Preliminary Activity Research Articles

Phase 1 study of isatuximab monotherapy in Chinese patients with relapsed/refractory multiple myeloma.

In this multi-center, Phase-1 study (NCT03733717), we characterized the pharmacokinetics (PK) of the anti-CD38 antibody isatuximab (Isa) after IV administration (primary objective), and evaluated safety, immunogenicity, and preliminary anti-myeloma activity in Chinese patients with relapsed/refractory multiple myeloma (RRMM). Isa 20-mg/kg was administered weekly (QW) in cycle 1, then biweekly (Q2W). Twenty-one extensively pretreated RRMM patients (median 4 prior lines; 95.2% refractory to last regimen), received ≥ 1 dose of Isa. After first IV-infusion, mean maximum observed concentration was 402μg/mL and mean area-under-the-concentration-versus-time curve (first 1-week dosing interval) 37,000μg·h/mL. After repeated administration, exposure (Ctrough) increased 3.11-folds (day 1/cycle 2) versus first administration (day 8/cycle 1). Safety findings were consistent with the known Isa safety profile, with no new safety signals. Any-causality, grade ≥ 3 treatment-emergent adverse events (TEAEs) were reported in 47.6% of patients. Serious, treatment-related AEs occurred in 2 patients. Isa treatment was generally well tolerated; only 1 patient discontinued due to TEAE. Preliminary efficacy results showed a 19.0% overall response rate (clinical benefit, 33.3%). Our results demonstrate a PK profile for Isa comparable to prior findings in Western and other East-Asian populations, as well as safety and tolerability of treatment with IV Isa 20-mg/kg QW-Q2W in Chinese RRMM patients.Trial registration: The trial was registered with ClinicalTrials.gov; NCT03733717. Date of first trial registration: 07/11/2018.

Safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856, a SIRT6 modulator, in coeliac disease: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial

IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a protein that serves as a transcriptional regulator of bowel epithelium regeneration. We aimed to evaluate the safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856 in healthy participants and in patients with coeliac disease. This study reports the results from a completed first-in-human, three-part, double-blind, randomised, placebo-controlled, clinical trial of IMU-856 in healthy participants and patients with coeliac disease done in Australia and New Zealand. In part A, healthy participants were enrolled in six cohorts and randomly assigned (3:1) using a block randomisation algorithm to receive single ascending doses of IMU-856 ranging from 10 mg to 160 mg or matching placebo. Based on the results from part A, three doses were selected for part B to evaluate the safety, tolerability, and pharmacokinetics of IMU-856 once daily for 14 days using the same randomisation algorithm. Part C enrolled patients with well controlled coeliac disease. Participants were centrally randomised 1:1:1 using an interactive web response system to receive either low dose or high dose of IMU-856 or placebo once daily for 28 days that included a 15-day gluten challenge starting on day 14. The primary objective was safety and tolerability of IMU-856. Safety analyses were done on all patients who received at least one dose of the study drug. The trial is registered with the ANZCTR registry (ACTRN12620000901909). Between July 27, 2020, and Oct 28, 2022, 71 healthy participants were enrolled in part A and B and assigned to either placebo (n=19) or IMU-856 (n=52). In part A and B, the IMU-856 doses were 10 mg (n=6), 20 mg (n=6), 40 mg (n=13), 80 mg (n=12), 120 mg (n=4), 160 mg (n=11). 43 patients with coeliac disease were enrolled in part C and assigned to either placebo (n=14), IMU-856 80 mg (n=14), or IMU-856 160 mg (n=15). Treatment-emergent adverse events (TEAEs) occurred in 24 (73%) of 33 participants in part A and 15 (79%) of 19 participants in part B receiving any dose of IMU-856 compared with six (50%) of 12 participants in part A and five (71%) of seven participants in part B with placebo. TEAEs were mainly mild in severity. In part C, TEAEs occured in 26 (90%) of 29 patients on any dose of IMU-856 and ten (71%) of 14 receiving placebo; the most common TEAEs with any dose of IMU-856 by preferred term were headache (13 [45%] of 29), nausea (nine [31%]), diarrhoea (eight [28%]), and abdominal distension (seven [24%]). Two serious adverse events occurred with IMU-856 treatment (one in part B [bacterial myocarditis] and one in part C [biliary colic]), both of which were unrelated to IMU-856. No dose-limiting toxicities, systematic safety laboratory changes, or deaths occurred during the study. In part C, mean decrease in villous height was -20·9 μm (SD 34·8) among patients who received IMU-856 80 mg, -22·5 μm (51·1) among those who received IMU-856 160 mg, and -60·3 μm (52·2) among those who received placebo. The favourable safety profile, along with preliminary activity, suggests that IMU-856 should be studied in future trials of coeliac disease. Immunic Australia.

