Rapid Early Development Research Articles

Innovative approaches to enhancing crack repair: Performance optimization of biopolymer-infused CXT

Abstract Biopolymer-modified cementitious repair material (CXT) is a composite material designed to enhance the properties of traditional cementitious materials through the incorporation of biopolymers. CXT is formed by blending cement (C) with biopolymers such as xanthan gum (XG) and additives like tartaric acid (TA), which improve the material’s performance characteristics. This study investigates the effects of varying dosages of XG, TA contents, and curing durations on the performance characteristics of CXT. We evaluated key performance indicators, including the flowability, workability, setting time, compressive strength, and shrinkage. The optimal formulation XG 1:2 TA0.6 achieved a maximum compressive strength of 25 N·mm−² and a flexural strength of 9.4 N·mm−², with negligible shrinkage. The results showed rapid early strength development, with the material reaching over 77% of its final compressive strength within the first 14 days. These findings highlight the potential of CXT for crack-repair applications, offering improved workability, accelerated setting times, and reduced environmental impact compared to traditional repair materials. This study provides valuable insights for optimizing the formulation of CXT for enhanced performance in real-world applications.

ASReml-based estimation of early genetic parameters in hybrid mutton sheep populations

The aim of this study was to analyze the effects of non-genetic factors on the estimation of genetic parameters of early growth traits in hybrid mutton sheep using ASReml software, in order to provide theoretical basis for screening the optimal hybriding combinations and accelerating the breeding process of new breeds of specialized housed-feeding mutton sheep. We selected the wellgrown hybrid Southhu (Southdown × Hu sheep) and Dorhu (Dorset × Hu sheep) sheep as the research objects, constructed weight correction formulae for SH and DH sheep at 60 and 180 days; and used ASReml software to investigate the effects of non-genetic factors on the estimation of genetic parameters of early growth traits in hybrid sheep. The results showed that the birth month and birth type were found significant for all traits (p < 0.001); the heritability of maternal effects ranged from 0.0709 to 0.1859. It was found that both SH and DH sheep emerged the potential for rapid early growth and development, early growth traits are significantly affected by maternal genetic effects, thereby the maternal effect should be taken into consideration for the purpose of improving accuracy in parameter estimations and therefore increasing the success of breeding programs.

Formulation of high-recycled-content hydraulic cements based on alkali aluminosilicate chemistry and mechanochemical processing techniques

The current study investigates the potential of various waste materials and industrial by-products for formulating high-recycled content hydraulic cement, leveraging alkali aluminosilicate chemistry principles. Through rigorous characterization employing X-ray fluorescence (XRF), X-ray diffraction (XRD), Fourier Transform Infrared (FTIR) Spectroscopy, thermogravimetric analysis (TGA), and Scanning Electron Microscopy (SEM), alongside alkalinity and alkali solubility assessments, the chemical and mineralogical compositions of waste brick, lime kiln dust, cement kiln dust, waste glass, gypsum, foundry sand, granulated blast furnace slag, and impounded coal ash were unveiled. Silicon and aluminum were found abundantly in these materials, with lime kiln dust and slag contributing calcium. A thoroughly crafted blend, enriched with alkalis, underwent mechanochemical activation to yield a hydraulic cement finely tuned to meet specific chemical ratios required for effective alkali aluminosilicate reactions. Upon hydration, this innovative cement exhibited rapid early strength development, achieving a commendable compressive strength of 32 MPa within 28 days a performance on par with standard Portland cement. Remarkably, the heat of hydration profiles revealed a prompt onset of hydration reactions, marked by a significant exothermic peak within the initial hours, in contrast to the gradual peak observed with Portland cement. TGA/DTA results further corroborated the thermal stability of the hydration products formed. Alkali-solubility assessments of the raw materials emerged as reliable indicators of their reactivity within the cement matrix, with solubility values exceeding 20 % for waste glass and impounded coal ash, signifying their high potential for alkali activation. The culmination of this research underscores the feasibility of re-composing waste materials to craft alkali aluminosilicate cement, offering performance akin to conventional options. These findings advocate for the adoption of sustainable material utilization in construction, paving the way for enhanced industrial symbiosis in cement production.

