Recommended Dose Research Articles

Abstract CT185: A phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of BC3402 in advanced solid malignancies

Abstract Background: BC3402, an IgG4 monoclonal antibody (mAb) that targets TIM-3, is being developed for solid and hematological malignancies. In preclinical studies in immunocompetent cancers, BC3402 demonstrated synergy when combined with mAbs to PD-1 and/or CTLA-4, supporting a rationale for combination strategies in the clinic. As a first step, the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary anti-tumor activity of BC3402 monotherapy was evaluated in patients (pts) with advanced solid malignancies. Methods: In this phase I, open-label study, multiple doses of BC3402 were explored in pts with advanced solid cancers who had been previously treated with standard therapies to evaluate its safety and tolerability and recommend doses for further development. An accelerated titration design was used to select doses in the first two dose levels (0.02 and 0.2mg/kg IV Q3W) followed by a standard “3+3” design in the remainder of the study (1, 5, 10, 20 and 30 mg/kg IV Q3W). Results: Nineteen pts (median [range] age: 59 [29-73]; 63.2% male; 94.7% ECOG 1) were treated with at least one 3-week cycle of BC3402. DLT was not observed, and adverse events (AEs) were not dose related. The most common TEAEs (incidence ≥20%) and TRAEs (incidence ≥10%) were grade 1-2. The most common (incidence ≥10%) TEAE ≥ grade 3 was dysphagia (2/19 pts, 10.5%), which occurred in the 5 mg/kg and 10 mg/kg dose cohorts. Two pts reported grade 3 or above TRAEs – grade 3 hypertension (5 mg/kg) and grade 3 gamma-glutamyl transferase increase (10 mg/kg), There were neither dose interruptions nor treatment discontinuation due to AEs. There were no objective responses. Seven of 18 pts who were evaluable for tumor assessment had stable disease as best response with one pt (20 mg/kg dose cohort) with NSCLC having sustained reductions (32 weeks) in target lesions. Median Tmax values ranged from 1.08 to 2.96 hours, and mean T1/2 values ranged from 119 to 182 hours at doses ranging from 5-30 mg/kg. Exposure was linear in the dose range of 1 -30 mg/kg, and there was no drug accumulation after the second cycle. Receptor occupancy saturation was observed within the tested dose range. Based on these data, the RP2D was determined as 20mg/kg every 2 weeks or 30mg/kg every 3 weeks. Conclusions: BC3402 exhibited favorable safety profile and PK characteristics when administered as single infusion at doses ranging from 0.02 mg/kg to 30 mg/kg Q3W in pts with advanced solid cancers, and its safety profile supports further disease-directed studies in combination with other immune checkpoint inhibitors and/or rational therapeutic modalities. Citation Format: Yi-Long Wu, Huajun Chen, Sheng Wang, Rui Zhang, En-Tzu Tang, Weiwei Zhang, Kaicun Gu, Yiwei Wang, Yongjiang Hei. A phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of BC3402 in advanced solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT185.

Assessing Growth, Productivity, Profitability and Yield Gaps of Spring Maize Using Site Specific Nutrient Management Approaches in Kailali

A field experiment was conducted during spring season of 2023 at the sub-tropical climate of Tikapur, Kailali to evaluate the impact of site-specific nutrient management on growth, productivity, profitability and yield gaps of spring maize. The experiment followed a Randomized Complete Block Design (RCBD) with six treatment combinations and four replications. Maize seeds were sown in four different farms on 27 February, 2023 with different site-specific nutrient management (SSNM) approaches viz. with Nutrient Expert®-Maize recommended dose (T1), three omission plots i.e., Omission of Nitrogen (T2), Omission of Phosphorus (T3), Omission of Potassium (T4), Government Recommended Dose (T5), and Farmer’s Fertilizer Practices (T6). Using the Nutrient Expert® Maize model Computer Software, the SSNM+NE dose was recommended via a household survey in the respective farmer's field before the start-up of the experimentation. Various growth parameters, yield, yield attributing traits, and total cost of production of spring maize were recorded and subjected to analysis using Duncan's Multiple Range Test (DMRT) in R-studio. The results revealed that the highest grain yield (3.71 t ha-1) was achieved with SSNM+NE, which was statistically at par with the Government Recommendation Dose (3.12 t ha-1). Moreover, SSNM+NE showed significantly higher thousand grains weight (442.75 g) and straw yield (6.81 t ha-1), respectively. Notably, the straw yield, grain yield, and thousand grain weight of SSNM+NE were statistically comparable to those obtained with the government recommendation. Economic analysis showed higher benefit-cost ratio as well as increased net and gross returns in SSNM+NE as compared to the other nutrient management practices. The SSNM+NE and Governmental Recommended Fertilizer based treatments were about 231% and 178% advantageous over the Farmer’s Fertilizer Practices. It could be suggested that SSNM+NE would the best approach for increasing the growth, productivity and profitability of spring maize in the sub-tropical terai of Far Western Nepal.

