bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct radiological patterns of drug-induced pneumonitis (R-DIP) in early-phase clinical trials and predictive factors affecting outcome: A 10-year systematic review from the Royal Marsden Hospital Phase I Drug Development Unit experience.
Authors: Terbuch Angelika , Moreno Candilejo Irene , Scaranti Mariana , Bar Daniel , Estevez Timon Miriam , Ameratunga Malaka , Ang Joo Ern , Ratoff Jonathan , Minchom Anna , Banerji Udai , De Bono Johann S. , Tunariu Nina , Lopez Juanita Suzanne 
Published: May 2019

3088 Background: We studied clinical and radiological parameters influencing DIP in patients (pts) participating in phase I clinical trials, aiming to investigate predictive factors affecting DIP, in particular those affecting outcome. Methods: 2439 consecutive stage IV cancer pts on phase I clinical trials from 2007 to 2017 were identified. Pts with respiratory symptoms or abnormal lung imaging were reviewed in detail, with longitudinal analysis of imaging by an experienced radiologist. R-DIP was categorized according to internationally recognized criteria. Results: 60 pts developed R-DIP (overall incidence 2.5%); most frequent in pts receiving drug conjugates (31.1%) followed by targeted therapies (8.3%). Hypersensitivity pneumonitis was most common (33.3%) followed by non-specific interstitial pneumonitis (30%) and cryptogenic organising pneumonitis (26.7%). 45% pts who developed R-DIP were clinically asymptomatic. The number of affected lobes (OR 1.47, 95% CI: 1.19-1.81, p < 0.001) and the pattern of R-DIP (OR 5.83 for ARDS, 95% CI: 0.38-90.26, p = 0.002) were significantly associated with a higher CTCAE pneumonitis grading. 23% pts (14/60) had investigational medicinal product (IMP) temporarily discontinued or had a dose reduction while 42% pts (25/60) had IMP permanently discontinued. 48% pts were treated with steroids. The number of affected lobes, pattern of R-DIP and steroid therapy did not influence an improvement in R-DIP (p = 0.65, 0.27 and 0.23 respectively). Continuation of treatment resulted in worsening of DIP in 42.9% of cases. The only predictive factor for an improvement in DIP was an interruption of treatment (OR 0.05, 95% CI: 0.01-0.35, p = 0.01). 14 pts were retreated with a reoccurrence of R-DIP in 4 pts (28.6%). Conclusions: R-DIP from novel agents in early phase clinical trials presents in varied radiological patterns, with findings often preceding clinical symptoms. Treatment interruption leads to improvement of DIP and should be considered early. Close clinical and radiological surveillance is recommended should IMP be restarted.
Phase 1 of ABTL0812, a proautophagic drug, in combination with paclitaxel and carboplatin at first-line in advanced endometrial cancer and squamous cell lung carcinoma.
Authors: Farinas-Madrid Lorena , Estévez-García Purificación , Perez-Fidalgo Jose Alejandro , Bosch-Barrera Joaquim , Moran Teresa , Nadal Ernest , Rodriguez Freixinos Victor , Calvo Elisa , Falcon Alejandro , Martín-Martorell Paloma , Huerta Alvaro Marisol , Barretina-Ginesta Maria Pilar , Romeo Margarita , Gil-Martin Marta , Garralda Elena , Rodon Jordi , Lizcano Jose M. , Domenech Carles , Alfon Jose Alberto , Oaknin Ana 
Published: May 2019

3089 Background: ABTL0812 is a novel anti-cancer agent that induces a strong autophagy-mediated cell death by a dual mechanism. It inhibits the Akt/mTOR axis by upregulating TRIB3, an endogenous Akt inhibitor, and induces reticular (ER)-stress. Preclinical data in squamous non-small cell lung carcinoma (Sq-NSCLC) and endometrial cancer (EC) has indicated drug efficacy as a single agent and potentiation of chemotherapy. Methods: A phase 1 clinical study was designed where ABTL0812 was administered orally in combination with 175 mg/m2 paclitaxel/carboplatin AUC5 D1 every 3 weeks (P/C), and posterior ABTL0812 as a maintenance therapy until disease progression or unacceptable toxicity. The study included first-line patients (pts) with advanced Sq-NSCLC or advanced/recurrent EC. The design included a 3+3 de-escalation trial followed by an expansion cohort, where the starting dose of ABTL0812 was 1300 mg tid and if at least 2 