bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1/2a study of GEN-009, a neoantigen vaccine based on autologous peptide immune responses.
Authors: Cohen Roger B. , Johnson Melissa Lynne , Twardowski Przemyslaw , Stein Mark N. , Vaishampayan Ulka N. , Dobson Jason R. , Foti James , Agnihotri Parul , Dowal Louisa , Broom Wendy , McNeil Lisa , Davis Thomas A. , Flechtner Jessica 
Published: May 2019

2611 Background: Tumor-specific neoantigens provide individualized targets for immunotherapy. In silico selection methods are sub-optimal at predicting immunogenic targets, missing up to 70% of true neoantigens. ATLAS is a powerful tool that screens all candidate neoantigens for pre-existing patient-specific CD4 or CD8 responses in an HLA agnostic assessment. ATLAS also identifies inhibitory peptides that may suppress tumor immunity and accelerate tumor progression. The GEN-009 vaccine contains stimulatory but no inhibitory peptide antigens. Methods: GEN-009-101 is a first-in-human phase 1/2a study testing platform feasibility, safety, immunogenicity and clinical activity in selected solid tumors. After next-generation tumor sequencing and cytokine-based ATLAS assessment using autologous T cells and APCs, up to 20 stimulatory synthetic long peptides are used in each personalized vaccine. GEN-009 is administered with poly-ICLC on weeks 0, 3, 6, 12 and 24. Part A, a safety and immunogenicity pilot, has completed target enrollment of patients without evidence of disease to receive GEN-009; Part B has 5 tumor-specific cohorts of up to 15 pts naïve to PD-1 blockade who will receive GEN-009 with a SOC immunotherapy; Part C: up to 15 pts refractory to PD-1 inhibitors will receive GEN-009 monotherapy. Results: GEN-009 has been successfully generated for patients. Repeated dosing has been well tolerated with mild local discomfort and no DLT. ATLAS screening results below show notable interpatient variability; one subject had only CD4 neoantigens, one had only CD8, another had a strong CD8 bias, and one patient had prominent inhibitory peptides. Conclusions: GEN-009 is a neoantigen vaccine that personalizes tumor specific targets and the individual patient’s capacity to respond. Immunogenicity data will assess CD4 and CD8 T cell responses to each vaccine neoantigen. Clinical trial information: NCT03633110. [Table: see text]
Interim analysis of a phase II study of nivolumab combined with ipilimumab in patients with pediatric solid tumors in adulthood (GETHI021).
Authors: Mielgo Xabier , Diaz-Beveridge Robert , Sepulveda Juan Manuel , Pineda Estela , Lecumberri Maria Jose , De Las Penas Ramon , Rodriguez Salas Nuria , Valverde Claudia , López Castro Rafael , Vaz Maria Angeles , Lopez Lopez Carlos , Virizuela Juan Antonio , Medina Javier , Lopez Rafael , Rodríguez-Antona Cristina , Berraondo Pedro , Rodriguez-Moreno Juan Francisco , Moreno Diana , Martin Hernandez Raquel , Garcia-Donas Jesus 
Published: May 2019

2613 Background: Solid pediatric tumors that appear in adulthood are a heterogeneous group characterized by a low incidence, lack of standard therapeutic options and reduced survival. We have designed the first phase II clinical trial of nivolumab and ipilimumab in this setting, Here, we present the results of the first cohort with 30 evaluable patients. Methods: This is a multicenter, open-label, single arm Phase II study conducted in 15 centers of the Spanish Group for Rare Cancer (GETHI). We aimed to evaluate efficacy and safety of the combination of nivolumab and ipilimumab in adult patients ( 18 years) with locally advanced or metastatic childhood malignancies that have progressed or are not candidates to standard therapy. Treatment consisted on nivolumab 3 mg/kg IV q2w + ipilimumab 1 mg/kg IV q6w for 6 months or until progression/unacceptable toxicity, for a maximum of 24 months. Primary endpoint was overall response rate (ORR) according to RECIST v1.1 criteria. We used a Simon optimal two-stage design, with a first stage including first 30 evaluable patients. Results: 20 patients were male and median age was 43 (range 20-75). Most frequent histologies were medulloblastoma (4) neuroblastoma (4) and Ewing family tumors (3). 90% had received prior systemic therapy with 37% presenting progressive disease as best response. Median previous treatment lines were 3 (range 1-9). 27 patients were PS0-1, and 3 PS2. 6 patients have been treated for ≥6 months . Only one discontinued for adverse events. With a median follow up of 4,3 months (range 0,4-11,3), 1 patient has achieved a deep partial response (PR) (3,6%), 10 stable disease (SD) (35,7%) and 17 progressive disease (PD) (60,7%). 2 patients died before radiologic evaluation. Clinical benefit rate (CR+PR+SD) was 39,3%. Median progression free survival (PFS) was 1,8 months (95% CI 1,3-2,3), with a 3-months-PFS of 32,7% and 6-months-PFS of 20%. Median overall survival (OS) was 6,8 months (95% CI 3,3-10,2). 12 (40%) patients presented adverse events (AE) of any grade and 6 (20%) experienced a grade AE deemed as possibly related to treatment. Conclusions: The combination of nivolumab and ipilimumab showed significant clinical benefit in this population with little therapeutic options. One case of metastatic esthesioneuroblastoma, achieved a dramatic tumor response and represents the first patient with this extremely rare histology treated with immunotherapy. Clinical trial information: EudraCT 2016-003946-99.
Overestimation of tumor mutational burden (TMB) using algorithms compared to germline subtraction.
Authors: Parikh Kaushal , Huether Robert , White Kevin , Hoskinson Derick , Dong Haidong , Adjei Alex A. , Mansfield Aaron Scott 
Published: May 2019

