bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) and tislelizumab (TIS) as first-line (1L) therapy for patients (pts) with advanced HER2-positive gastric/gastroesophageal junction adenocarcinoma (G/GEJC): Preliminary results from a phase 1b/2 study.
Authors: Lee Keun Wook , Bai Li-Yuan , Jung Minkyu , Ying Jieer , Im Young Hyuck , Oh Do-Youn , Cho Jae Yong , Oh Sang Cheul , Chao Yee , Li Huiyan , Zhou Ping , Bao Yuanyuan , Kang Yoon-Koo 
Published: June 2022

4032 Background: Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that targets two distinct extracellular domains of HER2. Zani has shown preliminary antitumor activity and tolerability in pts with HER2+ gastroesophageal adenocarcinoma as monotherapy/with chemo in Phase 1/2 studies (NCT02892123, NCT03929666). TIS, an anti-PD-1 antibody, has demonstrated antitumor activity in pts with advanced solid tumors. Combining anti-HER2 therapy with anti-PD-1 therapy and chemo increased tumor response in G/GEJC in a Phase 3 clinical trial. Methods: Cohort 2 of this ongoing open-label, Phase 1b/2 study was in pts with untreated locally advanced/metastatic HER2+ G/GEJC (NCT04276493). Cohort A received zani 30 mg/kg IV, Cohort B received zani 1800 mg IV (weight < 70 kg) or 2400 mg IV (weight ≥ 70 kg), both with TIS 200 mg IV and capecitabine/oxaliplatin (CAPOX) Q3W. Primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS). Results: As of Nov 26, 2021, 33 pts with a median age of 64.0 years (range: 29.0–80.0) were assigned to Cohort A (n=19) or B (n=14). Median study follow-up was 7.7 months (range: 2.1–19.0) and the median number of treatment cycles was 10 (range: 1–28), 20 (60.6%) pts remained on treatment. All pts were efficacy evaluable ([EE], n=33), confirmed ORR was 72.7% (95% CI: 54.5, 86.7). Median PFS was 10.9 months (95% CI: 6.9, NE). Efficacy data are summarized in the Table. All pts experienced ≥ 1 treatment emergent adverse event (TEAE), and 24 (72.7%) pts experienced ≥ Grade 3 TEAEs. All pts experienced treatment related TEAEs (trTEAEs), 20 (60.6%) pts experienced ≥ Grade 3 trTEAEs and trTEAEs leading to death occurred in two (6.1%) pts. Immune-mediated AEs (imAEs) occurred in nine (27.3%) pts, of which seven (21.2%) pts experienced ≥ Grade 3 imAEs. Conclusions: Zani, TIS and CAPOX combination demonstrated a manageable safety profile and antitumor activity as 1L therapy for pts with HER2+ G/GEJC. Clinical trial information: NCT04276493. [Table: see text]
A phase II study evaluating KN026 monotherapy in patients (pts) with previously treated, advanced HER2-expressing gastric or gastroesophageal junction cancers (GC/GEJC).
