bluuebunny/crossref_metadata_2025_split huggingface dataset:
SOlar: A translational phase II study of single-agent olaparib in the treatment of advanced esophagogastric cancer.
Authors: Cartwright Elizabeth , Fong Caroline Yean Kit , Hubank Michael , Saffery Claire , Kalaitzaki Eleftheria , Young Kate , Coyne Tracy , Musallam Annette , Fotiadis Nicos , Wotherspoon Andrew , Begum Ruwaida , Zerizer Imene , Rao Sheela , Watkins David J. , Gerlinger Marco , Chong Irene Yu-Shing , Lord Christopher J. , Chau Ian , Cunningham David , Starling Naureen 
Published: February 2020

TPS471 Background: Oesophagogastric (OG) cancers represent a significant health burden and leading cause of cancer related death. Prognosis in advanced disease is poor and novel therapies are needed to improve outcomes. Molecular features of advanced OG cancer suggest that assessment of DDR (DNA damage repair) targeted agents is warranted. Specifically, ATM and ARID1A defects and mutational scars indicative of homologous recombination defects are present in a subset of OG cancers and are associated with polyadenosine 5’diphosphoribose polymerase inhibitor (PARPi) sensitivity. Methods: SOlar is a multi-centre, open-label, single arm, phase II study of olaparib, a PARPi, in patients with advanced oesophageal, gastro-oesophageal junction and gastric adenocarcinoma. The trial will use a single-arm Simon two-stage design to evaluate the anti-tumour activity of olaparib in advanced OG cancers. The primary endpoint is disease control rate (DCR) at 8 weeks by RECIST v1.1. To rule out a DCR of ≤15% while aiming for DCR ≥30% (alpha = 0.09, power = 89%), 54 patients must be recruited it total. An interim analysis will take place when 27 patients have been accrued, dosed and followed until the 8-week disease evaluation. If 4 or fewer patients have disease control (DC) the study will be terminated. If 5 or more patients have DC, an additional 27 patients will be enrolled to a total of 54 patients. If ≥12/54 have DC in the final analysis then it will be concluded that the treatment has shown anti-tumour activity compatible with 30% and an investigation of potential biomarkers of response will be carried out. Secondary endpoints are ORR, DoR, OS, PFS, time to radiological progression and safety. This highly translational study incorporating serial tumour biopsies will investigate candidate predictive biomarkers of PARPi sensitivity with the aim of identifying responder/non-responder subpopulations. Further exploratory objectives will investigate the predictive role of early FDG-PET/CT in assessing tumour response and the creation of an organoid biobank. The trial opened to recruitment in July 2019 and will recruit up to 54 patients over 3 years. Clinical trial information: NCT03829345.
A phase II study of enterade in neuroendocrine tumor (NET) patients with quality-of-life limiting bowel movement frequency.
Authors: Das Satya , Koyama Tatsuki , Luque Laura , Cheuvront Samuel , Berlin Jordan 
Published: February 2020