Genetic confounding in the association of early motor development with childhood and adolescent exercise behavior

IntroductionEarly motor development has been found to be a predictor of exercise behavior in children and adolescents, but whether this reflects a causal effect or confounding by genetic or shared environmental factors remains to be established.MethodsFor 20,911 complete twin pairs from the Netherlands Twin Register a motor development score was obtained from maternal reports on the timing of five motor milestones. During a 12-year follow-up, subsamples of the mothers reported on the twins’ ability to perform seven gross motor skills ability (N = 17,189 pairs), and weekly minutes of total metabolic equivalents of task (MET) spent on sports and exercise activities at age 7 (N = 3632 pairs), age 10 (N = 3735 pairs), age 12 (N = 7043 pairs), and age 14 (N = 3990 pairs). Multivariate phenotypic and genetic regression analyses were used to establish the predictive strength of the two motor development traits for future exercise behavior, the contribution of genetic and shared environmental factors to the variance in all traits, and the contribution of familial confounding to the phenotypic prediction.ResultsSignificant heritability (h2) and shared environmental (c2) effects were found for early motor development in boys and girls (h2 = 43-65%; c2 = 16-48%). For exercise behavior, genetic influences increased with age (boys: h2age7 = 22% to h2age14 = 51%; girls: h2age7 = 3% to h2age14 = 18%) paired to a parallel decrease in the influence of the shared environment (boys: c2age7 = 68% to c2age14 = 19%; girls: c2age7 = 80% to c2age14 = 48%). Early motor development explained 4.3% (p < 0.001) of the variance in future exercise behavior in boys but only 1.9% (p < 0.001) in girls. If the effect in boys was due to a causal effect of motor development on exercise behavior, all of the factors influencing motor development would, through the causal chain, also influence future exercise behavior. Instead, only the genetic parts of the regression of exercise behavior on motor development were significant. Shared and unique environmental parts of the regression were largely non-significant, which is at odds with the causal hypothesis.ConclusionNo support was found for a direct causal effect in the association between rapid early motor development on future exercise behavior. In boys, early motor development appears to be an expression of the same genetic factors that underlie the heritability of childhood and early adolescent exercise behavior.

Increasing Early Childhood Creativity and Fine Motor Abilities Using Traditional Games (Bermain Lempung) in The Digital Age

Early childhood is a golden age. It is a time when the basic physical, motor, language, cognitive, independence, socializing, and creative abilities are developing rapidly. The potential for rapid early childhood development is not in line with the stimulus obtained by the child. This digital era cannot be separated from the use of gadgets for adults and children. One of the setbacks or not optimal development of children, one of which is the development of fine motor skills and creativity. This study aims to measure the effect of traditional games (Bermain Lempung) on increasing creativity and fine motor skills in early childhood. This study uses a quantitative approach with nonequivalent experimental methods (pretest and posttest) control group design. This research was conducted on students of grade B Kindergarten at RA Al Ittihad Jogoroto Jombang (n=27). The results of the pretest showed that there were 22 children in the category of medium and low creativity. And fine motor abilities showed that most of the children’s fine motor abilities were still below the average of children at their age. Subjects who had medium and low categories were divided into two control (n=11) and experimental (n=11) groups, which would be treated with Bermain Lempung activities. Collecting data using creative observation instruments and the bender gestalt for fine motor skills. Data were analyzed using SPSS 18.0 with the statistical technique independent sample T-test. The results showed that the influence of traditional games, namely Bermain Lempung with increased creativity and fine motor skills, had no effect because of the limited time intensity.&#x0D; Keywords: traditional game, childhood, motor skill

Phase 2 study of tarlatamab, a DLL3-targeting, half life–extended, bispecific T-cell engager (HLE BiTE)immuno-oncology therapy, in relapsed/refractory small cell lung cancer (SCLC).

