Daily Continuous Infusion Research Articles

Phase III randomized trial comparing neoadjuvant paclitaxel+platinum to 5-fluorouracil+platinum in esophageal/GEJ squamous cell carcinoma.

Standard neoadjuvant chemotherapy (NACT) for locally advanced esophageal/gastroesophageal junction squamous cancer (LAEGSC), 5-fluorouracil (5FU)+platinum, is toxic and logistically challenging; alternative regimens are needed. Phase III randomized open-label non-inferiority trial at Tata Memorial Center, India, in resectable LAEGSC. Patients were randomized 1:1 to three cycles of 3-weekly platinum (cisplatin 75 mg/m2 or carboplatin AUC 6) with paclitaxel 175 mg/m2 (day 1) or 5FU 1000 mg/m2 continuous infusion (days 1-4), followed by surgery. Between August 2014 and June 2022, we enrolled 420 patients; 210 to each arm. Significantly more patients on paclitaxel + platinum (194 (92.3%)] received all 3 chemotherapy cycles than on 5FU+platinum (170 [85.9%]), P = .009. 5FU + platinum caused more grade ≥ 3 toxicities (124 [69.7%]) than paclitaxel + platinum (97 [51.9%]), P = .001. Surgery was performed in 131 (62.4%) patients on 5FU + platinum vs 139 (66.2%) on paclitaxel + platinum, P = .415. Paclitaxel + platinum resulted in higher pathologic primary tumor clearance (33 [25.8%]) vs 17 [15%]; P = .04), and pathologic complete responses in 21.9% compared to 12.4% from 5FU + platinum, P = .053. Median OS was 27.5 months (95% CI, 18.6-43.5) from paclitaxel + platinum, which was non-inferior to 27.1 months (95% CI, 18.8-40.7) from 5FU + platinum; HR, 0.89 (95% CI, 0.72-1.09); P = .346. Neoadjuvant paclitaxel + platinum chemotherapy is safer, and results in similar R0 resections, higher pathologic tumor clearance and non-inferior survival, compared to 5FU + platinum. Paclitaxel + platinum should replace 5FU + platinum as NACT for resectable LAEGSC. CTRI/2014/04/004516.

Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma.

Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES. TK216 was administered intravenously as a continuous infusion to patients with R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators' choice. The trial used a 3 + 3 design with an expansion cohort at the recommended phase II dose (RP2D). A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11. TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.

Prolonged 14-day continuous infusion of high-dose ifosfamide for patients with relapsed and refractory high-grade osteosarcoma: a retrospective multicentre cohort study

BackgroundThe prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting.Patients and methodsThe study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5.ResultsThe trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3–4 non-haematological toxicities.Conclusions14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

Combination therapy with the oncolytic virus CF33-CD19 and blinatumomab for the treatment of advanced solid tumors.

TPS2687 Background: CF33-CD19 is a novel chimeric vaccinia virus that selectively replicates in tumor cells and can provoke anti-tumor immunity. CF33-CD19 expresses a truncated and non-signaling CD19 protein on the surface of infected tumor cells before virus-mediated tumor lysis, labeling them for CD19-targeted therapies. Preclinical studies with CF33-CD19 have shown that combination therapy with CD19 targeting chimeric antigen receptor T cells is more effective than either monotherapy in murine xenograft and syngeneic models [1]. Likewise, combination therapy with bispecific T-cell engagers (BiTE)s that bind CD3-positive T cells and infected solid tumor cells that express de novo CD19, showed pronounced recruitment of T cells to the tumor microenvironment, resulting in tumor growth inhibition in mouse models. CD19xCD3 targeting BiTEs such as blinatumomab may offer an off-the-shelf alternative to adoptive cell therapies. This phase I study, called OASIS, dose escalates CF33-CD19 administered intravenously (IV) or intratumorally (IT) combined with blinatumomab in adults with advanced or metastatic solid tumors. Methods: The OASIS study (NCT06063317) is enrolling patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy. Patients who have received prior treatment with a poxvirus based oncolytic virus or a bispecific CD19-directed CD3 T-cell engager are excluded. A safety run-in will evaluate the safety of CF33-CD19 monotherapy administered IT or IV before initiating the combination therapy regimen. Combination therapy will be administered in 28-day cycles with CF33-CD19 on days 1 and 15. Following viral transduction to promote de novo CD19 expression, blinatumomab is given on days 2-9 and 16-23 via a 7-day continuous infusion. Patients > 45 kg will receive 9 mcg of blinatumomab during the first week of cycle 1, then 28 mcg during the third week of cycle 1 and subsequent cycles. The study consists of two parts. Part 1 follows a 3+3 dose escalation scheme independently of each route of CF33-CD19 administration (IT and IV) with dose levels of CF33-CD19 ranging from 1.0x107 to 3.0x109 PFU. Part 2 is a cohort expansion in select indications at the optimal dose. The co-primary endpoints are safety and identification of the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST. Enrollment began in October 2023. 1. Park et al. Sci Transl Med. 2020 Sep 2;12(559):eaaz1863. doi: 10.1126/scitranslmed.aaz1863. PMID: 32878978. Clinical trial information: NCT06063317 .

A Phase II Study About Efficacy and Safety of the Continuous IntraVenous Infusion of Ketamine as Adjuvant to Opioids in Terminally Ill Cancer Patients With Refractory Cancer Pain (CIVIK Trial).