Production and Antimicrobial Activities of Pyocyanin Extracts from Pseudomonas aeruginosa

Pyocyanin is a blue-green phenazine pigment synthesized by Pseudomonas aeruginosa that has significant biotechnological applications. The present study aims to investigate pyocyanin extracts of multi-drug resistant P. aeruginosa isolates sourced from hospital wastewater and evaluate their antimicrobial activity against a panel of clinically relevant pathogens such as Staphylococcus aureus, Salmonella typhi, Achromobacter xylosoxidans and Candida albicans. Nutrient broth and King’s A broth supplemented with 1% nutrient supplements such as rice water and groundnut cake powder were used as a production medium. Extracted pyocyanin was confirmed by FTIR analysis. The isolates P8 and P9 demonstrated of varying concentrations of pyocyanin in different media. Isolate P8 showed maximum pyocyanin production in King’s A broth compared to nutrient broth with pyocyanin yields 14.34 (µg/mL) and 5.63 (µg/mL), respectively, without the nutrient supplements. Preliminary antimicrobial activity of the pyocyanin extracts exhibited substantial inhibition of tested bacterial culture at a concentration of 25 mg/µl; however, did not show any antifungal activity against tested fungi.

First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors

Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).

PHYTOCHEMICAL CONTENTS, GC-MS PROFILE AND ALPHA-AMYLASE INHIBITORY POTENTIAL OF Rauwolfia vomitoria n-HEXANE ROOT EXTRACT

Rauwolfia vomitoria is a tropical medicinal plant that has been used traditionally in the management of several diseases. In this study, the phytocontents and the preliminary alpha-amylase inhibitory activity of the n-hexane extracts of R. vomitoria was investigated. The dried plant material, R. vomitoria root was extracted by macerating in n-hexane for 72 h. The phytochemical screening and quantity of the alkaloids, flavonoid, and saponins in the extract and plant materials was determined using standard methods. The Preliminary alpha amylase inhibitory activity of the extract was carried out using starch iodide reagent assay. The phytochemical contents of the root extract were determined out using Gas Chromatography and Mass spectrophotometry (GC-MS). The extraction of R. vomitoria yielded 2.30% n-Hexane extract. The phytochemical screening of the extract shows the presence of alkaloid, flavonoid, saponins, reducing sugar, de-oxy sugars and steroids while quantitative phytochemical analysis showed the root contain alkaloids: 11.2±0.06, flavonoids: 16.6 ±0.12 and saponins: 14.8 ±0.18. The extract gave a positive alpha-amylase inhibitory activity. The GC-MS indicated the presence of twelve compounds, which are basically long chain fatty acids and esters and the most abundant compound is n-Hexadecanoic acid. Most of the compounds detected have antioxidant, anti-inflammatory, antidiabetic and enzyme inhibitory activities which may explain the various traditional uses of this plant and the observed alpha-amylase inhibitory activity

Spectroscopic and biological studies of Pd(II) complexes of 5-(p-tolyl)-1,3,4-oxadiazole-2-thiol

