tbuckley/cabot-search huggingface dataset:
MiR-148a deregulation and colorectal cancer liver metastases.
Authors: Jaime Rubio Pérez, Ion Cristobal, Cristina Carames Sanchez, Ana Leon, Jose Ignacio Martin-Valades, Ana Ruperez, Manuel Domine, Blanca Torrejon, Roberto Hernández, Manuel Pedregal, Eva Ruiz-Hispán, Imanol Martinez, Jesus Garcia-Foncillas
Journal: Journal of Clinical Oncology (2018)

e15556 Background: It has been recently reported that miR-148a promotes hepatocytic differentiation and its expression levels correlates with hepatocytic markers such as the hepatocyte-specific miR-122. Moreover, miR-148a is downregulated in hepatocarcinoma cells and its restoration impaires tumor growth, reduces liver fibrosis and induces an increased hepatic differentiated phenotype in vivo. The liver represents the most common metastatic niche in colorectal (CRC) and based on these novel findings we hypothesized that miR-148a could be playing a relevant role in the establishment of liver metastasis. Although little is known about the significance of miR-148a in CRC, some data in the literature would suggest its tumor suppressor role. Methods: We analyzed miR-148a in an initial set of 17 CRC patients with paired primary and metastatic tissues. To measure miR expression levels in tumor samples we performed real‐time RT‐PCR on formalin‐fixed paraffin‐embedded (FFPE). To further investigate our hypothesis we also analyzed in our patient cohort the expression of the hepatocyte-specific miR-122. Results: We found no changes in miR-148a expression between primary and metastatic samples from 5 CRC patients with lung metastasis (p = 0.225). However, we observed that miR-148a was overexpressed in the metastatic tissues of those 12 CRC cases with liver metastasis (p = 0.019). Finally, MiR-122 was found markedly overexpressed in CRC liver metastases compared to the paired primary tumors (p < 0.001). Conclusions: Our results would suggest that restoration of miR-148a levels is a relevant molecular event that contributes to the establishment of the metastatic CRC cell in the liver. The short number of patients included is a limitation of this study. Thus, the potential role of miR-148a in CRC liver metastasis has to be further confirmed in forthcoming studies.
Dual MAPK inhibition (dMAPKi) as an effective therapeutic strategy for class II BRAF mutant (mt) metastatic melanoma (MM).
Authors: Matthew Dankner, Mathieu Lajoie, Dan Moldoveanu, Shivshankari Rajkumar, Tan Trieu Nguyen, Paul Savage, Marie-Christine Guiot, Xiu Huang, Alexei Protopopov, Maria Lvova, Dana Vuzman, Morag Park, Kevin Petrecca, David Hogg, Marcus O. Butler, Anna Spreafico, Catalin Liviu Dragos Mihalcioiu, Ian Watson, Peter Siegel, April A. N. Rose
Journal: Journal of Clinical Oncology (2018)

12093 Background: dMAPKi with BRAFi and MEKi improves survival in BRAF V600E/K mt MM, but the effects of these inhibitors on nonV600 BRAF mt MM is poorly understood. We sought to characterize nonV600/class II (enhanced kinase activity, dimerization dependent) BRAF mt MM and to investigate their responsiveness to MAPKi. Methods: We analyzed 3 MM datasets (PMH next generation sequencing (NGS) cohort, TCGA, GENIE) for clinicopathologic correlations and outcomes of nonV600 BRAF mt MM pts. Tumors from patients with BRAF WT, V600E (class I), and L597S (class II) MM were used to generate patient-derived xenografts (PDX); both were subjected to NGS analysis with the CANCERPLEX assay. We generated and obtained 8 MM cell lines with class IIa (activation segment) or IIb (p-loop) mt and compared these to BRAF WT and V600E/K MM cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib) and MEKi (cobimetinib, trametinib, binimetinib), or the combination. They were investigated with immunoblots, in vitro, and in vivo growth assays. We identified two patients with BRAF L597S MM who were treated with dMAPKi. Results: NonV600 BRAF mutants comprise 10-35% of all BRAF mts in MM. NonV600 BRAF mts are frequently co-expressed with NRAS mts and associated with poor survival compared to BRAF V600E/K MM (HR 1.49, 95% CI 1.09-2.06). BRAFi impaired Erk phosphorylation and cell growth in class I and IIa BRAF mt cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class IIa and IIb cell lines tested. PDXs retained high genomic fidelity to the primary tumors from which they were derived. In two independent BRAF L597S (class IIa) PDX models, single MAPKi only slowed the progression of tumor growth whereas dMAPKi resulted in significant tumor shrinkage. Two patients with BRAF L597S mt melanoma obtained objective clinical responses to dual MAPKi. Conclusions: NonV600 BRAF mt MM are associated with poor prognosis. Class II BRAF mt MM are growth inhibited by dMAPKi. Responses to dMAPKi have been observed in two patients with class II BRAF mt MM. Our data provide rationale for clinical investigation of dual MAPKi in patients with class II BRAF mt MM.