pts experienced a DLT, the dose level would be de-escalated to 1000 mg tid. Safety and tolerability were the primary endpoints and preliminary efficacy according to RECIST v1.1 criteria and pharmacodynamic biomarkers (TRIB3 and CHOP an ER-stress biomarker, by qPCR in whole blood) were the secondary endpoints. Results: 16 EC and 5 Sq-NSCLC pts were enrolled. One DLT, a grade 4 neutropenia, appeared in the first cohort of 6 pts and no de-escalation was applied. Fourteen pts were included in an expansion cohort with the same dose level (1300 mg tid), and 1 DLT, a grade 3 febrile neutropenia, was observed. Therefore, the dose of 1300 mg tid was selected as RP2D in combination with P/C. Most frequent grades 2-4 AEs were neutrophil count decreased (n = 9, 43%), nausea (n = 5, 24%), fatigue (n = 4, 19%), followed by anemia, vomiting, dyspepsia, platelet count decreased, arthralgia and neurotoxicity (n = 2, 10% each). Seventeen pts (13 EC and 4 Sq-NSCLC) who completed at least two treatment cycles were evaluable for efficacy; 1 CR (EC), 8 PR (7 EC and 1 Sq-NSCLC), 7 SD (5 EC and 2 Sq-NSCLC) and 1 PD (Sq-NSCLC) were observed. Pharmacodynamic biomarkers showed increased TRIB3 and CHOP levels. Conclusions: The combination of ABTL0812+P/C was safe and tolerated, efficacy signals were observed, and biomarker modulation confirmed drug activity. The triple combination is currently being evaluated in both indications in a Phase 2 study. Clinical trial information: NCT03366480.
A phase Ib study of prexasertib, a checkpoint kinase (CHK1) inhibitor, and LY3023414, a dual inhibitor of class I phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) in patients with advanced solid tumors.
Authors: Hong David S. , Moore Kathleen N. , Bendell Johanna C. , Karp Daniel D. , Wang Judy Sing-Zan , Ulahannan Susanna Varkey , Johnson Melissa Lynne , Aljumaily Raid , Hynes Scott , Callies Sophie , Decker Rodney , LaBell Elizabeth , Niland Michele , Wang Xuejing Aimee , Bence Lin Aimee , Patel Manish R. 
Published: May 2019

3091 Background: Prexasertib inhibits CHK1, a kinase involved in DNA repair and replication. LY3023414 inhibits PI3K/mTOR signaling, implicated in the development of malignant disease. Prexasertib + LY3023414 has resulted in enhanced antitumor activity in triple negative breast cancer (TNBC) in vitro models. Methods: This Phase 1b study in patients (pts) with solid tumors assessed escalating doses of prexasertib (60-105 mg/m2 IV every 14 days [q14d]) and LY3023414 (100-200 mg orally twice daily [BID]). Dose escalation ceased once the maximum tolerated dose of each monotherapy was reached. An initial expansion cohort (Arm E) explored prexasertib 105 mg/m2 q14d + LY3023414 200 mg BID. Subsequent expansion cohorts evaluated prexasertib 105 mg/m2 q14d + LY3023414 150 mg BID in pts with solid tumors with PIK3CA mutations (Arm E2) or TNBC (Arm E3). Results: Fifty pts were enrolled (escalation: n = 13; Arm E: n = 9; Arm E2: n = 15; Arm E3: n = 13). No dose-limiting toxicities (DLTs) were observed during escalation however DLT-equivalent toxicities were observed in 2 pts in Arm E (anemia, neutropenia, thrombocytopenia, oral mucositis, abdominal pain, fatigue). Due to toxicity, a reduced dose of LY3023414 (150 mg BID) was assessed in Arm E2/E3. In the 28 patients treated in Arms E2/E3, common treatment-related adverse events (any grade; grade ≥3) were: leukopenia/neutropenia (82%; 79%), thrombocytopenia (46%; 36%), nausea (46%; 0%), stomatitis (39%, 4%), vomiting (36%; 0%), and anemia (29%; 18%). Febrile neutropenia was reported in 25% of pts. Dose reductions in Arm E2/E3 were common. In escalation, 2 pts achieved a partial response (PR) and 3 pts achieved stable disease (SD). In Arm E, 78% of pts achieved SD. Of the pts evaluable at the time of data transfer, PRs were achieved in 1 pt with an unknown primary (Arm E2) and 2 pts with TNBC (Arm E3). Each agent’s pharmacokinetic profile was consistent with prior monotherapy data. Conclusions: Prexasertib + LY3023414 showed preliminary efficacy in heavily pretreated pts with solid tumors but was associated with toxicity, suggesting supportive care may be required. Clinical trial information: NCT02124148.
