bluuebunny/crossref_metadata_2025_split huggingface dataset:
BrUOG 324: Adjuvant nivolumab and low-dose ipilimumab for stage IIC, III, and resected stage IV melanoma: A phase II Brown University Oncology Research Group trial.
Authors: Constantinou Maria , Vezeridis Michael P. , Weinstock Martin A. , Walker Joanna , Miner Thomas J. , Barth Peter , Rosati Kayla , Mitchell Kristen , Dionson Sopha , Turchetti Wendy , Vatkevich John , Rafelson William Matthew , Mantripragada Kalyan C. , Safran Howard 
Published: February 2018

TPS202 Background: Adjuvant ipilimumab improves survival in stage III melanoma. Adjuvant nivolumab improves progression-free survival as compared to ipilimumab with reduced toxicity. Checkpoint 067 showed that the combination of ipilimumab and nivolumab is more active in advanced melanoma than either agent alone. The Brown University Oncology Research Group sought to evaluate dual checkpoint inhibition in the adjuvant setting. This may be particularly beneficial to patients with melanoma with low PD-L1 expression. To balance safety and efficacy, the combination of low dose ipilimumab and standard dose nivolumab was investigated. Methods: Patients with stage IIc, III and resected stage IV disease are eligible. No prior treatment for melanoma other than surgery or radiation was allowed. All patients received nivolumab 3mg/kg (maximum 240 mg) every 2 weeks and ipilimumab 1mg/kg every 6 weeks for 6 months. The primary goal is to determine the toxicity of adjuvant ipilimumab and nivolumab in patients with melanoma. Unacceptable toxicity has been defined as the development of grade 4 hematologic toxicity (neutropenia or thrombocytopenia), any transient grade ≥3 or persistent grade 2 treatment-related non-hematologic toxicity that prevents completion of the planned 6 month course of treatment in more than 35% of the enrolled patients; thus, if such events occur in 10 or more patients out of 25 evaluable patients, the study will have exceeded the limit for unacceptable adverse events. Secondary objectives are to determine the recurrence-free and overall survival. Results: Between August 2016 and August 2017, 17 patients have been enrolled, 11 male and 6 female. Median age is 59 (range 25-84). Twelve patients were Stage III disease, 2 patients were stage IIC and 3 were stage IV. Conclusions: BrUOG 324 represents one of the first trials investigating adjuvant dual checkpoint inhibition in melanoma. Preliminary safety and efficacy are being assessed. Acknowledgements: This study was supported in part by the Washington Trust Company and LIFEcycle Clinical trial information: NCT02656.
CREAM study: Clinical correlation between immunotherapy-RElated clinical outcome and intestinal microbiote in metastatic patients.
Authors: Orgiano Laura , Cubeddu Alessio , Camera Silvia , Mascia Roberta , Dessi Mariele , Pedditzi Elisabetta , Murru Maura , Piredda Paolo , Barca Michela , Saba Emma , Palmas Vanessa , Camboni Tania , Massa Elena , Astara Giorgio , Manzin Aldo , Madeddu Clelia , Scartozzi Mario 
Published: February 2018