2621 Background: TMB is an emerging predictor of survival with immunotherapy. TMB is determined by taking the difference between somatic and germline datasets when tumor-normal pairs are available. In the case of commonly utilized tumor-only sequencing, additional steps are needed to estimate the somatic alterations. Computational tools have been developed that determine germline contribution based on sample copy state, purity estimates and occurrence of the variant in population databases. Given the potential bias of population datasets, we hypothesized that tumor-only filtering approaches may overestimate the actual TMB. Methods: We assessed the TMB from 50 tumors in 10 diseases including all missense, indels, and frameshift variants with an allelic fraction (AF) ≥5% and Coverage ≥100X within the tumor. Tumor-only TMB was evaluated against the gold standard of matched germline subtracted TMB at three levels. Level 1 removed all the tumor-only variants with AF in the non-TCGA ExAC database ≥1%. Level 2 removed all variants observed in population databases simulating a naive approach of removing germline variation. Level 3 used an internal tumor-only pipeline for calculating TMB. Results: There were significantly higher estimates of TMB with Level 1, Level 2 and Level 3 tumor-only filtering approaches than that determined by germline subtraction, resulting in significant bias. Whereas there was no correlation between TMB estimates and tumor-germline TMB for Level 1 filtering, there were improvements in correlations for Level 2 and Level 3. Conclusions: The tumor-only approaches that filter variants in population databases overestimate TMB compared to that determined by germline subtraction. Despite improved correlations with more stringent filtering approaches, these falsely elevated estimates may result in the inappropriate categorization of tumor specimens and negatively impact clinical trial results and patient outcomes. [Table: see text]
TMB standardization by alignment to reference standards: Phase II of the Friends of Cancer Research TMB Harmonization Project.
Authors: Merino Diana M. , McShane Lisa , Butler Matt , Funari Vincent Anthony , Hellmann Matthew David , Chaudhary Ruchi , Chen Shu-Jen , Chen Wangjuh Sting , Conroy Jeffrey M. , Fabrizio David , MacConaill Laura E , Pallavajjala Aparna , Papin Arnaud , Sausen Mark , Weigman Victor J , Xie Mingchao , Zehir Ahmet , Zhao Chen , Williams Paul M. ,   Friends of Cancer Research TMB Harmonization Team
Published: May 2019

