Surface heterojunction based on n-type low-dimensional perovskite film for highly efficient perovskite tandem solar cells.

Enhancing the quality of junctions is crucial for optimizing carrier extraction and suppressing recombination in semiconductor devices. In recent years, metal halide perovskite has emerged as the most promising next-generation material for optoelectronic devices. However, the construction of high-quality perovskite junctions, as well as characterization and understanding of their carrier polarity and density, remains a challenge. In this study, using combined electrical and spectroscopic characterization techniques, we investigate the doping characteristics of perovskite films by remote molecules, which is corroborated by our theoretical simulations indicating Schottky defects consisting of double ions as effective charge dopants. Through a post-treatment process involving a combination of biammonium and monoammonium molecules, we create a surface layer of n-type low-dimensional perovskite. This surface layer forms a heterojunction with the underlying 3D perovskite film, resulting in a favorable doping profile that enhances carrier extraction. The fabricated device exhibits an outstanding open-circuit voltage (VOC) up to 1.34 V and achieves a certified efficiency of 19.31% for single-junction wide-bandgap (1.77 eV) perovskite solar cells, together with significantly enhanced operational stability, thanks to the improved separation of carriers. Furthermore, we demonstrate the potential of this wide-bandgap device by achieving a certified efficiency of 27.04% and a VOC of 2.12 V in a perovskite/perovskite tandem solar cell configuration.

Impact of University agricultural research and development spillovers on Chinese agribusiness firms' performance.

The spillover effect of university-based agricultural research and development (R&D) has been recognized as a crucial factor contributing to the enhanced performance of the agricultural industry. Nonetheless, the psychological impact of organizational inertia on individuals and groups may shape the influence of such spillovers for agribusiness firms. To date, there has been limited exploration of the interplay between university agricultural R&D spillovers and agribusiness firms. Utilizing panel data from Chinese listed agribusiness firms between 2009 and 2019, our empirical investigation reveals a negative short-term relationship between university agricultural R&D spillovers and agribusiness firm performance due to the similarity in knowledge backgrounds. In the short term, organizational inertia, stemming from familiar and parallel knowledge, renders university agricultural R&D spillovers unfavorable to agribusiness firm performance, thereby reducing their value to the enterprises. Conversely, the long-term influence of university agricultural R&D spillovers on agricultural enterprise performance is positive, as organizational inertia dissipates over time. Additionally, our findings indicate that university non-agricultural R&D spillovers serve to positively moderate the relationship between agricultural R&D spillovers and agribusiness firm performance in the short term, while exerting a negative moderating effect in the long term. Lastly, our analysis reveals a negative correlation between the effect of university agricultural R&D spillovers and the geographical distance between agribusiness firms and universities. This suggests that proximity to academic institutions may play a role in shaping the impact of R&D spillovers on agribusiness performance. In summary, our study highlights the complex dynamics between university agricultural R&D spillovers and agribusiness firm performance, revealing both short-term and long-term effects. We also underscore the importance of considering the influence of organizational inertia and the moderating role of non-agricultural R&D spillovers. Understanding these relationships is crucial for informing strategic decisions and fostering innovation within the agricultural industry.

ESG performance, investor attention, and company reputation: Threshold model analysis based on panel data from listed companies in China.

Amid heightened inter-company competition and the global drive towards ESG reforms, this study investigates whether enhancing the ESG performance of listed companies in China assists in elevating their reputation. It also examines the mediating role of investor attention in the relationship between ESG performance and company reputation, and further delves into whether there's a threshold effect of investor attention on the ESG-performance relationship. Utilizing sample data from Chinese listed companies spanning 2011 to 2021, and employing methods such as the panel two-way fixed-effects regression model, mediation effect testing, and threshold effect models, the study reveals that there is a significant positive relationship between ESG performance and the reputation of these companies. Moreover, a unique threshold effect is observed in the relationship between ESG performance and reputation. Innovatively, our research confirms the mediating role of investor attention in the relationship between ESG performance and company reputation, noting a more pronounced mediation effect in non-state-owned companies as opposed to state-owned ones. This study builds upon the existing literature on the relationship between CSR and company reputation, as well as between investor attention and reputation. By elucidating the mediating role of investor attention and its dual threshold effect, we provide a nuanced perspective on how ESG performance influences company reputation. Practically speaking, this research offers strategic recommendations for companies, investors, and regulators in the Chinese market on reputation management aligned with ESG principles. For instance, companies should prioritize their ESG performance, striving to maintain it above the market average, thus optimizing its effect on their reputation. Furthermore, companies should nurture their relationships with investors, aiming to elevate investor attention above the market mean. Policymakers should encourage companies to bolster their ESG performance, even contemplating more rewards and incentives for those with notable ESG achievements. Lastly, auditors should intensify their focus on non-financial information during audits, especially ensuring the accuracy and completeness of a company's ESG reports.

