bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ectopic expression and oncogenesis of Mer tyrosine kinase in E2A-PBX1 expressing B-cell acute lymphoblastic leukemia
Authors: Sawczyn K. K. , Porter C. C. , DeGregori J. , Graham D. K. 
Published: March 2020

9561 Background: Mer is a receptor tyrosine kinase that belongs to a tyrosine kinase subfamily including Axl and Tyro-3. Mer is expressed in monocytes/macrophages, dendritic cells and platelets, but not in lymphocytes or thymocytes. However, prior DNA array studies have suggested an aberrant expression of Mer in B-cell ALL (B-ALL) expressing the E2A-PBX1 fusion protein associated with t(1;19). We investigated the potential oncogenic role of Mer in E2A-PBX1 expressing B-ALL. Methods: Mer expression was evaluated in diagnostic bone marrow samples in pediatric patients with E2A-PBX1 B-ALL (EP+) and non-E2A-PBX1 B-ALL (EP-) by quantitative RT-PCR, Western blot, and flow cytometry. Using the REH B-ALL cell line with a zinc-inducible E2A-PBX1, induction of Mer expression was evaluated by Western blot. A mouse model was developed by retroviral infection of E2A-PBX1 fusion protein into Mer wild-type (WT), transgenic (TG), and knock-out (KO) mouse bone marrow cells followed by transplantation of these cells into sublethally irradiated WT recipients. Evaluation was done for E2A-PBX1 expression in peripheral blood and bone marrow cells were analyzed by flow cytometry for the development of leukemia. Results: Thirteen EP+ and 14 EP- patient samples were processed. All 13 EP+ samples had Mer protein expression by flow cytometry and/or Western blot. Conversely, 1/14 EP- samples was weakly positive for Mer protein expression by flow cytometry and Western blot. Quantitative RT-PCR was performed on 4 EP+ samples and 6 EP- samples. There was a 7–324 fold increase in Mer expression in EP+ samples when compared to the mean Mer expression of EP- samples. In our mouse transplant model, the median time to develop leukemia from Mer TG/E2A-PBX1 and Mer KO/E2A-PBX1 mice was 92 days and 117 days, respectively, with one KO mouse still surviving disease free at 140 days post-transplant. Conclusions: Mer is ectopically expressed in E2A-PBX1 expressing B-ALL. Mer TG/E2A-PBX1 mice develop leukemia sooner than Mer KO/E2A-PBX1 mice, suggesting cooperativity between the oncogenes. Mer may be an attractive therapeutic target for patients with E2A-PBX1 expressing ALL. No significant financial relationships to disclose.
Multivariate analysis based risk grouping of ewing tumours (ET) with extra-pulmonary metastatic disease (EPMD): Final results from the Euro Ewing 99 study
Authors: Ladenstein R. , Whelan J. , Oberlin O. , Weston C. , Jürgens H. 
Published: March 2020

9562 Background: To identify an effective treatment for patients with EPMD. Methods: 192 patients (pts) were registered. Median age is 15.8 years (yrs) (0.4–49.29). Primary site was extremity in 57 pts and axial/other in 135 pts (40.6% in the pelvis). Tumour volume was ≥ 200 ml in 114pts. Metastatic spread was bone marrow (BM) only in 19 pts, bone only in 93 pts and bone and BM in 79 pts. Six VIDE induction cycles were completed by 168 pts (85%). Local treatment included surgery when possible and/or radiotherapy (Rx) as indicated. Recommended HDT was busulphan (BU) 600 mg/m2 and melphalan (MEL) 140 mg/m2 with PSCR. Median follow up is 4.2 years (range: 1.9–6.6). Results: Partial remission or better was achieved after cycle 6 in 75/116 pts subjected to HDT/SCR (65%). The overall survival at 3 years for all 192 pts is 29% (95% CI=0.04). Significantly favourable univariate factors in the unselected cohort at diagnosis (Dx) were age < 14 yrs (event free survival at 3 yrs (EFS) 37%, p=0.006), BM involvement only (EFS 47%, p=0.024), single bone lesions only (EFS 35%, p=0.009), extremities (EFS 34%, p=0.007) and tumour volume of <200 ml (EFS 47%, p<0.001). For pts receiving BuMel it is noteworthy that 37 pts of <14a and EPMD achieved an EFS of 47% in comparison to older counterparts >14a (EFS 22% (p=0.026). Multivariate analysis identified two major risk factors at Dx: primary tumour volume >200 ml p<0.001 (RR 2.25) and > 5 bone metastases p=0.064 (RR 2.11). In these risk groups the 3 yr EFS was 56% for 35 pts with <200 ml and <5 bone lesions, for 17pts with <200 ml > 5 bone lesions 29%, for 67 pts >200 ml or < 5 bone lesions 19% and extremely dismal for 47 pts with >200 ml and > 5 bone lesions with 7% (p<0.001). Conclusions: Groups with differing prognoses from EPMD have been identified from this prospectively followed cohort. Aggressive treatment with HDT appears effective only for sub groups of patients with EPMD and ET. No significant financial relationships to disclose.