TPS634 Background: BM frequency in NET pts is a major cause of morbidity. Though typically associated with serotonin excess in pts with carcinoid syndrome (CS), it can also occur in pts without CS due to etiologies such as short bowel syndrome, bile acid malabsorption, steatorrhea from somatostatin analogs (SSAs) and complications from chemotherapy/immunotherapy/biologics. Enterade is an oral rehydration solution, comprised of 5 amino acids, which has demonstrated pre-clinical and clinical potential to improve small intestinal resorption, thereby offering a potential treatment for limiting BM frequency in NET pts. Methods: We are conducting a phase II parallel cohort study in CS and non-CS NET pts (NCT 4073017). To be eligible, pts must be experiencing an average of ≥ 4 daily BM while on standard-of-care (SOC) therapies (SSAs, anti-diarrheals). Pts will be categorized into CS or non-CS cohorts based upon biochemical evaluation which includes plasma 5-HIAA/24-hour urine 5-HIAA, VIP or gastrin levels. Eligible pts will undergo observation during weeks 1-4 (baseline period). During weeks 5-8, pts will consume Enterade twice per day (Enterade period) while during weeks 9-12, pts will stop Enterade and resume observation. Daily stool diaries for each pt will be assessed to compute differences in mean bowel movement number between baseline and Enterade periods. Endpoints: The primary endpoint of the study is reduction in BM frequency in individual pts between baseline and Enterade periods. Based on parameters utilized in a prior study, we will assume that the mean daily reduction in bowel movements from baseline is equal to 1.5 (standard deviation of change = 1.5) representing a large effect size = 1.0. A sample of 12 pts in each cohort will provide nearly 90% power to detect this effect size based on a one-sample t-test (α = .05). An additional 3 pts will be added to each cohort to account for potential dropouts. Key secondary study endpoints include differences in pt-reported QOL outcomes (FACIT-D), pt weight, intravenous fluid requirement and utilization of SOC anti-diarrheals between baseline and Enterade periods. Accrual for the study will be ensuing shortly. Clinical trial information: NCT04073017.
A phase I study of nanoliposomal irinotecan and 5-fluorouracil/folinic acid in combination with interleukin-1-alpha antagonist for advanced pancreatic cancer patients with cachexia (OnFX).
Authors: Atkins Katelyn Mae , Gong Jun , Tighiouart Mourad , Klempner Samuel J. , Tuli Richard , Placencio-Hickok Veronica , Hendifar Andrew Eugene 
Published: February 2020

TPS780 Background: Patients with pancreatic cancer have the highest rate of weight loss among all advanced cancers. Of which, the majority develop cachexia, characterized by progressive and involuntary loss of weight and skeletal muscle mass. In preclinical studies, interleukin-1-alpha (IL-1α) antagonism has been found to neutralize tumor angiogenesis and onco-inflammation. Early phase single-agent studies in cancer cachexia have demonstrated increased lean body mass and decreased fatigue, pain, and appetite loss. The present study aims to establish the safety of an IL-1α antagonist (Bermekimab) in combination with nanoliposomal irinotecan (Nal-Iri) and 5-fluorouracil (5FU)/folinic acid (FA) in patients with advanced pancreatic adenocarcinoma and cachexia who have failed gemcitabine-based chemotherapy. Methods: This is a single arm, single center, phase I study. The primary objective is to assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nal-Iri and 5FU/FA. MTD is defined as the dose such that the probability of dose-limiting toxicities at MTD is θ = 0.33. The first cohort of up to 3 patients will receive 7.5 mg/kg Bermekimab, 50 mg/m2 nanoliposomal irinotecan, 2000 mg/m2 5FU, and 400 mg/m2 FA and the subsequent doses will be determined by the escalation with overdose control (EWOC) algorithm. Treatment is administered on days 1 and 15 of each 28-day cycle. Key inclusion criteria include: advanced or locally advanced pancreatic adenocarcinoma that has progressed through or intolerant of gemcitabine-based chemotherapy, cachexia defined as > 5% unexplained weight loss 6 months prior to screening or as documented by physician, ECOG PS 0-2 or KPS ≥ 60%, and normal organ and marrow function. Secondary objectives are to assess weight, lean body mass, inflammatory cytokines, overall survival, progression free survival, patient quality of life, and functional status. Since January 2019, 23 patients have been screened and 21 enrolled. Clinical trial information: NCT03207724.
Atypical Stevens-Johnson syndrome-like reaction in the setting of immune checkpoint inhibition.
Authors: Molina Gabriel E. , Yu Zizi , Foreman Ruth K. , Reynolds Kerry Lynn , Chen Steven T. 
Published: February 2020