Ketamine has been used to control refractory cancer pain as an adjuvant to opioids. We conducted a prospective phase II study to investigate the efficacy and safety of 5-day continuous intravenous infusion (CIVI) of Ketamine in terminally ill cancer patients with refractory cancer pain. Hospitalized terminally ill cancer patients with refractory cancer pain were enrolled. Refractory cancer pain was indicated by requirements for 4 or more rescue opioids or pain intensity using numerical rating scale > personalized pain goal (PPG) despite of intravenous morphine equivalent daily dose (IV MEDD) ≥ 120mg/day. The CIVI of ketamine was increased from .05mg/kg/hour to .5mg/kg/hour by .05 every 8 hours if pain intensity exceeded PPG or if number of rescue opioids ≥2 during prior 8 hours was required. The primary end-point was overall pain response rate, which indicates complete response (both rescue opioid ≤3/day and pain intensity ≤ PPG) plus partial response (rescue opioid ≤3/day), without unacceptable toxicities. Among 21 eligible patients enrolled between September 2019 and January 2023, 20 were analyzed. Most pain mechanisms were mixed type (n = 15, 75%), with neuropathic component (n = 17, 85%). The baseline background opioids were IV MEDD 186mg/24hour (range, 124-592), number of rescue opioids was 6 (IQR, 5-9), and median PPG was 4 (IQR, 3-4). The overall pain response rate was 50% (n = 10) including 40% (n = 8) for complete pain response and 10% (n = 2) for partial pain response. This study showed efficacy of gradually increasing CIVI of ketamine for terminally ill cancer patients with refractory cancer pain. CIVI of ketamine could be a useful tool in these patients considering the limited treatment options. (NCT03362073, Initial Release: November 15, 2017).

The efficacy and safety of continuous intravenous infusion of rh-endostatin combined with platinum-based doublet chemotherapy for advanced non-small-cell lung cancer

BackgroundPlatinum-based doublet chemotherapy is commonly used in the treatment of non-small cell lung cancer (NSCLC). A growing body of evidence indicates that incorporating antiangiogenic agents into platinum-based chemotherapy may enhance the survival outcomes for NSCLC patients. However, the optimal administration protocol for intravenous recombinant human endostatin (rh-endostatin), an antiangiogenic agent, remains uncertain at present.AimThis study aims to investigate the efficacy and safety of 5-d continuous intravenous infusion of rh-endostatin in combination with chemotherapy for patients with advanced NSCLC. The predictive biomarkers for this treatment regimen were further probed.MethodsThis prospective, single-arm multicenter study enrolled a total of 48 patients with advanced NSCLC who were histologically or cytologically confirmed but had not received any prior treatment from January 2021 to December 2022. Prior to the chemotherapy, these patients received a continuous intravenous infusion of rh-endostatin (210 mg) over a period of 120 h, using an infusion pump. The chemotherapy regimen included a combination of platinum with either pemetrexed or paclitaxel, given in 21-day cycles. The primary endpoint of the study was median progression-free survival (mPFS), and the secondary endpoints included median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and assessment of adverse events (AEs).ResultsThe mPFS was 6.5 months (95% confidence interval (CI): 3.8–9.1 m) while the mOS was 12.3 months (95% CI: 7.6–18.5 m). The ORR and DCR was 52.1% and 75.0%, respectively. Leukopenia (52.1%), anemia (33.3%), and thrombocytopenia (20.8%) were the most common adverse effects and these toxicities were deemed acceptable and manageable. In addition, a correlation was noted between elevated serum carcinoembryonic antigen (CEA) levels and decreased PFS and OS.ConclusionsThe incorporation of a 5-day continuous intravenous infusion of rh-endostatin into platinum-based doublet chemotherapy has demonstrated both safety and efficacy in the treatment of advanced NSCLC. Furthermore, the baseline serum levels of CEA may potentially function as a predictor for the efficacy of rh-endostatin when combined with chemotherapy in NSCLC patients.ClinicalTrials.govNCT05574998.

Short-Term Blinatumomab As a Bridge Therapy for Hematopoietic Stem Cell Transplantation in B-Cell Acute Lymphoblastic Leukemia with Low Leukemia Burden

Introduction The influence of pre-transplant leukemic load on relapse and long-term survival is well-documented among patients with B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab, a bispecific T cell engager, has shown promising results as an effective treatment for relapsed B-ALL. However, the dosage (28μg/day) and duration (28 days of continuous infusion) of blinatumomab have been predominantly determined in a relapsed leukemia context. Therefore, in the minimal residual disease (MRD) scenario, the standard dosing may exceed the required amount, potentially leading to increased toxicity, delays in transitioning to the scheduled transplant, and superfluous economic expenditure. Methods We enrolled B-ALL patients with ≤10% MRD who were slated for allogeneic hematopoietic stem cell transplantation (ASCT). MRD was quantified via multi-parameter flow cytometry or polymerase chain reaction (PCR) for the target gene. Blinatumomab therapy began at 8 μg/day, gradually escalating to 28 μg/day over only 5-10 days. Bone marrow cells were harvested post-blinatumomab therapy. Upon acquiring MRD negativity, patients proceeded to the transplantation protocol. All patients underwent myeloablative conditioning with chidamide, fludarabine, cytarabine, and busulfan. Peripheral stem-cell grafts were harvested from HLA-matched sibling donors (MSD), matched unrelated donors (MUD), or haploidentical donors (HID). Post-transplantation acute GVHD prophylaxis consisted of cyclophosphamide and cyclosporine. For HID transplant recipients, mycophenolate mofetil was added from day +5 to day +35. Follow-up examinations were scheduled at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results Our study cohort comprised 20 patients (13 females, 7 males), median age 35.5 years (range 15-58). Patient and disease characteristics are summarized in Table 1. During the blinatumomab therapy, 8 patients (40%) experienced grade 1 cytokine release syndrome (CRS), and 1 patient (5%) experienced grade 2 CRS, with no instances of grade 3 or higher CRS observed. All patients achieved complete remission (CR) and MRD clearance evaluated by flow cytometry following blinatumomab treatment. Eleven patients were diagnosed with Philadelphia chromosome-positive ALL, and 5 of them didn't achieve MRD clearance evaluated by PCR. Allo-SCT was conducted following blinatumomab at a median interval of 5.5 days (range 1-29) using MSD in 4 patients, MUD in 2 patients, and HID in 14 patients. The median time to neutrophil and platelet engraftment was 12 days (range 9-17) and 13 days (range 9-28), respectively. The median follow-up duration was 10.2 months (range 2-21.7). By day +30 post-ASCT, all patients achieved CR and MRD clearance with full donor chimerism. Acute GVHD (aGVHD) (grades II-IV) and (grades III-IV) incidences were recorded at 10.0% and 5.3% respectively (Figure 1A). One fatality occurred due to COVID-19-associated pulmonary aspergillosis 7.2 months post-transplantation. Among the 18 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) was 44.4%, with no instances of severe cGVHD observed (Figure 1B). No patient relapsed at the last follow-up on July 31, 2023. The estimated 1-year progression-free survival (PFS) and overall survival (OS) both stood at 90% (Figure 1C). Conclusion Short-term blinatumomab as a bridging therapy for adult patients with low-burden B-ALL transitioning to ASCT demonstrates comparable efficacy to standard dosing regarding disease control and survival outcomes.