ARF1 maintains intestinal homeostasis by modulating gut microbiota and stem cell function.

AIMS: The small GTPase protein ARF1 has been shown to be involved in the lipolysis pathway and to selectively kill stem cells in Drosophila melanogaster. However, the role of ARF1 in mammalian intestinal homeostasis remains elusive. This study aimed to explore the role of ARF1 in intestinal epithelial cells (IECs) and reveal the possible mechanism. MATERIALS AND METHODS: IEC-specific ARF1 deletion mouse model was used to evaluate the role of ARF1 in intestine. Immunohistochemistry and immunofluorescence analyses were performed to detect specific cell type markers, and intestinal organoids were cultured to assess intestinal stem cell (ISC) proliferation and differentiation. Fluorescence in situ hybridization, 16S rRNA-seq analysis, and antibiotic treatments were conducted to elucidate the role of gut microbes in ARF1-mediated intestinal function and the underlying mechanism. Colitis was induced in control and ARF1-deficient mice by dextran sulfate sodium (DSS). RNA-seq was performed to elucidate the transcriptomic changes after ARF1 deletion. KEY FINDINGS: ARF1 was essential for ISC proliferation and differentiation. Loss of ARF1 increased susceptibility to DSS-induced colitis and gut microbial dysbiosis. Gut microbiota depletion by antibiotics could rescue the intestinal abnormalities to a certain extent. Furthermore, RNA-seq analysis revealed alterations in multiple metabolic pathways. SIGNIFICANCE: This work is the first to elucidate the essential role of ARF1 in regulating gut homeostasis, and provides novel insights into the pathogenesis of intestinal diseases and potential therapeutic targets.

Enabling financial development: linking innovation and CO2 emissions through equity and credit financing.

Over the past decade, financial development has been a prominent debate for stakeholders and policymakers alike. Financial development are prerequisites for innovation and CO2 emissions, followed by the Paris Climate Summit (COP21). In the wake of the global economic recession, financial development continues to address CO2 emissions efforts. However, scant attention is paid to the role of financial development in innovation and CO2 emissions relationship, especially in the context of developing countries. The current study explores the relationship between innovation and CO2 emissions through moderating role of financial development, especially in the context of developing countries. Utilizing a dynamic panel threshold approach, the current study utilizes data from 26 countries between 1990 and 2014. Our findings reveal that innovation positively impacts the reduction of carbon emissions when the stock market value-to-private credit ratio is below 1.71, while an opposite effect is observed when the ratio exceeds this threshold. We believe that the findings broaden the debate on financial development in developing countries. The results revealed that developing countries should allocate their domestic resources to financial development and poverty reduction, rather than solely addressing environmental concerns. In addition, a more sustainable balance between innovation and CO2 emissions could benefit through financial development and the impact may be the result in terms of achieving sustainable development.

In-situ growth of low-dimensional perovskite-based insular nanocrystals for highly efficient light emitting diodes.

Regulation of perovskite growth plays a critical role in the development of high-performance optoelectronic devices. However, judicious control of the grain growth for perovskite light emitting diodes is elusive due to its multiple requirements in terms of morphology, composition, and defect. Herein, we demonstrate a supramolecular dynamic coordination strategy to regulate perovskite crystallization. The combined use of crown ether and sodium trifluoroacetate can coordinate with A site and B site cations in ABX3 perovskite, respectively. The formation of supramolecular structure retard perovskite nucleation, while the transformation of supramolecular intermediate structure enables the release of components for slow perovskite growth. This judicious control enables a segmented growth, inducing the growth of insular nanocrystal consist of low-dimensional structure. Light emitting diode based on this perovskite film eventually brings a peak external quantum efficiency up to 23.9%, ranking among the highest efficiency achieved. The homogeneous nano-island structure also enables high-efficiency large area (1 cm2) device up to 21.6%, and a record high value of 13.6% for highly semi-transparent ones.

Symmetry-Broken 2D Lead-Tin Mixed Chiral Perovskite for High Asymmetry Factor Circularly Polarized Light Detection.