Conjoint Application of Lime, Organics, Inorganic Fertilizers, and Bio-fertilizers Increases Groundnut Productivity, Available Phosphorus and Microbial Biomass Phosphorus in Acidic Soil of Tripura, India

In Tripura, India the soil productivity is less due to its light texture, acidic in nature, low fertility status, low microbial activity. Thus, a field experiment on groundnut (Arachis hypogaea L.) was carried out on acidic soil of Khowai district of Tripura during 2017 and 2018 to evaluate the impact of the application of various combinations of lime, farm yard manure (FYM), poultry manure (PM), and rhizobium with the recommended doses of NPK on groundnut productivity, available phosphorus (P) and microbial biomass phosphorus (MBP) content of acidic experimental soil. The experiment was conducted using a randomized block design (RBD) with 13 treatments with various combinations of application of lime, farm yard manure (FYM), poultry manure (PM), and rhizobium with the recommended doses (RD) of NPK, each having 3 replications. Both initial and post-harvest soil samples were collected and analyzed to estimate the available P and MBP content. Results indicated that the use of the different combinations of the RD of NPK accompanied by the application of lime, organic manure (FYM or PM) and seed treatment with Rhizobium significantly increased available P and MBP content in the post-harvest soil which has resulted in increased seed yield of groundnut compared to the RD of NPK alone. Again, the use of RD of NPK @ 20:60:40 kg ha-1 conjointly with lime (@ 1/5th LR), PM (@ 5 t ha-1), and treating the seeds with Rhizobium @ 20 g kg-1 of seed might be recommended to the growers in achieving higher groundnut productivity with better return in acid soil of Tripura, India, as it showed maximum enhancement in groundnut productivity as well as available P2O5 content in post-harvest soil.

Influence of Date of Transplanting and Level of Nitrogen on the Yield of Nizershail Rice Grown in Boro Season

Proper nitrogen (N) management is vital for gaining potential yield benefits of a variety. Adjusting transplanting time enables the plant taking benefit from natural conditions favorable for its growth. In light of these, an investigation was carried out in the Boro season at the Agronomy Field Laboratory, Bangladesh Agricultural University from November 2022 to April 2023 to investigate the impact of various transplanting dates and N levels on the yield of Nizershail rice. The study involved four dates of transplanting viz. 16 December, 31 December, 15 January, 30 January and four nitrogen (N) levels viz. 0, 50, 100 and 150% of the recommended dose (RD) of N from urea where the recommended dose was 90 kg urea per ha. The trial was replicated thrice using Randomized Complete Block Design (RCBD). Results showed that the tallest plant, the uppermost grains/panicle and 1000 grains weight were detected in 16 December transplanting and the maximum grain yield was observed in 31 December transplanting. For N, total tillers and effective tillers/hill, grains/panicle, the highest grain and straw yields were found from 100% RD of N and the highest panicle length and sterile spikelets/panicle were found from 150% RD of N. In interactions, the maximum effective tillers/ hill and straw yield were observed from 100% RD of N in combination with 15 January transplanting. The maximum 1000 grains weight and the grain yield were obtained from 100% RD of N in combination with 16 December transplanting. From the result, it may be assumed that to get the maximum yield of Nizershail rice in Boro season could be transplanted between 16 December to 15 January with 100% RD of N from urea.

Establishing the processing factor and degradation kinetics of hexaconazole residues in vinification and its residual impact on wine quality and aroma characteristics by GCxGC-ToF/MS analysis

Hexaconazole (HX), a triazole fungicide, is widely used for controlling mildews in commercial viticulture, and residues at harvest are a challenge. The pesticide residues in the harvested grapes may impact the grape and wine quality. In this study, we have investigated the fate of HX residues in the vinification with wine aroma and quality. HX was applied at the recommended dose (RD) and 10 times RD (10 RD). The HX residue dissipation exhibited first-order kinetics with a half-life of 3.5 and 2.5 days for RD and 10 RD, respectively. The processing factor from grape to wine ranged from 0.04 to 0.09, the transfer rate ranged from 2.46% to 6.47%. The HS-SPME-GCxGC-ToF/MS analysis revealed a significant impact on volatile organic compounds (VOCs). The concentration of key VOCs varied in control as esters (147.62 μg L−1), alcohols (144.81 μg L−1), acids (82.92 μg L−1) and in HX RD treated wines showed reduction in alcohols (111.32 μg L−1), esters (91.57 μg L−1) and acids (67.10 μg L−1). In 10 RD, alcohols, esters, acids were declined as 131.42 μg L−1, 118.65 μg L−1, and 75.73 μg L−1 respectively. In HX RD, 28 were up and 58 VOCs were down-regulated. 40 VOCs were up and 46 were down-regulated in HX 10 RD wine. The pathway enrichment analysis revealed impact of HX residues on glycolysis and pyruvate metabolism. Quality analysis showed variation in total flavonoids, phenols, and anthocyanin content. The results revealed that HX residues have a negative impact on wine aroma and metabolism during vinification.