THU520 Successful Treatment Of Ectopic ACTH From Metastatic Gastrinoma With Temozolomide Monotherapy

Abstract Disclosure: A. Syeda: None. A. Khan: None. D. Larosa: None. P. Kunz: None. B. Esayag-Tendler: None. Background: Temozolomide is a promising therapeutic agent for the treatment of refractory ACTH-secreting pituitary tumors. However, its role in the management of ectopic ACTH secretion due to neuro endocrine tumors (NETs) has not been well elucidated. Case: A 46-year-old man with a refractory functional pancreatic NET/ high grade metastatic gastrinoma, post distal pancreatectomy and splenectomy, briefly on everolimus therapy, presented with altered mentation and worsening edema. Clinically he had proximal muscle weakness, anasarca and hypokalemia with a potassium of 2.8mmol/L (n:3.6-5.1 mmol/L). Further work up revealed AM cortisol 79.6 ug/dL (n:7-23 ug/dL), 24-hour urine cortisol was 1820 ug/d (n: < 60 ug/d), ACTH 807 pg/mL (n:7.2-63.3 pg/mL) and gastrin level >10,000 pg/mL (n:0-100 pg/mL). Imaging studies of the brain, chest, abdomen, and pelvis were unremarkable. Octreotide infusion at 100 mg/hour was started with a goal to decrease gastrin and ectopic ACTH production. There was no response to Octreotide even after 5 days of continuous infusion, hence it was switched to subcutaneous injection form to control diarrhea. Lutathera/Peptide receptor radionuclide therapy was considered but held off due to the patient's delirium. As hypercortisolism is associated with multiple risks including thromboembolic events, rapid reduction of cortisol biosynthesis was achieved with Ketoconazole. Other options to inhibit steroidogenesis were available; the goal was to decrease both ACTH and Gastrin levels and for this reason Temozolomide was started. It crosses the blood-brain-barrier and hence was a preferred agent in this patient as he was noted to have atypical cells in the CSF. He received Temozolomide 150 mg/m² for 5 days of a 28-day cycle. Subsequently, AM cortisol decreased to 3.4 ug/dL, ACTH and gastrin started to trend down to 144 pg/mL and 3505 pg/mL respectively. Thereafter, the patient was given steroids and ketoconazole as part of a block and replace strategy to avoid adrenal insufficiency and hypercortisolism respectively. Temozolomide was very well tolerated; there were different reasons to hold Capecitabine including severe thrombocytopenia. Bilateral adrenalectomy was discussed but deferred as the ACTH levels decreased. Clinically, the patient reported improved muscle strength, edema and weight decreased significantly. The hospital stay was complicated by several other comorbidities which were managed appropriately by a multidisciplinary approach. Conclusion: Temozolomide should be considered in ACTH producing NETs refractory to conventional treatment strategies. Presentation: Thursday, June 15, 2023

Impact of the implementation of a sedation and analgesia protocol in a pediatric intensive care unit.

Introduction. Adequate sedation and analgesia is essential in the management of patients requiring mechanical ventilation (MV). The implementation of protocols and their monitoring is recommended; mixed results on adherence and impact have been reported. Objectives. To assess the impact of the implementation of a sedation and analgesia protocol on the use of benzodiazepines, opioids, and evolution in the pediatric intensive care unit (PICU) in patients requiring MV for more than 72 hours. Methods. Before-and-after, uncontrolled study in the PICU of a children’s hospital. The study was developed in 3 stages: pre-intervention for situational diagnosis (from April to September 2019), intervention,and post-intervention for implementation of a sedation and analgesia protocol, education on use, and monitoring of adherence and impact (from October 2019 to October 2021). Results. A total of 99 and 92 patients were included in the study in the pre- and post-intervention stages, respectively. Patients had a more severe condition, were younger, and had a lower weight in the preintervention period. After adjusting for severity and age, the group comparison in the post-intervention stage showed a reduction in days of continuous infusion of opioids (6 ± 5.2 versus 7.6–5.8, p = 0.018) and days of continuous infusion of benzodiazepines (3.3 ± 3.5 versus 7.6 ± 6.8, p=0.001).Nosignificantdifferences were observed in days of MV and total days of benzodiazepine use. Conclusion. The implementation of a sedation and analgesia protocol resulted in a reduction in the use of continuous infusion of drugs.

Prolonged 14-day continuous infusion of high-dose ifosfamide (14IFO) for relapsed/refractory high-grade osteosarcoma (R/R HOS): A retrospective multicenter cohort study.