Organ-preserving surgery for localized renal cell carcinoma: Current approaches.
Authors: Sergey N Dimitriadi, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Natalya Dmitrievna Ushakova, Dmitry Rozenko, Dmitry Aleksandrovich Shvyrev, Aleksandr V. Faenson, Sergey I. Goncharov
Journal: Journal of Clinical Oncology (2017)

e16077 Background: Introduction of modern organ-preservingapproaches in surgical treatment of kidney cancer is limited by the duration of warm ischemia used during the partial nephrectomy (PN), including surgery for elective indications. Some resection procedures require prolonged warm ischemia time resulting in acute kidney injury and development of renal failure in the postoperative period. The purpose of the study was to analyze the effectiveness of a new organ-preserving surgery method for kidney cancer. Methods: 46 patients with clinically localized renal cancer, R.E.N.A.L. score 6-10, underwent PN for elective indications. Patients were divided into two groups: the first group – 20 patients (8 patients – laparoscopic PN (LPN), 12 – open PN (OPN)) with bilateral perirenal procaine blockade (BPPB) before the resection. The second group included 26 patients (19- LPN, 7– OPN) receiving surgery without BPPB. BPPB was performed under US-control. 50 ml of 0.25% procaine solution was successively injected to the perinephric fat in upper, middle and lower kidney segments at both sides. Acute kidney injury (AKI) was diagnosed by serum creatinine level increase by 50% of the initial level and higher. Results: Patients in both groups were comparable by age – 58.35±7.5 (44–70) and 58.7±5.6 (50–65) years, and resection difficulty by R.E.N.A.L. score – 7.35±1.1 (6–10) and 7.15±1.2 (6–10), respectively. Median warm ischemia time did not differ significantly in both groups and was 20.0±2.99 (15–25) and 18.42±2.93 (15–25) min., respectively. Morphologically, all patients were diagnosed with renal cancer, surgical margins were negative. 9 (34.6%) patients of the second group developed AKI, while no AKI was registered in the first group. Urinary fistula and delayed bleeding were not observed. Conclusions: The results suppose renal protective effect of BPPB during partial nephrectomy for kidney cancer with warm ischemia time of 15-25-minutes.
Duration of second line treatment and survival in multiple myeloma.