TPS215 Background: It's known that composition of intestinal flora can influence the development of inflammatory gastrointestinal diseases, even though the association of inflammation with specific intestinal microbes is still unknown, because the inflammation and its treatment can change the composition of microbiote. Some bacterial species are essential to maintain the mucosal physiological tolerance, although species such as Bacteroides, Clostridium and Faecalibacterium can induce the up-regulation of T-cells and stimulate the production of anti-inflammatory cytokines. Innovative therapies such as anti-CTLA-4 antibody and inhibitors of the PD-1 receptor are particularly involved in the up-regulation of lymphocyte system: among their side effects, the most relevant are those immune-mediated such as hypophysitis, thyroiditis and colitis. In particular this last one usually occurs within 16weeks from the start of treatment: about one third of patients develop intestinal inflammation of any grade as a result of immune system dysregulation. So, the high incidence of colitis in patients treated with immunotherapy offers the possibility to characterize the intestinal microbiote before the development of immune-mediated inflammation. In addition, our curiosity has been oriented to the response to immunotherapy and the HLA class expressed by our patients: which any better predictor of response to immunological treatment than this one? Methods: Our is a single-center study of clinical and biological parameters prospectively stratified. Specifically, we collect from patients eligible for immunotherapy a blood sample to analyze HLA class and an other one to analyze serum cytokines levels, inflammatory indices and a sample of fecal material at baseline and at least after 3 administrations of treatment: actually we enrolled 34 out of 40 planned patients; we suppose to complete the enrollment in 2 months. According to preliminary data published in literature, we expect to find an alteration of intestinal microbiote in metastatic patients treated with immunotherapy. Once we'll identify it, we want to assess whether there is any correlation with the patient's clinical outcome.
Phase I adoptive cellular therapy trial with ex-vivo stimulated autologous CD8+ T-cells against multiple targets (ACTolog IMA101) in patients with relapsed and/or refractory solid cancers.
Authors: Tsimberidou Apostolia Maria , Stewart Chad , Reinhardt Carsten , Ma Hong , Walter Steffen , Weinschenk Toni , Jazaeri Amir A. , Andersson Borje , Hwu Patrick , Yee Cassian , Singh Harpreet 
Published: February 2018

TPS77 Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy; however, only a small proportion of solid tumor patients have benefited from these advances due to i) heterogeneity of tumor antigen expression, ii) tumor escape (e.g. only one target is addressed), or iii) off-target toxicities (e.g. expression of targets on normal tissues). The ACTolog concept, utilizing antigen specific T cells (IMA101) against targets identified by the Immatics’ proprietary XPRESIDENT technology, is intended to overcome these limitations by addressing multiple novel relevant tumor antigens per patient. ACTolog is a personalized, multi-targeted ACT approach in which autologous T-cell products are manufactured against the most relevant tumor target peptides for individual patients whose tumors are positive against a predefined target warehouse. Methods: This study is an open-label first-in-human phase I trial in patients with relapsed or refractory solid tumors expressing at least one target from a warehouse of 8 cancer targets. Key eligibility criteria include: HLA-A*02:01 phenotype, qPCR expression of warehouse target(s), prior established lines of therapy, RECIST v1.1 measurable lesions, and ECOG performance status 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells for manufacturing of IMA101 cells. Patients will receive their last line of established therapy during the production phase of IMA101. IMA101 will be infused after a pre-conditioning regimen (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and tolerability of IMA101. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objective is to assess the in vivo persistence and ex vivo functionality of transferred T cells in addition to evaluation of target expression in tumors. Enrollment to the study is currently ongoing. Clinical trial information: NCT02876510 .
Phase I study of immunotherapy for advanced ROR1+ malignancies with autologous ROR1-specific chimeric antigen receptor-modified (CAR)-T cells.
Authors: Specht Jennifer M , Lee Sylvia , Turtle Cameron , Berger Carolina , Veatch Josh , Gooley Ted , Mullane Erin , Chaney Colette , Riddell Stanley , Maloney David G. 
Published: February 2018