TPS8603 Background: SCLC is characterized by rapid growth and early development of metastases. Platinum-based first-line chemotherapy is associated with a high initial response rate; however, disease recurrence is common. Delta-like ligand 3 (DLL3) is a Notch ligand that is upregulated and aberrantly expressed on the cell surface in most SCLC, making it a compelling therapeutic target. Tarlatamab is an HLE BiTE immuno-oncology therapy designed to bind DLL3 on target cancer cells and CD3 on T cells, forming a cytolytic synapse inducing T cell activation and expansion and T cell-dependent killing of tumor cells. Interim results of an ongoing first-in-human study in patients with relapsed/refractory SCLC (NCT03319940) show preliminary evidence for tarlatamab efficacy in pretreated patients with confirmed partial responses in 20% of patients and duration of response of 8.7 months (Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4–8, 2021; Virtual). Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 27% of patients and TRAEs resulted in discontinuation in 5% of patients. This promising efficacy/safety profile supports further study of tarlatamab in SCLC. Methods: NCT05060016 is a phase 2, open-label study evaluating tarlatamab in patients with relapsed/refractory SCLC after two or more lines of prior treatment. Part 1 is a dose characterization phase in which subjects will be randomized 1:1 to two active doses of tarlatamab. Part 2 will continue enrollment for the selected target dose only based on interim analysis of Part 1. Key eligibility criteria include adults with histologically or cytologically confirmed SCLC whose disease progressed/recurred after two or more lines of prior treatment including at least 1 platinum-based regimen (including a PD-L1 inhibitor, if standard of care, with certain exceptions per protocol), treated brain metastases, ECOG performance status ≤1, and life expectancy ≥ 12 weeks in the opinion of the investigator. The primary endpoint for the primary analysis is ORR per RECIST 1.1 as assessed by blinded independent central review. Secondary objectives are to evaluate antitumor activity by additional measures (duration of response, progression-free survival, disease control rate and duration, overall survival), safety and tolerability, immunogenicity, and pharmacokinetics. Sites in North America, Asia and Europe are participating in the trial with subjects already enrolled and enrollment ongoing. Clinical trial information: NCT05060016.

P64.01 The Canadian Small Cell Lung Cancer Database (CASCaDe): A Multi-Institutional Real-World Evidence Collaboration

Small cell lung cancer (SCLC), a poorly differentiated neuroendocrine tumor distinguished by rapid doubling time and early development of metastases, represents approximately 15% of all diagnosed lung cancers. Median survival is poor regardless of stage at diagnosis. Good evidence exists to guide upfront management of both limited (LS) and extensive stage (ES) SCLC, and several recent trials have shown significant survival benefits with the addition of immunotherapy to chemotherapy in ES-SCLC. However, upon relapse, there is modest prospective evidence available to guide management.

Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by a rapid initial response and early development of resistance to systemic therapy and radiation. The management of SCLC significantly changed for the first time in decades with the introduction of immune checkpoint inhibitors. Pembrolizumab, a humanized IgG4 isotype antibody, targets the programmed cell death protein 1 (PD-1) pathway to restore anti-tumor immunity. Prospective trials of pembrolizumab in patients with previously treated SCLC showed significant durability of responses. These results led to the U.S. Food and Drug Administration (FDA) granting pembrolizumab accelerated approval as second- or third-line monotherapy for patients with extensive-stage (ES) SCLC. In a recent clinical trial that included patients with previously untreated ES-SCLC, pembrolizumab in combination with platinum/etoposide met its progression-free survival endpoint, but overall survival (OS) did not cross the threshold for superiority. With the therapeutic landscape for SCLC rapidly evolving, we review prior experience and future directions of pembrolizumab in ES-SCLC.

Hydration behaviour of limestone-calcined clay and limestone-slag blends in ternary cement

The effect of kaolinitic calcined clay and slag on the hydration of limestone-containing ternary blended cements was investigated. The effect of alumina from different sources of SCMs was considered to activate the formation of carboaluminates. Ternary blends with 50% ordinary portland cement clinker, 45% blends of limestone calcined clay (LC2) in 1:2 blend and slag limestone blend (SLS) in 2:1 mix proportion with 5% of gypsum were studied. The hydration behaviour was analysed based on cement mortar compressive strength, heat of hydration using an isothermal calorimeter and bound water measured using thermal gravimetric analysis (TGA). In addition, the degree of hydration of clinker phases and the composition of calcium - alumino - silicate - hydrate (C-A-S-H) gels forming in two different systems were compared on 90 days hydrated samples analysed using X-Ray diffractometry (XRD) and scanning electron microscopy - energy dispersive X-ray spectroscopy (SEM-EDX) respectively. The results show a rapid early strength development in limestone calcined clay cement blend (LC3) but a lower clinker hydration in comparison with slag limestone cement blend (SLSC) at later ages. In both the cement blends the formation of hemicarboaluminate (Hc) and monocarboaluminate (Mc) was confirmed at 90 days, but the conversion of Hc to Mc was higher in SLSC. Results further confirmed a lower degree of hydration and higher alumina incorporation in the C-A-S-H gel in the LC3 comparison to SLSC. The presence of calcium hydroxide was also confirmed in the SLSC blend due to the hydraulic nature of slag that supported the later age conversion of Hc to Mc as not seen in LC3.