Authors: Xu Jianming , Liu Rongrui , Ying Jieer , Wu Jun , Ye Feng , Xu Nong , Zhang Yanqiao , Zhao Rusen , Xiang Xiaojun , Wang Jianhong , Lin Xiaoyan , Xu Huiting , Gao Shegan , Luo SuXia , Guo Baohong , Li Xionghui , Su Yangzhi , Wang Qian 
Published: June 2022

4040 Background: Outcomes of second or later-line treatment for pts with advanced GC/GEJC remain inferior. KN026 is a novel HER2-targeted bispecific antibody composed of VH regions of trastuzumab and pertuzumab, targeting the HER2 juxtamembrane domain (IV) and the dimerization domain (II) simultaneously. KN026 has shown promising antitumor efficacy in preclinical and phase I studies. Here we present the results of KN026 monotherapy in previously treated, advanced HER2-expressing GC/GEJC. Methods: In this multi-center, single-arm, open-label, 2-cohort phase II study, adult pts with previously treated, advanced GC/GEJC were assigned into a HER2 high-level cohort (Cohort 1: IHC3+ or IHC 2+ ISH+) or a HER2 low-level cohort (Cohort 2: IHC 1+/2+ ISH- or IHC 0/1+ISH+). KN026 was given intravenously in 10 mg/kg QW, 20 mg/kg Q2W, or 30 mg/kg Q3W. Primary endpoints were objective response rate (ORR) and duration of response (DoR) assessed by investigators per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety outcomes. This trial is registered at ClinicalTrials.gov (NCT03925974). Results: At data cut-off (Oct. 29, 2021), 45 pts were enrolled and treated with KN026; 39 were eligible for response evaluation (25 pts in Cohort 1 and 14 pts in Cohort 2). In Cohort 1, ORR was 56% (95%CI 35%-76%) with 14 PR; the median DoR was 9.7 months (mo) (95%CI 4.2-not evaluable (NE)). At a median follow-up of 14.7 mo (95%CI 9.4-16.5), the median PFS was 8.3 mo (95%CI 4.2-11.4), and median OS was 16.3 mo (95% CI 11.0- NE). In Cohort 2, ORR was 14% (95%CI 2%-43%), with median DoR being 6.2 mo (95%CI 3.2-NE). At a median follow-up of 27.5 mo (95%CI 4.1-NE), the median PFS was 1.4 mo (95%CI 1.4-4.1), and median OS was 9.6 mo (95% CI 3.5-14.9). The table shows efficacy in Cohort 1 pts who have progressed on the prior trastuzumab treatment. KN026-related adverse events (TRAEs) were observed in 37 (82%) pts; the most common TRAEs (any grade) were increased aspartate aminotransferase (12, 27%), increased alanine aminotransferase (9, 20%), rash (7,16%), anemia (7,16%), and infusion-related reaction (7,16%). Four pts reported 5 grade 3 TRAEs, including infusion-related reaction, renal hydrocele, ureteral stenosis, increased blood pressure, and abnormal hepatic function (1 each). No grade 4 or 5 TRAEs occurred. Conclusions: KN026 monotherapy yielded promising efficacy with mild to moderate toxicities in pts with previously treated, advanced GC/GEJC. Further investigation is warranted. Clinical trial information: NCT03925974. [Table: see text]
Clinical efficacy of laparoscopic sentinel node navigation surgery for early gastric cancer: Five-year results of SENORITA trial.
Authors: Hur Hoon , Lee Young Joon , Kim Young-Woo , Min Jae-Seok , Yoon Hong Man , An Ji Yeong , Eom Bang Wool , Cho Gyu Seok , Park Young-Kyu , Jung Mi Ran , Park Ji-Ho , Hyung Woo Jin , Jeong Sang-Ho , Kook Myeong-Cherl , Han Mira , Nam Byung-Ho , Ryu Keun Won 
Published: June 2022

4050 Background: A phase III multicenter randomized controlled clinical trial (SEntinel Node ORIented Tailored Approach [SENORITA] trial) has been performed to confirm the oncologic safety of laparoscopic sentinel node navigation surgery (LSNNS) for early gastric cancer (EGC). The results did not show the non-inferiority of LSNNS relative to laparoscopic standard gastrectomy (LSG) in terms of 3-year disease-free survival (DFS), the primary endpoint of the SENORITA trial even though the improved quality of life (QOL) in the LSNNS group. However, the long-term oncologic outcomes of LSNNS have not been compared with conventional surgery. This study was planned to investigate the comparison of LSG and LSNNS for EGC in terms of 5 years survival. Methods: We collected 5-year follow-up data of 527 patients recruited in the SENORITA trial. The overall survival (OS), disease-free survival (DFS), and recurrence pattern were evaluated in full analysis sets of both LSG (n = 269) and LSNNS (n = 258). Results: The mean follow-up period was 58.5 and 57.7 months in LSNNS and LSG groups. There was no statistically significant difference in 5-year OS (p = 0.7403) and DFS (p = 0.0561) between LSG and LSNNS. In terms of DFS, additional five events in the LSG group and 7 in LSNNS occurred after a 3-year follow-up until 5-years. Primary site recurrence in 1 LSNNS, and metachronous gastric cancer occurred in one LSG and two in LSNNS were diagnosed from 3 to 5-year follow-up period. Other organ cancer developed in two vs. three and other deaths occurred in two v s. one in each group, respectively, from 3 to 5-year follow-up. Overall survival events were 6 in LSG and 7 in LSNNS, and disease-specific death events were two patients in both groups until five years. Conclusions: Although the SENORITA trial did not show non-inferiority of LSNNS in the primary endpoint, 3-year DFS relative to LSG, the 5-year DFS and OS did not reveal the statistical difference between the two groups. Considering the benefit of LSNNS regarding the postoperative QOL, LSNNS could be recommended as an alternative treatment option of LSG for EGC. Clinical trial information: NCT01804998.