Decitabine (DAC) in combination with doxorubicin (DOX) and cyclophosphamide (CTX) in relapsed neuroblastoma (NBL): A Children's Oncology Group Study
Authors: George R. , Lahti J. , Ingle M. , Krailo M. , Blaney S. , Adamson P. , Murgo A. , Kidd V. , Diller L. 
Published: March 2020

9565 Background: Loss of caspase-8 expression causes resistance to apoptosis-inducing agents and potentiates metastasis in NBL. In vitro treatment of NBL cell lines with DAC results in increased caspase-8 expression and enhanced apoptosis following exposure to DOX. As a component of a pediatric phase 1 study, we evaluated low-dose DAC with DOX and CTX in a cohort of children with relapsed NBL. Promoter specific DNA methylation in peripheral blood mononuclear cells (PBMC) was studied. Methods: Patients received a 1-hour infusion of DAC, 5 mg/m2, daily on days 0–6, followed on day 7 by 45 mg/m2 of DOX (with dexrazoxane) and 1 g/m2 of CTX. All patients received G-CSF. Cycles were repeated every 28 days. Methylation-specific and quantitative PCR were used to measure promoter-specific DNA methylation in PBMC prior to and after DAC (day 7 and day 28). Results: Twelve patients with recurrent NBL (median age 9 years, 10 males) were enrolled. DAC/DOX/CTX was well tolerated with grade 4 myelosuppression being the predominant toxicity. Grade 4 neutropenia, median 11 days duration, occurred in 10 pts and grade 4 thrombocytopenia, median 10 days, in 7 patients. Eight patients had progressive disease after = 2 courses of therapy. The remaining 4 patients had stable disease with 5 to 8 courses. Methylation and subsequent demethylation (40–90% decreased methylation) of the MAGE-1 promoter was detected before and after DAC respectively, in PBMC from 6 of 9 patients analyzed to date. Re-expression of MAGE-1 mRNA was also demonstrated in post treatment samples. Caspase-8 demethylation was not detected in PBMC; nor was hypermethylation of caspase-8 detected in pre-treatment PBMC, possibly due to low tumor burden in blood. Conclusions: DAC in combination with cytotoxic chemotherapy was relatively well tolerated in heavily pre-treated children with relapsed NBL. Low-dose DAC induces demethylation and re-expression of MAGE-1 in PBMC, and may be a potential surrogate marker of demethylation within tumor cells. The use of low dose DAC in combination with other agents warrants further study in NBL. No significant financial relationships to disclose.
Phase I study of oral irinotecan and temozolomide in children with relapsed high-risk neuroblastoma: A New Approach to Neuroblastoma Therapy (NANT) Consortium study
Authors: Wagner L. M. , Villablanca J. G. , Stewart C. F. , Crews K. R. , O'Shaughnessy M. A. , Groshen S. , Reynolds C. P. , Park J. R. , Maris J. M. , Matthay K. K. 
