key: cord-0323156-ae9yaftn authors: Chew, C. K. T.; Hogan, H.; Jani, Y. title: A scoping review exploring the impact of digital systems on processes and outcomes in the care management of acute kidney injury and progress towards establishing learning healthcare systems date: 2021-02-25 journal: nan DOI: 10.1101/2021.02.23.21252060 sha: 0d5a552c52071b413fd3ce73c66ee04a4c559436 doc_id: 323156 cord_uid: ae9yaftn Background Digital systems have long been used to improve the quality and safety of care when managing Acute Kidney Injury (AKI). The availability of digitised clinical data can also turn organisations and their networks into Learning Healthcare Systems (LHSs) if used across all levels of health and care. This review explores the impact of digital systems on AKI patient care to gauge progress towards establishing LHSs and to identify existing gaps in the research. Method Embase, PubMed, Medline, Cochrane, Scopus and Web of Science databases were searched. Studies of real-time or near real-time digital AKI management systems which reported process and outcome measures were included. Results Thematic analysis of 43 studies showed that most interventions used real-time SCr levels to trigger responses to enable risk prediction, early recognition of AKI or harm prevention by individual clinicians (micro level) or specialist teams (meso level). Interventions at system (macro level) were rare. There was limited evidence of change in outcomes. Conclusion Whilst the benefits of real time digital clinical data at micro level for AKI management have been evident for some time, their application at meso and macro levels is emergent therefore limiting progress towards establishing LHSs. Lack of progress is due to digital maturity, system design, human factors and policy levers. Future approaches need to harness the potential of interoperability and data analytic advances and include multiple stakeholder perspectives to overcome these factors. The pleotropic TWEAK:Fn14 signaling pathway is involved in a multitude of pathological processes including cancer. High expression of TWEAK has been shown to promote tumor growth and survival and is a negative prognostic for several types of cancer. Here we report on the phase I proof-of-concept multicenter trial of RG7212, a novel fully humanized IgG1κ monoclonal antibody that targets the TWEAK/Fn14 signaling pathway. We demonstrate the feasibility of patient selection based on tumor Fn14 expression in solid tumors and show that RG7212 treatment reduced free and total TWEAK ligand quickly and durably with encouraging evidence of prolonged stable disease. Moreover, the exceptional safety profile of RG7212 across a broad range of doses suggests that RG7212 is quite safe for multi-cycle administration. Results presented support additional studies of this first-in-class Conclusion RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Research. on February 25, 2021. © 2014 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 11, 2014; DOI: 10.1158/1078-0432.CCR- Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a widely expressed member of the TNF superfamily identified as having proapoptotic activity in combination with gamma-interferon (1) . Other studies have identified TWEAK as a multifunctional cytokine involved in diverse cellular processes encompassing tissue repair and remodeling (particularly in bone and skeletal muscle (2) (3) (4) ), promotion of inflammation, cellular proliferation, angiogenesis, and cell survival (5, 6) . TWEAK mediates signaling through its cognate receptor fibroblast growth factor-inducible molecule 14 (Fn14), which is broadly expressed in nearly all nonhematopoietic cell types. TWEAK is synthesized as a transmembrane protein with a C-terminal extracellular region containing a TNF homology domain (1, 7) . Full-length TWEAK is proteolytically cleaved at furin endoprotease site(s) resulting in a soluble cytokine. Circulating TWEAK ligand trimerizes to bind and activate Fn14. Intracellular signaling is then mediated through the Fn14 cytoplasmic domain via TNF receptor-associated factors (TRAFs) 1, 2, 3, and 5. This results in activation of canonical and noncanonical NFκB pathways as well as MAPK signaling ( Fig. 1) (8) . TWEAK:Fn14 signaling plays a role in numerous pathological processes, including rheumatoid arthritis (9, 10) , systemic lupus erythematosis (11) , ischemic stroke (12) , and cancer (8) . TWEAK and Fn14 expressed in tumor tissue may activate proliferation, invasion, angiogenesis, and inflammation (8, 13, 14) . Other studies have identified TWEAK as curtailing the innate immune response and inhibiting the transition to adaptive immunity (15) . High expression of Fn14 has been shown in several tumor types, including colorectal cancer, pancreatic carcinoma, non-small cell lung cancer (NSCLC) and ovarian cancer (16) (17) (18) . Moreover, Fn14 expression is considered a negative prognostic factor in glioblastoma multiforme (6) , breast cancer (19) , gastric cancer (20) , and NSCLC (21) . Therefore, targeting TWEAK:Fn14 signaling has led to the development of several anticancer therapeutic strategies, including the antibodies enavatuzumab, BIIB036, and RG7212 (22-24). RG7212, a fully humanized IgG1κ monoclonal antibody, blocks TWEAK ligand binding to Fn14 (IC 50 =13 ng/mL) (25) . Single-agent tumor growth inhibition has been demonstrated for RG7212 in multiple in vivo models, including renal cell carcinoma (RCC), breast, and pancreatic cancer (25) . This activity is accompanied by changes in TWEAK signaling pathways, including a reduction of AKT and ERK phosphorylation and a reduction of the transcriptional targets of NFκB. Additionally, immunophenotypic changes associated with antitumor activity have been observed with anti-TWEAK antibody treatment in mice (25) and in TWEAK knockout mice (15) . CD3+ T cells were significantly increased in blood and spleen and slightly, but not significantly increased in tumors, while monocytes/macrophages (CD11b+/F4/80+) were significantly decreased in blood and significantly increased in tumors from anti-TWEAK treated mice (25) . Increases in tumor and spleen T cell numbers were reported for TWEAK knockout mouse studies (15) . In vivo activity was greatest in models with high Fn14 receptor expression and absent in models lacking Fn14 expression (25) . Based on these findings, a phase I multicenter trial of RG7212 monotherapy in patients with Fn14-expressing advanced solid tumors was initiated. Major objectives for this study were assessment of single-agent safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy. This open-label phase Ia study of single-agent RG7212 was initiated in July 2011 at four centers. All patients were adults aged ≥18 years with Fn14-positive, advanced, refractory solid tumors for which no treatment options were available. Tumor Fn14 expression was determined by immunohistochemistry (IHC), as described below. Fn14 positivity was defined as ≥10% of tumor cells staining with at least weak intensity in cytoplasm and/or in membrane, hereafter referred to as "IHC≥1+". Assessments were permitted on either archival or fresh tumor biopsy samples. Additionally, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate hepatic, renal, and bone marrow function at study baseline were required. Patients were ineligible if they had received a registered or investigational cancer therapy <21 days prior to the first study day. Other exclusion criteria included cardiovascular disease (congestive heart failure > New York Heart Association class II, uncontrolled arrhythmia, recent myocardial infarction, or cerebrovascular accident), other uncontrolled concurrent disease (e.g., diabetes, active infection), or immunosuppressive therapy. Patients with central nervous system or leptomeningeal metastases were ineligible, except those with clinically stable disease for >3 weeks prior to study treatment. The study was conducted in full conformance as outlined by institutional review boards of participant institutions. The trial followed the principles A 3+3 dose-escalation design was used. RG7212 was administered on weekly (QW), bi-weekly (Q2W) and every-three-week (Q3W) schedules (Fig. S1 ). The individual doses examined are listed in Table 1 . Patients were initially enrolled in the QW schedule at a dose of 200 mg, which provided a more than 15-fold safety margin from the NOAEL observed in monkey 13 week GLP toxicology studies. The Q3W regimen was employed subsequent to the QW schedule, beginning at an 800-mg dose based on the absence of dose-limiting toxicities (DLTs) observed for QW schedule patients. Preliminary analysis of Q3W pharmacokinetic data revealed RG7212 half life shorter than that anticipated by simulations of preclinical data. Therefore an every 2 week schedule (Q2W) was later adopted to support an effective therapeutic steady state C min at practical dose levels. The primary study objectives were to evaluate safety, determine MTD, and identify a recommended phase II dose (RP2D) for each of the three treatment schedules. Secondary objectives included evaluation of the pharmacokinetic and pharmacodynamic profile of RG7212 in peripheral blood (e.g., TWEAK and NFκB transcription products), in tumor expression (including Fn14, Ki-67, and TRAF1), by 18 F fluoro-deoxyglucose (FDG)-PET imaging, and by evaluation of antitumor activity using anatomical imaging (RECIST 1.1). Descriptive statistical methods were used for efficacy and safety analyses. Pharmacodynamic parameters from tumor tissue and peripheral blood were analyzed as a function of post-dose change from study baseline for each