A pivotal bridging study of lurbinectedin as second-line therapy in Chinese patients with small cell lung cancer

This single-arm, multi-center clinical trial aimed to evaluate the safety, tolerability, DLT, recommended dose (RD), preliminary efficacy, and pharmacokinetics (PK) characteristics of lurbinectedin, a selective inhibitor of oncogenic transcription, in Chinese patients with advanced solid tumors, including relapsed SCLC. Patients with advanced solid tumors were recruited in the dose-escalation stage and received lurbinectedin in a 3 + 3 design (two cohorts: 2.5 mg/m2 and 3.2 mg/m2, IV, q3wk). The RD was expanded in the following dose-expansion stage, including relapsed SCLC patients after first-line platinum-based chemotherapy. The primary endpoints included safety profile, tolerability, DLT, RD, and preliminary efficacy profile, while the secondary endpoints included PK characteristics. In the dose-escalation stage, ten patients were included, while one patient had DLT in the 3.2 mg/m2 cohort, which was also the RD for the dose-expansion stage. At cutoff (May 31, 2022), 22 SCLC patients were treated in the ongoing dose-expansion stage, and the median follow-up was 8.1 months (range 3.0–11.7). The most common grade ≥ 3 treatment-related adverse events (TRAEs) included neutropenia (77.3%), leukopenia (63.6%), thrombocytopenia (40.9%), anemia (18.2%), and ALT increased (18.2%). The most common severe adverse events (SAEs) included neutropenia (27.3%), leukopenia (22.7%), thrombocytopenia (18.2%), and vomiting (9.1%). No treatment-related deaths occurred. The Independent Review Committee (IRC)-assessed ORR was 45.5% (95% CI 26.9–65.3). Lurbinectedin at the RD (3.2 mg/m2) showed manageable safety and acceptable tolerability in Chinese patients with advanced solid tumors, and demonstrates promising efficacy in Chinese patients with SCLC as second-line therapy.Trial registration: This study was registered with ClinicalTrials.gov NCT04638491, 20/11/2020.

Residue dissipation kinetics, safety evaluation and decontamination of Deltamethrin in tomato and the soil

Tomato powdery mildew, fruit rot, and twig blight are all managed with Deltamethrin. Its residues could still be present in the crops, posing a health risk. The pesticide residue analysis, dissipation rate, and safety assessments were thus examined in green tomatoes. The analytical method for residue analysis was validated according to international standards. Tomato fruits and soil were used to study the dissipation of Deltamethrin 100 EC (11% w/w) at 12.5 g a.i ha−1 for the recommended dose (RD) and 25.0 g a.i ha−1 for the double of the recommended dose (DD). Ethyl acetate was used to extract residues from tomato fruit, and PSA and magnesium sulphate were used for cleanup.The fruits had recoveries ranging from 83% to 93% and the soil sample from 81.67% to 89.6%, with the limit of detection (LOQ) estimated at 0.01 mg kg−1. The matrix effect (ME) was calculated to be less than 20% for the tomato fruits and the soil.Half-lives for RD and DD were 1.95 and 1.84 days, respectively. All sampling days for both doses had dietary exposures of residues below the maximum permissible intake (MPI) of 0.16 mg person−1 day−1. The most effective method of decontaminating tomato residue containing Deltamethrin is blanching.

Application of ZnO NPs, SiO2 NPs and Date Pollen Extract as Partial Substitutes to Nitrogen, Phosphorus, and Potassium Fertilizers for Sweet Basil Production.

The reduction in mineral fertilizer usage is crucial to the production of medicinal and aromatic products for safety and health purposes. Presently, nanotechnology and the utilization of natural extracts have been extensively studied due to their significant contribution. Ocimum basilicum is commonly employed for various medicinal and aromatic applications. Therefore, randomized complete block design field experiments containing 10 treatments were conducted during the 2021 and 2022 seasons to investigate the effect of nanoparticles (NPs) of ZnO (1.5 and 2.0 g/L) and SiO2 (100 and 150 mg/L) and date palm pollen extract (DPPE) at 10 and 20 g/L either alone or in combination with the ¾ or ½ NPK recommended dose (RD). The NPK RD was served as a control treatment on basil plant production in each season. The effectiveness of ZnO NPs, SiO2 NPs, and DPPE for the decrease in NPK utilization was evaluated. Meanwhile, the most effective treatment for vegetative traits (except for plant height), essential oil %, and yield was ½ NPK RD + 20 g/L DPPE + 2.0 g/L ZnO NPs. Such a treatment increased the branch number/plant, main stem diameter, relevant chlorophyll content, fresh weight/plant, dry weight/plant, essential oil %, and essential oil yield/plant by 21.00 and 9.94%, 58.70 and 40.00%, 20.69 and 15.83%, 68.83 and 58.28%, 48.70 and 56.16%, 45.71 and 35.53%, and 113.22 and 110.32% over the control in the two seasons, respectively. For total phenol and antioxidant activity, the most effective treatments were the ¾ NPK +1.5 g/L ZnO NPs and ½ NPK +2.0 g/L ZnO NPs, respectively. Simultaneously, essential oil composition (with their compound numbers identified (11-29 for control and ¾ NPK RD + 1.5 g/L ZnO NPs)) and the percentage of total compounds, monoterpene hydrocarbons, sesquiterpene hydrocarbons, and oxygenated hydrocarbons were varied among the used applications. The major observed compounds (>8%) estragole, methyl eugenol, linalool, cineole, and caryophyllene were found in different treatments. Thus, the findings of this study indicate the favorable utilization of ZnO NPs, SiO2 NPs, and DPPE in reducing the application of NPK, which may present a novel strategy and beneficial approach.