2624 Background: Tumor mutational burden (TMB) is a predictive biomarker of response to immune checkpoint inhibitors across multiple cancers. In Phase 1 of the Friends of Cancer Research Harmonization Project, we demonstrated a robust correlation between TMB estimated using targeted next-generation sequencing (NGS) gene panels and whole exome sequencing (WES) applied to MC3-TCGA data. These findings demonstrated variability in TMB estimates across different panels. Phase 2 evaluates sustainable TMB reference standard materials for TMB alignment to assess this variability. The goal of this effort is to establish best practices for estimating TMB in order to improve consistency across panels, for the sake of optimizing clinical application and facilitating integration of datasets generated from multiple assays. Methods: Fifteen laboratories with targeted panels at different stages of development participated. We identified a set of reference standards consisting of 10 well-characterized human-derived lung and breast tumor-normal matched cell lines. WES was performed using a uniform bioinformatics pipeline agreed upon by all team members (WES-TMB). Each laboratory used their own sequencing and bioinformatics pipelines (tumor-only and tumor-normal) to estimate TMB according to genes represented in their respective panels (panel-TMB). The association between WES-TMB and each panel-TMB was investigated using regression analyses. Bias (relative to WES-TMB) and variability in TMB estimates across panels were rigorously assessed. All analyses were blinded. Results: The set of reference standards spanned a clinically meaningful TMB range (4.3 to 31.4 mut/Mb). Preliminary data from 12 laboratories shows a good correlation between panel-TMB and WES-TMB in this empirical analysis. Across panels, regression R2 values range 0.77-0.96 with slopes ranging 0.60-1.26. Calibration analyses that seek to minimize variability of TMB estimates across panels using the established set of reference standards are ongoing, as well as investigating cancer type dependence on the relationship between panel-TMB vs. WES-TMB, which will be available at the time of presentation. Conclusions: Preliminary findings demonstrate feasibility of using sustainable reference control cell lines to standardize and align estimation of TMB across different targeted NGS assays. Future studies aim to validate reference standard material as a reliable alignment tool by using formalin-fixed paraffin-embedded human tumor samples.
Association of genetic variations within the T-cell costimulatory LIGHT gene with outcome in stage II and III colon cancer.
Authors: Berger Martin D. , Cao Shu , Zlobec Inti , Miyamoto Yuji , Suenaga Mitsukuni , Hanna Diana L. , Soni Shivani , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Battaglin Francesca , Zhang Wu , Lugli Alessandro , Lenz Heinz-Josef 
Published: May 2019

2633 Background: T-cell activation plays a key role in maintaining an effective host immunity and antitumor control. Targeting costimulatory immune checkpoint proteins can lead to increased antitumor immunity. We hypothesize, that variations in genes encoding for T-cell activation molecules may predict outcome in stage II and III colon cancer patients. Methods: The impact of 4 functional single nucleotide polymorphisms (SNPs) within the LIGHT, ICOS, CD80 and GITR genes on time to recurrence and overall survival was evaluated in 209 patients with stage II and III colon cancer. Genomic DNA was extracted from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: median age = 70y (19-91); female/male ratio = 41.6% / 58.4%; 111 patients had stage II, and 98 stage III colon cancer. The LIGHT rs3760746 SNP showed significant association with recurrence rate in the overall population. Patients harboring any G allele had a lower 3-years recurrence rate compared to those with a A/A genotype (16% vs 30%) in both univariate (HR 0.53, 95% Confidence intervall (CI) 0.29-0.96, p = 0.033) and multivariate analyses (HR 0.52, 95% CI 0.29-0.95, p = 0.034). This trend was most evident among patients with stage III colon cancer. Here again, G allele carriers had both a lower 3-years recurrence and a longer 5-years overall survival rate compared to those having a A/A genotype (21% vs 40% and 77% vs 43%) in both univariate (HR 0.42, 95% CI 0.19-0.90, p = 0.021 and HR 0.51, 95% CI 0.25-1.03, p = 0.046) and multivariate analyses (HR 0.43, 95% CI 0.20-0.93, p = 0.033 and HR 0.30, 95% CI 0.14-0.65, p = 0.002). Conclusions: Our results provide the first evidence that polymorphisms within the T-cell costimulatory LIGHT gene might serve as prognostic markers in patients with stage II and III colon cancer. Targeting LIGHT might be a promising approach to further optimize treatment options and to improve outcome of colon cancer patients in the adjuvant setting.
Phase I trial of a modified vaccinia ankara (MVA) priming vaccine followed by a fowlpox virus (FPV) boosting vaccine modified to express brachyury and costimulatory molecules in advanced solid tumors.
Authors: Collins Julie Marie , Donahue Renee Nicole , Tsai Yo-Ting , Palena Claudia , Marte Jennifer L. , Madan Ravi Amrit , Karzai Fatima , Heery Christopher Ryan , Strauss Julius , Gatti-Mays Margaret Elena , Cordes Lisa M. , Schlom Jeffrey , Gulley James L. , Bilusic Marijo 
Published: May 2019