patient. Changes to PD parameters relative to RG7212 exposure (AUC inf ) were identified for individual study patients, for all patients in a given dose schedule, and for the entire study cohort. Since AUC inf and dose had a linear relationship over the dose ranges tested and interpatient variability within dose cohorts was low, AUC inf was used as the exposure variable. Changes to free and RG7212-bound (total) TWEAK ligand were analyzed for individual patients following each treatment cycle. Additionally, changes to tumor Ki-67, TRAF1, phosphorylated ERK (pERK), and CD3 expression were analyzed as a function of RG7212 AUC inf for each of these groups following cycle 1 (biopsy day 17 for QW schedule; day 8 for Q2W and Q3W schedules). 18 F FDG-PET assessments were obtained prior to dosing for all patients and during cycle 1 (day 15 for QW schedule; day 4 for Q2W and Q3W schedule) and following cycle 2 for patients with tumors having baseline 18 F FDG uptake (cycle 3, day 1 for QW and Q2W schedules; cycle 2, day 22 for Q3W schedule). Among patients meeting all study eligibility criteria, 54 (Table 1) Table 1 provides a summary of patient enrollment and drug administration for all schedules. Research. (CV%=38, n=12). Plasma exposures, assessed as C max and AUC 0-inf , increased linearly over the 200-5400 mg dose range for all three schedules. The relationship between C max and dose can be described by linear regression, with R 2 =0.85, P<0.0001 ( Fig. 2A) . Clearance values across the dose range of 200-7200 mg also indicated linear pharmacokinetics for RG7212 (Fig. 2B) . A slight reduction in clearance was observed at the 7200-mg dose. This was likely due to data variation, but a trend of saturation of clearance at this dose level cannot be ruled out. The accumulation ratios for each schedule, calculated as AUC τ following first infusion in cycle 2 versus AUC τ following cycle 1 first infusion were 2.17±0.50 from Schedule QW, 1.51±0.42 from Schedule Q2W, and 1.28±0.35 from Schedule Q3W. An alternative administration schedule was also assessed. After Day 22, with repeated dosing, drug exposures from 7200-mg Q2W and 3600-mg QW dosing cohorts reached a similar level (Fig. 2C) , supporting the feasibility of the more convenient Q2W schedule. This study employed multiple pharmacodynamic endpoints in peripheral blood and tumor and 18 F FDG PET imaging to characterize RG7212 treatment-related changes. The modulation of circulating TWEAK levels was assessed following administration of RG7212. Following initiation of treatment, free TWEAK concentration dropped TRAFs 1, 2, 3, and 5 are proteins known to complex with Fn14 at cytoplasmic domain binding sites (26, 27) . TRAF binding may be important as a proximal event in Fn14-mediated signaling, promoting activation of signal transduction cascades involving the NFκB and ERK pathways (Fig. 1) . A nonsignificant correlation toward decreased tumor TRAF1 protein expression relative to baseline with increased RG7212 exposure was observed among 31 patients with data from pre-and post treatment tumor biopsy samples (R=−0.267; P=0.147; Fig. 3B, C) . Ki-67 expression was assessed as a measure of tumor anti-proliferative effects following RG7212 treatment. Three patients, two 1600 mg QW and one 3200 mg Q3W, had >40% post treatment reduction in tumor Ki-67 expression (Fig. 3B) . Among 33 patients with data from pre-and posttreatment tumor biopsy samples, a significant correlation of decreased Ki-67 expression with increasing RG7212 exposure was observed (R=−0.381, P=0.029). 18 Preclinical studies have demonstrated that in vivo RG7212 activity is accompanied by reductions in tumor AKT phosphorylation (25) . As previous clinical studies have suggested that 18 F FDG-PET may be useful as a noninvasive pharmacodynamic marker for PI3K/AKT pathway inhibition, we examined metabolic responses (28). Partial metabolic responses in cycle 1 or cycle 2 were observed for five patients, as verified by independent, centralized review (ICON plc, North Wales, PA). Responses by FDG-PET were noted in patients from both the QW and Q3W schedules but were not well correlated with RECIST responses, duration of study treatments, or RG7212 exposure (data not shown). A 72-year-old female with heavily pretreated BRAF wild-type, stage M1 melanoma had evidence of tumor regression during RG7212 treatment. Prestudy treatments included nab-paclitaxel, ipilimumab, and temozolomide completed 12, 6, and 2 months prior to RG7212 treatment, respectively. Tumor reduction was apparent in both examination of cutaneous-based disease and nodal metastases in the axilla and mediastinum. The patient's CT radiographs prior to study treatment and following the fourth treatment cycle are provided (Fig. 4A) . A 14.5% overall reduction in assessable lesions (RECIST) was observed, while