tbuckley/cabot-search huggingface dataset:
A phase I study of PolyPEPI1018 vaccine plus maintenance therapy in patients with metastatic colorectal cancer with a predictive biomarker (OBERTO).
Authors: Joleen Marie Hubbard, Chiara Cremolini, Rondell P Graham, Roberto Moretto, Jessica L Mitchelll, Jaclynn Wessling, Eniko Rita Toke, Zsolt Csiszovszki, Orsolya Lőrincz, Levente Molnar, Eszter Somogyi, Mónika Megyesi, Kata Pantya, József Tóth, István Miklós, Julianna Lisziewicz, Franco Lori, Alfredo Falcone
Journal: Journal of Clinical Oncology (2019)

3557 Background: The goal of this study was to evaluate the safety, tolerability and immunogenicity of a single dose of PolyPEPI1018 as an add-on to maintenance therapy in subjects with metastatic colorectal cancer (mCRC). PolyPEPI1018 is a peptide vaccine containing 12 unique epitopes derived from 7 conserved cancer testis antigens (CTAs) frequently expressed in mCRC. These epitopes were designed to be Personal EPItopes (PEPIs), i.e. predicted by our novel PEPI test to bind to at least three autologous HLA alleles and more likely to induce T-cell responses than epitopes presented by a single HLA. Methods: mCRC patients in the first line setting received the vaccine (dose: 0.2 mg/peptide) just after the transition to maintenance therapy with a fluoropyrimidine and bevacizumab. Vaccine-specific T-cell responses were first predicted by the PEPI test (using the patient’s complete HLA genotype and antigen expression rate) and then measured by ELISpot after one cycle of vaccination. Results: Eleven patients were vaccinated with PolyPEPI1018. The most common adverse events were transient skin reactions (local inflammation at the site of the injections, e.g. erythema, redness and itchiness) and flu-like syndrome. No grade 3 or higher adverse events related to the vaccine occurred. Initial analysis on 4 patients demonstrated that T-cell responses were elicited by 96% of vaccine peptides. The overall percentage agreement between PEPI test-predicted and Elispot-measured CD8+ T cell responses was 71%, consistent with our retrospective analysis on 64 vaccine clinical trials involving 1,790 patients. Two of these 4 patients had unexpected tumor size reduction. Based on these encouraging results, the trial was amended to administer 3 doses of PolyPEPI1018 given 12 weeks apart. Conclusions: PolyPEPI1018 combined with maintenance therapy was safe and well-tolerated in mCRC patients. Unprecedented immune responses were induced after single dose, with broad CRC-specific T cell responses and high accuracy prediction of CD8+ T cell responses. This promising activity in mCRC patients led to a trial amendment to administer 3 doses of PolyPEPI1018 in combination with systemic therapy. Clinical trial information: NCT03391232.
An umbrella for the cytokine storm: Enabling precision detection of CRS in CAR-T therapy.
Authors: Qimin Quan
Journal: Journal of Clinical Oncology (2019)

e14223 Background: Cytokine release syndrome (CRS), a systemic inflammatory response observed with monoclonal antibody drugs and adoptive T cell treatments, has become a major issue for CAR-T therapy. CRS can present as a mild reaction requiring minimally invasive supportive care up to a severe systemic response resulting in patient death. Monitoring this response during these therapeutic treatments is non-trivial due the wide range of biomarker concentrations, small sample volumes, and long assay times. Current analytical methods are unable to address these needs, limiting the precision of CAR-T therapy and effective management of its side effects. Methods: Emerging studies in this area have focused in establishing a panel of predictive biomarkers to manage dosing and early interventions, among them, IFNγ, IL6, TNFα, MIP1 have shown predicative powers in pediatric patients. Nevertheless, a significant improvement (100x) on the detection sensitivity is required to predict the CRS response with currently available methods. In addition, CRS-associated biomarkers including CRP and ferritin vary from 10ng/mL-10mg/mL while other predictive biomarkers (eg, IL6, IFNγ, etc.) vary from 1pg/mL-100ng/mL. At present, no analytical tool, known to us, can provide this large dynamic range ( &gt; 9 logs), with the requisite lower limit of detection, in a rapid single test to predict and differentiate low, medium or high grade responses. Results: We present the NanoMosaic platform, the technology that has requisite sensitivity and breadth of dynamic range to enable precision detection based on precise quantitation of CRS-relevant biomarkers. NanoMosaic technology is enabled by single molecule nanoneedle sensors that are densely integrated on a silicon chip and manufactured with a CMOS-compatible process. Absolute quantitation is achieved by imaging the spectrum of nanoneedles, corresponding directly to the number of molecules. Conclusions: Direct comparison of different protein biomarkers with orders of magnitude concentration variations becomes possible in one platform and small sample sizes. We envision NanoMosaic technology will not only drive biomarker discovery, but also enable precise dosing management for CAR-T therapy.
Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment
Authors: Hamzah Abu-Sbeih, Cynthia Nguyen Tran, Phillip S. Ge, Manoop S. Bhutani, Mazen Alasadi, Aung Naing, Amir A. Jazaeri, Yinghong Wang
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint inhibitors (ICIs) represent a promising novel class of cancer therapy, but immune-mediated adverse events can complicate ICI treatment. Acute cholecystitis in patients receiving ICI therapy has not been characterized. We aimed to describe the clinical features of patients who developed ICI-related cholecystitis. <h3>Methods</h3> We evaluated a case series of patients at a tertiary cancer center who received ICI therapy and developed cholecystitis, diagnosed by clinical presentation and diagnostic imaging, during 2010–2018. Patients with a history of chronic cholecystitis or other etiologies of acute cholecystitis, such as cholelithiasis, were excluded. A chi-square test was used to compare the frequency of cholecystitis between ICI regimens. Kaplan-Meier and log rank analyses were used to compare survival between subgroups. <h3>Results</h3> Of the 4253 patients who received ICIs in the study period, 25 (0.6%) patients developed suspected ICI-related cholecystitis. Alternatively, of the 31,426 cancer-matched patients who received non-ICI therapy, 72 (0.2%) developed acalculous cholecystitis (<i>P</i> &lt; 0.001). Among the 25 included patients, the median time from ICI initiation to cholecystitis was 6 months (range, 0.1–31 months). Fifteen (60%) patients received an inhibitor of programmed death protein 1 (anti–PD-1) or of its ligand (anti–PD-L1) as a single agent, and 10 (40%) patients received an inhibitor of cytotoxic T-lymphocyte associated protein 4 (anti–CTLA-4) therapy alone or combined with anti–PD-1/L1. Anti–CTLA-4 monotherapy was associated with a higher risk of cholecystitis (<i>P</i> = 0.006). ICI therapy was discontinued in 20 patients, in three (12%) as a result of acute cholecystitis. Two (8%) patients developed sepsis, and four (16%) had perforation of the gallbladder wall. Five (20%) patients underwent surgical cholecystectomy, and eight (32%) underwent percutaneous drainage. Five (20%) patients were treated with steroids; two of them required surgery. Ten (40%) patients were able to restart ICI therapy. Patients who received a combination of anti–CTLA-4 and anti–PD-1/L1 had more complications of cholecystitis than did patients who received either agent alone (<i>P</i> = 0.03). <h3>Conclusions</h3> ICI treatment can result in a clinical condition similar to typical acute cholecystitis in a minority of patients. ICI-related cholecystitis should be managed in a similar fashion to typical cholecystitis. The efficacy of steroids for the treatment of ICI-related cholecystitis is unclear.
Modified FOLFOX versus modified FOLFOX plus nivolumab and ipilimumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Moonlight, a randomized phase 2 trial of the German Gastric Group of the AIO.
Authors: Salah-Eddin Al-Batran, Claudia Pauligk, Thorsten Oliver Goetze, Jorge Riera-Knorrenschild, Eray Goekkurt, Stefan Angermeier, Frank Kullmann, Peter C. Thuss-Patience, Nils Homann, Thomas Jens Ettrich, Sabine Junge, Ralf Hofheinz, Sylvie Lorenzen
Journal: Journal of Clinical Oncology (2019)

TPS4144 Background: The majority of patients (pts) with gastroesophageal cancer present with inoperable or metastatic disease and there is a strong need for efficient and tolerable first-line (1L) treatment. Oxaliplatin-based regimens like FOLFOX have become one standard of care. However, median survival is still below 12 months. Results from trials using nivolumab plus ipilimumab treatment of subjects with advanced/metastatic GC and GEJ cancers demonstrated clinical activity, in pts whose tumors did or did not express PD-L1; in addition, nivolumab alone and in combination with ipilimumab demonstrated clinical benefits in various other tumor types. Based on this clinical experience, the AIO-STO-0417 trial (Moonlight) has been designed to evaluate the combination of chemotherapy with two checkpoint inhibitors in first-line therapy of pts with gastroesophageal adenocarcinoma. Methods: This is a prospective, multicenter, randomized, investigator-initiated phase II trial. Pts with Her2-negative, inoperable, advanced or metastatic gastric or esophagogastric junction cancer will be randomized 1:1 to 1L treatment with FOLFOX (Oxaliplatin 85 mg/m²; Leucovorin 400 mg/m²; 5FU 400 mg/m² on d1 of each treatment cycle and 5FU 1200 mg/m² continuous infusion over 24 hrs d1 and d2) every 2 weeks plus Nivolumab 240 mg every 2 weeks and Ipilimumab 1mg/kg every 6 weeks (Arm A) or FOLFOX alone (Arm B). Primary endpoint of the trial is progression-free survival based on the ITT population. Main secondary endpoints are overall survival, objective response rate, Safety and Quality of life (EORTC QLQ-C30). 118 pts (59 per arm) will be enrolled to provide 80% power for detecting an average HR of 0.68 using the log rank test at a one-sided type I error of 10%. At the date of submission, (Feb 2019), 28 of planned 118 pts are randomized. Clinical trial information: NCT03647969.