Ramucirumab, avelumab, and paclitaxel (RAP) as second-line treatment in gastro-esophageal adenocarcinoma, a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
Authors: Thuss-Patience Peter C. , Högner Anica , Goekkurt Eray , Stahl Michael , Kretzschmar Albrecht , Schädlich Bärbel , Goetze Thorsten Oliver , Stocker Gertraud , Reichardt Peter , Kullmann Frank , Pink Daniel , Bartels Prisca , Ballhausen Alexej , Jarosch Armin , Hinke Axel , Binder Mascha , Stein Alexander 
Published: June 2022

4051 Background: Combination of ramucirumab and paclitaxel is a standard second line therapy in gastro-esophageal adenocarcinoma (GEAC) (RAINBOW trial, Wilke et al., 2014). We integrated the PD-L1 inhibitor avelumab into this regimen aiming for synergistic efficacy. Methods: In a multicenter phase II trial (NCT03966118) pts with metastatic GEAC, after progression on platinum / fluoropyrimidine based palliative 1st-line, ECOG 0 or 1, were treated with ramucirumab 8 mg/kg (d1,15) + avelumab 10 mg/kg (d1,15) + paclitaxel 80 mg/m² (d1,8,15), q4w. Sample size calculation was based on a Simon 2-stage design with overall survival rate at 6 months as the primary endpoint (H0≤50%, H1≥65%). Results: 60 pts were enrolled, 59 were evaluable (ITT), median age 64.0 yrs (range 18-81), male 80%, female 20%, primary gastric 52%, GEJ 48%, histology intestinal 59.6%, diffuse 24.6%, mixed 15.8%. Previous treatment with platin/fluoropyrimidine 100%, previous taxanes 66%. At central pathology MSI-H 7%, PD-L1 CPS < 5: 54%; ≥5: 41%, NA 5%. Response by investigator (%) CR 3.4, PR 27.1, SD 49.2, PD 20.3; DCR 79.7%, independent radiology review will be presented. DOR: 8.2 mo (95%CI 6.7-9.7), PFS 5.4 mo (95%CI 4.2-6.6); 6-mo OS rate 71.2%; 12-mo OS rate 45.8%; med OS (ITT) 10.6 mo (95%CI 8.2-13.1), med OS CPS < 5: 9.4 mo (95%CI 7.2-11.2), CPS ≥5: 14.0 mo (95%CI 12.8-15.3), translational data (ct-DNA) will be analysed. Treatment was generally well tolerated and no unexpected toxicities occurred: Grade 3/4 AE above 5%: anemia 5%, leucopenia 12%, neutropenia 22%, diarrhea 5%, pain 10%, peripheral neuropathy 10%, hypertension 5%, non-neutropenic infection 5% including 1 CTC grade 5 due to an esophago-tracheal fistula. Conclusions: The med OS of 10.6 mo (in a population of 66% pretreated with taxanes) compares very favourably to 8.6 mo in the Western population RAINBOW trial (Shitara et al., 2016) and 7.6 mo in the RAMIRIS trial (Lorenzen et al., 2022). PD-L1 CPS≥ 5 seems to predict for an even better efficacy (med OS 14.0 mo). Second-line RAP is a very efficacious and well tolerated combination. Clinical trial information: NCT03966118.