Reactions of Na2PdCl4 with two equivalents of 5-(p-tolyl)-1,3,4-oxadiazole-2-thiol (MoxSH), afford complex of the type [Pd(MoxS)2] (1). Further reaction with equivalent mole of diphosphine ligand {Ph2P(CH2)nPPh2} ( where n = 1 dppm, 2 dppe, 3 dppp, 4 dppb, (CH2)n = dppf ) or two equivalents of triphenyl phosphine or triphenyl phosphine sulfide affords mixed-ligand complexes of the type [Pd(MoxS)2(Ph2P(CH2)nPPh2)] (2-6), [Pd(MoxS)2(PPh3)2] (7) and [Pd(MoxS)2(SPPh3)2](8). The prepared complexes were characterized using different physical and spectroscopic methods. The results indicated that the MoxS ligand behave as coordinate in a anion monodentate fashion sulfur atom to give a square planer around the metal ion. Preliminary anti-bacterial activity has been assessed against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis bacteria. The prepared complexes show good activity in compared with standard drug. [Pd(MoxS)2(dppf)] (6) displays good activity (18, 22 and 20 mm) against certain tested microbes Escherichia coli, Staphylococcus aureus and Bacillus subtilis, respectively. KEY WORDS: Complexes, Palladium, Thione, Anti-bacteria, Phosphine Bull. Chem. Soc. Ethiop. 2025, 39(1), 79-90. DOI: https://dx.doi.org/10.4314/bcse.v39i1.6

ω‐Aminomethyl Longifolene Amide Derivatives: Synthesis, Crystal Structure, Hirshfeld Surface, DFT, Antimicrobial, and Molecular Docking Studies

AbstractTwelve novel ω‐aminomethyl longifolene amide derivatives (6 a–6 l) were synthesized and characterized. The intermolecular contacts and the relationship of structure‐property for the synthesized compounds were performed with the use of two‐dimensional fingerprint plots and Hirshfeld surface method. Moreover, the chemical reactivity and geometrical characteristics of target compounds were investigated using density functional theory (DFT) method. Molecular docking studies were performed to investigate the interactions between compounds 6 a–6 l and sortase A (SrtA) from S. aureus, the carboxy terminal domain of colicin E5 (E5‐CRD) and Serine/Threonine phosphatase Z1 (PPZ1) from C. albicans, respectively, and together with their biological activities. The docking results of the synthesized compounds 6 a–6 l showed different binding efficiencies and inhibitory effects on S. aureus, E. coli and C. albicans. Furthermore, preliminary antimicrobial activity assay showed that compounds 6 f, 6 i and 6 k exhibited comparable or superior antibacterial activity against S. aureus, B. subtilis and K. pneumoniae compared to rifampicin with minimum inhibitory concentration (MIC) values from 0.488 to 0.977 μg/mL. In addition, the absorption, distribution, metabolism and excretion (ADME) and drug‐likeness properties of the synthesized derivatives were evaluated as well.

A Preliminary Antidepressant Assessment of a Novel Piperoyl Amide (Y3) Isolated and Elucidated from Piper nigrum Drupes Extract, Justifying Interaction Over MAO-A enzyme: An in vivo, in vitro and Molecular Docking Approach