Treatment with tumor-infiltrating lymphocytes in the changing treatment landscape of metastatic melanoma.
Authors: Troels Borch, Rikke Andersen, Eva Ellebaek, Özcan Met, Marco Donia, Inge Marie Svane
Journal: Journal of Clinical Oncology (2019)

e14024 Background: Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) has been shown to induce durable complete responses in patients with metastatic melanoma (MM) who are anti-PD-1 naïve. Whether progression on or after anti-PD-1 therapy affects the outcome of TIL therapy given as a subsequent treatment line is largely unknown. To elucidate this, we analyzed updated clinical data covering a decade of TIL trials carried out in Denmark. Methods: Data from three clinical trials were pooled and data from 55 treated patients were available (ClinicalTrials.gov Identifiers: NCT00937625 (n = 31), NCT02379195 (n = 12) and NCT02354690 (n = 12)). Survival curves were computed according to the Kaplan-Meier method. Clinical response rate (RR) was evaluated according to RECIST criteria. Results: Median overall survival in the pooled cohort was 15.9 months and progression-free survival (PFS) was 3.7 months. Six patients achieved a complete response (11%), of which four are ongoing. Fourteen patients achieved a partial response (26%), of which three are ongoing. Median overall survival of responders was not reached with a median follow-up time of 40 months. RR was not statistically different depending on prior anti-PD-1 therapy (42% no prior anti-PD-1 therapy vs. 32% with prior anti-PD-1 therapy). However, there was a trend towards a shorter duration of partial responses in patients previously treated with both anti-CTLA-4 monotherapy and anti-PD-1 monotherapy, compared to patients previously treated with anti-CTLA-4 but not anti-PD-1 (P = 0.06). The two groups were balanced in respect to number of prior treatment lines. Conclusions: After progression on anti-PD-1 therapy, partial responses following TIL therapy might be shorter, but durable complete responses can be induced despite progression on prior anti-PD-1 therapy. Thus, TIL therapy remains an important treatment strategy in MM. Clinical trial information: NCT00937625, NCT02379195, NCT02354690.
Active postmarketing surveillance: Results from a manufacturer's patient support program for patients under treatment with the first biosimilar trastuzumab (MYL-1401O) approved in Brazil.
Authors: Allisson Monteiro da Silva, Gislaine Villarta Capeleti Dib, Emanuela Lopez Fernandes Saraiva, Thais Tiemi Watanabe, Jaqueline Amália de Paulo
Journal: Journal of Clinical Oncology (2019)

e14000 Background: The development of biosimilars is increasing around the world, and facilitates patient’s access to these high-tech therapies. Active pharmacovigilance is considered one of the main tools for monitoring the safety of biologics and biosimilars, especially in post marketing. In 2017, trastuzumab (MYL-1401O) became the first trastuzumab biosimilar approved in Brazil. A program to support patients under trastuzumab (MYL-14010) treatment was sponsored by the manufacturer in order to closely monitor adverse events (AE). Methods: This is a prospective observational study based in data from a manufacturer’s patient support program. Patient diagnosed with initial or advanced HER2+ breast cancer (BC) and HER2+ gastric cancer (GC) who received prescription for trastuzumab (MYL-1401O) were invited to participate. They are followed by periodical phone calls after each infusion and up to 3 months after the last infusion of trastuzumab. Treatment related data and AEs were collected. Results: A total of 21 female patients with HER2+ BC receiving trastuzumab (MYL-14010) were enrolled in the program between May 2018 and January 2019. 16 (76,2%) out of these patients with median age 52 years (range 33 to 76) reported 101 AEs (all-causality): 94 (93,1%) non-serious (73 expected / 21 unexpected) and 7 (6,9%) serious (5 expected / 2 unexpected). Considering all unexpected AEs causality assessment was unlikely in 47,8% AEs. The most frequently reported AEs according SOC (system organ classification) were general disorders and administration site conditions (18,8%), nervous system disorders (14,9%) and gastrointestinal disorders (14,9%). The most reported symptoms were nausea, asthenia, infusion reactions, paresthesias and pain in the body. Conclusions: Safety data for biosimilar trastuzumab (MYL-1401O) is consistent with original trastuzumab in female patients with HER2+ BC. Most of the reported AEs were non-serious (93,1%) and expected (77,2%). No new safety signals were detected.