In vitro spore germination and early gametophyte development of Cibotium barometz (L.) J. Sm. in different media

Abstract. Isnaini Y, Praptosuwiryo TNg. 2020. In vitro spore germination and early gametophyte development of Cibotium barometz (L.) J. Sm. in different media. Biodiversitas 21: 5373-5381. Cibotium barometz (L.) J. Sm. is known as the golden chicken fern and included in Appendix II of CITES. It is an important export commodity for traditional and modern medicine. Globally, populations of this species are under significant pressure due to overexploitation in the wild. In vitro culture is one of the technologies used for ex-situ propagation and conservation of rare and endangered ferns and lycophytes. This study’s objectives were: (i) to observe in vitro spore germination and early gametophyte development of C. barometz, and (ii) to determine the best culture medium for rapid spore germination and early development of the gametophytes. The sterilized spores were sown in half-strength Murashige &amp; Skoog (½MS) basal medium supplemented with combinations of 6-Benzylaminopurine (BAP) and α-Naphthalene acetic acid (NAA). A factorial combination of four BAP concentrations (0, 2, 4, and 6 mg L-1) with four concentrations of NAA (0; 0.01; 0.03 and 0.05 mg L-1) created 16 treatments replicated in a Completely Randomized Design. Spore germination of C. barometz was observed to be Vittaria-type, and its prothallial development was Drynaria-type. Spore germination started 7-14 days after sowing. Young heart-shape gametophytes consisting of 110-240 cells were formed in 45-61 days after sowing. The two best spore culture media for rapid spore germination and development of C. barometz gametophytes were ½ MS with or without 2 mg L-1 BAP.

Rapid Early Brain Development Highlights a Critical Period and Possible Intervention Window

Rapid Early Brain Development Highlights a Critical Period and Possible Intervention Window

The older plant gets the sun: Age‐related changes in Miscanthus × giganteus phenology

AbstractAge‐related changes are usually overlooked in perennial grass research; when they are considered it is usually as a change in plant size (e.g., biomass). Whether other physiological or developmental aspects change as stands age, and how those aspects may impact long‐term stand dynamics, remains unclear. Conventional experimental designs study a single stand over multiple growing seasons and thereby confound age‐related changes with growing season conditions. Here we used a staggered‐start experimental design with three repeated planting years over two growing seasons to isolate growing season effects. We studied changes in Miscanthus × giganteus phenology during its yield‐building stage (first 3 years) and estimated age, growing season and nitrogen (N) effects on development using nonlinear regression parameters. Stand age clearly changed plant growth; faster developmental rates were usually seen in 1‐year‐old stands (young), but because 2‐ and 3‐year‐old stands (mature) emerged 3 months earlier than newly planted stands they produced 30% more stems with 30%–60% more leaves. Nitrogen fertilization modulated some age‐related phenological changes. Fertilized 2‐year‐old stands reached similar stem densities as unfertilized 3‐year‐old stands and had fewer number of senesced leaves like 1‐year‐old stands. In addition, N fertilization had no effect on young M. × giganteus, but extended mature stands’ growing season more than 2 weeks by hastening emergence and delaying senescence. It also delayed flowering regardless of stand age. Our results suggest that, along with changes in size, M. × giganteus stands showed shifts in developmental strategies: young stands emerged later and developed faster, while mature stands grew for longer but more slowly. In temperate regions, where hard frost events are likely to interrupt development in late autumn, rapid early development is critical to plant survival. Nonlinear regression parameter differences proved effective in identifying phenological shifts.

Engineered Cementitious Composites (ECC) with limestone calcined clay cement (LC3)

Recent research have recognized that coupled use of calcined clay, limestone and cement clinker in concrete is viable to reduce environmental footprints at manufacture and to enhance material durability. In this study, a novel application of the limestone calcined clay cement (LC3) is demonstrated by substituting the Ordinary Portland Cement (OPC) in Engineered Cementitious Composites (ECC). The composite mechanical properties including σ-δ and σ-ε relationships and residual crack widths were evaluated to 28 days under uniaxial tension. Matrix chemistry was characterized using thermogravimetric analysis and X-ray diffraction, while the pore structure of matrices and composites was analyzed using mercury intrusion porosimetry. The LC3-based ECC showed more rapid early strength development but lower 28-day strength (~32 MPa) due to a 20% higher water-to-solid ratio for attaining adequate workability and fiber dispersion. Nevertheless, the tensile strain capacity of LC3-based ECC achieved over 6% with an average residual crack width less than 50 μm. Additionally, the composite pore structure exhibited a decreasing volume fraction of large pores and voids (>100 nm) after substituting LC3 for OPC. The use of LC3 marginally decreased the embodied material energy and cost, but led to about 32% and 28% reductions in CO2 emissions compared to traditional OPC-based ECC and concrete, respectively. As a preliminary study, LC3-based ECC shows promise as a greener ductile concrete compared with OPC-based ECC.