TPS79 Background: CAR-T cells have demonstrated marked tumor regression in patients (pts) with hematologic malignancies. ROR1, a tyrosine kinase orphan receptor, is expressed in triple negative breast cancers (TNBC) and non-small cell lung cancers (NSCLC) and is a novel candidate for CAR-T cell therapy. ROR1-specific CAR-T cells are engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. Methods: NCT02706362 is a phase I study evaluating the safety and anti-tumor activity of adoptively transferred autologous ROR1 CAR-T cells in pts with advanced ROR1+ TNBC and NSCLC. Eligibility criteria include: metastatic TNBC or NSCLC; measurable disease; prior standard therapy with no maximum on number of prior regimens; tumor ROR1 expression > 20% by IHC; KPS > 70%; age ≥18; negative pregnancy test for women of childbearing potential; informed consent; adequate organ function. Exclusions are: active autoimmune disease or uncontrolled infection, HIV seropositive status, contraindication to cyclophosphamide, anticipated survival < 3 months, and/or untreated CNS metastases. After screening, leukapheresis is performed, CD8+ and CD4+ T cells are selected, then transduced with the ROR1+ CAR lentivirus and expanded. Lymphodepletion with cyclophosphamide and fludarabine is followed 36-96 hours later by infusion of ROR1 CAR-T cells in escalating doses (3.3 x 105/kg - 1 x 107/kg cells with defined CD8+ and CD4+ composition). Pts are treated in cohorts of 2 to determine cell dose associated with an estimated toxicity rate of < 25%. Primary aim is to determine the maximum tolerated dose (MTD) and safety of ex vivo expanded ROR1 CAR-T cells. Secondary aims include persistence and phenotype of transferred T cells, trafficking of T cells to tumor site, in vivo function, and preliminary antitumor activity of ROR1 CAR-T cells by RECIST 1.1. Dose escalation is determined by CRM algorithm with minimum of 21-day interval following infusion between pts. Preliminary estimates of efficacy will be obtained among all pts and those treated at estimated MTD. Six of 30 pts have been enrolled with no DLTs observed. Clinical trial information: NCT02706392.
A phase I study to evaluate the safety of trigriluzole (BHV-4157) in combination with PD-1 blocking antibodies.
Authors: Silk Ann W. , Berman Robert , Coric Vlad , Ruggiero Laura , Reitz Allen B. , Shih Weichung , Kane Michael P. , Mehnert Janice M. , Pelletier Jeffrey C , Zloza Andrew , Goydos James Steven 
Published: February 2018

TPS80 Background: The Metabotropic Glutamate Receptor 1 (GRM1) is expressed in 60-100% of human melanomas, breast cancers, and other solid tumors. Riluzole, an FDA-approved drug for ALS, inhibits GRM1 signal transduction. A phase 0 trial in melanoma patients demonstrated that riluzole suppressed signaling through the MAPK and PI3K/AKT pathways but no objective responses were seen in a phase 2 study.The clinical use of riluzole outside of ALS has been limited by: (i) poor oral bioavailability, (ii) extensive first-pass hepatic metabolism, (iii) high variability in PK parameters, (iv) food-related decrease in bioavailability, and (v) dose-related hepatotoxicity. Trigriluzole (BHV-4157) is a third generation prodrug of riluzole with improved PK/PD properties. In our MASS20 in vivo murine model of melanoma, GRM1 signal transduction appears to suppress tumor immunity through up-regulation of M-CSF and CCL2 expression with a subsequent increase in the percentage of M2 macrophages in the tumor microenvironment. In an immunocompetent mouse model, treatment with trigriluzole and anti-PD-1 antibody was more effective than either drug alone. Methods: Subjects with advanced or refractory solid cancers or lymphoma will be treated with increasing doses of trigriluzole in this phase 1b study. The dosing cohorts of trigriluzole will be using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Trigriluzole monotherapy will be given for a 14-day lead in period and then patients will receive trigriluzole in combination with nivolumab 240mg IV every 2 weeks. After the maximum tolerated dose (MTD) of trigriluzole is identified, it will be checked in a cohort of 6 patients in combination with pembrolizumab. Total sample size will be 12 – 27 subjects. PD-1-directed therapy prior to entry is allowed. Blood samples and optional biopsies will be collected for correlative analysis. PBMCs and fresh tumor tissue will be grafted into NSG mice to create a patient-derived autologous double-humanized murine model for each participant. Clinical trial information: NCT03229278.
Phase 1, multicenter, open-label study of single-agent bispecific antibody T-cell engager GBR 1342 in relapsed/refractory multiple myeloma.
Authors: Richter Joshua Ryan , Wermke Martin , Kauh John S. , Back Jonathan , Salhi Yacine , Reddy Venkateshwar , Bayever Eliel , Landgren Carl Ola 
Published: February 2018