11534 Background: The prognosis of patients (pts) with relapsed/refractory (R/R) High-Grade Osteosarcoma (HOS) remains dismal without an agreement on systemic therapy. The use of 14IFO with an external pump in outpatient setting (1g/sqm/day x 14 days every 21) in R/R HOS pts is limited. This is the first retrospective cohort study focused on 14IFO activity and toxicity in this setting (NCT04651569). Methods: Five Centers of the Italian Association of Pediatric Onco-Hematology and Italian Sarcoma Group participated to the study. Primary aim is to investigate 14IFO activity in pts with R/R HOS younger than 40 years. Secondary aim is to evaluate toxicity, according to CTCAE v.5, and clinical benefit. Progression Free Survival (PFS) and Overall Survival (OS) analysis are performed using the Kaplan Meier method with 95% confidence interval (CI). Results: Between 2012 and 2021, 26 R/R HOS pts were treated with 14IFO (median follow-up: 17,5 months, range: 4,6 – 83 months). Median age is 19 years at the beginning of 14IFO; eleven pts (42%) are ≤ 18 years. Three pts (12%) have a localized HOS, twelve pts (46%) have pulmonary disease only and eleven pts (42%) have a pluri-metastatic HOS. Eleven pts (42%) have a relapsed HOS with a median disease-free interval (DFI) of 13 months before 14IFO, the remaining (58%) have a refractory disease to two or more treatments. Overall, thirteen pts (50%) receive 14IFO as second line therapy and fifteen pts (57%) are pre-treated with Ifosfamide in first line. Disease Control Rate is 57,5% (5 Partial Response + 10 Stable Disease). Seven pts (27%) receive a local treatment after 14IFO (5 surgery, 1 Radiotherapy (Rt), 1 Carbon Ion Rt). The median PFS is 4,1 months (95% CI 2.13, 7.37). 6-month and 1-year PFS are 38% (95% CI 24-63) and 8% (95% CI 2-29), respectively. The median OS is 13.7 months (95% CI 10.6 – 23.7). 1-year and 2-year OS are 51% (95% CI 35-75) and 22% (95% CI 9.5-49), respectively. Relapsed pts have both longer median PFS and OS compared to pts with a refractory disease [PFS: 7.33 months vs 2.13 months (p = 0.02); OS: 19.4 months vs 10.7 months (p = 0.1)]. Sixteen pts (61%) receive at least 4 cycles and an amount of 101 cycles are evaluated for toxicity. Grade 4 hematological toxicity is reported in 15 cycles (14,8%) as follows: i) white-blood cell decrease in 6 cycles (6%); ii) neutropenia in 7 cycles (7%); iii) thrombocytopenia in 2 cycles (2%). One patient has one episode of febrile neutropenia. No grade 3-4 non hematological toxicities are reported. Conclusions: This trial shows a non inferiority activity of 14IFO compared to other treatments in this setting, despite the small number of pts. Therefore, 14IFO should be considered as a treatment option in R/R HOS, especially for its well tolerated toxicity profile and the home-administration that improve patient’s quality of life and it could significantly reduce cancer care cost. Clinical trial information: NCT04651569 .

Pilot dose-ranging of rhIGF-1/rhIGFBP-3 in a preterm lamb model of evolving bronchopulmonary dysplasia.

Low levels of insulin-like growth factor-1 (IGF-1) protein in preterm human infants are associated with bronchopulmonary dysplasia (BPD). We used our preterm lamb model of BPD to determine (1) dosage of recombinant human (rh) IGF-1 bound to binding protein-3 (IGFBP-3) to reach infant physiologic plasma levels; and (2) whether repletion of plasma IGF-1 improves pulmonary and cardiovascular outcomes. Group 1: normal, unventilated lambs from 128 days gestation through postnatal age 5 months defined normal plasma levels of IGF-1. Group 2: continuous infusion of rhIGF-1/rhIGFBP-3 (0.5, 1.5, or 4.5 mg/kg/day; n = 2) for 3 days in mechanically ventilated (MV) preterm lambs determined that 1.5 mg/kg/day dosage attained physiologic plasma IGF-1 concentration of ~125 ng/mL, which was infused in four more MV preterm lambs. Group 1: plasma IGF-1 protein increased from ~75 ng/mL at 128 days gestation to ~220 ng/L at 5 months. Group 2: pilot study of the optimal dosage (1.5 mg/kg/day rhIGF-1/rhIGFBP-3) in six MV preterm lambs significantly improved some pulmonary and cardiovascular outcomes (p < 0.1) compared to six MV preterm controls. RhIGF-1/rhIGFBP-3 was not toxic to the liver, kidneys, or lungs. Three days of continuous iv infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/kg/day improved some pulmonary and cardiovascular outcomes without toxicity. Preterm birth is associated with rapid decreases in serum or plasma IGF-1 protein level. This decline adversely impacts the growth and development of the lung and cardiovascular system. For this pilot study, continuous infusion of optimal dosage of rhIGF-1/rhIGFBP-3 (1.5 mg/kg/day) to maintain physiologic plasma IGF-1 level of ~125 ng/mL during mechanical ventilation for 3 days statistically improved some structural and biochemical outcomes related to the alveolar formation that would favor improved gas exchange compared to vehicle-control. We conclude that 3 days of continuous iv infusion of rhIGF-1/rhIGFBP-3 improved some physiological, morphological, and biochemical outcomes, without toxicity, in mechanically ventilated preterm lambs.