Evaluation of Chloride Resistance of Early-Strength Concrete Using Blended Binder and Polycarboxylate-Based Chemical Admixture

The mixing proportions of concrete were examined with regard to the durability performance and early strength in coastal areas. Research was conducted to improve the C24 mix (characteristic strength of 24 MPa). C35 concrete (characteristic strength of 35 MPa) was selected as a comparison group, as it exhibits the minimum proposed strength criterion for concrete in the marine environment. To secure the early strength of the C24 concrete, 50% of the total ordinary Portland cement (OPC) binder was replaced with early Portland cement (EPC); and to provide durability, 20% was substituted with ground granulated blast-furnace slag (GGBS). In addition, a polycarboxylate (PC)-based superplasticizer was used to reduce the unit water content. The compressive strength, chloride ion diffusion coefficient, chloride penetration depth, and pore structure were evaluated. After one day, the compressive strength improved by 40% when using EPC and GGBS, and an average increase of 20% was observed over 91 days. EPC and GGBS also reduced the overall porosity, which may increase the watertightness of concrete. The salt resistance performance was improved because the rapid early development of strength increased the watertightness of the surface and immobilization of chloride ions, decreasing the chloride diffusion coefficient by 50%.

SARS-CoV-2: an unknown agent and challenges in vaccine development

SARS-CoV-2: an unknown agent and challenges in vaccine development

Early maturation of the social brain: How brain development provides a platform for the acquisition of social-cognitive competence.

Across the last century psychology has provided a lot of insight about social-cognitive competence. Recognizing facial expressions, joint attention, discrimination of cues and experiencing empathy are just a few examples of the social skills humans acquire from birth to adolescence. However, how very early brain maturation provides a platform to support the attainment of highly complex social behavior later in development remains poorly understood. Magnetic Resonance Imaging provides a safe means to investigate the typical and atypical maturation of regions of the brain responsible for social cognition in as early as the perinatal period. Here, we first review some technical challenges and advances of using functional magnetic resonance imaging on developing infants to then describe current knowledge on the development of diverse systems associated with social function. We will then explain how these characteristics might differ in infants with genetic or environmental risk factors, who are vulnerable to atypical neurodevelopment. Finally, given the rapid early development of systems necessary for social skills, we propose a new framework to investigate sensitive time windows of development when neural substrates might be more vulnerable to impairment due to a genetic or environmental insult.

Rapid early development and feeding benefits an invasive population of lake trout

Lake trout (Salvelinus namaycush) were discovered in Yellowstone Lake in 1994 and their population expanded dramatically despite intensive suppression. The lake is species-depauperate, with no major lake trout embryo predators. We hypothesized that without this predation threat, lake trout free embryo feeding and growth may be greater than in their native range, leading to increased survival of age-0 individuals and rapid population growth. We compared length, developmental rate, and feeding patterns of lake trout free embryos captured at a spawning site in Yellowstone Lake with free embryos captured in their native range in Lake Champlain, Vermont. More embryos were feeding, contained more food, and were significantly longer at the same developmental stages in Yellowstone Lake. With an abundance of available food and minimal threat of predation, free embryos remained on the spawning site in Yellowstone Lake later into the summer than in Lake Champlain and achieved a greater maximum length before they dispersed. Greater food consumption and associated growth likely leads to high survival of lake trout free embryos in Yellowstone Lake, contributing to rapid population growth.