volumetric image analysis revealed a 50% reduction in a right axillary nodal lesion. Pharmacodynamic endpoints for this patient were also encouraging, including a partial metabolic response on cycle 2 18 F FDG-PET imaging (Fig. 4A) T-cell infiltration (CD3) in this tumor biopsy and a 74% reduction in post-treatment pERK expression were also noted (Fig. 4B) . This patient was treated in the 3200-mg cohort of the Q3W schedule and received 12 treatment cycles (36 weeks) prior to terminating study treatments for disease progression. This phase Ia study demonstrated the feasibility of patient selection based on tumor In the absence of DLTs, pharmacodynamic data were taken into consideration with respect to defining RP2D. A trend towards a plateau in exposure-dependent reductions in Ki-67 and TRAF1 expression suggests that a 3600-mg dose may provide maximal antitumor effect. Pharmacokinetic data demonstrate equivalent exposures overall for 3600-mg QW and 7200-mg Q2W dosing. Therefore, 7200 mg was considered the RP2D for the Q2W schedule. CT evidence of tumor regression was noted in a patient with treatment-refractory melanoma who received 36 weeks of therapy. In addition, evidence of prolonged TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis TWEAK induces angiogenesis and proliferation of endothelial cells TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration Genetic ablation of TWEAK augments regeneration and post-injury growth of skeletal muscle in mice TWEAKing tissue remodeling by a multifunctional cytokine: Role of TWEAK/Fn14 pathway in health and disease Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function Identification of a ligand for the death-domain-containing receptor Apo3 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on The TWEAK-Fn14 cytokine-receptor axis: Discovery, biology and therapeutic targeting TWEAK is a novel arthritogenic mediator Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collageninduced arthritis TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus Tumor necrosis factor-like weak inducer of apoptosis-induced neurodegeneration TWEAK and Fn14: New molecular targets for cancer therapy? Role of TWEAK and Fn14 in tumor biology TWEAK attenuates the transition from innate to adaptive immunity American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on Antibodies to TWEAK receptor inhibit human tumor growth through dual mechanisms Elevated expression of Fn14 in non-small cell lung cancer correlates with activated EGFR and promotes tumor cell migration and invasion TWEAK promotes ovarian cancer cell metastasis via NF-kappaB pathway activation and VEGF expression The fibroblast growth factor-inducible 14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity Elevated fibroblast growth factor-inducible 14 expression promotes gastric cancer growth via nuclear factor-kappaB and is associated with poor patient outcome Correction of fibroblast growth factor-inducible molecules 14 (Fn14) expression with mutational profile and clinical outcome in patients (pts) non-small cell lung cancer (NSCLC) American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Expression of TweakR in breast cancer and preclinical activity of enavatuzumab, a humanized anti-TweakR mAb The anti-Fn14 antibody BIIB036 inhibits tumor growth in xenografts and patient derived primary tumor models and enhances efficacy of chemotherapeutic agents in multiple xenograft models A firstin-human phase I monotherapy study of RG7212 (R), a novel monoclonal antibody targeting TWEAK signaling in patients with advanced solid tumors RG7212 anti-TWEAK mAb inhibits tumor growth through inhibition of tumor cell proliferation and survival signaling and by enhancing the host antitumor immune response TWEAK binding to the Fn14 cysteine-rich domain depends on charged residues located in both the A1 and D2 modules TNF-related weak inducer of apoptosis receptor, a TNF receptor superfamily member, activates NF-kappa B through TNF receptor-associated factors American Association for Cancer clincancerres.aacrjournals.org Downloaded from 28 18F]fluorodeoxyglucose positron emission tomography correlates with akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy A guide to rational dosing of monoclonal antibodies Fixed dosing versus body sizebased dosing of monoclonal antibodies in adult clinical trials American Association for Cancer clincancerres.aacrjournals.org Downloaded from We thank the patients who participated in this study and their families. Additionally, we thank Shirin Jadidi, Deborah Keller, Michael Leiss, Sabine Lohmann, Stacey Ukrainsky, James Song, Jean Tessier, Martin Weisser, as well as the nurses, investigators, and others on local study teams for their contributions to this trial. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.