Symmetry-broken-induced spin splitting plays a key role for selective circularly polarized light absorption and spin carrier transport. Asymmetrical chiral perovskite is rising as the most promising material for direct semiconductor-based circularly polarized light detection. However, the increase of asymmetry factor and extension of response region remain to be a challenge. Herein, we fabricated a two-dimensional tin-lead mixed chiral perovskite with tunable absorption in the visible region. Theoretical simulation indicates that the mixing of the tin and lead in chiral perovskite breaks the symmetry of the pure ones, resulting in pure spin splitting. We then fabricated a chiral circularly polarized light detector based on this tin-lead mixed perovskite. A high asymmetry factor for the photocurrent of 0.44 is achieved, which is 144% higher than pure lead 2D perovskite, and it is the highest value reported for the pure chiral 2D perovskite-based circularly polarized light detector using a simple device structure.

Surface-Energy-Regulated Growth of α-Phase Cs0.03 FA0.97 PbI3 for Highly Efficient and Stable Inverted Perovskite Solar Cells.

Methylammonium (MA)-free formamidinium (FA)-dominated Csx FA1-x PbI3 is rising as the most promising candidate for highly efficient and stable perovskite solar cells. However, the growth of high-quality Csx FA1-x PbI3 black-phase perovskite structure without ion doping in the lattice remains a challenge. Herein, propeller-shaped halogenated tertiary ammonium is synthesized, showing high binding energy on the perovskite surface and large steric hindrance. This molecule can significantly reduce the barrier of high surface energy that suppresses the growth of the α-phase Csx FA1-x PbI3 structure. As a result, the α-phase structure can be formed at room temperature, which can further act as a seed for the growth of high-quality film. Solar cells based on the film show a record efficiency up to 23.6% for MA free Csx FA1- x PbI3 solar cells with inverted structure and excellent stability at 85 °C over 200 h.

Quinoid Conjugated Polymer Nanoparticles with NIR-II Absorption Peak Toward Efficient Photothermal Therapy.

Recently, extensive efforts have been devoted to the development of the second near-infrared bio-window (NIR-II, 1000-1700 nm) theranostic agents owing to the excellent tissue-penetration capability of NIR-II light. The exploration of organic NIR-II photothermal therapy materials, especially those with absorption peak over 1000 nm, is an appealing yet significantly challenging task. Herein, we have designed conjugated polymer nanoparticles (PIS NPs) with NIR-II absorption peak at 1026 nm through a combined strategy of introducing quinoid donor-acceptor (D-A) structures, constructing intramolecular "conformational locks" and extending the conjugation area to narrow the band gap. Irradiated at 1064 nm, PIS NPs showed remarkable photothermal conversion performance for efficient photothermal ablation of tumor cells in vitro and in vivo. This study provides useful insights into the rational design of organic NIR-II photothermal agents based on multiple strategies.

State ownership, information asymmetry and cash holding: Impact of COVID-19 on Chinese-listed firms.

This study investigates the relationship between information asymmetry and cash holdings under the impact of the coronavirus disease 2019 (COVID-19) in China. It likewise explores how state ownership dominates their nexus, particularly during the pandemic. COVID-19 caused increases in cash holdings, and that the information asymmetry's effect on cash holdings is more pronounced over the COVID-19 period. Additionally, information asymmetry has a weaker effect on corporate cash holdings for state-owned enterprises (SOEs) under the pandemic. Overall, the study shows that state ownership moderates information asymmetry's impact on cash holdings and softens firms' precautionary motive for cash holdings during the pandemic.

Fostering Green Innovation Adoption through Green Dynamic Capability: The Moderating Role of Environmental Dynamism and Big Data Analytic Capability.

Though the concept of green dynamic capability has been increasingly gaining traction among academics, practitioners, and policymakers, its association with green innovation adoption remains unclear. The present study addresses this gap and aims to provide clarity by distinguishing green innovation adoption in the context of developing countries. Drawing on dynamic capability and stakeholder theory, this research shed light on the significance of green dynamic capability for green innovation adoption. Additionally, this study examines the moderating role of environmental dynamism and big data analytics capability in the link between green dynamic capability and green innovation adoption. Adopting a two-wave research design, the sample for this study contained SMEs from Pakistan and Malaysia. Data was obtained from 220 SMEs (105 from Pakistan, 115 from Malaysia). To test the hypotheses, covariance-based structural equation modelling was performed to analyze causal relationships in the model, by using AMOS 23 software. The results showed that green dynamic capability positively impacts green innovation adoption, but environmental dynamism does not positively moderate between green dynamic capability and green innovation adoption. In addition, big data analytics capability positively moderates between green dynamic capability and green innovation adoption. We believe that this study opens a new avenue in the environmental literature under which green innovation adoption is useful for SMEs.