LOCL-07 LOCO-REGIONAL INFUSION OF GB-13 (IL13.E13K-PE4E) AS A POTENTIALLY PROMISING TREATMENT FOR RECURRENT HIGH-GRADE GLIOMA

INTRODUCTIONHigh grade gliomas (HGG) are devastating diseases with largely unchanged survival outcomes despite decades of research. Recent studies suggest the interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is selectively upregulated in up to 80% of HGG, including glioblastoma (GBM) and diffuse midline gliomas (DMG) harboring H3K27 alterations. Immunotoxins targeting IL-13Rα2 have been demonstrated as safe and have shown some benefit for patients with HGG in previous phase I/II and III clinical trials. We hypothesized that by using GB-13 (IL13.E13K-PE4E), a novel peptide-toxin that binds IL-13Rα2 with high specificity and possesses a Pseudomonas exotoxin moiety, we would enhance the anti-tumor effects of this immunotherapy for HGG in vitro and in vivo while decreasing off-target toxicity. METHODSWe examined the pharmacological effects of GB-13 in multiple patient-derived cell lines and rodent models of HGG. GBM and DMG lines were used to confirm IL-13Rα2 expression and sensitivity towards GB-13. Tumor naïve rats were evaluated for toxicity, and orthotopic PDX mice were used to monitor tumor size and survival following loco-regional infusion of GB-13. RESULTSGB-13 induced a potent cytotoxic response strongly predicated on IL-13Rα2 expression in vitro. No treatment-related adverse effects were noted after 7-day continuous intracranial infusion of GB-13 in tumor naïve rats. Further, in IL-13Rα2-upregulated orthotopic PDX mice, direct intratumoral administration of GB-13 via convection-enhanced delivery abrogated tumor growth and prolonged survival. CONCLUSIONSGiven these promising results as well as the critical need for novel therapies in CNS malignancies, we are progressing to human trials using GB-13 targeting recurrent HGG. Ongoing safety studies in tumor-bearing animals will be able to define dose levels for the initial adult study-arm and the following pediatric study-arm. In this Phase 1 clinical trial, we hypothesize that loco-regional infusion of GB-13 will safely enhance tumor clearance by causing selective killing of IL-13Rα2-upregulated HGG cells.

MODL-05 Metronomic Intrathecal Delivery of CDK4/6 Inhibitors in Preclinical Models of Pediatric Brain Tumors

INTRODUCTION: CDK4/6 inhibitors have shown promise against central nervous system (CNS) tumors in vitro. This class of drugs relies on long-term exposure. Their use in early phase clinical studies in children with CNS tumors has defined dose limitations due to systemic toxicity. We have sought to circumvent these limitations in using CDK4/6 inhibitors for pediatric CNS tumors by first demonstrating enhanced efficiency with long-term administration and exploiting prolonged intrathecal delivery (IT). METHODS: Pediatric CNS tumor cell lines were used for cell viability assays: ATRT (BT-12, BT-16), CPC (CCHE-45), diffuse midline glioma (DIPG-XIII, HSJD-007), and medulloblastoma (DAOY); the assays were conducted at 24h, 72h, and 7d post-administration of CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib). Half maximal growth inhibitory concentrations (GI50) and areas under the curve (AUC) were compared for short-term (24h, 72h) and long-term (7d) dose-response curves. Toxicity with chronic IT administration was assessed using a neurobehavioral safety profile of 7-day continuous infusion of 2.5mM palbociclib (n = 5) into the mouse lateral ventricle compared with vehicle (n = 4). RESULTS: Our results demonstrate increased CDK4/6 inhibitor potency with longer administration. The greatest reductions in short-term to long-term GI50 were observed in ATRT, CPC, and DIPG across all inhibitors. The most pronounced time-dependent efficacy was observed with palbociclib for ATRT and abemaciclib for CPC and DIPG. AUCs significantly decreased (P < 0.05) with increasing drug exposure time across all inhibitors. 7-day intraventricular palbociclib infusion was equivalent in safety to PBS at doses ranging from 1,000 to 10,000-fold the in vitro GI50. CONCLUSIONS: The efficiency of CDK4/6 inhibitors in pediatric CNS tumors is enhanced with prolonged exposure. Long-term IT administration can achieve high CNS doses without associated systemic toxicities. Translational efforts using a metronomic IT strategy are logical to explore for pediatric CNS tumors which have potential for a leptomeningeal disease pattern.

A sensitive and robust bioanalytical assay for pharmacokinetic analysis of ROR1xCD3 bispecific T cell engager (NVG-111) in a first-in-human study.

e19505 Background: Receptor tyrosine kinase-like Orphan Receptor-1 (ROR1) is widely expressed on hematological and solid tumors. NVG-111, a first in class humanized tandem scFv ROR1xCD3 bispecific antibody elicits potent killing of ROR1+ tumor cells in vitro and in vivo. This bispecific T-cell engager (TCE) is being evaluated in a first in human, Phase I trial in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The predicted therapeutic dose and steady state serum concentrations of NVG-111 were estimated by allometric scaling using relevant doses from a murine PK study. To assess free drug levels in patients following 21 days of continuous infusion of NVG-111, a bespoke, sensitive pharmacokinetics (PK) assay with high levels of specificity and sensitivity was developed. Methods: Anti-idiotype (anti-ID) antibodies directed to anti-ROR1 (αROR1-ID) and anti-CD3 (αCD3-ID) were generated by mouse immunization or by phage display from customized libraries. A proof-of-concept sandwich ELISA assay was developed using αCD3-ID to capture NVG-111 and detection by biotinylated hROR1-streptavidin-HRP. Gyrolab and Quanterix Simoa high sensitivity ELISA platforms were used to detect NVG-111 by αCD3-ID capture and αROR1-ID detection. The mesoscale discovery electrochemiluminescence assay (MSD-ECLA) was developed using a reversed format; NVG-111 capture with αROR1-ID and detection with αCD3-ID. Results: Allometric scaling predicted a theoretically relevant therapeutic dose and steady state serum concentration of 1ng/mL NVG-111 in humans, which was just at the level of sensitivity of a conventional ELISA under non-matrix conditions. Transferring the format to Quanterix Simoa had limited success due to high background levels in all configurations evaluated. The Gyrolab platform increased sensitivity to 75pg/mL, but suboptimal individual human sera matrix selectivity limited assay validity. Assessment of MSD-ECLA provided the best signal/noise, enhanced human disease and healthy sera selectivity, and a dynamic sensitivity range of 250pg/mL to 32ng/mL, which enabled the development of a GCLP qualified PK assay. The MSD-ECLA assay was employed to measure NVG-111 concentrations in CLL or MCL subjects dosed with 0.3-30µg/day NVG-111. MSD-ECLA detected drug in patients receiving NVG-111, with a range of steady-state serum concentrations (Cavg.ss) of 168-610pg/mL. This was in-line with the predicted drug levels from the single species allometric scaling, albeit with observed levels being marginally lower than expected. Conclusions: Development, custom optimization and validation of a highly sensitive MSD-ECLA PK assay has enabled GCLP-compliant measurement of circulating NVG-111 in CLL or MCL patients treated with at least 10µg/day cIV NVG-111.