Authors: Parameswaran Hari, Linh Mai Tran, Candice Yong, Stephen J Noga, Eileen Farrelly, Aditya Raju, Brian S. Seal, Richard Labotka, Marlo Blazer, Mehul Rajesh Jhaveri, Dorothy Romanus
Journal: Journal of Clinical Oncology (2016)

e18107 Background: Evidence from post-hoc analyses of clinical trials supports the paradigm of extended treatment leading to an overall survival (OS) benefit in relapsed/refractory multiple myeloma (RRMM). This observational study evaluated whether longer 2nd line treatment (SLT) duration is associated with improved OS among pts with RRMM. Methods: In this retrospective cohort study of a US national EMR database, newly diagnosed adults with MM initiating 1stline therapy (FLT) and SLT between 1/2008 and 12/2014 were followed through earliest of either 1 yr or death/loss to follow up/end of study period (12/31/2014) after start of SLT. FLT began with the first claim for MM-directed therapy following diagnosis (dx). SLT was identified by: 1) retreatment with follow-up regimen with gap of >3 mo after end of FLT, or 2) switch to another drug combination after FLT. A logistic marginal structural model was used to estimate the causal effect of SLT duration on 1-yr OS probability, adjusting for time-dependent confounders and baseline covariates. Immortal time bias was addressed by estimating the effect of SLT duration on outcome within each monthly interval from start of SLT. Results: Among 340 pts, mean age was 70 yrs (SD: 10); 51% were male; 9% had known high risk MM; 46% pts received immunomodulatory (IMID-), 35% proteasome inhibitor (PI-), and 6% PI+IMID-based SLT. Median duration of SLT was 6.87 mos (95% CI: 6.17, 8.40). The odds of 1-yr OS were 1.17 times higher for each additional month of SLT (OR: 1.17 [95% CI: 1.10, 1.25] p-value <.001), controlling for age, gender, cytogenetic risk, comorbidities, race, ethnicity, region, insurance type, treatment-free interval prior to SLT, FLT/SLT regimen type, yr of dx, time since initial dx, time-dependent treatment- and MM-related symptoms, and post SLT regimens. Conclusions: Longer duration of SLT was significantly associated with longer OS. Despite substantial heterogeneity in pt/disease characteristics, and treatment patterns, the clinical benefit of continued longer term therapy at relapse appears to be generalizable to pts receiving care in the real-world setting. Adjusted predicted 1-yr OS probability. SLT Duration (mos) 1-yr OS 1 0.61 3 0.68 4 0.72 6 0.78 7 0.81 8 0.83 9 0.85 10 0.87 12 0.90
The PRIMO study: A phase 2 study of duvelisib efficacy and safety in patients with relapsed or refractory peripheral t-cell lymphoma (PTCL).
Authors: Steven M. Horwitz, Jasminder Soto, Hagop Youssoufian, Deborah Lloyd, Ngocdiep T. Le
Journal: Journal of Clinical Oncology (2018)

TPS7590 Background: Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ being developed for the treatment of hematologic malignancies. In preclinical investigations, duvelisib potently killed TCL cell lines with constitutive phospho-AKT (S473) and reprogrammed tumor-associated macrophages from an immunosuppressive to immunostimulatory phenotype in PTCL mouse xenograft models (Horwitz, Blood 2017). In a Phase 1 study duvelisib monotherapy demonstrated encouraging clinical activity and an acceptable safety profile (Flinn, Blood 2017), with an overall response rate (ORR) of 50% (3 complete responses [CRs], 5 partial responses [PRs]) in patients (pts) with PTCL (n = 16). These results suggest duvelisib monotherapy may provide a meaningful benefit in relapsed/refractory (RR) PTCL, a population in need of new and effective therapies. Methods: This Phase 2, open-label, study of duvelisib monotherapy in adult pts PTCL employs a Dose Optimization Phase (DOP) and an Expansion Phase (EP) (NCT03372057). The primary objectives are to identify the optimal dose of duvelisib and examine the efficacy, safety, and tolerability of duvelisib at the optimal dose. The study will enroll up to 120 pts with histologically confirmed PTCL subtypes of PTCL-NOS, angioimmunoblastic TCL, anaplastic large cell lymphoma, and natural-killer TCL. Disease responses will be measured by 18FDG-PET-CT scanning as assessed by an independent review committee per IWG criteria. The DOP, to be conducted at 4-6 centers in the U.S., will include 20 pts randomly assigned to 1 of 2 parallel cohorts. Cohort 1 will receive a starting dose of 25 mg duvelisib PO BID, with potential sequential escalation to 50 mg and then 75 mg based on responses and tolerance of therapy. Pts in Cohort 2 will receive 75 mg duvelisib PO BID. The EP, to be conducted globally at ~40 centers, will include pts treated at the optimal dose as determined from the DOP. The primary endpoint is ORR (CR + PR) in all pts receiving the optimal dose for at least 1 cycle in either phase. Secondary endpoints include AEs, duration of response, and PFS. This study is open for enrollment. Clinical trial information: NCT03372057.
Growing teratoma syndrome: Is it a subtype of germ-cell tumors or another entity?