Bempegaldesleukin plus Nivolumab in First-line Metastatic Urothelial Carcinoma: Results from PIVOT-02.

BACKGROUND: Despite recent changes in the treatment landscape, there remains an unmet need for effective, tolerable, chemotherapy-free treatments for patients with advanced/metastatic urothelial carcinoma (mUC), especially cisplatin-ineligible patients. OBJECTIVE: To evaluate the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab in patients with advanced/mUC from the phase 2 multicenter PIVOT-02 study. DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicohort phase 1/2 study enrolled patients with previously untreated locally advanced/surgically unresectable or mUC (N = 41). INTERVENTION: Patients received BEMPEG 0.006 mg/kg plus nivolumab 360 mg intravenously every 3 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objectives were safety and the objective response rate (ORR) in patients with measurable disease at baseline and at least one postbaseline tumor response assessment (response-evaluable). Secondary objectives were overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses via univariate logistic regression were performed to test the association between potential biomarkers (CD8+ tumor-infiltrating lymphocytes, tumor mutational burden, and IFN-γ gene expression profile) and response. RESULTS AND LIMITATIONS: The ORR was 35% (13/37 evaluable patients) and the complete response rate was 19% (7/37 patients); the median duration of response was not reached. Median PFS was 4.1 mo (95% confidence interval [CI] 2.1-8.7) and median OS was 23.7 mo (95% CI 15.8-not reached). Overall, 40/41 patients (98%) experienced at least one treatment-related adverse event (TRAE); grade 3/4 TRAEs occurred in 11 patients (27%), most commonly pyrexia (4.9%; 2 patients). Exploratory biomarker analyses showed no association between biomarkers and response. Limitations include the small sample size and single-arm design. CONCLUSIONS: BEMPEG plus nivolumab was well tolerated and showed antitumor activity as first-line treatment in patients with locally advanced/mUC. PATIENT SUMMARY: We investigated an immune-stimulating prodrug called bempegaldesleukin plus the antibody nivolumab as the first therapy for patients with advanced or metastatic cancer of the urinary tract. This combination had manageable treatment-related side effects and was effective in a subset of patients. This trial is registered at ClinicalTrials.gov as NCT02983045.

Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma: results from the PIVOT-02 study.

BACKGROUND: Immune checkpoint inhibitor-based combinations have expanded the treatment options for patients with renal cell carcinoma (RCC); however, tolerability remains challenging. The aim of this study was to evaluate the safety and efficacy of the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) as first-line therapy in patients with advanced clear-cell RCC. METHODS: This was an open-label multicohort, multicenter, single-arm phase 1/2 study; here, we report results from the phase 1/2 first-line RCC cohort (N=49). Patients received BEMPEG 0.006 mg/kg plus NIVO 360 mg intravenously every 3 weeks. The primary objectives were safety and objective response rate (ORR; patients with measurable disease at baseline and at least one postbaseline tumor response assessment). Secondary objectives included overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses: association between baseline biomarkers and ORR. RESULTS: At a median follow-up of 32.7 months, the ORR was 34.7% (17/49 patients); 3/49 patients (6.1%) had a complete response. Of the 17 patients with response, 14 remained in response for >6 months, and 6 remained in response for >24 months. Median PFS was 7.7 months (95% CI 3.8 to 13.9), and median OS was not reached (95% CI 37.3 to not reached). Ninety-eight per cent (48/49) of patients experienced ≥1 treatment-related adverse event (TRAE) and 38.8% (19/49) had grade 3/4 TRAEs, most commonly syncope (8.2%; 4/49) and increased lipase (6.1%; 3/49). No association between exploratory biomarkers and ORR was observed. Limitations include the small sample size and single-arm design. CONCLUSIONS: BEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation.

Quasi-2D Bilayer Surface Passivation for High Efficiency Narrow Bandgap Perovskite Solar Cells.

The combination of comprehensive surface passivation and effective interface carriers transfer plays a critical role in high-performance perovskite solar cells. A 2D structure is an important approach for surface passivation of perovskite film, however, its large band gap could compromise carrier transfer. Herein, we synthesize a new molecule 2-thiopheneethylamine thiocyanate (TEASCN) for the construction of bilayer quasi-2D structure precisely on a tin-lead mixed perovskite surface. This bilayer structure can passivate the perovskite surface and ensure effective carriers transfer simultaneously. As a result, the open-circuit voltage (Voc ) of the device is increased without sacrificing short-circuit current density (Jsc ), giving rise to a high certified efficiency from a credible third-party certification of narrow band gap perovskite solar cells. Furthermore, theoretical simulation indicates that the inclusion of TEASCN makes the bilayer structure thermodynamically more stable, which provides a strategy to tailor the number of layers of quasi-2D perovskite structures.