Published: March 2020

9567 Background: Irinotecan (IRN) and temozolomide (TEM) have single-agent activity and schedule-dependent synergy against neuroblastoma. Because intravenous IRN is costly and inconvenient, especially with protracted scheduling common in pediatric trials, we sought to determine the maximum tolerated dose (MTD) of oral IRN combined with TEM in children with recurrent/resistant high-risk neuroblastoma, using the antibiotic cefixime to reduce IRN-associated diarrhea. Methods: Patients received oral TEM on days 1–5 and oral IRN on days 1–5 and 8–12, with courses repeated every 21 days. Oral cefixime 8 mg/kg (max 400 mg/day) was started on day -5 and continued daily. Results: Fifteen patients (median age 7 years, range 2–22) with a median of 3.5 previous treatment regimens were evaluable for toxicity and have to date received 71 courses (median 2, range 1–19+). Neutropenia and thrombocytopenia were dose-limiting in the first 6 patients, and TEM was reduced from 100 to 75 mg/m2/day for all subsequent patients. IRN was then escalated from 30 to 60 mg/m2/day. First-course grade 3 diarrhea was dose-limiting in 1 of 6 patients treated at the IRN MTD of 60 mg/m2/day. Other toxicities were mild and reversible. No grade 4 therapy-related toxicity occurred in 27 courses administered at the MTD. The median SN-38 lactone AUC at this dose was 72 ng*hr/ml, similar to that reported with protracted intravenous IRN at the single-agent MTD. Of 14 patients evaluable for response, one with measurable nodal disease had a very good partial response through 6 courses. Six additional patients had stable disease for a median of 7.5 courses (range 6–19+). Two patients remain on study after 10 and 19 courses. Conclusions: This combination was well tolerated in heavily-pretreated children with resistant neuroblastoma, and 7 (50%) of 14 evaluable patients had response/stable disease for 6 or more courses in this Phase I trial. This all-oral regimen was feasible and resulted in favorable SN-38-lactone exposures. The dose recommended for further study in this patient population is TEM 75 mg/m2/day plus IRN 60 mg/m2/day when given with cefixime. No significant financial relationships to disclose.
A phase I trial of vorinostat in children with refractory solid tumors: A Children's Oncology Group Study
Authors: Fouladi M. , Park J. , Sun J. , Fraga C. , Ames M. M. , Stewart C. F. , Gilbertson R. J. , Zweibel J. , Adamson P. C. , Blaney S. M. 
Published: March 2020

9569 Background: Vorinostat, an orally administered histone deacetylase inhibitor, has potent antitumor activity against human cell lines in vitro (IC50 0.5 to 5 μM) and in xenograft models. A phase I trial of vorinostat was conducted in children with recurrent or refractory solid tumors to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) of vorinostat, and to assess accumulation of histone acetylation in peripheral blood mononuclear cells (PBMCs). Methods: Vorinostat was administered once daily at dose levels of 180, 230, and 300 mg/m2/d. Courses were 28 days in duration, without interruption. PK analysis was performed during the 1st course. Vorinostat's ability to induce acetyl-histone (H3) accumulation in vivo was studied by western blot analysis. Results: 30 patients, 17 males, median age 15 years (range 4–21), were enrolled; 24 patients were fully evaluable for toxicity. At 180 mg/m2/d, 1/6 pts developed DLT (deep vein thrombosis) and at 230 mg/m2/d 1/6 pts developed DLT (hypokalemia). At 300 mg/m2/d, DLTs consisted of reversible hypokalemia (n=1), neutropenia (n=1) and thrombocytopenia (n=2), defining the MTD as 230 mg/m2/d. Other non-dose limiting grade 3 or 4 toxicities included elevated ALT/AST, hyperbilirubinemia, leucopenia, and lymphopenia. Western blot analysis of PBMC protein isolates found clear evidence of dose- dependent accumulation of acetylated H3 histones. 1 patient with a spindle cell sarcoma received 8 courses and 1 patient with a low-grade astrocytoma had an unconfirmed minor response. Conclusions: Vorinostat is well tolerated in children with recurrent or refractory solid tumors and inhibits histone deacetylase activity in PBMC. The recommended phase II dose for children with solid tumors is 230 mg/m2/d. No significant financial relationships to disclose.
Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine (PCG) and gemcitabine/cisplatin (GC) in patients with locally advanced (LA) or metastatic (M) urothelial cancer without prior systemic therapy; EORTC30987/Intergroup Study
Authors: Bellmunt J. , von der Maase H. , Mead G. M. , Heyer J. , Houede N. , Paz-Ares L. G. , Winquist E. , Laufman L. R. , de Wit R. , Sylvester R. 