Authors: Mutlu Dogan, Oznur Bal, Erkan Olcucuoglu, Efnan Algin, Nurullah Zengin
Journal: Journal of Clinical Oncology (2017)

e16040 Background: Growing teratoma syndrome(GTS ) is a process presenting with growing masses despite normal tumor marker levels(TML) after chemotherapy in non-seminomatous germ cell tumors (NSGCT). Methods: GTS patients between 2000-2016 were evaluated for clinicopathological features and survival outcomes retrospectively. Results: 17 (6,4%) of 266 NSGCT had GTS. Median follow-up was 57.7 ( 13.8-132.7) months. Median age 27 (17-51) years . Most (n = 14) of them had mixed germ-cell tumors &amp; 12 had mature/immature teratoma in primary pathology at diagnosis. Most (n = 11) of them had stage 3 disease &amp; 10 had high TML (S1-3). 11 GTS patients had good risk NSGCT. All (n = 17) had 4 BEP(bleomycin, etoposide, cisplatin) cycles. Recurrence occured in retroperitoneum (n = 13), lung (n = 3) &amp; brain (n = 1). They were considered as GTS since they had normal TML despite growing masses. 5 patients were referred to surgery without salvage chemotherapy and they had teratoma on postoperative surgery. 13 had surgery after salvage chemotherapy (TIP: taxane, ifosfamide, platin) but 4 had unresectable disease and they had clinical benefit with interferone α2b. Two operated patients had diffuse necrosis on pathology whereas others had documented teratoma. Median DFS was 12.3 ( 5.7-18.8) months whereas median OS was 64.8 (15.5-158) months. 3 patients had no recurrence after surgery for GTS. 9 had salvage chemotherapy (gemcitabine/oxaliplatin, TIP) for NSGCT metastatic lesions with TML elevation and 2 of them had autolog stem cell transplantation. Conclusions: GTS is rare in NSGCT, but it should be considered in NSGCT patients with both growing masses &amp; normal TML after primary treatment approach. GTS patients surgery with resectable masses should be referred to surgery since teratoma without viable tumor seems to have less benefit from chemotherapy and/or radiotherapy. Interferon α2b might be an option in unresectable GTS.
Adjuvant nivolumab (NIVO) plus ipilimumab (IPI) for resected high-risk stages IIIC/IV melanoma (MEL).
Authors: Nikhil I. Khushalani, Youngchul Kim, Geoffrey Thomas Gibney, Ragini Reiney Kudchadkar, Zeynep Eroglu, Joseph Markowitz, Maria P. Czupryn, Melissa S. Thebeau, Lori McCormick, Allison Richards, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2016)

9586 Background: Patients (pts) with resected stage IIIC or IV melanoma are at very high-risk for recurrence and effective strategies for adjuvant therapy are needed. Combination NIVO + IPI yields high response rates but has a high rate of grades (G) 3-4 toxicities in advanced MEL. We examined the safety and efficacy of 2 dosing schedules of NIVO + IPI in resected stage IIIC and IV MEL pts. Methods: Resected stage IIIC/IV MEL pts who were free of disease, with adequate laboratory indices and performance status of 0-1 were treated with NIVO (1mg/kg) + IPI (3mg/kg) Q3 weeks X 4 doses (induction) followed by 2 years of NIVO at 3mg/kg Q2 weeks (Cohort A). Toxicities observed during induction led to opening of cohort B consisting of NIVO (3mg/kg) + IPI (1mg/kg) Q3 weeks X 4 doses followed by the same maintenance. Pre-defined criteria permitted initiation of NIVO maintenance following recovery from induction toxicity in both cohorts. Results: Twenty pts were treated in each cohort. Median age was 50 (22-78) in cohort A and 55 (29-77) in cohort B; stage IIIC pts constituted 65% and 60% of the respective cohorts. Toxicity precluded completion of all 4 induction doses in 50% in cohort A (most common was G3-4 ↑ AST and/or ALT in 7 pts) and 35% in cohort B. The most common G3-4 toxicities (minimum 5 events) are listed in the table. Hypophysitis developed in 28% (7 pts in cohort A). The incidence of ↑ AST/ALT, nausea, anorexia, cough, weight loss, neurotoxicity & endocrine toxicity was significantly higher in cohort A. In this group, 5 pts (25%) completed all induction doses and remain on NIVO maintenance; in group B, this number was 40%. There have been 4 relapses in cohort A, and 3 in cohort B. Only 1 pt in this high-risk study group has succumbed to MEL recurrence. At median follow-up of 21.3 months and 11 months respectively for the two cohorts, the median progression-free survival and overall survival have not been reached. Conclusions: In very high-risk resected MEL, adjuvant NIVO + IPI followed by maintenance NIVO has encouraging activity. Dosing per cohort B appears better tolerated and warrants further study. Clinical trial information: NCT01176474. A (n = 20) B (n = 20) ↑ Lipase 8 6 ↑ ALT / AST 8 / 5 1 / 1 ↑ Glucose 2 4 ↑ Amylase 3 3 Colitis 3 2 Vomiting 1 4