A phase I study of the APE1 protein inhibitor APX3330 in patients with advanced solid tumors.
Authors: Shahda Safi , Lakhani Nehal J. , O'Neil Bert , Rasco Drew W. , Wan Jun , Mosley Amber L , Liu Hao , Kelley Mark R. , Messmann Richard Adam 
Published: May 2019

3097 Background: APX3330 is an orally administered anti-cancer, anti-CIPN agent targeting the APE1 protein. APE1 maintains NFkB, STAT3, AP-1 and HIF-1a in a reduced form, acting as a regulator of transcription factors. A dual function protein, APE1 also plays a role in protecting against oxidative DNA damage in neurons. APX3330 is a highly selective inhibitor of APE1 redox function in tumors that enhances the neuronal protection function of APE1. Methods: We report on study NCT03375086 evaluating APX3330 in patients with incurable malignancies. Eligibility required adequate organ function, PS 0-2 and tumors not amenable to curative therapy. 1° and 2° objectives included determining the recommended phase 2 dose (RP2D), the safety and PK/PD profiles of APX3330 and reporting any RECIST anti-tumor activity. Patients received APX3330 b.i.d, in 21-day cycles. AE evaluation included 1 pt/cohort until the occurrence of ≥ G2 toxicity at which time the study proceeded in a 3+3 design. Additional patient were also recruited in cohorts in order to attain PK/PD and biopsy samples. Results: Between 2/18 and 8/18, 19 subjects (13M, 6F) with median age of 69 y started therapy. Dose (mg/d) escalation and number of patients treated (n) per each cohort proceeded as follows: 240 mg (1), 360 (4), 480 (2), 600 (6) and 720 (6). APX3330 was well tolerated at dose levels from 240-600 mg/d. The most frequent treatment-related adverse event (all grades) was G1 fatigue. A G3 rash occurred in two subjects at the 720 mg level defining 600 mg/d as the RP2D for further development. Six subjects had disease stabilization for ≥ 4 cycles, and of these, four subjects with the following diagnosis, RECIST response and days on study included: (CRC, PR, 356), (Endometrial, SD, 316), (Melanoma, SD, 245), (Prostate, SD, 246). Final PK and PD data, including proteomic, transcriptome, APE1 serum levels and CTC analyses are pending and will be reported at the conference. Conclusions: APX3330 is an orally administered inhibitor of APE1. This phase I study identified 600 mg PO daily as the RP2D for further development. RECIST evaluation identified signs of clinical activity in this un-selected population of patients with advanced cancer. PD analyses indicate APX3330 mediated targeting of the APE1 protein. Clinical trial information: NCT03375086.
First-in-human phase I trial of anti-hepatocyte growth factor (HGF) antibody (YYB101) in refractory solid tumor patients: Integrative pathologic-genomic analysis and the final results.
Authors: Lee Jeeyun , Kim Seung , Nam Do-Hyun , Lee Su Jin , Park Se Hoon , Park Joon Oh , Lee Jeong-Won , Kim Kyoung-Mee , Lee Hukeun , Park Neunggyu , Kim Hoon-Kyo , Lee Song-Jae , Song Seong-Won , Kim Jung Ju , Park Young Suk , Lim Ho Yeong , Kang Won Ki 
Published: May 2019

3104 Background: It has been demonstrated in vivo that HGF-MET signaling axis is a key molecular determinant in tumor invasion and there is a significant association in HGF expression and mesenchymal phenotype in addition to immune cell recruitment. We have developed a HGF neutralizing humanized monoclonal antibody antibody, YYB-101. The aim of this study was to determine the maximum tolerate dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of YYB101, in patients with refractory solid tumors. Methods: YYB101 was administered intravenously at once every 2 weeks doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Enrolled patients were planned to receive YYB101 until disease progression or intolerable toxicity. The escalation and expansion cohorts (20mg/kg) were completed. Pre-planned biomarker analysis was performed in parallel. Results: 39 heavily pre-treated refractory cancer patients were enrolled and received YYB101. No DLT was observed. YYB101 demonstrated dose proportional PK up to the dose of 30 mg/kg. No patients discontinued treatment because of adverse events. Based on PK analysis and toxicity data, the recommended dose was determined as 20 mg/kg. Of 39 evaluation patients, there was 1 confirmed partial response for > +14months (2.5%, N = 1; 1 (of 2) sebaceous carcinoma) and 17 stable disease as best response (43.5%, N = 17; 7 (of 13) CRC, 3 (of 4) melanoma, 1 (of 2) sebaceous carcinoma, 1 (of 3) gastric, 1 (of 1) basal cell carcinoma, 2 (of 10) ovarian cancer, 1 (of 1) HCC, 1 (of 1) lung cancer). Of note, 1 sebaceous carcinoma patient who have failed to ≥2+ lines of chemotherapy, have been responding to YYB for 14 months. The MET and HGF expressions by immunohistochemistry (IHC) were evaluated in 19 and 17 tumor specimens, respectively. Neither protein expressions were significant predictors for treatment response to anti-HGF antibody. However, we have observed significant reduction in HGF in responders to YYB. Two long-term responders had mesenchymal signature in RNA sequencing. Conclusions: YYB101 has a favorable safety profile in patients with refractory solid tumors and a dose-proportional PK. Efficacy data are encouraging and phase II combination therapy with YYB101 is planned to be open in metastatic CRC patients as salvage treatment. The predictive power of mesenchymal signature in YYB responders will be defined prospectively. Clinical trial information: 02499224.