2640 Background: Brachyury, a transcription factor, plays an integral role in epithelial-to-mesenchymal transition, metastasis, poor prognosis, and resistance to chemotherapy. It is expressed in many tumor types, and rare in normal tissue, making it an ideal immunologic target. BN-Brachyury comprises heterologous vaccination with recombinant MVA priming followed by FPV boosting, each encoding transgenes for brachyury and three costimulatory molecules (B7-1, ICAM1, and LFA-3). Heterologous prime boost approach is intended to optimize immunogenicity, as previously observed. Methods: Pts with metastatic solid tumors were treated with 2 monthly doses of MVA-brachyury SC at the previously tested dose, 2.2 x 109 infectious units (IU), followed by FPV-brachyury SC, 1 x 109 IU, for 6 monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability and establish the RP2D. Immune assays were conducted to evaluate immunogenicity. Results: In 10 pts (3 chordoma, 6 GI, 1 papillary thyroid), no dose-limiting toxicities or serious treatment-related adverse events (TRAEs) were observed. The only Grade 3 TRAE was sedation associated with fever, which resolved spontaneously and did not recur with subsequent cycles. All other TRAEs were Grade 1 or 2; the most common was injection-site reaction in all patients. Five pts have had stable disease for > 24 wks (per RECIST v1.1) and remain on treatment. One pt with chordoma, for which BN-Brachyury was granted orphan drug designation, has had a 13.2% reduction in tumor size. As previously demonstrated, brachyury-specific T cell responses were observed, as were responses against cascade antigens (non-encoded antigens) CEA and MUC-1. Conclusions: Heterologous MVA- and FPV-brachyury is well tolerated and induced immune responses to brachyury and cascade antigens, suggesting induction of immunologically relevant tumor cell destruction. These data have informed combining BN-Brachyury with checkpoint inhibition (NCT03493945) and radiation (NCT03595228) to evaluate potential for synergetic activity in selected populations. Clinical trial information: NCT03349983.
Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors.
Authors: Fakih Marwan , O'Neil Bert , Price Timothy Jay , Falchook Gerald Steven , Desai Jayesh , Kuo James , Govindan Ramaswamy , Rasmussen Erik , Morrow Phuong Khanh H. , Ngang Jude , Henary Haby A. , Hong David S. 
Published: May 2019

3003 Background: The KRASG12C mutation is found in approximately 13% of lung adenocarcinomas and 1–3% of other solid tumors, but there is no approved therapy that targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state. Methods: This phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult patients (pts) with locally-advanced or metastatic KRASG12C mutant solid tumors. The primary endpoint is safety; key secondary endpoints include PK, ORR (assessed every 6 weeks [wks]), DOR, and PFS. Key inclusion criteria: KRASG12C mutation identified through DNA sequencing, measurable or evaluable disease, ECOG PS ≤2, life expectancy >3 months (mo). Key exclusion criteria: active brain metastases, myocardial infarction within 6 mo. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). A dose expansion will enroll pts with NSCLC, CRC, and other advanced solid tumors carrying the KRASG12C mutation. AMG 510 will be given PO until disease progression, intolerance, or withdrawal of consent. Results: 22 pts (8 men, 14 women; median age 55.5 y) were enrolled in the first 3 dose cohorts. Tumor types: 6 NSCLC, 15 CRC, 1 other. Most pts (n=17) had ≥3 prior lines of treatment (tx). Median tx duration was 28 d (range: 8–134). 5 pts reported 10 treatment-related AEs (grade 1, n=9; grade 2, n=1); there were no DLTs. Tumor response was evaluated in 9 pts (4 with ≥2 assessments); 13 pts have not reached their first assessment.1 pt had a PR (NSCLC at wks 6 and 12, tx ongoing), 6 pts had SD (4 CRC and 2 NSCLC; median tx duration 9.7 wks [range: 6.3–19.1], tx ongoing), 2 pts had PD. 20 pts are continuing to receive AMG 510. A second PR (NSCLC at wk 6, tx ongoing) was reported after data cutoff. Conclusions: AMG 510 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to patients with advanced KRAS G12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883.
Single agent ONC201 in adult recurrent H3 K27M-mutant glioma.
Authors: Arrillaga Isabel , Kurz Sylvia , Sumrall Ashley , Butowski Nicholas A. , Harrison Rebecca A. , De Groot John Frederick , Shonka Nicole A. , Lieberman Frank S. , Odia Yazmin , Tarapore Rohinton , Merdinger Krystal , Allen Joshua E. , Oster Wolfgang , Mehta Minesh P. , Cloughesy Timothy Francis , Chi Andrew S. , Lassman Andrew B. , Batchelor Tracy , Wen Patrick Y. 
Published: May 2019