Foliar Spray of Urea: A Sustainable Way to Minimize the Rate of Fertilizer Application for Mustard Production in Drought Prone Area of Bangladesh

From the beginning of November 2021 to February 2022, an agricultural investigation was conducted at the Agronomy Field Laboratory of Rajshahi University, Bangladesh. Three sets of replications including a Randomized Complete Block Design (RCBD) were used by this design. In this study mustard variety BARI Sarisha-11 was used with five fertilizer levels viz. T₁ = control (no fertilizer), T2 =60 % of recommended dose (RD) urea [50% of RD as soil application (SA) + 10% RD as foliar application (FA)], T3=85% of recommended dose (RD) urea [70% of RD as soil application (SA) + 15% of RD as foliar application (FA)], T4= 100% of recommended dose of urea (Traditional practice), T5= 100% of recommended dose of urea +3% magic growth as foliar application. In case of T2 and T3 (except T1 & T4) magic growth was sprayed with urea i.e. liquid fertilizers, in case of T5, only magic growth given by three times (25 DAS, 35 DAS and 45 DAS). The yield indicators under investigation were all significantly impacted by liquid fertilizer. The use of T3 treatment yielded the best figure (2.45 t ha-1 ) across yield as well as yield attributes. The following second positional values was displayed in the circumstances where T4 (2.24 t ha-1 ) or customary methods were used. The lowest values for all of traits were observed from T1 (1.45 t ha- ¹) treatment. So, it is concluded that, through the foliar application of liquid fertilizer (urea with magic growth), 15% urea can be saved compared to traditional practice.

Toxicity evaluation of oxamyl against tomato russet mite, Aculops lycopersici (Massee) (Acari: Eriophyideae) and two spotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae) under greenhouse conditions.

Agriculture sector of Saudi Arabia is growing swiftly and tomato is an important crop cultivated mostly under green houses. Unfortunately, it is facing severe infestation due to divers mite species. Present study, relates to evaluation of toxicity of oxamyl against two phytophagous mites; Aculops lycopersici and Tetranychus urticae, isolated from tomato plants suffering from infestation. Simultaneous effect of oxamyl on two predatory mites; Neosiulus cucumeris and Euseius scutalis, was also evaluated. Three concentrations of oxamyl; half of the recommended dose (HRD), recommended dose (RD) and double recommended dose (DRD), were used against each mite specie to observe mortality within seven days as compared to the control. Significant mortality of 97.91% and 93.92% was observed in A. lycopersici and T. urticae, respectively at RD. In case of predatory mites; N. cucumeris and E. scutalis, mortality was 60.61% and 64.48%, respectively, under same conditions. Mortality of mites observed at HRD was insignificant and there was negligible increase in mortality at DRD. Oxamyl being less toxic to predatory mites and significantly mortal to phytophagous mites is recommended as a tool to as a tool to achieve biological control parallel to pesticidal effect.

Growth and production of upland rice (Oryza sativa L.) in ultisol using liquid organic fertilizer and NPK

One of the efforts to increase rice production in the dry land of ultisol such as in Riau is extensification. To alter low nutrient availability in ultisol, liquid organic fertilizer (LOF) from waste of banana corm and NPK fertilizers are evaluated. Research aimed to obtain the best dose of LOF and NPK fertilizers to improve the productivity of upland rice on ultisols. This experiment was arranged in a completely randomized factorial design consisting of two factors. The first factor was LOF from banana corm (0 mL, 50 mL, 100 mL, and 150 mL per polybag). The second factor was NPK fertilizers (0%, 25%, 50%, and 100% recommendation dose); the recommendation base was: 300 kg Urea, 100 kg TSP, and 100 kg KCl ha-1. The results indicated that the application of 150 mL LOF per polybag and NPK fertilizers at 100% recommendation significantly enhances plant height, number of tiller numbers, productive tiller, filled grain per panicle, and dry grain weight of Inpago 9 variety.
 Keywords: rice; organic matter; inorganic; sub-optimal soil

Clinical Phase I Study of TAS102/Irinotecan/Bevacizumab Combination Therapy in Japanese Patients With Unresectable Metastatic Colorectal Cancer (mCRC).

In this phase I study, we aimed to examine the safety of a triple combination (TAS-102/irinotecan/bevacizumab) therapy in patients with previously treated metastatic colorectal cancer (mCRC). In the TAS-102 dose-escalation phase, we determined dose-limiting toxicity (DLT), estimated the maximum tolerated dose (MTD), and determined the recommended dose (RD); in the expansion phase, we evaluated safety. The RD was administered in advance for 10 patients. The TAS-102 dose was increased to 25-35 mg/m2 and administered orally twice on days 1-5 and 8-12. Irinotecan (100 mg/m2) and bevacizumab (5 mg/m2) were administered on days 1 and 15 of the treatment, respectively. Fifteen patients were enrolled in dose-escalation Levels 1-3, and ten in the expansion phase. A 30 mg/m2 TAS-102 dose at Level 2 was administered to three patients, with one presenting grade 4 neutropenia. A 35 mg/m2 TAS-102 dose at Level 3 was administered to five patients, with three patients presenting grade 4 neutropenia and grade 3 DLTs. We added three patients at Level 2 and set the MTD at 30 mg/m2, with no DLTs. The RD was fixed at 25 mg/m2, with no DLTs (N = 10) or treatment-related deaths. One patient showed complete response at Level 2, four presented partial response, and eleven individuals maintained stable disease for over four months. The median progression-free survival duration was 7.6 months, while the median overall survival period was 16.9 months. The TAS-102/irinotecan/bevacizumab combination therapy was safe, effective, and well-tolerated in patients previously treated with mCRC.