The landscape of ARID1A variants and correlation with tumor mutational burden in Chinese solid tumor patients.
Authors: Jia Wei, JieJie Zhang, Qiang Wen, Xiaoyi Zhu, Dapeng Li, Baorui Liu, Jinwei Hu, Weifeng Wang, Ming Yao, Kai Wang
Journal: Journal of Clinical Oncology (2019)

e14624 Background: ARID1A (the AT-rich interaction domain 1A) is one of the most commonly mutated genes in cancer, mostly caused by frameshift variants. Here, we describe the mutational landscape of ARID1A in Chinese cancer patients and its correlation with tumor mutational burden (TMB). Methods: Formalin fixed paraffin embedded (FFPE) samples of 3,828 Chinese solid tumor patients were collected for next‐generation sequencing (NGS) based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. Microsatellite stable (MSS) status and TMB were also acquired by NGS algorithms. Results: A total of 340 (8.9%) patients were found to have ARID1A variants. The frequency of ARID1A mutations was 4% in lung adenocarcinoma (N = 74/1833), 8% in squamous cell lung carcinoma (N = 23/278), 12% in colorectal adenocarcinoma (N = 61/530), 11% in hepatocellular carcinoma (N = 52/484), 14% in pancreatic adenocarcinoma (N = 25/177), 15% in gallbladder adenocarcinoma (N = 14/94), 22% in intrahepatic cholangiocarcinoma (N = 47/213), 20% in gastric adenocarcinoma (N = 39/200) and 26% in endometrial adenocarcinoma (N = 5/19). ARID1A variants included truncation (78%), missense/indel (non-frameshift substitution/indel) (16%), splicing site (4%) and rearrangement (2%). Truncation was the most common, recurring in a few hot spots (R1276*, D1850Gfs*4, A339Lfs*24, P224Rfs*8 and Q372Afs*28/Sfs*19). In general, ARID1A mutations correlated with higher TMB (median 17.6 vs 7.4 muts/Mb, P &lt; 0.001) in MSS tumors; especially in lung adenocarcinoma (17 vs 7.5 muts/Mb, P &lt; 0.01), squamous cell lung carcinoma (16.8 vs 11.2 muts/Mb, P &lt; 0.01). TP53 (60%), APC (34%) and KRAS (32%) were the most common co-occurred mutated gene in ARID1A (+) tumors. In more than 20% of ARID1A mutations, PI3K/mTOR pathway genes were altered, such as PIK3CA, PTEN, RNF43 and PIK3R1 genes. Conclusions: Since ARID1A mutations correlate with higher TMB, it could be a potential predictor of response to PD-1/PD-L1 immune checkpoint pathway inhibitors. As reported, ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Patients harboring ARID1A and PI3K/mTOR pathway mutations may provide useful information for drug discovery and biomarker exploration.
Responder analysis of patient-reported outcomes measurement information system (PROMIS) physical function (PF) and worst stiffness among patients with tenosynovial giant cell tumors (TGCT) in the ENLIVEN study.