Clinical, pathological and genetic predictors of patient-derived xenograft (PDX) engraftment in EGFR-mutated lung adenocarcinoma (LUAD).
Authors: Martins-Filho Sebastiao N. , Weiss Jessica , Pham Nhu-An , Cabanero Michael , Fares Aline Fusco , Stewart Erin L. , Patel Devalben , McConnell Judy , Bradbury Penelope Ann , Sacher Adrian G. , Leighl Natasha B. , Grindlay Alexandria , Allison Frances , LI Ming , Yasufuku Kazuhiro , Shepherd Frances A. , Moghal Nadeem , Tsao Ming Sound , Liu Geoffrey 
Published: May 2019

3110 Background: PDX are useful preclinical models to study drug response and resistance. Different specimen types have been used to generate PDX models including histological (surgery and CT-guided biopsy) and cytological preparations (EBUS and pleural effusions). We hypothesize that engraftment is not stochastic and is affected by many factors including sample type and tumor pathological and molecular properties. To improve sample selection and cost-effectiveness of PDX experiments, we investigated clinical, histological and genetic correlates of engraftment in EGFR-mutated LUAD. Methods: We assessed PDX engraftment from 96 surgical resections, 13 CT-guided biopsies, 21 EBUS and 14 pleural effusions of EGFR-mutated LUAD. Sixty-five samples, including 6 engrafted (XG) and 54 non-engrafted (noXG) were evaluated by exome sequencing. Results: Engraftment was successful in 9/96 (9%) surgical resections, 6/13 (46%) CT-guided biopsies, and 0/35 cytological samples. Biopsies taken at time of treatment failure (compared to treatment naive biopsies) correlated with greater engraftment (p=0.007, AUC = 0.68). Multivariable regression analysis of clinical variables at the time of sampling identified advanced (vs early) stage (p = 0.003) and histological (vs cytological) preparations (p < 0.001) as the strongest predictors of engraftment (AUC = 0.79). Among tumor histologic features, solid (vs lepidic, acinar and papillary) pattern was associated with greater engraftment (p < 0.001). Presence of EGFR-T790M (p = 0.004) and TP53 (p = 0.009) mutations were associated with greater engraftment; all XG samples carried TP53 mutations. EGFR-Ex19del (p = 0.076) showed a trend towards engraftment whereas EGFR-L858R (p = 0.086) trended towards non-engraftment. Conclusions: Advanced stage, post-therapy tumors, T790M+ and TP53+ EGFR-mutated LUAD samples obtained for histological processing are more likely to engraft as PDXs. Despite low engraftment rates, these models are useful to study novel therapeutic strategy and elucidation of resistance mechanisms.
Genomic somatic alterations of human epidermal growth factor-2 (HER2) gene: A pan-cancer analysis.