TPS81 Background: Available therapies have improved outcomes in multiple myeloma but patients eventually relapse, requiring treatment with agents that are active in refractory disease. CD38, a transmembrane glycoprotein, is upregulated on myeloma cells and is a validated disease target, evidenced by the anti-myeloma activity of daratumumab, an anti-CD38 human IgG1κ monoclonal antibody. GBR 1342 is a CD3xCD38 bispecific antibody engineered (using Glenmark’s BEAT® platform) to direct T-cells to CD38-expressing myeloma cells. In preclinical studies, GBR 1342 redirected the cytotoxic potential of T-cells to human myeloma cell lines in vitro and in mouse xenograft models. This ongoing, 2-part, first-in-human study aims to: (1) evaluate the safety profile and maximum tolerable dose (MTD) of GBR 1342 monotherapy in subjects with relapsed/refractory multiple myeloma ( > 3 prior therapies); and (2) further elucidate the safety, tolerability, and preliminary clinical activity of GBR 1342 at the MTD. The study is also evaluating the mechanisms by which GBR 1342 redirects T-cells to tumor and enhances cytolytic activity of cytotoxic T-cells. Methods: In Part 1, intravenous GBR 1342 is administered on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels (Table). The first 4 cohorts consist of a single subject. Subsequent cohorts will enroll using a 3+3 design. In Part 2, 65 evaluable subjects will be treated at the MTD identified in Part 1 until disease progression or unacceptable toxicity occurs. Primary endpoints include frequency and severity of AEs, number of dose-limiting toxicities during Cycle 1 (Part 1 only), and objective response to GBR 1342 (Part 2 only). Secondary endpoints include pharmacokinetics and anti-tumor activity of GBR 1342 (objective response, progression-free and overall survival). [Table: see text]
Personalized risk stratification for patients with early prostate cancer (PRONTO): A Canadian team biomarker project.
Authors: Berman David Monty , Lesurf Robert , Lee Anna YW , Patel Palak , Jamaspishvili Tamara , Ebrahimizadeh Walead , Okello John , Rouzbeh Shaghayegh , Boufaied Nadia , Lee Laura A , Chevalier Simone , Brimo Fadi , Venkateswaran Vasundara , Park Paul C , Buttyan Ralph , Thomson Axel A , Lapointe Jacques , Boutros Paul Christopher , Bartlett John 
Published: February 2018

109 Background: Current practice stratifies men with prostate cancer into risk groups based primarily on Gleason grade. When applied to biopsy samples, the Gleason grading is inaccurate due to sampling error and inter-observer variation. The result is that men either receive unnecessary surgical treatment, or they don’t receive adequate treatment, leading to worse outcomes. Previously published genomic tests have not successfully distinguished indolent low grade (G6 or GG1) cancers from their more aggressive intermediate grade (G7 or GG2 and 3) counterparts. PRONTO is specifically aimed at creating a multi-modal risk stratification tool to improve treatment stratification following a core biopsy diagnosis. Methods: PRONTO links 7 projects, each with novel diagnostic assays for risk stratification that focus on analysis of copy number variations (CNV), DNA hypermethylation, trans-differentiation, cancer metabolism, or the tumor microenvironment. We merged the best transcripts from each project into a single NanoString gene expression assay, measuring 393 transcripts, in a cohort of 365 cases of radical prostatectomy from low-to-intermediaterisk patients. To minimize sampling error, we took multiple samples, and obtained high grade, low grade and benign areas for each radical prostatectomy case. Results: Our primary goal was to develop a multivariate molecular classifier of grade that distinguished G6 from G7 (3+4 or 4+3). Cases were randomly partitioned into five equally sized groups. A supervised machine learning algorithm (random forests) was trained on samples from four of the groups, and then evaluated by testing on the fifth group. This process was repeated for each of the five groups, yielding a combined clinical and molecular classifier. DNA methylation profiles and CNV profiles are currently being integrated into our classifier Conclusions: We have developed a multivariate classifier that distinguishes low grade from intermediate grade prostate cancer. It will be clinically validated in biopsy samples from large cohorts of early prostate cancer patients.
Active surveillance criteria in the age of targeted biopsies.
Authors: Bloom Jonathan , Hale Graham R. , Rayn Kareem , Gold Samuel , Valera Vladimir , Mehralivand Sherif , Wood Brad J. , Turkbey Baris , Parnes Howard L. , Pinto Peter A. 
Published: February 2018