Abstract B130: Phase 1 study of Zanidatamab Zovodotin (ZW49): Safety Profile and Recommended Dose (RD) in patients with Human Epidermal Growth Factor 2 (HER2)-positive solid cancers

Abstract Background ZW49 is a novel, humanized, antibody-drug conjugate comprised of a bispecific antibody directed against 2 non-overlapping HER2 epitopes and attached to a proprietary auristatin toxin with a protease-cleavable linker. Here we present data supporting the selection of the ZW49 RD in an ongoing, first-in-human, dose escalation (DE) and dose expansion (DX) study (NCT03821233).1 Methods The 3+3 DE phase evaluated safety and tolerability of ZW49 IV (1-1.75 mg/kg QW; 1-2 mg/kg Q2W; and 2-3 mg/kg Q3W) in pts with HER2+ cancers. The DX phase further evaluated safety and antitumor activity of ZW49 IV (1.25 and 1.5 mg/kg QW; 2.5 mg/kg Q3W) in pts with centrally confirmed HER2+ (IHC 3+ or IHC 2+/FISH+) cancers. Primary endpoints are safety, tolerability, and maximum tolerated dose/RD. Secondary endpoints are pharmacokinetics (PK) parameters and response per RECIST1.1. Analyses of data for 66 pts treated with ZW49 at select cohorts/regimens in DE and DX are herein presented. Results As of 19 Dec 2022, 66 pts (n = 18, 1.25 mg/kg QW; n = 18, 1.5 mg/kg QW; and n = 30, 2.5 mg/kg Q3W; male, 52%; median age, 60.5 years [range, 32 – 83]) were treated with ZW49 in the selected population. The most common cancer types were gastric (35%) and breast (15%); 67% of pts had received prior HER2-targeted therapy; median number of prior metastatic therapies was 3 (range, 1 – 13). The overall incidence of treatment-related adverse events (TRAEs) was 91% (100% [18/18 pts] in 1.5 mg/kg QW, 93% [28/30 pts] in 2.5 mg/kg Q3W, and 78% [14/18 pts] in 1.25 mg/kg QW regimens). Overall, the most common (≥ 20%) TRAEs were keratitis (44%), alopecia (26%), and diarrhea (24%); the majority were Grade (Gr) 1 or 2 in severity; Gr 3 or 4 TRAEs occurred in 14 (21%) pts. Serious TRAEs occurred in 4 (6%) pts. Eight pts discontinued (D/C) due to TRAEs, including 1 pt D/C due to a serious TRAE (Gr 4 infusion-related reaction [IRR]; 2.5 mg/kg Q3W). No interstitial lung disease or TR-deaths were reported. Seven dose-limiting toxicities (DLTs) occurred, including 4 DLTs in 1.5 mg/kg QW (3 Gr 2 keratitis events and 1 Gr 3 diarrhea), 2 DLTs in 1.25 mg/kg QW (Gr 3 blurred vision and Gr 3 IRR), and 1 DLT in 2.5 mg/kg Q3W (Gr 2 keratitis) regimens. The 1.5 mg/kg QW regimen was closed due to the frequency of DLTs and dose modifications observed. The safety profile was comparable between the 1.25 mg/kg QW and 2.5 mg/kg Q3W regimens. Preliminary PK analyses indicated that the half-life was similar across these dose/regimens. The confirmed objective response rate and disease control rate in HER2+ response-evaluable pts were 6% (1/17 pt) and 53% (9/17 pts) in 1.25 mg/kg QW regimen; and 31% (9/29 pts) and 72% (21/29 pts) in 2.5 mg/kg Q3W regimen, respectively. Based on these results, 2.5 mg/kg Q3W regimen was chosen as the RD. Conclusions ZW49 2.5 mg/kg Q3W IV was well tolerated, showed encouraging antitumor activity in heavily pretreated pts with advanced HER2+ cancers, and has been identified as the RD for further clinical development. References 1 Jhaveri K, et al.; ESMO; Sep 09 -13 2022 Citation Format: Do-Youn Oh, Philippe L Bedard, Keun-Wook Lee, Hyo Sook Han, Yoon-Koo Kang, Wilson H Miller, Sun Young Rha, Jwa Hoon Kim, Efrat Dotan, Chih-Yi Liao, Anthony Tolcher, Alexander Spira, Erika Hamilton, Christos Karapetis, Lisa Boyken, Charles Chen, Joseph Woolery, Komal Jhaveri. Phase 1 study of Zanidatamab Zovodotin (ZW49): Safety Profile and Recommended Dose (RD) in patients with Human Epidermal Growth Factor 2 (HER2)-positive solid cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B130.

Safety and Preliminary Efficacy of DFV890 in Adult Patients with Myeloid Diseases: A Phase 1b Study