Three days of CIV rh-Endostatin in combination with PD-1 antibody plus chemotherapy as first-line regimen for EGFR/ALK-negative, advanced or metastatic, non-squamous non–small cell lung cancer (NSCLC): A open label, multicenter, phase II and cohort study (ENPOWER).

9031 Background: rh-Endostatin, an antiangiogenic agent, in combination with chemotherapy is recommended by the CSCO guideline as the first-line treatment for EGFR/ALK-negative, advanced or metastatic, non-squamous non–small-cell lung cancer (NSCLC). However, evidence supporting the application of rh-Endostatin plus PD-1 antibody in clinical settings has been limited. The ENPOWER study is an open-label, multicenter, phase II and cohort study to evaluate the efficacy and safety of three days of continuous intravenous infusion (CIV) of rh-Endostatin in combination with PD-1 antibody plus chemotherapy as the first-line regimen for EGFR/ALK-negative, advanced or metastatic, non-squamous NSCLC. Methods: ENPOWER was an open label, multicenter, phase II and cohort study. Patients with EGFR/ALK-negative, advanced or metastatic, non-squamous NSCLC were enrolled and assigned into the following two cohorts. Patients in Cohort 1 (PD-1 combination) received rh-Endostatin plus PD-1 antibody plus standard chemotherapy (Carboplatin or Cisplatin plus Pemetrexed) during the induction period up to 4 - 6 cycles and rh-Endostatin plus PD-1 antibody during the maintenance period until disease progression or intolerable adverse events. Those in cohort 2 different from in cohort 1 was not subject to PD-1 antibody. Results: 43 subjects were evaluable for efficacy analysis, with 15 in Cohort 1 (PD-1 combination) and 28 in Cohort 2. ORR and DCR was 53% and 93% in Cohort 1 (CR, 0; PR, 8; SD, 6; PD,1) and 39% and 86% in Cohort 2 (CR 0; PR 11; SD, 13; PD, 4), respectively. 50 subjects were included in safety analysis. The overall incidence of AEs of any grade was 89%. 92% of the patients in the cohort 1 and 85% in the cohort 2. The majority of AEs was grade 1 or 2. Adverse events of any grade that occurred in at least 10% of patients were neutropenia（76%），nausea/vomiting (61%), AST/ALT abnormal (33%), palpitate (28%), anemia (22%) and skin hypersensitivity (11%) in the cohort 1 and neutropenia（68%），nausea/vomiting (59%), AST/ALT abnormal (21%), palpitate (16%), anemia (40%) in the cohort 2, respectively. Adverse events of grade 3 or higher found in the cohort 1 were neutropenia (23%) and those were neutropenia (19%), AST/ALT abnormal (3%) and anemia (3%) in the cohort 2. Seemingly, Adverse events that occurred more frequently in the cohort 1 than in the cohort 2 were AST/ALT abnormal, palpitate and skin hypersensitivity. Conclusions: Three days of CIV rh-Endostatin in combination with PD-1 antibody plus chemotherapy for the first line treatment of EGFR/ALK negative, advanced or metastatic, non-squamous NSCLC could obtain the better improvement in the efficacy and result in the higher frequent in some of AEs. Clinical trial information: NCT: 04063449.

Pharmacokinetic study of anti-human T-cell porcine immunoglobulin combined with cyclosporine A immunosuppressive therapy in patients with severe aplastic anemia

目的研究抗人T细胞猪免疫球蛋白（p-ATG）在重型再生障碍性贫血（SAA）患者的药物代谢特点。方法2017年2月至2017年12月纳入接受p-ATG联合环孢素A（CsA）免疫抑制治疗的SAA患者，p-ATG剂量为20 mg·kg−1·d−1，持续12 h静脉给药，连续5 d。应用三抗体夹心ELISA方法检测p-ATG血药浓度，药代动力学分析软件拟合，计算相关参数并绘制药物代谢曲线。随访记录不良事件并评估治疗后6个月血液学反应。结果入组16例接受p-ATG治疗的SAA患者，女8例，男8例，中位年龄22（12～49）岁，中位体重62.5（37.5～82.0）kg。其中14例可进行p-ATG药代动力学评价。p-ATG在体内分布为二室模型，平均药物浓度峰值时间（Tmax）为（5.786±2.486）d，平均峰浓度（Cmax）为（616±452）mg/L，平均半衰期（T1/2）为（10.479±8.242）d。平均药物浓度时间曲线下面积［AUC（0-t）］为（5.807±3.236）mg/L·d。14例患者治疗后6个月8例获得血液学反应，有效组与无效组患者AUC（0-t）分别为（7.50±3.26）mg/L·d对（4.50±2.18）mg/L·d，Cmax分别为（627±476）mg/L对（584±382）mg/L。结论连续5 d输注后p-ATG血药浓度达峰值，后缓慢下降，半衰期10.479 d，用药后60 d体内检测到残存药物浓度。尚不能得出药物代谢与疗效及不良反应的关系。

Three-Day Continuous Oxytocin Infusion Attenuates Thermal and Mechanical Nociception by Rescuing Neuronal Chloride Homeostasis via Upregulation KCC2 Expression and Function.