Published: March 2020

LBA5030 Background: GC is a standard alternative to M-VAC for LA/M urothelial cancer (UC) based on comparable efficacy and a more favorable toxicity profile. Based on a phaseII trial, it has been suggested that the PCG triplet might provide improved response and survival. To evaluate the role of paclitaxel when added to GC, a randomized, international study (EORTC30987/Intergroup Study) comparing GC with PCG in LA/M UC was initiated in 2001, with the main endpoint being overall survival (OS). Methods: Chemo naive patients with histologic evidence of LA or M transitional UC, with GFR>60ml/min were eligible. After stratification for institution, PS(WHO 0–1) and presence/absence of metastatic disease, patients were randomized to receive PCG(armA) or GC(armB). PCG treatment included: paclitaxel(P) 80mg/m2 d1&8, cisplatin(C) 70mg/m2 d1 and gemcitabine(G) 1000mg/m2 d1&8, every 21d. GC: C70mg/m2 d1 or 2, G1000mg/m2 d1,8,15 every 28d. To detect an increase in median survival from 14 to 18m(HR=0.778) based on a two sided logrank test at error rates a=0.05 and β=0.20, 498 deaths were required. The planned sample size was of 610 pts. Results: From June 01 to May 04, 627pts (82% primary bladder) were included, (312 PCG, 315 GC). Median age was 61y with 81% males and similar baseline prognostic characteristics on both arms. PS 1 in 47%PCG and 46%GC pts. On PCG 47% had visceral and 83% M; on CG 49%-83% respectively. Overall response rate (RR): 57,1% for PCG (CR15%) and 46,4% for GC (CR10%), p=0.02. Median PFS: 8.4m and 7.7m for PCG and GC, p=0.10. 478 pts have died; the EORTC IDMC has released the study because the required number of events will occur prior to presentation. Median survival is 15.7m for PCG and 12.8m for CG, with no significant difference in OS (p=0.10, HR0.86, CI95% 0.72–1.03, p=0.12 adjusted for risk factors). Both treatments were overall well tolerated, with more thrombopenia and bleeding on GC (12%vs7%) and more febrile neutropenia on PCG (13%vs4%). Conclusions: This large, multicenter, Phase III study shows that PCG provided a better RR when compared with GC in LA/M UC; however the predefined endpoint for PFS and OS improvement was not reached. [Table: see text]
Hypofractionation for early breast cancer: First results of the UK standardization of breast radiotherapy (START) trials
Authors: Dewar J. A. , Haviland J. S. , Agrawal R. K. , Bliss J. M. , Hopwood P. , Magee B. , Owen J. R. , Sydenham M. A. , Venables K. , Yarnold J. R. 
Published: March 2020

LBA518 Background: The START Trials (ST-A and ST-B) test the hypothesis that breast cancer is as sensitive to fraction (Fr) size as late reacting normal tissues, with an a/β value of about 4Gy. Methods: The phase III randomised START Trials tested hypofractionated post-operative RT in women with completely excised invasive breast cancer (T1–3, N0–1, M0). Centres opted for either ST-A or ST-B. ST-A tested 50Gy in 25Fr (5 wks) vs 41.6Gy vs 39Gy, both in 13Fr (5 wks). ST-B tested 50Gy in 25Fr (5 wks) vs 40Gy in 15Fr (3 wks). Stratification was by centre, surgery and boost. The primary endpoint was local-regional (LR) relapse. Late normal tissue effects (NTE) were assessed by breast photographs, clinical examination and quality of life (QL) questionnaires. Survival analysis methods were used to estimate rates of relapse and NTEs, and hazard ratios (HR) (with 95%CI). Smoothed estimates of absolute differences in relapse rates were obtained from the rates in the 50Gy control arms and the HR. Results: 2236 (ST-A) and 2215 (ST-B) patients were recruited from 35 UK centres during 1999–2002. Median follow-up is 5.1 years (ST-A) and 6.0 years (ST-B). There were 93 LR relapses in ST-A (4.1% at 5 years, 3.2- 5.0%), with absolute differences in LR relapse rates at 5 years compared with 50Gy of 0.2% (−1.3%−2.6%) for 41.6Gy and 0.9% (−0.8%−3.7%) for 39Gy. The a/β estimate for tumour control was 5.0Gy (−2.7–12.7). In ST-B, there were 65 LR relapses (2.8% at 5 years, 2.1–3.5%), with an absolute difference in LR relapse rates at 5 years of −0.6% (−1.7%−0.9%) for 40Gy vs 50Gy. In ST-A the rate of mild/marked change in photographic breast appearance was lower in 39Gy vs 50Gy (HR 0.69, 0.52–0.91), and similarly for 40Gy vs 50Gy in ST-B (HR 0.83, 0.66–1.04). The a/β estimate for change in breast appearance was 3.1Gy (1.6–4.6). Rates of induration, telangiectasia and breast oedema were lower in 39Gy (ST-A) and 40Gy (ST-B) compared with the 50Gy arms. QL results were consistent with the clinical findings. Conclusions: The fractionation sensitivity of breast cancer is comparable to that of late reacting normal tissues, confirming the results of a recent pilot trial. These results support the use of hypofractionated RT schedules for early breast cancer. No significant financial relationships to disclose.