Heterozygosity of Chaperone Grp78 Reduces Intestinal Stem Cell Regeneration Potential and Protects against Adenoma Formation
Authors: Jooske F. van Lidth de Jeude, Claudia N. Spaan, Bartolomeus J. Meijer, Wouter L. Smit, Tanya T.D. Soeratram, Mattheus C.B. Wielenga, B. Florien Westendorp, Amy S. Lee, Sander Meisner, Jacqueline L.M. Vermeulen, Manon E. Wildenberg, Gijs R. van den Brink, Vanesa Muncan, Jarom Heijmans
Journal: Cancer Research (2018)

Deletion of endoplasmic reticulum resident chaperone Grp78 results in activation of the unfolded protein response and causes rapid depletion of the entire intestinal epithelium. Whether modest reduction of Grp78 may affect stem cell fate without compromising intestinal integrity remains unknown. Here, we employ a model of epithelial-specific, heterozygous Grp78 deletion by use of VillinCreERT2-Rosa26ZsGreen/LacZ-Grp78+/fl mice and organoids. We examine models of irradiation and tumorigenesis, both in vitro and in vivo Although we observed no phenotypic changes in Grp78 heterozygous mice, Grp78 heterozygous organoid growth was markedly reduced. Irradiation of Grp78 heterozygous mice resulted in less frequent regeneration of crypts compared with nonrecombined (wild-type) mice, exposing reduced capacity for self-renewal upon genotoxic insult. We crossed mice to Apc-mutant animals for adenoma studies and found that adenomagenesis in Apc heterozygous-Grp78 heterozygous mice was reduced compared with Apc heterozygous controls (1.43 vs. 3.33; P < 0.01). In conclusion, epithelium-specific Grp78 heterozygosity compromises epithelial fitness under conditions requiring expansive growth such as adenomagenesis or regeneration after γ-irradiation. These results suggest that Grp78 may be a therapeutic target in prevention of intestinal neoplasms without affecting normal tissue.Significance: Heterozygous disruption of chaperone protein Grp78 reduces tissue regeneration and expansive growth and protects from tumor formation without affecting intestinal homeostasis. Cancer Res; 78(21); 6098-106. ©2018 AACR.
Incidence rate and clinic-pathologic features of EBV-associated gastric carcinoma in China.
Authors: Rui-hua Xu, Miaozhen Qiu, Cai-Yun He
Journal: Journal of Clinical Oncology (2018)

e16048 Background: Nine percent of tumors in the TCGA study were assigned to be EBV-associated gastric carcinoma (EBVaGC). Previous reports on EBVaGC were small sample size studies. Methods: From July 1, 2014 to February 10, 2018, we prospectively detected EBER status in 2760 gastric adenocarcinoma patients from Sun Yat-sen University Cancer Center. DNA from plasma samples was extracted using the Qiamp Blood Kit (Qiagen, Hilden, Germany). EBV-DNA load was measured by real-time quantitative PCR. The cut-off value for positive EBV-DNA was set as 1000 copy/ml. Results: The incidence rate of EBVaGC in our cohort was 5.07% (140/2760). Compared with EBV-negative gastric carcinoma (EBVnGC), EBVaGC were younger and male predominance, preferential Lauren diffuse subtype, less HER2 positive, earlier T and N stage, less distant metastasis. The survival data need longer time to follow up. The HP infection rate was not significant difference between EBVaGC (15.0%) and EBVnGC (16.03%) patients, P = 0.851. Among the 2760 patients, there were 69 patients had paired biopsy and surgical resection samples. The consistent rate between biopsy and surgical resection samples was 98.6% (68/69). Only 1 patient was EBER negative in the biopsy and positive in the resection sample. The mean concentration of plasma EBV DNA in EBVaGC and EBVnGC patients were 11007.6 copy/ml and 162.8 copy/ml respectively. When we set 1000 copy/ml as cutoff value, the positive rate of EBV DNA in EBVaGC and EBVnGC patients were 25.71% and 1.87% respectively. We monitored the change of plasma EBV-DNA during chemotherapy in 11 stage IV EBVaGC patients whose baseline EBV-DNA was positive. EBV-DNA elevated when the disease progressed (N = 4) while it decreased when the patients got response (N = 7). Conclusions: This is the largest sample size study of EBVaGC in China. The incidence rate of EBVaGC was lower in China than TCGA study. There was no relationship between HP infection and EBV status. EBER detections between biopsy and surgical resection samples were highly consistent. Only one quarter of EBVaGC patients had positive plasma EBV-DNA. Plasma EBV DNA can be used for real-time monitoring of tumor progression in EBVaGC patients.