This research aims to confirm the preliminary antidepressant activity of a newly discovered piperoyl amide (Y3) obtained from the extract of Piper nigrum (P. nigrum) drupes, through the inhibition of MAO-A enzyme. Column chromatography was employed for isolation and purification of Novel piperoyl-alkyl amide (Y3) which was eluted in a solvent mixture of Chloroform-Methanol (97:3). Structure elucidation was performed by implying spectroscopic techniques. Invitro in-comparison MAO activity assessment was performed between Y3 and piperine further confirmed by Molecular docking via Auto Dock Tools 1.5.6, Vina, and PyMOL. Invivo antidepressant activity was evaluated by the Despair Test in albino mice. Novel piperoyl-alkyl amide (Y3) was isolated and purified by column chromatography and elucidated spectroscopically. The antidepressant activity of Y3 at 10 and 20 mg/kg doses shown a significant decrease in immobility-time (IT) in contrast to stressed-control group at 107.0±7.6 sec (P<0.05) and 96.0±7.6 sec (P<0.01), respectively. Y3 shown a decent MAO-A inhibitory activity but lower than piperine showing IC50=20.24 µM, Vmax=1.375±0.3 nM/min/mg, Km=1.379×10-16 µM with a stronger interaction and better affinity (-12.6 kcal/mol) towards the active-site of MAO-A. Y3 was isolated and elucidated as (12E,14E)-15-(benzo[d] [1,3] dioxol-5-yl)-N-ethylpentadeca-12,14-dienamide. It proved a good antidepressant at 10 and 20 mg/kg doses. Molecular docking over MAO-A and QSAR studies depicted a better affinity score of Y3 than Piperine. Keywords: Piperoyl amide, Structure elucidation, antidepressant activity, molecular modeling, Piperine

Goondapyrones A-J: Polyketide α and γ Pyrone Anthelmintics from an Australian Soil-Derived Streptomyces sp.

An investigation of ×19 soil samples collected under the auspices of the Australian citizen science initiative, Soils for Science, returned ×559 chemically dereplicated microbial isolates, of which ×54 exhibited noteworthy anthelmintic activity against either the heartworm Dirofilaria immitis microfilaria and/or the gastrointestinal parasite Haemonchus contortus L1-L3 larvae. Chemical (GNPS and UPLC-DAD) and cultivation (MATRIX) profiling prompted a detailed chemical investigation of Streptomyces sp. S4S-00196A10, which yielded new anthelmintic polyketide goondapyrones A-J (1-10), together with the known actinopyrones A (11) and C (12). Structures for 1-12 were assigned on the basis of detailed spectroscopic and chemical analysis, with preliminary structure activity relationship analysis revealing selected γ-pyrones >50-fold and >13-fold more potent than isomeric α-pyrones against D. immitis mf motility (e.g., EC50 0.05 μM for 1; EC50 2.7 μM for 5) and H. contortus L1-L3 larvae development (e.g., EC50 0.58 μM for 1; EC50 8.2 μM for 5), respectively.

First-In-Human Dose-Escalation Study of Fianlimab, an Anti-Lymphocyte Activation Gene-3 Antibody, with Cemiplimab in patients with advanced malignancies.

Preclinical data indicate that fianlimab (anti-lymphocyte activation gene-3) plus cemiplimab (anti-programmed cell death-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies. Adult patients received fianlimab 1-40 mg/kg ± cemiplimab 350 mg every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were rate of dose-limiting toxicities, adverse events (including immune-mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables. Seventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, 87% with fianlimab + cemiplimab, and 87% who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose-proportional, and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response; three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1600 mg Q3W (20 mg/kg in an 80 kg individual) is the selected dose for phase 2 and 3 studies. Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.

Modeling the Geometry and Filter Composite of the Air Cleaner.

Air pollution is currently the most significant environmental factor posing a threat to the health and lives of European residents. It is a key cause of poor health, particularly respiratory and cardiovascular diseases. The primary aim of the study was to numerically determine the impact of the air purifier model's geometry on the distribution of air within a room and to conduct experimental tests on the filtration efficiency and preliminary antibacterial activity of filtration composites. The scope of the work included designing an air purifier model in the form of a pendant lamp and performing computer simulations in Ansys software to identify the optimal shape. The experimental research focused on developing filtration composites consisting of nonwoven fabric with an active hydrosol layer, meltblown nonwovens and a carbon filter. The study results showed that the SMMS composite with 50% thyme and carbon nonwoven exhibited the highest filtration efficiency for both small and large particles.