Tumor microenvironment (TME) dynamics following capecitabine/oxaliplatin (CapeOx) plus pembrolizumab in patients with advanced gastric cancer.
Authors: An Minae , Lee Song-Yi , Kim Seung Tae , Kang Won Ki , Lee Jeeyun 
Published: June 2022

4053 Background: Immune checkpoint inhibition (ICI) has made significant breakthroughs in several tumor types including gastric cancer (GC) in recent years. However, single-agent pembrolizumab demonstrated remarkable and durable response in MSI and EBV GC because they are immune-enriched types. Recently, we reported on-treatment remodeling of the TME during chemotherapy in MSS AGC ( Cancer Discov. 2021). We defined altered features including decreased tumor-associated macrophages (TAM), M1- macrophages repolarization and recruitment of NK cells, effector T cells. Methods: This phase 2, open-label, single-arm study was designed to assess the safety and efficacy of the CapeOx-pembrolizumab combination in advanced gastric cancer patients with HER2-negative. 38 patients were enrolled onto our CapeOx plus Pembrolizumab trial (NCT #04249739). All patients had MSS status with EBV-negative. Endoscopic biopsies were collected at baseline, after 1 cycle of chemotherapy alone and after 4 to 5 cycles of CapeOx + pembrolizumab to understand the impact of treatment to tumor TME. We performed coupling whole exome sequencing and whole transcriptome sequencing. Molecular features were extracted by exonic analysis. TME subtype was estimated by gene expression analysis. Results: Between 2020 and 2021, 38 patients were enrolled. There were 2 CR, 25 PR, 11 SD as best response.First, we found a number of somatic mutations (median 157.5, range 7-25,719) in pre-and on-treatment samples. Despite the creation and destruction of somatic mutation, we observed that ancestor mutations including TP53, MUC6 and APC previously reported in TCGA GC cohort, were preserved. At baseline (before chemotherapy), patients were classified to 5 immune-enriched (IE) subtye, 21 immune-depleted (D) subtype, ETC. Second, we observed a dynamic change following one cycle of CapeOx before the addition of pembrolizumab to chemotherapy. Nine (23.68%) out of thirty eight patients with immune-depleted or fibrotic pre-treatment TME became immune-favorable during treatment. Interestingly, seventeen (58.62%) out of twenty nine patients with immune-unfavorable pre-treatment TME became immune-favorable following CapeOx plus Pembrolizumab chemotherapy. Conclusions: This is the first study to demonstrate TME change during CapeOx plus pembrolizumab at molecular levels and will have clinically meaningful performance in patients with metastatic GC. Clinical trial information: NCT#04249739.
Circulating tumor DNA and recurrence risk in stage II-III gastric cancer.
Authors: Yuan Shu-Qiang , Huang You-Sheng , Nie Run-Cong , Chen Yingbo , Wang Si-Yu , Sun Xiaowei , Li Yuanfang , Liu Ze-Kun , Chen Yan-Xing , Yao Yi-Chen , Xu Yu , Qiu Haibo , Liang Yao , Wang Wei , Zhou Zhiwei , Xu Rui-hua , Wang Feng 
Published: June 2022

4054 Background: Circulating tumor DNA (ctDNA) is a promising biomarker for detecting molecular residual disease (MRD) and relapse after definitive treatment in multiple solid cancers. However, the significance of ctDNA is rarely clarified in locoregional gastric cancer (GC). Here, we conducted a prospective and observational study to evaluate the utility of ctDNA in predicting the recurrence risk of GC. Methods: From October 2016 to June 2019, 100 patients with stage II/III resectable GC were recruited in this study (NCT02887612). Primary tumors and plasma samples were collected perioperatively