Phase 3 Study: Canfosfamide (C, TLK286) plus carboplatin (P) vs liposomal doxorubicin (D) as 2nd line therapy of platinum (P) resistant ovarian cancer (OC)
Authors: Rose P. , Edwards R. , Finkler N. , Seiden M. , Duska L. , Krasner C. , Cappuccini F. , Kolevska T. , Brand E. , Brown G. , Runowicz C. 
Published: March 2020

LBA5529 Background: Canfosfamide (C) is a novel glutathione analog prodrug activated by glutathione S-transferase P1–1. C has single agent activity in P resistant OC and is synergistic with P. Methods: Pts with P resistant OC following ≤ 2 P regimens, measurable disease (RECIST) were eligible. Pts received C (750 mg/m2) and P (AUC 5) or D (50 mg/m2) IV q4wks until progression. Randomization was stratified by ECOG PS, best prior P response and bulky disease (≥ 5cm). Results: All 247 P refractory or resistant pts received 505/494 cycles median 3 (range 1–17), CP/D respectively. Most common toxicities for CP were hematologic and as expected for each drug alone. By independent radiologic review (IRR), 25% of pts discontinued treatment without documented progression. Overall ORR varied between clinician and IRR assessments. Overall median PFS was 3.5 mos for both CP and D. Overall median survival (MS) has not been reached. Planned analysis of the effect of time from last P dose to study treatment (TFP; not from time of recurrence) identified a P resistant subgroup for TFP ≥ 6 mos (med 7.1) [ Table ]. Subgroup ORR for CP was 31.6% vs 10.5% for D. Subgroup median PFS for CP has not been reached vs 3.5 mos for D (p=0.0099). Subgroup MS for CP has not been reached vs 11.1 mos for D(p=0.0014). Subgroup CP had superior QOL outcomes per FACIT-FACT-O. Conclusions: Primary endpoint of overall PFS was comparable. Subgroup TFP ≥ 6 mos reported large differences in ORR and QOL and statistical significance in PFS and survival for CP. OC trials with C in combination with other standard agents are in progress. [Table: see text] [Table: see text]
Retrospective analysis of outcomes among more than 1,000 patients with newly diagnosed anaplastic oligodendroglial tumors
Authors: Lassman A. B. 
