sing-Zan , Rodrigo Imedio Esteban , Kumar Sanjeev , Motlagh Pejvack , Miah Kowser , Mugundu Ganesh M. , Jones Suzanne Fields , Spigel David R. , Hamilton Erika Paige 
Published: May 2019

2562 Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]
Early incidence of immune-related adverse events (irAEs) predicts efficacy in patients (pts) with solid tumors treated with immune-checkpoint inhibitors (ICIs).
Authors: Morehouse Chris , Abdullah Shaad Essa , Gao Chen , Dar Mohammed M. , Ranade Koustubh , Higgs Brandon W. 
Published: May 2019

2563 Background: Treatment with ICIs can manifest immune-related adverse events (irAEs), which have correlated with clinical outcomes in certain tumors. However, timing of these events and how early irAEs correlate with outcomes is unclear. We assessed whether early occurring irAEs could predict survival in pts treated with durvalumab (D), an anti-PDL1 and combined with tremelimumab (D+T), an anti-CTLA4 in two clinical studies. Methods: Two phase 2 non-randomized clinical trials evaluating D (D4190C00001 (1108), N=756; available data per internal data re-use policy) or D+T (D4190C00010 (C10), N=327; expansion and ICI naïve cohorts) in multiple solid tumor types were analyzed. Prevalence of pts experiencing irAEs, regardless of grade was 30% and 59% in studies 1108 and C10, respectively, with most frequent including dermatitis/rash (25%), thyroid (15%), diarrhea/colitis (14%), and pancreatic enzyme elevation (5%). Overall survival (OS) was correlated with irAE timing prior to 6, 8, 12, 16, 20 and 24 weeks following D or D+T treatment. Kaplan Meier and log-rank analyses were used. Results: In both studies, pts who experienced at least one irAE by study completion had improved median OS (mOS, 1108: 23.1 mos [18.2, 26.9]; C10: 16.3 mos [12.5, 31.4]) relative to those who experienced none (1108: 6.3 mos [5.4, 7.3]; C10 4.6 mos [3.3, 6.1]). Median time (weeks) to first and second irAE occurred earlier in C10 compared to 1108, 3.9 vs. 5.6 and 6.9 vs. 10.1, respectively. When associating timing of irAEs with survival, there was a significant differential in mOS at each time interval evaluated between pts with at least one irAE and those with none, with differentiation at 6 weeks and maximal survival benefit at 24 weeks following treatment with D or D+T (Table). Conclusions: Early occurrence of irAEs may be predictive of survival benefit in pts treated with D or D+T. OS by 1+ or no irAE(s) occurring up to 6 or 24 weeks post treatment. [Table: see text]
Association between past medical history (PMH) of autoimmune events and adverse events of special interest (AESI).
Authors: Brewer Jamie Renee , Maher Virginia Ellen , Weinstock Chana , Agrawal Sundeep , Brave Michael Holman , Ning Yang-Min , Singh Harpreet , Suzman Daniel L. , Xu James , Ibrahim Amna , Beaver Julia A. , Pazdur Richard 
Published: May 2019

2565 Background: PD-1/L1 inhibitor therapy has become the standard of care for many advanced solid tumors. A notable limitation of PD-1/L1 inhibitor therapy is the concern for AESI that are likely to be immune related. It is unclear whether a history of autoimmune events is a predisposing risk making these adverse events more likely. We aimed to evaluate the association between autoimmune-associated PMH and AESI on PD-1/L1 inhibitors. Methods: We pooled data across seven pivotal trials for PD-1/L1 inhibitors in urothelial cancer (UC) identifying patients with AESI submitted from 2016 - 2017. AESI were determined using a pooled preferred term list for each trial. Information collected from trials included PMH, AESI events and toxicity grade. Results: In total, 1747 immunotherapy treated patients were identified, with 1068 (61%) having an AESI and 277 (26%) having an autoimmune-related PMH. The most common autoimmune-associated events in the PMH were thyroid disorders (64%), asthma (23%), atopic dermatitis/eczema (6%), irritable bowel syndrome (5%), and psoriasis (4%). AESI occurred in 68% of patients with an autoimmune-related PMH and 60% of patients without an autoimmune-related PMH. The most common AESI in patients with an autoimmune-related PMH were diarrhea (35%), rash (27%), renal disorder (27%), and pruritis (23%). The most common AESI in the general trial population were diarrhea (28%), pruritis (26%), rash (25%), increased creatinine (14%), and elevated AST and ALT (10% and 9%). The majority of events were Grade 1-2 (87% in patients with an autoimmune-related PMH and 84% in the general trial population). Conclusions: Pooled clinical trial data shows a slight numeric increase in AESIs in patients with autoimmune-associated PMH. Limitations include potential lack of consistency of PMH documentation and adverse event reporting. There did not appear to be a pattern of association between PMH and type of AESI event. Grades of AESI events in the population with autoimmune-associated PMH were similar to the general trial population. This suggests that PD-1/L1 inhibitors may be safely administered to patients with UC and a PMH of some autoimmune-associated events. Further exploration is needed.