3005 Background: H3 K27M-mutant glioma is associated with a poor prognosis and there is no effective therapy following radiation. We report the clinical experience with single agent ONC201, the first small molecule DRD2 antagonist in oncology, in adults with recurrent H3 K27M-mutant glioma. Methods: Twenty-nine adult patients with recurrent H3 K27M-mutant glioma have been treated with single agent ONC201 as of January 20, 2019: 19 patients on NCT03295396; 8 patients on NCT02525692; 2 patients on compassionate use protocols under the Sponsor’s IND. Median age was 57 years old (range: 17-74), median prior lines of therapy was 2 (range: 1-4) and all patients received prior radiation (median 8.5 months from radiation completion to ONC201 initiation). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. Results: As of February 5, 2019, 13 of 29 patients remain on-trial within median follow up of 6.5 months (range: 0.6-33.6), 8 patients are alive but off-trial with median follow up of 2.4 months (range: 0.2-9), and 8 patients have expired. Nine of 29 patients (31%) remain progression-free on ONC201 with a median follow up of 6.5 months (range 0.6-33.6). No dose-limiting toxicities or treatment discontinuations due to toxicity occurred. Three patients have experienced durable partial responses by RANO (4.3-28.5 months). In addition, one patient experienced complete regression that continues for > 14 months of all < 1 cm tumor lesions that are not measurable by RANO. Furthermore, 10 patients had a best response of stable disease by RANO, 12 patients experienced progressive disease, and 3 patients are not yet evaluable. Among the patients with a best response of stable disease by RANO, one patient had > 50% tumor regression in the basal ganglia that did not qualify as a partial response by RANO due to a new lesion on a confirmatory scan. Another patient with stable disease by RANO has had 37% tumor regression so far in the brainstem and remains on-treatment for 6 months. All tumor regressions remain durable to date and some were associated with improvements in disease-associated neurological symptoms. Conclusions: Single agent ONC201 is well tolerated and clinically active in adult recurrent H3 K27M-mutant glioma patients. Clinical trial information: NCT03295396; NCT02525692.
Phase 1/2 trial of FF-10502-01, a pyrimidine antimetabolite, in patients with advanced cholangiocarcinoma and solid tumors.
Authors: Janku Filip , Sen Shiraj , Pant Shubham , Bramwell Lindsay , Subbiah Vivek , Way Tracey , Javle Milind M. , Stone Cassie , Prajapati Bhumika , Hagiwara Shinji , Johansen Mary , Madden Timothy , Maier Gary , Subach Ruth Ann , Saeki Kazunori , Suzuki Takeaki , Wages David S. , Wheeler Catherine A. , Falchook Gerald Steven 
Published: May 2019

3008 Background: FF10502 is a synthetic pyrimidine nucleoside similar to gemcitabine (gem) with a sulfur in the pentose ring. FF10502 is a more potent inhibitor of DNA polymerase Beta than gem with activity in gem resistant patient (pt) derived xenograft models. FF10502 is avidly taken up into DNA and has greater activity against quiescent cells than gem. Methods: Pts > 18 years old with advanced disease who had progressed on standard of care were enrolled into 9 dose levels to determine maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) and subsequently into two expansion cohorts: biliary or solid tumors (ST). FF10502 at doses of 8 to 135 mg/m2 was administered iv on days 1, 8, 15 of a 28-day cycle until progressive disease or toxicity. PK/PD evaluations were performed on all pts. Response was assessed by RECIST 1.1. Results: 76 pts were treated; 35 pts in dose escalation, including 7 cholangiocarcinoma pts. MTD was 90 mg/m2. DLTs included 2 pts with hypotension at 135mg/m2 (G3 and G4) and 1 pt each with G3 fatigue and G2 rash at 100mg/m2. In expansion, 19 cholangiocarcinoma, 3 gallbladder and 19 other pts (13 pancreatic, 2 urothelial, and 1 each ovarian, prostate, NSCLC, SCCHN each) were treated. 1 pt with prior rituximab for ITP developed PML. G3 treatment-related low platelets occurred in 3 pts at 90mg/m2 after cycle 1. There were 5 partial responses (PRs), including 4 pts who had progressed on prior gemcitabine: 3 of 26 pts with cholangiocarcinoma, 1 urothelial carcinoma and 1 chondroblastic osteosarcoma. 7 cholangiocarcinoma pts stayed on therapy for ≥6 months. FF10502 incorporation intoperipheral blood cellular DNA was seen, andbiomarkeranalysisdata to identify pts with higher potential for clinical response will be presented. Conclusions: FF10502 is well tolerated in pts with advanced cancers refractory to standard therapies. Early signals of efficacy warranting further exploration were seen in heavily pretreated cholangiocarcinoma pts (median: 4 prior therapies). Patient selection based on differential effects of FF10502 on DNA polymerases will be explored. Clinical trial information: NCT02661542.