Oxidative degradation of p-chlorophenol by the persulfate-doped Fe-Mn bimetallic hydroxide, the parametrical significance, and systematical optimization.

Aqueous Fe(II)-catalyzed activation commonly deteriorates the oxidation performance of persulfate (PS) to the treatment of organic contaminants. In this study, a PS-doped layered bimetallic hydroxide (Fe-Mn hydroxide) was synthesized to construct a heterogeneously catalytic system to solve the issue brought by homogeneity. The molar ratio of Fe(II) to Mn(II) and the mass ratio of PS to Fe-Mn hydroxide both had a significant impact on the catalytic degradation of p-CP. Reaction temperatures engaged in the most essential role in influencing the degradation and removal of p-chlorophenol (p-CP). The optimal combination of factors for the preparation of PS-hydroxide and the treatment of p-CP was finally determined by significance analysis. The degradation process was appropriately fitted by the pseudo-first-order kinetic model. The benzene ring in p-CP was broken by PS-hydroxide during the adsorption. The surface modification of PS-hydroxide caused by the valence transition of Mn was beneficial to the adsorption and catalytic degradation of p-CP.

Dehydration-Reaction-Based Low-Temperature Synthesis of Amorphous SnOx for High-Performance Perovskite Solar Cells.

The development of methodologies for synthesizing carrier-transporting materials is critical for optoelectronic device fabrication. Amorphous metal oxides have emerged as potential carrier transport materials for perovskite tandem solar cells and flexible electronics due to their ease of fabrication and excellent electronic properties. However, perovskite solar cells employing amorphous metal oxides as the electron-transporting layers (ETLs) remain inefficient. This research describes a moderate dehydration reaction for the low-temperature synthesis of amorphous SnOx. We investigated this amorphous SnOx as the ETL for perovskite solar cells and demonstrated a maximum power conversion efficiency (PCE) of 20.4%, the greatest efficiency ever attained with an amorphous metal oxide ETL produced below 100 °C. Remarkably, the device maintained 85% of its initial efficiency for more than 4800 h. Furthermore, flexible perovskite solar cells based on this amorphous SnOx have a maximum PCE of 11.7%. Finally, this amorphous SnOx was used to fabricate LEDs and exhibited a maximum external quantum efficiency of over 3%.

Safety and Antitumor Activity of α-PD-L1 Antibody as Monotherapy or in Combination with α-TIM-3 Antibody in Patients with Microsatellite Instability-High/Mismatch Repair-Deficient Tumors.

PURPOSE: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors. However, 50%-60% do not respond to single-agent anti-programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6-12 months. This phase Ib trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors. PATIENTS AND METHODS: Eligible patients ≥18 years without prior anti-PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti-TIM-3 antibody (cycles 1-2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability. RESULTS: Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. CONCLUSIONS: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI-H/dMMR tumors.

Passivation of the Buried Interface via Preferential Crystallization of 2D Perovskite on Metal Oxide Transport Layers.

The open-circuit voltage (Voc ) of perovskite solar cells is limited by non-radiative recombination at perovskite/carrier transport layer (CTL) interfaces. 2D perovskite post-treatments offer a means to passivate the top interface; whereas, accessing and passivating the buried interface underneath the perovskite film requires new material synthesis strategies. It is posited that perovskite ink containing species that bind strongly to substrates can spontaneously form a passivating layer with the bottom CTL. The concept using organic spacer cations with rich NH2 groups is implemented, where readily available hydrogens have large binding affinity to under-coordinated oxygens on the metal oxide substrate surface, inducing preferential crystallization of a thin 2D layer at the buried interface. The passivation effect of this 2D layer is examined using steady-state and time-resolved photoluminescence spectroscopy: the 2D interlayer suppresses non-radiative recombination at the buried perovskite/CTL interface, leading to a 72% reduction in surface recombination velocity. This strategy enables a 65 mV increase in Voc for NiOx based p-i-n devices, and a 100 mV increase in Voc for SnO2 -based n-i-p devices. Inverted solar cells with 20.1% power conversion efficiency (PCE) for 1.70 eV and 22.9% PCE for 1.55 eV bandgap perovskites are demonstrated.

A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors.

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.

LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial.

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti-CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non-weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non-weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4-6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non-weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).