Published: March 2020

2014 Background: Treatment of anaplastic oligodendroglial tumors is controversial. Early results of randomized trials suggest chemotherapy (CT) with procarbazine-lomustine-vincristine (PCV) before or after radiotherapy (RT) improves progression-free but not overall survival (OS) versus RT alone. It is unknown if CT alone affects outcome versus CT&RT, or if temozolomide (TMZ) compares favorably with PCV. Methods: We retrospectively identified adults with newly diagnosed anaplastic oligodendroglioma (AO) or oligo-astrocytoma (AOA) seen at 17 medical centers from 1981–2007 exclusive of phase III or bone marrow transplant trials. Data were updated January 1, 2009. Survivals were estimated by Kaplan-Meier method and compared with log-rank. Results: There were 1054 patients: 594 men, 460 women; median age 42 (18–88); 661 with AO, 443 with AOA. Treatment was: observation (82, 8%), RT alone (n = 210, 20%), RT then chemotherapy (283, 27%), RT + CT concurrently (118, 11%), CT alone (205, 19%), CT then RT (137, 13%), or other (19, 2%). Median time to progression (TTP) and OS were 2.8 and 6.5 years, respectively, with median follow up of 4.1 years (0.03–20.8) on surviving patients (n = 560, 53%). 1p19q co-deletion was observed in 292 (48%) and no deletion in 232 (38%) of 606 tested tumors. Co-deletion predicted longer median TTP (4.2 vs. 1.8 years for no deletion, p = 0.0002) and OS (8.4 vs. 3.3 years, p < 0.0001). Median TTP was longer following CT&RT (sequential or concurrent) than CT alone (3.7 vs. 2.6 years, p = 0.0007), but median OS did not differ (6.6 vs. 7.1 years, p = 0.8); co-deletion was more common with CT alone than CT&RT (p < 0.0001, χ2), although restricting analysis of CT&RT versus CT to the co-deletion cohort yielded analogous results (median TTP 7.2 vs. 3.8 years, p = 0.011; OS 7.9 vs. 10.4 years, p = 0.26). Median TTP was longer following PCV alone (7.6 years, n = 17) than TMZ alone (3.3 years, n = 65) with co-deletion (p < 0.02); median OS was also longer (not reached, vs. 7.1 years), but did not reach statistical significance (p = 0.07 log-rank). Conclusions: 1p19q co-deletion predicted improved outcome. Treatment strategies varied widely. CT alone did not appear to shorten OS versus CT&RT. PCV may be superior in efficacy to TMZ. Multivariate analyses and additional 1p19q testing are in progress. [Table: see text]
Pilot study of NKTR214 and nivolumab in patients with sarcomas.
Authors: D'Angelo Sandra P. , Conley Anthony Paul , Kelly Ciara Marie , Dickson Mark Andrew , Gounder Mrinal M. , Chi Ping , Keohan Mary Louise , Livingston J. Andrew , Patel Shreyaskumar , Adamson Travis , Kiesler Hannah , Biniakewitz Matthew , Phelan Haley , Condy Mercedes M. , Agaram Narasimhan P , Qin Li-Xuan , Erinjeri Joseph Patrick , Hwang Sinchun , Tap William D. 
Published: March 2020

11010 Background: Monotherapy checkpoint inhibitors have minimal efficacy in most patients with metastatic sarcoma. NKTR-214 is a CD122-preferential IL-2 pathway agonist that activates and expands natural killer and CD8+ T cells. Phase I/II data demonstrated the safety and efficacy of nivolumab plus NKTR-214 in multiple tumor types. A trial of NKTR-214 plus nivolumab was initiated in patients with selected sarcomas. Methods: This is a multi-center pilot study enrolling patients (pts) failing prior regimens within 9 cohorts: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), chondrosarcoma (CS), osteosarcoma (OS), angiosarcoma (AS), alveolar soft part sarcoma (ASPS), synovial sarcoma/small blue round cell and other. Pts received NKTR 0.006mg/kg with nivolumab 360 mg every 3 weeks. Primary endpoint was objective response rate (ORR), secondary endpoints were adverse events (AEs), progression-free, overall survival (PFS,OS) and clinical benefit rate (CBR.) Pre/on treatment biopsies performed on patients for correlative studies including PD-L1 expression and TIL characterization by immunohistochemistry, whole exome sequencing and RNAseq. Results: Enrollment completed with 10 patients in cohorts below. 50 pts enrolled (median age 58, range 14-80), 54% female. Median follow-up time is 13m. 50% of patients were refractory ≥3 lines of therapy. Grade 3/4 treatment related adverse events occurred in 26% of patients. 2% of patients stopped due to AEs. Median time to response was 3.6m. Responses seen in LMS, UPS, dedifferentiated CS; on-going in UPS/CS. Prolonged disease stability in DDLPS. 6 patients remain on treatment. Conclusions: Nivolumab plus NKTR-214 was safe and tolerable in heavily pre-treated and refractory sarcoma patients. Responses were protracted overtime; on-going in UPS and dedifferentiated CS. Prolonged disease stability seen in DDLPS in patients. All correlative analyses are in progress and will be presented. Enrollment continues with plans to add a treatment naïve cohort. Clinical trial information: NCT03282344. [Table: see text]