Background and Significance: Patients (pts) with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) have a high unmet medical need, with limited standard-of-care therapeutic approaches, particularly after failure of response to first-line agents, and with allogeneic hematopoietic transplant as the only potential curative option. Through the production of interleukin (IL)-1β and IL-18, the NLRP3 inflammasome has been implicated as a major driver of inflammation associated with acute and chronic inflammatory diseases. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms such as MDS and CMML contributing to ineffective hematopoiesis and clonal progression (Hamarsheh 2020; Basiorka 2016). DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death in response to a wide variety of NLRP3-dependent danger signals, both in vitro and in vivo. Therefore, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to pts by improving hematopoiesis. Study Design and Methods: This is an open-label, phase 1b, multicenter study with a randomized dose-optimization part and a dose-expansion part consisting of two groups evaluating DFV890 in pts with very low, low, or intermediate risk MDS (LR-MDS) per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML (LR-CMML) per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). Eligible pts must be 18 years of age, with an Eastern Cooperative Oncology Group performance status ≤2, candidates for serial bone marrow assessments who are willing to undergo a bone marrow aspirate/biopsy during the trial, and meet one of the following: (a) IPSS-R-defined LR-MDS who failed to respond to or did not tolerate erythropoiesis-stimulating agents (ESAs) or luspatercept or hypomethylating agents (HMAs) and pts with del 5q who failed to respond to or did not tolerate lenalidomide; (b) CPSS-defined LR-CMML who failed to respond to or did not tolerate hydroxyurea or HMAs. Key exclusion criteria include treatment with systemic antineoplastic or any experimental therapies within 28 days (or 5 half-lives, whichever longer); unresolved treatment-related toxicities prior to the first dose of study treatment; previous treatment with agents targeting the NLRP3 inflammasome and the IL-1 pathways; prior use (≤1 week or 5 half-lives, whichever is longer) of hematopoietic colony-stimulating growth factors, thrombopoietin mimetics or ESAs; and concomitant medications, known to modulate cytochrome P450 enzymes. DFV890 is administered orally twice daily (bid) for a minimum of 24 weeks (6 cycles of treatment [1 cycle=28 days]) until treatment discontinuation. In the dose-optimization part, pts are randomized to receive either low dose or high dose bid and stratified by indications. The recommended dose (RD) determined from this part is further explored in the dose-expansion part to confirm safety and tolerability of DFV890 and explore preliminary efficacy. The primary objective is to assess safety (incidence and severity of adverse events, and dose-limiting toxicities) and tolerability to then determine the optimal RD for DFV980. Secondary objectives include assessment of DFV890 pharmacokinetics, evaluation of the preliminary efficacy of DFV890 on transfusion burden, and hematologic improvement: time to onset of transfusion independence; duration of response, best overall response, overall response rate, progression-free survival, and time to progression; and reduction in spleen volume (for CMML). Key exploratory objectives include patient perceptions of tolerability as measured by patient-reported outcomes; and determination of genetic characteristics and potential predictive markers of efficacy and/or resistance. The study is currently enrolling in Singapore, Hong Kong, and the USA with plans to treat approximately 80 pts. The first patient first visit was achieved on May 8, 2023.

A Phase 1, Open-Label, Multicenter, Dose-Escalation Study of Sgr-1505 As Monotherapy in Subjects with Mature B-Cell Malignancies

Background and Significance: MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a component of the MALT1-BCL10-CARD11 complex downstream from the Bruton Tyrosine Kinase (BTK) on the B-cell receptor signaling pathway. MALT1 is a key mediator of nuclear factor kappa B (NF-κB) signaling, which is the main driver of a subset of B-cell lymphomas. MALT1 is considered a potential therapeutic target for several subtypes of non-Hodgkin B-cell lymphomas and chronic lymphocytic leukemia (CLL), including tumors with acquired BTK inhibitor (BTKi) resistance. Constitutive activation of NF-κB is a molecular hallmark of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), and MALT1 may have utility as a treatment option for ABC-DLBCL. Furthermore, a MALT1 inhibitor (JNJ-67856633) showed efficacy in mature B cell malignancies from phase 1 studies (ref 1, 2). SGR-1505 is an oral potent small molecule allosteric inhibitor of MALT1 that inhibits MALT1 enzymatic activity and demonstrates anti-proliferative activity in BTKi-sensitive (OCI-LY10) and BTKi-resistant (OCI-LY3) ABC-DLBCL cell lines. SGR-1505 administered as a single agent and in combination with the approved Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, demonstrates tumorostatic and regressive antitumor activity in ABC-DLBCL cell line-derived and patient-derived xenograft models. These data suggest that SGR-1505-mediated MALT1 inhibition may expand therapeutic options for patients with selected B-cell lymphomas, supporting further evaluation of SGR-1505 in clinical trials. Study Design and Methods: SGR-1505-101 (NCT05544019) is a phase 1, multicenter trial of SGR-1505 as monotherapy in subjects with mature B-cell malignancies (figure 1). At present, the study is open to accrual at multiple investigative sites in the US with plans to expand to Europe. The primary objective is to evaluate safety and tolerability of SGR-1505 as monotherapy and to identify the maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary objectives are to evaluate the pharmacokinetic (PK) profile, food effect, drug-drug interaction, and preliminary anti-tumor activity of SGR-1505. Key inclusion criteria are: history of mature B-cell malignancy (including aggressive and indolent B-cell lymphomas, Waldenström macroglobulinemia, and CLL); measurable or detectable disease according to the applicable disease-specific classification system (Lugano, iwCLL, WWM6); Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Patients with indolent B-cell lymphomas or CLL must have an indication for treatment and not require immediate cytoreductive therapy. Subjects with symptomatic or active CNS involvement, and other conditions or laboratory findings placing them at increased risk to the use of an investigational drug are excluded. SGR-1505 is initially dose-escalated using an accelerated titration design in cohorts of 1-6 subjects, and at higher dose levels using a conventional 3+3 design.