116 Background: Many urologists are now using active surveillance (AS) to manage patients with low-risk prostate cancer. A variety of criteria have been proposed to select patients for AS. A key feature of these criteria is Gleason Group as determined by systematic or “random” biopsies (SB). In this study, we examined the progression of Gleason Group (GG) detected only on SB compared to patients with positive MRI-fusion or “targeted” biopsies (FB). Methods: A prospectively maintained database was queried for all patients who underwent an MRI guided FB and SB from 2007 to 2016 and chose AS as their primary management strategy. Patents with GG 1 or 2 were eligible. Patients were then followed with yearly PSA, exam, MRI and biopsy if warranted. FBs were reviewed to determine GG progression. We divided patients into those who had cancer detected on SB only and those who had positive FBs with or without a positive SB. Results: A total of 162 patients met our criteria with 73 having an initial positive FB and 89 having cancer only on SB and a negative FB. Median follow-up was 27.62 (4.14 – 96.56) and 33.83 (3.45-99.84) months, respectively. The two groups were similar in age (64.49 ± 6.57 vs. 62.08 ± 6.92 years, p = 0.03) and PSA (6.23 ± 4.23 vs. 5.67 ± 3.98 ng/ml, p = 0.39). The median time to pathologic progression for GG 1 patients with initial FB positive was 53.88 months and those with GG 1 on initial SB was 80.81 months (p = 0.003). The median time to pathologic progression for GG 2 patients with initial FB positive was 36.26 months and those with GG 2 on initial SB was 76.01 months (p = 0.099). Conclusions: Previously accepted AS criteria have been based on SBs. However, those patients placed on AS after a positive FB progressed fast than cancer detected only on SB. With MRI and FBs more routinely used in clinical practice, clinicians could use this information from FBs to better stratify and closely monitor patients during AS. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH.
Comparison of a low-cost immunohistochemistry marker panel with a cell-cycle progression assay for the prediction of outcome after radical prostatectomy.
Authors: Leapman Michael , Nguyen Hao Gia , Cowan Janet E. , Xue Lingru , Stohr Bradley , Simko Jeffry , Cooperberg Matthew R. , Carroll Peter 
Published: February 2018

118 Background: Gene expression assays appear to stratify prostate cancer risk, however tests involving amplification techniques are expensive and may strain payment systems. We aimed to compare the prognostic utility of a low-cost immunohistochemistry (IHC) panel consisting of three validated markers with an RNA expression based cell-cycle progression (CCP) score. Methods: Among 5,748 patients with PCa within an institutional database, we identified 424 with localized PCa treated with radical prostatectomy (RP). IHC analysis was performed using tissue microarrays to examine the expression status of PTEN, Ki67, and ERG compared with previously calculated CCP scores derived from 31 genes normalized to 15 housekeeper genes. Associations of IHC status, CCP scores, adjusted for clinical and pathologic characteristics (Cancer of the Prostate Risk Assessment Score, CAPRA-S) were performed using Cox proportional hazards regression to examine risk of biochemical recurrence (BCR), and metastasis or PCa- specific mortality (PCSM). We compared models using concordance index (c-index) testing. Results: Median age at treatment was 59 years and patients were followed for a median of 114 months post RP. By 10 years after RP, 27% experienced BCR and 4% developed metastasis or PCSM. Adjusted for CAPRA-S, the triad of PTEN loss, high Ki67, and positive ERG expression was independently associated with risk of BCR (HR 2.3, 95% CI 1.1-4.7) and metastasis/PCSM (HR 8.3, 95% CI 3.3-21.2). In a model including CAPRA-S, IHC panel, and CCP, the CCP score was independently associated with both recurrence and metastasis/PCSM (HR 1.9, 95% CI 1.5-2.5 and HR 2.5, 95% CI 1.5-4.1, respectively), but IHC expression status of PTEN/Ki67/ERG remained an independent predictor of both endpoints. The addition of the CCP assay marginally improved the c-index of a combined IHC and CAPRA-S model from 0.78 to 0.81 for the prediction of metastasis/PCSM. Conclusions: A low-cost three-marker IHC panel examining PTEN, Ki67, and ERG expression was independently associated with downstream PCa endpoints following RP. Efforts are warranted to reduce the cost of PCa prognostic tools in order to expand access.