Rational design, synthesis and anticancer screening of 1,2,4-oxadiazole incorporated thieno[2,3-d]thiazole-isoxazole-pyridine derivatives

We have design and synthesized a new series of 1,2,4-oxadiazole incorporated thieno[2,3-d]thiazole-isoxazole-pyridine analogues (13a-j) and were confirmed by 1H NMR, 13C NMR and mass spectral data. Further, the newly synthesized compounds (13a–j) were evaluated for their preliminary anticancer activity against a panel of four human cancer cell lines such as MCF-7 (breast cancer), A549 (lung cancer), Colo-205 (colon cancer) & A2780 (ovarian cancer) by using of MTT method, the known chemotherapeutic agent as etoposide used as positive control. Most of the tested compounds were displayed good to moderate activities on all cell lines. The IC50 values showed compound ranges from 0.01 ± 0.009 µM to 8.41 ± 5.48 µM. Where positive control showed values range from 3.34 ± 0.152 µM to 0.17 ± 0.034 µM. Among them, compound 13a, 13b, 13c, 13d, 13e and 13f were showed more potent activity than etoposide. Predominantly, The compound 13a showed potent anticancer activity against MCF-7, A549, Colo-205, and A2780 cancer cell lines with IC50 values of 0.02 ± 0.007 µM, 0.01 ± 0.009 µM, 0.13 ± 0.052 µM, and 0.11 ± 0.083 µM.

Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study.

Few treatment options exist for patients with non-Hodgkin lymphoma, and outcomes remain poor for relapsed or refractory disease. We evaluated the safety and preliminary clinical activity of valemetostat, a novel inhibitor of EZH2 and EZH1, in patients with relapsed or refractory non-Hodgkin lymphomas. This first-in-human, multicentre, open-label, single-arm, phase 1, dose-escalation and dose-expansion trial was done in 19 hospitals across Japan and the USA. Patients were included if they were aged 18 years or older in the USA or 20 years or older in Japan with a primary diagnosis of relapsed or refractory non-Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. In the dose-escalation part, patients received oral valemetostat at doses of 150 mg per day, 200 mg per day, 250 mg per day, and 300 mg per day continuously in 28-day cycles until progressive disease or unacceptable toxicities. All patients received 200 mg per day in the dose-expansion part. The primary endpoints were safety, pharmacokinetics, and the recommended phase 2 dose; the secondary endpoints were the maximum tolerated dose and the antitumour activity of valemetostat. Responses were assessed in patients who received at least one dose, with measurable lesions at baseline according to the International Working Group 2007 revised criteria for malignant lymphoma (peripheral T-cell lymphoma and B-cell non-Hodgkin lymphoma) and the modified 2009 criteria for adult T-cell leukaemia/lymphoma. The trial is registered with ClinicalTrials.gov, NCT02732275, and is currently active, but not recruiting. Between April 7, 2016, and June 10, 2021, 90 patients (53 [59%] males and 37 [41%] females; 49 [54%] Asian, 33 [37%] White, and eight [9%] Black) were enrolled and treated with valemetostat and included in the safety analysis set. 57 (63%) patients had peripheral T-cell lymphoma, 14 (16%) had adult T-cell leukaemia/lymphoma, and 19 (21%) had B-cell non-Hodgkin lymphoma. Seven (8%) patients received valemetostat 150 mg per day, 74 (82%) received 200 mg per day, seven received 250 mg per day, and two received 300 mg per day. Median follow-up was 7·4 months (IQR 3·4-17·6). All patients had at least one treatment-emergent adverse event; the most common treatment-emergent adverse events of any grade were decreased platelet count (52 [58%] of 90 patients), dysgeusia (45 [50%]), and anaemia (38 [42%]). The most common grade 3-4 adverse events were decreased neutrophil count (21 [23%]), decreased platelet count (18 [20%]), and decreased lymphocyte count (17 [19%]). The most common serious adverse event of any grade was Pneumocystis jirovecii pneumonia (four [4%]). No treatment-related deaths occurred. The overall response rate was 54·5% (48 of 88; 95% CI 43·6-65·2) for patients in the efficacy analysis set. The maximum tolerated dose was not reached; the recommended phase 2 dose of 200 mg per day was determined. Valemetostat exposure was variable between patients and was overlapped over the dose range of 150-250 mg per day. The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting. Daiichi Sankyo.