Effect of phosphorus fertilization on nodulation, growth, yield and quality of soybean varieties

Phosphorus is a very important nutritional element that affects soybean growth and nodule nitrogen fixation. The objective of the study was to assess the effect of phosphorus on the growth, yield and quality of different soybean varieties. In this regard, five different doses of phosphorus viz., control (no phosphorus), 50% of the recommended dose (RD) (18 kg ha-1), 100% of RD (36 kg ha-1), 150% of RD (54 kg ha-1) and 200% of RD (72 kg ha-1) were applied on eight distinct soybean varieties namely Shohag, BARI Soybean-5, BARI Soybean-6, PB-1, Binasoybean-1, Binasoybean-2, Binasoybean-3 and Binasoybean-4. The experiment was set up using a randomized complete block design with three replications, Soybean varieties showed variability in terms of plant stature, number of branches plant-1 and number of nodules plant-1. Application of 100% of RD of phosphorus gave maximum plant height, number of branches plant-1 and nodules plant-1 at 45, 60 and 75 DATs. In the case of variety, Binasoybean-1 showed the maximum number of pods plant-1, 100-seed weight, and seed yield. Application of 100% RD of phosphorus exhibited maximum number of branches plant-1, pod length, pods plant-1, seeds pod-1, seed yield, protein and oil contents. Considering the interaction effect, Binasoybean-1 responded well to the application of 100% of RD of phosphorus and gave the maximum seed yield with the highest protein content. Finally, it may be concluded that Binasoybean-1 with the application of 100% RD of phosphorus would be recommended to get desirable yield and quality of soybean.

A Phase 1 Study of PIT565, a First-in-Class, Anti-CD3, Anti-CD19, Anti-CD2 Trispecific Antibody in Patients with Relapsed and/or Refractory B-Cell Malignancies

Background and Significance: There is an unmet therapeutic need for patients with relapsed and/or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) and R/R B-cell acute lymphoblastic leukemia (B-ALL) who have failed multiple lines of therapy. PIT565 is an investigational, first-in-class, immunoglobulin G-like, trispecific antibody that targets CD19 on malignant B cells while engaging CD3 and CD2 (a costimulatory receptor) on T cells, leading to redirected T-cell cytotoxicity toward CD19-positive malignant B cells. CD2 signaling prevents transcriptional changes characteristic of exhaustion during persistent T-cell receptor stimulation of CD8 T cells. Furthermore, the loss of CD2 ligand, CD58, on tumor cells has been shown to mediate resistance to the antitumor activity by T cell-redirecting therapies, confirming the importance of CD2 activation in T cells. Findings from preclinical studies suggest that PIT565 mediates more potent and sustained antitumor T-cell responses compared with CD3 bispecifics (Lu H, ASH 2022). Study Design and Methods: This is an open-label, phase 1, multicenter study of PIT565 in patients with R/R B-NHL and R/R CD19-positive B-ALL who have relapsed/failed to respond to ≥2 lines of prior therapy (including an anti-CD20 monoclonal antibody-containing chemotherapy combination regimen for patients with R/R B-NHL) (NCT05397496). The study is ongoing with plans to enroll approximately 140 patients in Belgium, France, Israel, Italy, Japan, Singapore, Spain, and the USA. Eligible patients are ≥18 years with an Eastern Cooperative Oncology Group performance status ≤2 and have at least one bi-dimensionally measurable nodal lesion or one bi-dimensionally measurable extranodal lesion as measured via positron emission tomography-computed tomography for R/R B-NHL, and/ or morphologic disease in the bone marrow (³5% blasts) for R/R B-ALL. Patients with contraindication to tocilizumab; history of other malignant disease; active central nervous system involvement; autoimmune disease (other than patients with vitiligo, hypothyroidism only requiring hormone replacement, or psoriasis not requiring systemic treatment or conditions not expected to recur); or receiving systemic treatment with any immunosuppressive medication are not eligible. During the dose escalation part of the study, PIT565 is administered to patients with R/R B-NHL (Group A) and patients with R/R B-ALL (Group B). During the dose-expansion part, PIT565 is administered to patients with R/R large B-cell lymphoma (LBCL) who have received CD-19-directed chimeric antigen receptor (CAR)-T therapy (Group A1); patients with R/R LBCL who have not received CAR-T therapy (Group A2); and patients with R/R B-ALL (Group B1). PIT565 is administered either once weekly (Q1W) or once every 2 weeks (Q2W) with and without a priming dosing. Routes of administration (intravenous [IV] or subcutaneous [SC]) are explored in the dose-escalation phase. Patients initially receive PIT565 IV Q1W over a 28-day cycle. Q2W treatment in a 28-day cycle is explored if supported by preliminary pharmacokinetics (PK), pharmacodynamics, efficacy, and safety findings. The primary objective is to assess safety (including dose-limiting toxicities) and tolerability, and to identify the maximum tolerated dose (MTD) and/or recommended dose (RD), schedule, and route of administration for each indication. Secondary objectives include evaluation of preliminary antitumor activity (overall response rate, complete response rate, best overall response, duration of response, overall survival, and progression-free survival for B-NHL or event-free survival for B-ALL), assessment of PK and immunogenicity of PIT565 in R/R B-NHL and R/R B-ALL. The dose escalation phase is guided by an adaptive Bayesian logistic regression model following the escalation with overdose control principle. The MTD and/or RD are further explored during the dose-expansion phase.