Oxytocin (OT) and its receptor are promising targets for the treatment and prevention of the neuropathic pain. In the present study, we compared the effects of a single and continuous intrathecal infusion of OT on nerve injury-induced neuropathic pain behaviours in mice and further explore the mechanisms underlying their analgesic properties. We found that three days of continuous intrathecal OT infusion alleviated subsequent pain behaviours for 14 days, whereas a single OT injection induced a transient analgesia for 30 min, suggesting that only continuous intrathecal OT attenuated the establishment and development of neuropathic pain behaviours. Supporting this behavioural finding, continuous intrathecal infusion, but not short-term incubation of OT, reversed the nerve injury-induced depolarizing shift in Cl− reversal potential via restoring the function and expression of spinal K+-Cl- cotransporter 2 (KCC2), which may be caused by OT-induced enhancement of GABA inhibitory transmission. This result suggests that only continuous use of OT may reverse the pathological changes caused by nerve injury, thereby mechanistically blocking the establishment and development of pain. These findings provide novel evidence relevant for advancing understanding of the effects of continuous OT administration on the pathophysiology of pain.

Long-term costs and cost-effectiveness of adjunctive corticosteroids for patients with septic shock in New Zealand

ObjectiveThe aim of the study was to determine whether adjunctive hydrocortisone reduced healthcare expenditure and was cost-effective compared with placebo in New Zealand patients in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial. DesignThis is a health economic analysis using data linkage to New Zealand Ministry of Health databases to determine resource use, costs, and cost-effectiveness for a 24-month period. SettingThe study was conducted in New Zealand. Participants and interventionPatients with septic shock were randomised to receive a 7-day continuous infusion of 200 mg of hydrocortisone or placebo in the ADRENAL trial. Main outcome measuresHealthcare expenditure was associated with all hospital admissions, emergency department presentations, outpatient visits, and pharmacy expenditure. Effectiveness outcomes included mortality at 6 months and 24 months and quality of life at 6 months. Cost-effectiveness outcomes were assessed with reference to quality-adjusted life years gained at 6 months and life years gained at 24 months. ResultsOf 3800 patients in the ADRENAL trial, 419 (11.0%) were eligible, and 405 (96.7% of those eligible) were included. The mean total costs per patient over 24 months were $143,627 ± 100,890 and $143,772 ± 97,117 for the hydrocortisone and placebo groups, respectively (p = 0.99). Intensive care unit costs for the index admission were $50,492 and $62,288 per patient for the hydrocortisone and placebo groups, respectively (p = 0.09). The mean number of quality-adjusted life years gained at 6 months and mean number of life years gained at 24 months was not significantly different by treatment group, and the probability of hydrocortisone being cost-effective was 55% at 24 months. ConclusionsIn New Zealand, adjunctive hydrocortisone did not reduce total healthcare expenditure or improve outcomes compared with placebo in patients with septic shock.

Therapy for Acute Myeloid Leukemia (AML) Adjusted to Genetic Data and Minimal Residual Disease: Results of the AML12 Trial of the Spanish Cetlam Group in Adults up to the Age of 70 Years

BACKGROUND: Current AML risk stratification relies on genetic data (cytogenetics and molecular characteristics) and minimal residual disease (MRD) assessment. This approach allows optimizing the post-remission allocation to chemotherapy only or hematopoietic cell transplantation (HCT). We investigated the feasibility and results of a prospective risk-adapted phase II trial of intensive chemotherapy followed or not by autologous or allogeneic HCT based on these criteria.METHODS: Adult patients with primary AML treated at 15 academic hospitals from the Spanish CETLAM group were included between February 2012 and May 2017. Induction chemotherapy consisted of idarubicin 12 mg/m2 days 1-2-3 IV bolus and cytarabine 200 mg/m2 as continuous infusion days 1 to 7. Consolidation courses were the high-dose cytarabine schedule of the CALGB (3 g/m2 or 1.5 g/m2 if older than 60 years). The number of consolidation courses depending on genetic risk was: three in low-risk category (FR) (CBF, NPM1mut/FLT3-ITDwild or ratio<0.5, CEBPA biallelic mutation); two in intermediate risk category (IR) (intermediate cytogenetics without favorable or unfavorable molecular features (FLT3-ITD, MLL) followed by a HCT (autologous or allogeneic, depending on MRD levels, availability of an HLA matched donor and center preference); and one consolidation in high-risk group (AR) (adverse genetics) followed by alloHCT from the most suitable source available. Patients with FR or IR and high MRD after consolidations (flow cytometry >0.1% or high specific transcripts (RUNX1/RUNX1T1, CBFβ/MYH11, NPM1)) were moved to the AR.RESULTS: Five hundred patients have been enrolled with a median age (range) of 55 (18-70) years and 53% were male. Revised MRC classification in 476 informative cases was: CBF 11%, intermediate risk cytogenetics 66% (77% of them with a normal karyotype), and poor risk 23%. NPM1 mutation was present in 47% and FLT3-ITD in 30% of patients with intermediate cytogenetics.Complete remission (CR) rate was 75% (n=374), 89% of them after a single course of induction CR was 77% in patients up to the age of 60 years and 71% in those older than 60. Induction death occurred in 11% of patients, 8% and 17% the groups up to and above 60 years, respectively; 10% and 13% of patients up to and above 60 years had refractory leukemia and 2% had morphological leukemia-free status. Three hundred and forty-three of the 374 CR patients completed the consolidation phase. The remaining CR patients had early relapse (n=8), death in CR (n=5) or the treatment is ongoing (n=18). Of risk-allocated patients, 133 (38%) were in the genetics-MRD favorable category (FR), 81 (24%) in the IR and 129 (38%) in the AR; in the latter, 94 (73%) of patients received an alloHCT in first CR. Ten patients (4%) moved from FR or IR group to the AR because of high MRD at the end of consolidation. Median follow-up in the surviving patients is 25 months. Overall survival (OS) of the whole series at 4 years is 43±5%; relapse-free survivals are 77±8% in the FR group, 40±12% in the IR and 36±10% in the AR group (Figure 1) due to significantly different cumulative relapse incidence (18%, 43% and 46%, respectively). Remarkably, we confirmed our previous finding that patients with intermediate-risk MRC cytogenetics with NPM1 mutation and FLT3-ITDwild had comparable outcomes to those with NPM1 mutation and an allelic ratio below 0.5. Of the 10 patients who were MRD positive at the end of consolidation (FR and IR), 7 received an alloHCT in 1st CR (5 alive in CR, 1 transplant related mortality and 1 relapsed); the remaining 3 had a morphologic relapse before alloHCT and died. Nine patients from the FR became MRD positive during follow-up and all were allografted: one of them experienced TRM and the remaining 8 are alive in CR.CONCLUSIONRisk adapted therapy for primary AML based on genetics and MRD is feasible in a cooperative group setting. The proportion of patients in whom the risk of an alloSCT in first CR may be avoided is 38% when considering cytogenetics, molecular findings and MRD information after the end of consolidation phase. MRD assessment at the end of consolidation moved 4% of patients from FR and IR to AR. AlloSCT in AR patients was feasible in most instances, even in the AR group. Despite this, relapses remain above 40% in the intermediate and adverse AML categories and further approaches after transplant such as novel agents and immune therapy deserve investigation. [Display omitted] DisclosuresRibera:Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Roche: Honoraria; ARIAD: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Amgen Inc.: Research Funding, Speakers Bureau.