First in human phase 1/2a study of PEN-221 somatostatin analog (SSA)-DM1 conjugate for patients (PTS) with advanced neuroendocrine tumor (NET) or small cell lung cancer (SCLC): Phase 1 results.
Authors: Melissa Lynne Johnson, Tim Meyer, Daniel M. Halperin, Antonio Tito Fojo, Natalie Cook, Lawrence Scott Blaszkowsky, Benjamin L. Schlechter, James C. Yao, Yannis Jemiai, Kristina Kriksciukaite, Marsha Jones, Nneamaka Ezema, Laura Mei, Leila Alland, Matthew H. Kulke
Journal: Journal of Clinical Oncology (2018)

4097 Background: Somatostatin receptor 2 (SSTR2) is highly expressed in NET and SCLC. PEN-221, a SSA-DM1 conjugate that targets SSTR2, results in complete tumor regressions in SSTR2+ SCLC xenograft models. This study assesses safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-221. Methods: Pts with progressive, advanced, SSTR2+ (by imaging) NET or SCLC were enrolled in escalating cohorts of 2-6 pts. The primary objective was to determine the maximum tolerated dose (MTD) of PEN-221 given every (q) 3 wks. An adaptive Bayesian logistic regression model was used to recommend doses. Intra-patient dose escalation was permitted. Preliminary efficacy was assessed using RECIST 1.1. Results: 23 pts (13 M/ 10 F) with NET (GI, pancreatic, lung, renal or pheochromocytoma; n = 9, 5, 5, 1, 2), or SCLC (n = 1) were treated in 7 cohorts (range 1-25 mg). As of 31 Jan 2018, the median/mean number of cycles is 3/5.8 (range 1-18), with 5 pts ongoing. PEN-221 was well tolerated with no dose limiting toxicities (DLTs) in the first 6 cohorts (1-18 mg; 20 pts). In cohort 7 (25 mg), 2 of 3 pts had DLTs that rapidly and fully resolved: Grade(G)3 ALT/AST rise (2 pts), of whom 1 had concurrent G3 total bilirubin rise and G3 mucositis. The MTD was established at 18 mg. The most frequent (≥20% pts) PEN-221 related adverse events were fatigue (43%), nausea (43%), diarrhea (39%), vomiting (26%), abdominal pain (22%), and decreased appetite (22%). PK was dose proportional, median t1/2 ~1.7 h, with plasma exposures at MTD above preclinically efficacious levels. Among 15 NET pts who were evaluable for response, 11 had stable disease (SD) at 9 wks, of whom 8 were sustained for 18 – 45 wks, including 2 ongoing pts with SD for 44 and 45 wks. Target lesion shrinkage was observed in 3 pts (dose range 8-18 mg). One pt had a rapid and sustained decrease in chromogranin A and circulating tumor cells. One SCLC pt had SD for 12 wks. Conclusions: PEN-221 appears well tolerated with preliminary evidence of antitumor activity. PEN-221 (18 mg q 3 wks) will be evaluated in Phase 2a expansion cohorts enrolling midgut NET, pancreatic NET, and SCLC pts (EudraCT 2016-001468-12; NCT02936323). Clinical trial information: NCT02936323.