Nitrogen, Rhizobium and molybdenum for higher soil bacterial population, N uptake and productivity of lentil (Lens culinaris) grown under rice (Oryza sativa)-fallow conditions

A field experiment was conducted during the winter (rabi) seasons of 2014–15, 2015–16 and 2016–17 in loamy soils of the Regional Agricultural Research Station, Assam Agricultural University, Shillongani, Assam, to study the effect of varying doses of nitrogen, Rhizobium and molybdenum on bacterial population in soil, N uptake, yield attributes, grain yield and economics of lentil (Lens culinaris Medikus spp. culinaris) grown after the harvesting of winter rice (Oryza sativa L.) variety ‘Gitesh’. Soil bacterial population increased with the increase in nitrogen doses. The crop grown using seeds inoculated with Rhizobium @ 50 g/kg seed and sodium molybdate @ 1 g/kg seed along with 100% of recommended dose (RD) of N (15 kg/ha) accrued in the highest bacterial population in the soil at harvesting. Seed inoculation with Rhizobium and sodium molybdate led to considerably higher bacterial population build up in soil than seed inoculation with Rhizobium and sodium molybdate separately. Nitrogen uptake by lentil got reduced with decreasing N doses, being 28.54 kg/ha under RD of N and 28.03 kg/ha under 75% of recommended N. The treatment combinations involving RD and 75% of RD of N (11.25 kg/ha) and seed inoculation with Rhizobium and sodium molybdate recorded 35.16 kg/ha and 34.97 kg/ha N uptake respectively. These 2 treatment combinations ultimately accrued in higher values for plant height, pods/plant, seeds/pod and 100-seed weight and significantly higher grain yield (928.90 and 868.89 kg/ha respectively) as compared to all other treatment combinations. Benefit: cost ratios under these 2 treatment combinations were 2.18 and 2.09 respectively. The treatment combinations were tested for maximizing lentil production utilizing rice-fallows and farmers’ acceptability in farmers’ fields during rabi 2017–18 through 3 Krishi Vigyan Kendras (KVK) in Upper Brahmaputra Valley (UBV) in Jorhat district, Central Brahmaputra Valley (CBV) in Nagaon district and Lower Brahmaputra Valley (LBV) in Nalbari district of the state. The RD of N + seed inoculation with Rhizobium and sodium molybdate yielded the highest (5.8–8.2 q/ha) at all the locations closely followed by 75% RD of N + Rhizobium + sodium molybdate (5.93–7.25 q/ha).

Maximization of flower yield in safflower (Carthamus tinctorius L.)

A study was carried out on a non-spiny hybrid safflower (Carthamus tinctorius L.) NARI-NH-1 for maximization of flower yield by altering the agronomic practices viz., dates of sowing, fertilizer levels and plant spacings. The study showed that the differences due to sowing dates, fertilizer levels and plant spacings were significant for flower and seed yield in safflower. Delayed sowing beyond first fortnight of October resulted in a decrease in both flower and seed yield. Significantly highest flower yield (199 kg/ha) and seed yield (2014 kg/ha) were recorded with an application of 150% recommended dose (RD) of fertilizers, with flower yield being 26.85% higher and seed yield 28.89% higher than the control. However, if the net returns are considered, there is noadvantage in applying more than 100% RD of fertilizer to the crop. The spacing of 45 cm x 10 cm gave significantly higher flower and seed yield over the recommended spacing of 45 cm x 20 cm. The interaction effects between dates of sowing, spacings and fertilizer levels suggested that sowing of safflower in the first week of October either with a spacing of 45 cm x 10 cm and an application of 100% or 150% RD of fertilizer or with a spacing of 45 cm x 20 cm with an application of 150% RD of fertilizer can be recommended for obtaining maximum flower and seed yield in safflower.

Integrated nutrient management module to improve productivity and economics of short grain aromatic rice (Oryza sativa)- greengram (Vigna radiata) sequence

The present field study was carried out during 2017–18 and 2018–19 rainy (kharif) and winter (rabi) seasons in order to examine the impact caused by integrated nutrient management (INM) on the yield and quality of the short grain aromatic rice (Oryza sativa L.)-greengram (Vigna radiata L.) combination. Two years experimental data concluded that integration of 50% recommended dose (RD) as fertilizer + 50% RD of nitrogen via farm yield manure (FYM) resulted in considerably higher economic yield (3837.1 and 3917.7 kg/ha) of short grain aromatic rice cv. Nua Acharamati which were at par with 75% RD as fertilizer + green manuring of dhaincha (3438.5 and 3539.1 kg/ha). Pooled data revealed that, residual effect of 50% RD as fertilizer + 50% RD of nitrogen (FYM) and 75% RD as fertilizer + Rhizobium + PSB in greengram recorded the highest number of pods/plant (18.2), seeds/pod (11.3), pod length (9.3 cm), test weight (32.7 g), seed yield (925.7 kg/ha) and stover yield (2240.7 kg/ha) in greengram cv. IPM-02-03. Application of 50% RD as fertilizer + 50% RD of nitrogen (FYM) to aromatic rice recorded the highest hulling recovery (75.8 and 75.5%), milling recovery (68.0 and 68.3%), head rice recovery (60.0, 59.7%) and crude protein content (8.75 and 9.11%) during both of the years experiment being at par with application of 75% RD as fertilizer + green manuring. Economics of the system revealed the highest gross return, net return and B:C ratio by application of 50% RD as chemical fertilizer + 50% RD of nitrogen (FYM) in rice followed by 75% RD as chemical fertilizer + Rhizobium + PSB in greengram.