102 Background: Stevens-Johnson syndrome (SJS) is a rare, life-threatening mucocutaneous toxicity that can occur in patients receiving immune checkpoint inhibitors (ICIs). ICI-induced SJS is scarcely reported in the literature and thus remains poorly understood, particularly regarding features that may distinguish it from classic SJS. Methods: To describe the timing, clinical manifestations, and treatment course of ICI-induced SJS, this multicenter, retrospective study identified seven patients with SJS in the setting of ICI use from January 2011 through May 2019. Results: All seven patients presented initially as benign, limited drug eruptions after a median of 4 ICI cycles (range, 1-7) and 63 days (range, 13-253 days) from ICI initiation. While none of the patients had prior drug allergies, all 7 were receiving new, recently initiated – i.e., within two months – medications at the time of rash onset. Cases demonstrated characteristic histologic findings of SJS, such as epidermal necrosis, and occasional unusual features, including interface dermatitis. All patients responded favorably and rapidly to systemic therapy, primarily intravenous corticosteroids, with near immediate symptomatic resolution and cessation of progressive skin blistering or detachment. Median length of stay was 11 days and no patients died from SJS. Conclusions: Our cohort defines an atypical SJS-like reaction secondary to ICI use, which is distinct from classic SJS in its delayed onset, mild initial presentation, and rare ocular involvement. The association with concomitant medication use suggests a potential mechanism whereby ICIs reduce patient immune tolerance to subsequent drug exposures. Reassuringly, this atypical SJS-like phenomenon exhibits a benign clinical course and favorable response to standard treatments.
Anxiety among immunotherapy patients: Preliminary findings from Immunotherapy & Me.
Authors: Jaisle Alyssa Marie , Power Nicholas James , House Linda S. , Jones Tameka N. , Schwartzberg Lee S. 
Published: February 2020

104 Background: Immunotherapy is a relatively new method of cancer treatment which has seen little research into its psychosocial side effects. A clearer understanding of the source of anxiety for those undergoing immunotherapy is crucial as anxiety during cancer treatment can result in decreased treatment adherence, increased mortality rates, and other negative outcomes. This study surveyed 112 cancer patients undergoing immunotherapy to understand their top treatment-related concerns. Methods: RNs in twelve clinics across the U.S. recruited participants into Immunotherapy & Me, a study run by the Cancer Support Community (CSC). Participants were given access to a selection of CSC’s world-class support resources designed to help them and their loved ones manage their treatment. While accessing these resources, participants were encouraged to complete a monthly survey online either at their clinic or at home for seven months. This survey included CancerSupportSource – CSC’s scientifically-validated distress screening tool – as well as some additional questions specifically tailored to immunotherapy patients. Results: The most frequent source of concern related to diagnosis and treatment was “feeling too tired to do things you want to need or do” ( M = 1.21, SD = 1.01), closely followed by “exercising and being physically active” ( M = 1.05, SD = .93). Other concerns included the future ( M = 1.03, SD = .99) and financial ( M = 1.02, SD = 1.16). There were significant differences between age groups in concerns about disruption to life F(4, 97) = 3.52, p < .01; pain F(4,97) = p < .05; finances F(4,97) = 2.86, p < .05; and fatigue F(4, 96) = 2.47, p< .05. Older participants were significantly less concerned about disruption to life as compared to younger participants while younger participants were more concerned about pain than older participants. Conclusions: Cancer patients undergoing immunotherapy do not have a single, outstanding concern. Instead, these patients have several concerns, the level of which varies significantly between age groups and gender. This suggests the need for a subsequent study that explores a more refined list of categories and probes which specific aspects of diagnosis and treatment generate these concerns. Clinical trial information: NCT03347058.
A randomized phase II study with ilixadencel, a cell-based immune primer, plus sunitinib versus sunitinib alone in synchronous metastatic renal cell carcinoma.
Authors: Lindskog Magnus , Laurell Anna , Kjellman Anders , Melichar Bohuslav , Niezabitowski Jacek , Maroto Pablo , Zieliński Henryk , Villacampa Felipe , Bigot Pierre , Bajory Zoltan , Parikh Omi , Vazquez Alba David , Jellvert Asa , Flasko Tibor , Gallardo Diaz Enrique , Ribal Maria Jose , Purkalne Gunta , Suenaert Peter , Karlsson-Parra Alex , Ljungberg Borje 
Published: February 2020