Efficacy and Safety of Intensive Etoposide Aracytine Consolidation Following Rituximab Methotrexate Temozolomide Induction in Newly Diagnosed Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is reported as having a dismal prognosis, due to the limited blood-brain barrier crossing capacity of lymphoma chemotherapies. Long-term remission and even cure could be achieved for a significant proportion of PCNSL patients using methotrexate-based chemotherapy regimens and intensive consolidation strategies. We report our single center experience of 27 consecutive patients with newly diagnosed PCNSL treated with Rituximab Methotrexate Temozolomide (RMT) regimen, and high-dose Etoposide Aracytine (EA) consolidation, with particular consideration for safety data.Methods: All patients consecutively diagnosed with PCNSL from November 2013 to December 2016 at Cochin hospital (Paris, France) were retrospectively included. Primary vitro-retinal lymphoma without cerebral involvement (n=1) and immunodeficient patients (n=1) were excluded. Contrast-enhanced magnetic resonance imaging (MRI) was performed at diagnosis for all patients. Slit lamp evaluation and cerebrospinal fluid examination were performed at the diagnosis or during therapy. Induction therapy consisted of four cycles of 375mg/m² Rituximab and 8g/m² Methotrexate (with folinic acid rescue) at day 1 and 14, and Temozolomide 150mg/m² days 7 through 11, repeated every four weeks (the RMT regimen). Patients under 75 year-old without significant comorbidities and achieving a complete response (CR) or a partial response (PR) were treated with intravenous Etoposide 40mg/kg on a continuous 96h infusion days 1 through 4 and Aracytine 2g/m² twice a day days 1 through 4 (the EA regimen). MRI was performed after the second and fourth cycle of RMT and after treatment completion. Response was evaluated according to international PCNSL cooperative group (IPCG) criteria.Results: Median age was 68 and 26% of the patients were under 60. Median Karnofsky performans status was 60 (range, 40-100). After induction, we observed 16 (59.3%) CR/CRu, 6 (22.2%) progressive disease (PD), 2 (7.4%) unrelated lymphoma death and 3 (11.1%) were not evaluated but were in PR after 2 cycles. Nineteen patients achieved CR/PR and were eligible for subsequent consolidation therapy. Four patients received whole brain radiotherapy (30.6 Gy n=1, 23.4 Gy n=3), and two patients had a watchful waiting strategy. Thirteen (48.1%) patients received EA. Median age of EA cohort was 60. After 29 months (range, 8-43 months) of follow-up, 19 (70.4%) patients were alive in CR. Eight patients deceased, 4 (14.8%) from progressive disease and 4 (14.8%) from lymphoma-unrelated cause. Median of progression free survival (PFS) and overall survival (OS) were not reached. The two-year PFS and OS were 57% (CI 95%, 36-74%) and 67% (CI 95%, 44-82%), respectively when considering the whole cohort; and 82% (CI 95%, 44-95%) and 92% (CI 95%, 54-99%), respectively when focusing on patients who received EA consolidation (Figures 1a and 1b). Main toxic side-effects of RMT regimen, evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events V4.0 were infections (30% of grade 3-4) and liver enzymes modifications (37% of grade 3-4). We observed a single-case of fully-resolved grade 3 renal dysfunction. Regarding EA consolidation, median hospital stay and neutrophil recovery (neutrophil count over 0.5x109/l) was 22 (range, 20-183 days) and 11 days (range, 9-14 days), respectively. All patients developed grade 4 neutropenia and thrombocytopenia. Sixty one percent of patients experienced grade 3 anemia. Neutropenic fever was observed in 92.3% of patients. Grade 3-4 mucositis developed in 22.2% of patients. Sixty one percent of EA-treated patients experienced grade 3-4 infections, including documented bacterial infection in 6 patients (central venous catheter infection, n=3; septicemia, n=2 and Clostridium difficile colitis, n=1) and fungal infection in two patients (probable aspergillosis, n=1 and documented mucormycosis, n=1). We observed one case of vancomycine-induced grade 4 renal failure during febrile aplasia that fully recovered.Conclusion : The RMT regimen allowed a near 60% complete response rate with limited toxicity. Intensive Etoposide Aracytine consolidation is feasible but more toxic than previously reported. The high survival rate observed in patients receiving RMT induction and then EA consolidation support further comparative evaluation of this strategy in prospective trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.