Authors: Zhu Xinhua , Zhou Yong , Zhang Yuzi , Cai Shangli 
Published: May 2019

3112 Background: Human epidermal growth receptor 2 (HER2) is a well-known oncogenic drive gene with multiple targeted therapeutic options. In this study, we aim to assess the landscape of HER2 alterations in solid tumors and evaluate the feasibility of circulating tumor DNA (ctDNA) tested by next-generation sequence (NGS) as a tool to detect HER2 alterations. Methods: Alterations of HER2 by NGS (Illumina NextSeq 500) were queried in 3D Medicines database. The mean depth of tissue and circulating tumor DNA (ctDNA) test was 500X and 5000X, respectively. 11,013 patients tested using tumor tissue and 6,970 patients tested using ctDNA were included in this analysis. Results: Of 11,013 patients tested using tumor tissue, any HER2 and known or likely deleterious HER2 mutations were identified in 739 (6.7%) and 531 (4.8%) patients, respectively. Of 531 patients who carried known or likely deleterious HER2 mutations, 263 (49.5%) had HER2 amplification and 259 (48.8%) had single nucleotide variations (SNVs). Across all tumor types, breast cancer was found to have the highest frequency of HER2 amplification (14.9%, 48/323), followed by gastric cancer (6.6%, 31/470) and biliary tract cancer (5.8%, 33/571). Moreover, 11% (8/73) of duodenal cancer, 4.5% (7/154) of urothelial cancer, 3.8% (18/470) of gastric cancer, 3.1% (142/4555) of lung cancer, 2.9% (17/571) of biliary tract cancer, 2.8% (44/1562) of colorectal cancer and 2.7% (9/323) of breast cancer carried known or likely deleterious HER2 SNVs. Of 6970 patients tested using ctDNA, any HER2 and known or likely deleterious HER2 mutations were identified in 592 (8.5%) and 277 (4.0%) patients, respectively. In the ctDNA cohort, 15.7% (36/230) of breast cancer and 3.1% (5/161) of biliary tract cancer carried HER2 amplification. However, 11.6% (20/173) of gastric cancer had HER2 amplification tested by ctDNA which was higher than that tested using tissue. Furthermore, 5.6% (13/230) of breast cancer, 4.5% (2/44) of urothelial cancer, 3.4% (6/173), 2.5% of biliary tract cancer and 2.0% (94/4586) lung cancer harbored known or likely deleterious HER2 SNVs in ctDNA cohort. Conclusions: HER2 alterations existed across tumor types and the landscape of genomic alterations in HER2 gene varied according to different type of tumor. In addition, ctDNA can be used as a potential tool to detect HER2 alterations.
Development and clinical validation of Lantern Pharma’s AI engine: Response algorithm for drug positioning and rescue (RADR).
Authors: Kathad Umesh , Vedaraju Yuvanesh , Kulkarni Aditya , Tobin Gregory , Sharma Panna 
Published: May 2019

3114 Background: The Response Algorithm for Drug positioning and Rescue (RADR) technology is Lantern Pharma's proprietary Artificial Intelligence (Al)-based machine learning approach for biomarker identification and patient stratification. RADR is a combination of three automated modules working sequentially to generate drug- and tumor type-specific gene signatures predictive of response. Methods: RADR integrates genomics, drug sensitivity and systems biology inputs with supervised machine learning strategies and generates gene expression-based responder/ non-responder profiles for specific tumor indications with high accuracy, in addition to identification of new correlations of genetic biomarkers with drug activity. Pre-treatment patient gene expression profiles along with corresponding treatment outcomes were used as algorithm inputs. Model training was typically performed using an initial set of genes derived from cancer cell line data when available, and further applied to patient data for model tuning, cross-validation and final gene signature development. Model testing and performance computation were carried out on patient records held out as blinded datasets. Response prediction accuracy and sensitivity were among the model performance metrics calculated. Results: On average, RADR achieved a response prediction accuracy of 80% during clinical validation. We present retrospective analyses performed as part of RADR validation using more than 10 independent datasets of patients from selected cancer types treated with approved drugs including chemotherapy, targeted therapy and immunotherapy agents. For an instance, the application of the RADR program to a Paclitaxel trial in breast cancer patients could have potentially reduced the number of patients in the treatment arm from 92 unselected patients to 24 biomarker-selected patients to produce the same number of responders. Also, we cite published evidence correlating genes from RADR derived biomarkers with increased Paclitaxel sensitivity in breast cancer. Conclusions: The value of RADR platform architecture is derived from its validation through the analysis of about ~17 million oncology-specific clinical data points, and ~1000 patient records. By implementing unique biological, statistical and machine learning workflows, Lantern Pharma's RADR technology is capable of deriving robust biomarker panels for pre-selecting true responders for recruitment into clinical trials which may improve the success rate of oncology drug approvals.