11 Background: Ilixadencel is a cell-based allogeneic off-the-shelf product aimed to prime anti-cancer immune response when injected intratumorally. The present randomized Phase II multicenter trial (MERECA; NCT02432846) evaluated intratumoral ilixadencel administration (2 doses 2 weeks apart) pre-nephrectomy followed by sunitinib post-nephrectomy compared with sunitinib monotherapy post-nephrectomy as first-line systemic therapy in patients with newly diagnosed synchronous metastatic renal cell carcinoma (mRCC). Methods: Patients were randomly assigned at two-to-one ratio to the combination (COMBO) or sunitinib (SUN) arm. Overall survival (OS) was assessed from enrollment while progression free survival (PFS) and tumor response was assessed per RECIST 1.1 (independent blinded central review) from start of sunitinib. Results: From April 2014 to January 2017, 88 patients (58 COMBO, 30 SUN) were randomized. In the COMBO arm, 2 patients did not receive ilixadencel, 10 did not receive sunitinib, and 1 did not have any follow up CT-scan. Five patients in the SUN arm never received sunitinib. Five patients (11%) in the COMBO arm had a complete response as best response versus one patient (4%) in the SUN arm. Confirmed ORR was 42.2 % (19/45) versus 24.0% (6/25). Median Duration of Response was 7.1 months versus 2.9 months. Median PFS was 11.8 months versus 11.0 months. Median OS has still not been reached in either group. As of July 2019, 57% and 43% were alive in the COMBO and SUN arms, respectively. Treatment with ilixadencel did not add any treatment-related Grade 3-4 Adverse Events. Conclusions: Compared to sunitinib monotherapy, combined treatment with ilixadencel followed by sunitinib demonstrated higher confirmed ORR, including several complete responses and longer duration of response, in patients with newly diagnosed synchronous mRCC. Clinical trial information: 02432846.
PD-L1 targeted engineered toxin body provides direct cytotoxicity and T-cell mediated tumor targeting.
Authors: Waltzman Roger J. , Brieschke Brigitte , LeMar Sara , Dekker Joseph , Cornelison Garrett , Robinson Garrett L. , Sarkar Asis , Zhao Jay , Iberg Aimee T. , Ramos Hilario J. , Willert Erin K. 
Published: February 2020

12 Background: Engineered toxin bodies (ETBs) comprised of a proprietarily engineered Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains work through novel mechanisms of action and can force internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Our PD-L1 targeted ETB includes antigen seeding technology (AST), and additionally delivers a viral antigen for presentation in complex with MHC-I to resident viral-specific cytotoxic T lymphocytes (CTLs). The fusion protein provides a powerful, dual mechanism of action to specifically target and destroy PD-L1+ tumor and inhibitory immune cells. Methods: In vitro activity of ETBs was measured by cell viability and kinetic imaging of labeled target cells in an effector T-cell co-culture assay. Repeat dosing in non-human primates (NHPs) and murine models harboring human PD-L1+ patient derived tumors were used to evaluate tolerability and efficacy. Results: ETBs targeting PD-L1 have potent direct and specific activity across human tumor cell lines and human donor derived monocytes expressing PD-L1 in vitro. In co-culture assays, AST capable ETBs had a deeper response when target cells express both PD-L1 and the appropriate MHC-I allele in the presence of antigen specific CTLs. In vivo, PD-L1 targeted ETBs induced tumor growth delay, regression and survival benefit in multiple PD-L1+ NSCLC PDX models. These ETBs were also tolerated in repeat dosing NHP studies. Conclusions: The potent targeted activity of ETB mediated tumor cell destruction is demonstrated across tumor cell lines from multiple indications, on PD-L1+ immune cells ex-vivo, and by tumor growth and survival benefits in PDX models in vivo. The AST capable, PD-L1 targeted ETBs provide dual novel mechanisms to deplete PD-L1+ cells and control malignancies. Both the SLT-A mediated direct cell kill and activation of viral-specific CTLs circumvents a need for high mutational burden or anti-tumor immune-cell infiltrate at the tumor site, providing a potential treatment option for patients whose disease has progressed after checkpoint therapy.
Sustained, cell-intrinsic versus intermittent, cell-extrinsic checkpoint blockade in solid tumor CAR T-cell therapy.
Authors: Linot Camille , Saini Jasmeen , Adusumilli Prasad S. 
Published: February 2020