and after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma of patients was defined as ctDNA positive only if one or more variants detected in the plasma presented in at least 2% of the primary tumors. All the patients received curative-intent standard-of-care therapy. Results: Preoperative ctDNA was detectable in 38 (38.0%) patients but showed limited value for predicting recurrence. After surgery (median days, 4), the plasma of 25 (25.0%) patients were still ctDNA positive and they had higher recurrence risk than the non-positive patients (hazard ratio [HR], 2.74 (95% CI: 1.37–5.48); P = 0.003). Forty-one patients had evaluable plasma after ACT and 10 (24.4%) of them who were ctDNA positive had remarkably higher recurrence and death risk compared with ctDNA-negative patients (recurrence-free survival [RFS] HR = 14.99 (95% CI: 3.08–72.96); P < 0.001; overall survival HR, 11.88 (95% CI: 2.38–59.24); P < 0.001). In particular, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and post-treatment tumor biomarkers (i.e., CEA, CA199, and CA72-4). In all multivariate analyses, ctDNA positivity was an independent factor of RFS. Patients with ERBB4 mutation in their primary tumors had poorer RFS compared to those were ERBB4 wildtype (HR = 3.46 (95% CI: 1.32–9.03); P = 0.007). A comprehensive model incorporating ctDNA status for recurrence risk prediction showed a higher concordance index (0.78; 95%CI, 0.71–0.84) than the model without ctDNA status (0.71; 95%CI, 0.64–0.79; P = 0.009). Conclusions: Postoperative and post-ACT ctDNA was associated with MRD and high risk of relapse in patients with stage II/III GC and can be utilized to guide GC management in post-surgical settings.
Prognostic role of tumor stroma ratio, tumor-infiltrating lymphocytes, and tumor budding in patients with intestinal-type gastric cancer after radical resection.
Authors: Sha Dan , Tian Chunfang , Sinicrope Frank A. , Jing Haiyan , Wang Jinshen , Song Wei 
Published: June 2022

4055 Background: Tumor microenvironmental (TME) features including tumor stroma ratio (TSR), tumor infiltrating lymphocytes (TILs) and tumor budding (TB), may be associated with tumor metastatic potential. We sought to identify the association of these features with prognosis of patients with resectable intestinal-type gastric cancer. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 493 patients (stage I, n=225; stage II, n=119; stage III, n=149) at two university hospitals between 2010 and 2016. Cutpoints were as follows: TSR (50%), TILs (median), and TB (Bd0-Bd3). TME features and their association with clinicopathological characteristics, time-to-recurrence (TTR) and overall survival (OS) were analyzed by univariate and multivariate Cox methods.. Results: Among 493 patients, high TSR, low TILs and high TB (Bd1-Bd3) were significantly associated with higher histological grade, larger tumor size, and increased T and N stages. Each of these features was significantly associated with poorer TTR and OS at 5 years. In Cox multivariable analysis, N stage and TSR were the only variables that were significantly associated with TTR and OS (Table). The relative contribution (%) of TSR to TTR ranked second (17.5%) behind N stage (49.2%) and ahead of TILs (7.2%) and TB (0.1%). Conclusions: Among TME features, TSR was the most robust and was significantly and independently associated with TTR and OS. The relative contribution of TSR to TTR was second only to nodal status. [Table: see text]
Neoadjuvant atezolizumab plus docetaxel/oxaliplatin/capecitabine in non-metastatic gastric and gastroesophageal junction adenocarcinoma: The PANDA trial.