Authors: William D. Tap, Rebecca M Speck, Xin Ye, Emanuela Palmerini, Silvia Stacchiotti, Jayesh Desai, Andrew J. Wagner, Thierry Alcindor, Kristen N. Ganjoo, Javier Martin Broto, Qiang Wang, Dale Edward Shuster, Heather Gelhorn, Hans Gelderblom
Journal: Journal of Clinical Oncology (2019)

e18236 Background: The double-blind, randomized, placebo-controlled phase 3 ENLIVEN study in TGCT demonstrated a significant tumor response at week 25 by RECIST for pexidartinib (39% vs. 0% for placebo) and improvement in joint function and symptoms. The aim of this analysis was to identify a threshold score for responder definitions for PROMIS-PF scale and Worst Stiffness Numerical Rating Scale (WS-NRS) and compared responder rates for pexidartinib versus placebo. Methods: Anchor- and distribution-based estimates were calculated, and cumulative distribution function (CDF) plots were generated to derive responder definition threshold estimates. Anchor- and distribution-based results and CDFs were evaluated through triangulation, following FDA PRO Guidance, to determine a single responder definition threshold (i.e., meaningful change) for each instrument. The proportion of responders at Week 25 between treatments was compared with Fisher’s Exact Test (2-sided). Results: 120 patients were randomized to pexidartinib (n = 61) and placebo (n = 59) and assessed through 25 weeks of treatment. Anchor-based analysis showed one-level improvement on the patient global rating of PF item was associated with a mean change of 4.0 on PROMIS-PF. Distribution-based estimates (0.5 SD and 1 SEM) for PROMIS-PF were 2.8 and 2.5, respectively. For WS-NRS, a response of “A little improved” by patients on the perception of stiffness item was associated with a mean change of 1.1. The distribution-based estimates for the WS-NRS item were 0.9 and 0.5, respectively. This resulted in the following responder definition thresholds: ≥3 points for PROMIS-PF and ≥1 for WS-NRS improvement. A greater proportion of pexidartinib as compared to placebo patients were responders by PROMIS-PF (30% vs. 5%, p &lt; 0.001) and WS-NRS (39% vs. 19%, p = 0.02) at week 25, respectively. Conclusions: Triangulation yielded responder definitions of ≥3 points for PROMIS-PF and ≥1 for WS-NRS. With these definitions, a greater proportion of patients treated with pexidartinib compared to placebo had meaningful improvement in physical function and stiffness.
Trabectedin for recurrent WHO grade II or III meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).
Authors: Matthias Preusser, Antonio Silvani, Emilie Le Rhun, Riccardo Soffietti, Giuseppe Lombardi, Juan M. Sepúlveda, Petter Brandal, Ronald Philip Beaney, Alice Bonneville-Levard, Veronique Lorgis, Elodie Vauleon, Jacqueline Bromberg, Sara Erridge, Alison Cameron, Christine Marosi, Vassilis Golfinopoulos, Thierry Gorlia, Michael Weller, Wolfgang Wick
Journal: Journal of Clinical Oncology (2019)

2007 Background: EORTC-1320-BTG investigated the activity, safety and quality of life of therapy with the tetrahydroisoquinoline alkaloid trabectedin (Yondelis) in patients with recurrent higher-grade meningiomas. Trabectedin was originally derived from the Caribbean sea squirt, Ecteinascidia turbinata, and currently is manufactured by total synthesis. Methods: Adult patients with histological diagnosis of WHO grade II or III meningioma and radiologically documented progression after maximal feasible surgery and radiotherapy were randomly assigned in a 2:1 ratio to receive intravenous trabectedin (1.5 mg/m 2 every three weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Results: Within 22.1 months, we randomized a total of 90 patients (n=29 in LOC arm, n=61 in trabectedin arm) in 35 institutions and nine countries. In the LOC arm, the following treatments were administered: hydroxyurea (n=11), bevacizumab (n=9), none (n=4), chemotherapy (n=3), somatostatin analogue (n=1), combined chemotherapy and somatostatin analogue (n=1). With 71 PFS events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00-2.03; p=0.204) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) in the LOC and 21.1% (95% CI, 11.3%-32.9%) in the trabectedin arm. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR for death, 0.98; 95% CI, 0.54-1.76; p=0.94).Grade 3 to 5 adverse events occurred in 44.4% (18.5% related, 4 serious adverse events, 0 lethal events) of the patients in the LOC and 59% (32.8% related, 57 serious adverse events and 2 toxic deaths) of patient in the trabectedin arm. Conclusions: In this first prospective randomized trial performed in recurrent grade II or III meningioma, trabectedin did not improve PFS and OS and was associated with significantly higher toxicity as compared to LOC treatment. The data collected in this study may serve as benchmark for future clinical trials in this setting. Clinical trial information: NCT02234050.
Measuring psoriatic arthritis symptoms: A core domain in psoriasis clinical trials
Authors: Lourdes Maria Perez-Chada, Alice Bendix Gottlieb, Jeffrey Cohen, Philip Mease, Kristina Callis Duffin, Amit Garg, John Latella, April Wang Armstrong, Alexis Ogdie, Joseph Frank Merola
Journal: Journal of the American Academy of Dermatology (2019)