16 Background: We and others have published that antigen-stress induced functional exhaustion of chimeric antigen receptor (CAR) T cells can be rescued by addition of anti-PD1 agents. To avoid the need for multiple administrations of anti-PD1 agent, we developed CAR T-cell intrinsic PD1 dominant negative receptor (PD1 DNR). Herein, we investigated the anti-tumor efficacy of cell-extrinsic versus intrinsic anti-PD1 strategies. Methods: Human T cells transduced with CD28 costimulated mesothelin-targeted CAR T cells (M28z) with or without anti-PD1 agent, and M28zPD1DNR CAR T cells were investigated against mesothelin-expressing cancer cells with inducible or constitutive PDL1 over expression. In vitro, cytotoxicity upon single and multiple antigen stimulation and proliferation, inhibitory receptor expression (PD1, TIM3 LAG3) were tested. In vivo, tumor burden regression kinetics and median survival were determined in an orthotopic model of pleural mesothelioma. Results: Following single antigen stimulation, both CAR T cells exhibited equivalent cytotoxicity. Following multiple antigen stimulations (antigen stress test), M28z PD1DNR CARs showed sustained and relatively higher cytotoxicity and proliferation compared to M28z CAR T cells, even when combined with anti-PD1 agent. PD1, TIM3 and LAG3 expression upregulation was noticed in both CAR T cells. CAR T cell therapy combined with extrinsic PD1 blockade or intrinsic PD1 DNR demonstrated enhanced and sustained tumor regression and prolonged survival (median survival 66 and 60 days) compared to CAR T cell therapy alone (27.5 days). In mouse model with constitutive PDL1 overexpressing cancer, similar trend is observed (74, 69 versus 28 days). Conclusions: A single dose of M28z CAR T cells with cell-intrinsic PD1DNR demonstrated equal anti-tumor efficacy compared to multiple doses of extrinsic anti-PD1 agent administration in models with inducible and constitutive high-PDL1 expressing cancer with no on-target, off-tumor toxicity with either strategy. This data provides the rationale for our ongoing phase II trial of combination therapy with M28z CAR T cells and anti-PD1 agent, and upcoming M28zPD1DNR CAR T cell trial in 2020.
The impact of pretreatment absolute lymphocyte count (pALC) and neutrophil-lymphocyte ratio (pNLR) on checkpoint inhibitors (CPIs) response rates in renal cell carcinoma (RCC) and bladder urothelial cancers (BC).
Authors: Bah Tonjeh Mary Stella , Sommerhalder David , Haddad Philip A. 
Published: February 2020

31 Background: CPIs have been established as essential components of cancer immunotherapy across multiple cancer types with proven clinical benefit, improved outcomes, and less toxicity. Studies in lung and head and neck cancers found that low ALC, a marker of immune exhaustion, was associated with poor response to CPIs and worse progression-free survival. We explored the effect of pALC and pNLR on CPI response rates in patients with RCC and BC. Methods: We retrospectively reviewed every RCC and BC patient that received CPIs at Overton Brooks VA Medical Center and LSUHSC-S between 2015 and 2019. Patients’ pALC and pNLR were calculated. The patients were divided according to pALC into 2 groups: Group A with pALC > 1000 and Group B with pALC < 1000. Similarly, using NLR’s established upper normal limit of 3, 2 groups were created: Group 1 with pNLR < 3 and Group 2 with pNLR > 3. Our primary outcome of interest was defined as the presence or absence of CPI response. Patients who attained stable disease, partial response, and complete response were categorized as responders. Those who progressed on CPIs were labeled as non-responders. The significance of the association between pALC and pNLR groups and the occurrence of any response was analyzed statistically. Results: Twenty patients (13 RCC, 7 BC) were treated with CPIs and had documented responses. Twelve patients had pALC > 1000 (Group A) whereas 8 patients had pALC < 1000 (Group B). Both groups were comparable with respect to age, sex, race, and types of CPIs. Group A had a significantly higher response rate (75% vs 25%, p = 0.027). As to pNLR, 10 patients had pNLR < 3 (Group 1) and another 10 patients had pNLR > 3 (Group 2). Patients with pNLR > 3 had worse response rates to CPIs compared to those with pNLR < 3 (30% vs 80%, p = 0.024). Conclusions: This is the first report from a real-world clinical setting to show a detrimental association between pALC < 1000 and pNLR > 3 and CPI response rates in a retrospective cohort of consecutive non-selected kidney and bladder cancer patients. This association and its clinical utility require further confirmation in a prospective larger cohort.