Preliminary anticancer activity of Carpobrotus edulis (L.) Bolus exposed to low and high temperature conditions against cervical cancer

Introduction: Environmental temperature conditions might influence the composition of secondary metabolites in certain medicinal plants. This study aimed to examine how some of the phytochemicals and anticancer properties of Carpobrotus edulis may be impacted by temperature conditions. Methods: The plant specimens were kept in growth chambers at 15/10 °C and 45/35 °C (day/night), and harvested at 48-hour intervals (48, 96, and 144 hours). Control conditions were maintained at 25/15 °C. Standard phytochemical colour tests were used to determine the presence of eight phytochemicals. The anticancer activity against cervical cancer cell lines was determined using cell viability assay, cell morphology, Hoechst staining, and wound healing assays. Results: The phytochemical screening showed the presence of all tested phytochemicals (phenolics, flavonoids, terpenoids, saponins, tannins, steroids, and cardiac glycosides) in all treatments except for saponins in the 96- and 144-hour temperature treatments. A noteworthy IC50 value of 284.9 µg/mL was determined from the methanolic leaf extract exposed to high temperatures for 144 hours against cervical cancer. Treatment with this extract suggested changes in cancer cell morphology, signs of apoptosis, and cell migration inhibition. Conclusion: The preliminary results obtained suggest that the C. edulis methanolic extract has potential anticancer properties against cervical cancer. These observations may have implications for the indigenous plant use in treating various ailments and broaden the type of anticancer research involving this plant.

502LBA LBA Orals: Preliminary safety, pharmacokinetics, and antitumor activity of RMC-9805, an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors

502LBA LBA Orals: Preliminary safety, pharmacokinetics, and antitumor activity of RMC-9805, an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors

500LBA LBA Orals: Preliminary safety and anti-tumor activity of TYRA-300, a highly selective FGFR3 inhibitor, in participants with advanced solid tumors with activating FGFR3 mutations/fusions (SURF301)

500LBA LBA Orals: Preliminary safety and anti-tumor activity of TYRA-300, a highly selective FGFR3 inhibitor, in participants with advanced solid tumors with activating FGFR3 mutations/fusions (SURF301)

The Anticancer Properties, Cell-cycle Cytotoxicity and Apoptosis of Cissus rotundifolia, Trema orientalis, and Buddleja polystachya with Ocular Applications

BackgroundBuddleja polystachya, Trema orientalis, and Cissus rotundifolia were applied locally for various ocular purposes, while receiving few scientific evaluations. PurposeThis study aimed to screen the anticancer properties and determine the cell-cycle cytotoxicity and apoptotic activity of the most promising plant extract. MethodsIn this study, MTT assays with MCF7 (human breast adenocarcinoma), HT29 (human colorectal adenocarcinoma) and HepG2 (human liver adenocarcinoma) were used. In addition to MRC5 (normal human foetal lung fibroblast) was carried out for preliminary activity screening and selectivity. The most promising extract was subjected to GC-MS analysis to determine the phytochemical composition. Additionally, a clonogenic assay was performed to measure tumor cell survival and subsequent proliferative capacity after drug exposure was conducted for the most active extract(s) and finally western blotting was used to determine the expression change of the two selected proteins (survivin and CCND1) in order to determine the exact mechanistic features of the most promising plant extract. ResultsThe six extracts showed variable IC50 values ranging from 1.77- 40.97 μg/mL. The most active extracts were C. rotundifolia coded as (stem; BEP-03A and leaves; BEP-03B) on HepG2 cells and showed ∼ 4 and 8 fold selectivity compared to normal MRC5 cells. Both extracts showed a dose-dependent clonogenic effect on HepG2 cells, which was comparable to the effect of doxorubicin. The extract (BEP-03B) caused a significant decrease in the expression of survivin and CCND1 compared to the control GAPDH at its highest dose (12 µg/mL). The GC-MS chromatogram of the leaf of C. rotundifolia extract (BEP-03B) revealed the presence of 17 compounds, as the main phytoconstituents representing 57.5% of the total compounds present in BEP-03B. Three steroidal components (12, 14 and 15) were the main components, while compound stigmast-5-en-3-ol (compound 15) was the main component. ConclusionsLeaves of Cissus rotundifolia (Forssk.) Vahl, possess a significant cytotoxic effect and it may produce this effect, through apoptosis induction, perturbation, and disruption of the cell cycle. The detected phytoconstituents in the plant extract might be involved in the tested cytotoxic activity and its molecular apoptotic mechanism. Future studies are required to isolate the active ingredient(s) and confirm the therapeutic application(s).

Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology.

MOLECULAR CHARACTERIZATION AND DETERMINATION OF ANTIMICROBIAL POTENTIAL OF PROBIOTIC BACTERIA ISOLATED FROM TRADITIONAL DAIRY AND COMMERCIAL PRODUCTS

The objective of the present study was to isolate, identify, and characterize probiotic Lactic acid bacterial strains from traditional dairy and commercial products and determine their antagonistic activity against pathogenic bacteria. Fifty-five lactic acid bacterial (LAB) strains were isolated, and fifteen strains were selected based on probiotic potential after that antimicrobial activity was measured against bacterial pathogens. Among fifteen isolates, five isolates showed good (above 15 mm zone) antimicrobial activities against the tested pathogenic strains of humans. After the preliminary antimicrobial activity, the best five isolates were selected for the production of different antibacterial compounds such as bacteriocin, hydrogen peroxide, and organic acid. Two isolates showed bacteriocin production and one isolate gave maximum bacteriocin activity against most pathogens and was further identified as Enterococcus faecalis JY32 using 16 S rRNA sequencing. The study reveals that in comparison to commercial products, traditional products of dairy could be an alternative and readily available resource for probiotic bacteria with interesting functional characteristics.

Efficacy and Safety of Iparomlimab, an Anti-PD-1 Antibody, in Patients with Advanced Solid Tumors: A Phase 1c Study.

Iparomlimab (QL1604) is a humanized immunoglobulin G4 mAb against programmed cell death protein 1 (PD-1). Here, we report the preliminary efficacy, safety, pharmacokinetics, and immunogenicity of iparomlimab in patients with advanced solid tumors. In this open-label, phase 1c study, patients with advanced or metastatic solid tumors, either failed or had no standard therapies available, were enrolled and received intravenous iparomlimab at 3mg/kg once every 3weeks. The primary efficacy endpoint was the objective response rate (ORR) assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Between July 20, 2020, and September 6, 2021, 71 patients were enrolled and received at least one dose of iparomlimab. The ORR was 9.9% (7/71) and disease control rate was 36.6% (26/71). Median duration of response of all responders was 10.7months [95% confidence interval (CI), 1.4-not estimable]. Additionally, the median time to progression, progression-free survival, and overall survival were 1.4months (95% CI, 1.4-2.8), 1.4months (95% CI, 1.4-2.7), and 9.7months (95% CI, 7.2-15.3), respectively. A total of 52 (73.2%) patients experienced treatment-related adverse events (TRAEs) (grade≥3, 19.7%). The most common TRAE (≥10%) was anemia (18.3%). A total of 20 (28.2%) experienced immune-related adverse events (grade≥3, 7.0%). TRAEs leading to discontinuation of study drug occurred in 4 (5.6%) patients, including immune-mediated myocarditis (2 patients), Guillain-Barré syndrome (1 patient), and diarrhea (1 patient). Iparomlimab showed preliminary clinical activity and had a manageable safety profile in patients with advanced solid tumors. These results support further investigation of iparomlimab as monotherapy or in combination therapy in advanced solid tumors. ClinicalTrials.gov identifier, NCT05801094. Retrospectively registered in 2023-03-24.