Authors: Verschoor Yara L. , Kodach Liudmila , van den Berg José , van Sandick Johanna W. , van Dieren Jolanda , Balduzzi Sara , Grootscholten Cecile , Veenhof Xander , Hartemink Koen , Vollebergh Marieke A. , Owers E.C. , Bartels-Rutten Annemarieke , den Hartog Peggy , van Leerdam Monique E , Schumacher Ton , Voest Emile E. , Haanen John B. A. G. , Chalabi Myriam 
Published: June 2022

4059 Background: Immune checkpoint blockade improves clinical outcomes for patients with gastric and gastro-esophageal junction (GEJ) cancers, but its efficacy and impact on the tumor microenvironment in non-metastatic, resectable disease remains largely unknown. Peri-operative FLOT, the current standard-of-care, leads to pathologic complete responses (pCR) and major pathologic responses (MPR) in 16% and 37% of patients, respectively. An important open question is whether PDL-1 blockade monotherapy can prime the tumor microenvironment in a favorable manner, prior to combination with chemotherapy. Methods: We report results from the phase 2 PANDA trial (NCT03448835) of neoadjuvant atezolizumab (anti-PDL-1) plus docetaxel, oxaliplatin, and capecitabine (DOC) in patients with resectable gastric or GEJ adenocarcinoma. Patients received a single cycle of atezolizumab monotherapy, followed by 4 cycles of atezolizumab+DOC. Tumor tissue was collected at baseline, after atezolizumab monotherapy, the first atezolizumab+DOC, and at resection. The primary endpoints were safety and feasibility in 20 patients, and secondary endpoints included MPR (<10% viable tumor rest) and disease-free survival. Results: Twenty patients, of which 18 with mismatch repair (MMR) proficient and two with MMR-deficient tumors, were evaluable for safety and efficacy analyses. MPR was observed in 14/20 patients (70%; 95% CI 46–88%), including 9 pCR (45%; 95% CI 23-68%). Among patients with intestinal type adenocarcinoma, 12/15 (80%; 95% CI 52-96%) had an MPR, with 9/15 (60%; 95% CI 32-84%) pCR. Treatment was well tolerated, with two patients (10%) experiencing a grade 3 immune adverse event. At a median follow-up of 29 months (IQR 16-34), 15 patients (75%) were alive and disease-free. None of the patients with an MPR recurred. All patients underwent resections without treatment-related delays and no unexpected surgical complications were documented. Translational analyses, including baseline PDL-1 CPS score and whole exome sequencing (WES), plus CD8 T-cell infiltration and RNA sequencing at 4 timepoints will be presented at the meeting. Conclusions: Our data show that the addition of atezolizumab to neoadjuvant chemotherapy leads to promising pathologic responses in gastric/GEJ adenocarcinoma, which appears to be higher than in historical controls, with no recurrences in responders. These data should be validated in a large randomized controlled trial. Clinical trial information: NCT03448835.
REGOMUNE: A phase II study of regorafenib plus avelumab in solid tumors—Results of the oesophageal or gastric carcinoma (OGC) cohort.
Authors: Cousin Sophie , Metges Jean Philippe , Bellera Carine A. , Guégan Jean Philippe , Adenis Antoine , Gomez-Roca Carlos A. , Cassier Philippe Alexandre , Hollebecque Antoine , Cantarel Coralie , Palmieri Lola Jade , Kind Michèle , Soubeyran Isabelle , Palussière Jean , Bessede Alban , Italiano Antoine 
Published: June 2022

4060 Background: Combination VEGF and PD-1/PD-L1 axis blockade has shown benefit in various tumors and is emerging as a promising combination strategy. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of regorafenib (R) (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in advanced or metastatic oesophageal or gastric carcinoma (OGC) patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Dec. 2018 and Mar. 2021, 49 pts were enrolled in 6 centers: 33 adenocarcinoma (ADK), 16 squamous cell carcinoma (SCC). Median age was 63.9 (range 33 – 80). Median follow-up was 14.5 months. Median number of previous treatment lines was: 2 (range 1 – 6). 29 (59.2%) pts experienced at least 1 dose modification or treatment interruption due to an adverse event related to treatment. The most common grade 3/4 adverse events were : Hypertension (12.2% of pts), palmar-plantar erythrodysesthesia syndrome (10.2%), and hypophosphatemia (8.2%). No death was related to the treatment. Among the 42 (29 ADK and 13 SCC) pts who had at least one imaging tumor assessment, 8 (19.1%) achieved a partial response, 5 (17.2%) and 3 (23.1%) in the ADK and SCC group respectively. 12 pts (28.6%) demonstrated stable disease and 22 pts (52.3%) had progressive disease. The median PFS and OS were 1.9 months (95%CI 1.8 – 3.5) and 7.5 months (95%CI 4.5 – 15.7) respectively. Conclusions: The R+A combination is associated with encouraging antitumor activity in patients with OGC. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.