Behavioural development in southern right whale calves

ABSTRACT: Most baleen whales migrate to low-latitude breeding grounds during winter to give birth and nurse their calves during the early stages of growth and development. While mothers invest a large amount of energy into the early development of their calves, the time allocated to important behaviours associated with maternal care (e.g. nursing) as well as the energetics related to the rapid growth of calves are important to quantify and understand to inform conservation measures. To investigate this, we conducted behavioural focal follows of southern right whale Eubalaena australis mother-calf pairs on a breeding ground in South Australia using unmanned aerial vehicles. Over the breeding season, we conducted behavioural focal follows of 51 mother-calf pairs for a total of 58 h across 75 d. Our observations showed that the proportion of time calves spent in nursing position and the duration of potential nursing bouts increased with increasing calf size throughout the breeding season, suggesting that calves seek to maximise energy acquisition. With increasing body size, the absolute metabolic expenditure of calves increased, underlining the importance of mothers being able to maintain low energy expenditure to ensure sufficient energy available for their calves during the nursing season. Our findings from this undisturbed population (1) demonstrate the considerable changes that calves undergo during the ~3 mo they spend on the breeding ground and (2) highlight the importance of these areas to be protected from anthropogenic disturbances that could disrupt the crucial maternal care, energy transfer and rapid early development of calves.

Developmental dynamics of the epigenome: A longitudinal study of three toddlers

Epigenetic regulation plays an important role in development, at the embryonic stages and later during the lifespan. Some epigenetic marks are highly conserved throughout the lifespan whereas others are closely associated with specific age periods and/or particular environmental factors. Little is known about the dynamics of epigenetic regulation during childhood, especially during the period of rapid early development. Our study was aimed to determine whether the developmental program at the early stages of human development is accompanied by significant changes in the systems of genome regulation, specifically, by genome-wide changes in DNA methylation. Using a sequencing approach (MBD-seq) we investigated genome-wide DNA methylation patterns in the T-lymphocytes of three healthy toddlers at two timepoints within the second year of life. Pairwise comparison of the methylation patterns across the individuals and time points was conducted to determine common longitudinal changes in the DNA methylation patterns. Despite relatively high interindividual variability in their epigenetic profiles and the dynamics of these profiles during the second year of life, all children showed consistent changes in the DNA methylation patterns of genes involved in the control of the immune system and genes related to the development of the CNS. Thereby, we provide evidence that early development might be accompanied by epigenetic changes in specific functional groups of genes; many such epigenetic changes appear to be related to the rapid development of the CNS.

A phase 3, randomized study of first-line durvalumab (D) ± tremelimumab (T) + platinum-based chemotherapy (CT) vs CT alone in extensive disease small-cell lung cancer (ED-SCLC): Caspian.

TPS8586 Background: SCLC accounts for ~13% of all lung cancers and is characterized by rapid growth and early metastases development. Standard of care CT for pts presenting with ED-SCLC is associated with the development of resistance, leading to poor treatment outcomes. As such, new therapies are needed. The high mutation burden associated with SCLC provides a rationale for investigating immune checkpoint blockade in this tumor type. D is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. T is a selective human IgG2 mAb against CTLA-4. D alone and in combination with T has demonstrated a manageable safety profile and encouraging antitumor activity in non-small cell lung cancer (NSCLC). D ± T in combination with CT has also shown acceptable tolerability and preliminary signs of clinical activity in advanced NSCLC and thus may provide benefit in SCLC. Methods: CASPIAN (NCT03043872) is a Phase 3, randomized, multicenter, open-label, global study to determine the efficacy of CT in combination with D ± T as first-line treatment in ED-SCLC (Stage IV). Treatment-naïve pts (N = ~795; WHO/ECOG PS 0 or 1) will be randomized 1:1:1 to receive D (1500 mg) + T (75 mg) i.v. every 3 weeks (q3w) + CT (Arm 1); D (75 mg) i.v. q3w + CT (Arm 2); or CT alone (Arm 3). D ± T will be concurrently administered with CT in Arms 1 and 2 and will continue post-CT (1 further dose for T; until confirmed progressive disease for D). CT (etoposide [80–100 mg/m2] i.v. on Days 1–3 q3w + carboplatin [AUC 5–6] i.v. on Day 1 q3w or cisplatin [75–80 mg/m2] i.v. on Day 1 q3w) will be given for up to 4 cycles in Arms 1 and 2 and up to 6 cycles in Arm 3. The co-primary endpoints are overall survival (OS) and progression-free survival (PFS) using blinded independent central review (RECIST v1.1), for Arm 1 vs Arm 3. Secondary endpoints include OS and PFS for Arm 2 vs Arm 3 and Arm 1 vs Arm 2, ORR, OS at 18 months, proportion of patients alive and progression free at 6 and 12 months, PK, immunogenicity, HRQoL, and safety and tolerability. Exploratory endpoints include PFS after subsequent anticancer therapy and correlation of biomarkers with response to treatment. Recruitment is ongoing. Clinical trial information: NCT03043872.