Dysregulated signaling by mesenchymal epithelial transition factor (MET) and heightened AXL activation are implicated in the pathogenesis of non-small cell lung cancer (NSCLC). Glesatinib (MGCD265) is an investigational, oral inhibitor of MET and AXL.
This open-label, Phase II study investigated glesatinib (free-base suspension [FBS] capsule 1050 mg BID or spray-dried dispersion [SDD] tablet 750 mg BID) in patients with advanced, previously treated NSCLC across four cohorts grouped according to presence of MET activating mutations or amplification in tumor or ctDNA. The primary endpoint was objective response rate (ORR).
Sixty-eight patients were enrolled: n = 28 and n = 8 with MET exon 14 skipping mutations in tumor tissue and ctDNA, respectively, and n = 20 and n = 12 with MET gene amplification in tumor tissue and ctDNA, respectively. Overall, ORR was 11.8 %, median progression-free survival was 4.0 months, and median overall survival was 7.0 months. Among patients with MET activating mutations, ORR was 10.7 % with tumor testing and 25.0 % with ctDNA testing. For MET amplification, responses were observed only in patients enrolled by tumor testing (ORR 15.0 %). Diarrhea (82.4 %), nausea (50.0 %), increased alanine aminotransferase (41.2 %), fatigue (38.2 %), and increased aspartate aminotransferase (36.8 %) were the most frequent adverse events assessed as related to study medication. Glesatinib exposure was similar with the SDD tablet and FBS capsule formulations. The study was terminated early by the sponsor due to modest clinical activity.
Glesatinib had an acceptable safety profile in patients with advanced, pre-treated NSCLC with MET activating alterations. Modest clinical activity was observed, which likely reflects suboptimal drug bioavailability suggested by previously reported Phase I data, and pharmacodynamic findings of lower than anticipated increases in circulating soluble shed MET ectodomain (s-MET).

UNASSIGNED: Immune checkpoint inhibitors (ICI) have been a potential treatment option for patients with cervical cancer in several clinical studies. We investigated the safety and efficacy of cadonilimab, a bispecific antibody targeting PD-1 and CTLA-4, plus standard therapy for the first-line treatment of R/M CC (recurrent and/or metastatic cervical cancer).
UNASSIGNED: Eligible patients were assigned to 3 cohorts: cohort A-15 (cadonilimab 15 mg/kg every 3 weeks (Q3W) plus chemotherapy), cohort A-10 (cadonilimb 10 mg/kg Q3W plus chemotherapy), and cohort B-10 (cadonilimab 10 mg/kg Q3W plus chemotherapy and bevacizumab). They received the corresponding treatments until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. The primary objective was safety; the secondary endpoints included objective overall response (ORR), duration of response, disease control rate, progression-free survival, and overall survival. This study is registered with ClinicalTrials.gov (NCT04868708).
UNASSIGNED: As of February 13, 2023, treatment-related adverse events (TRAE) occurred in 45 (100.0%) patients. Grade ≥3 TRAEs were reported in 33 (73.3%) patients. Immune-related adverse events (irAE) occurred in 29 (64.4%) patients and grade ≥3 irAEs were observed in 9 (20.0%) patients. Seven (15.6%) of 45 patients permanently discontinued cadonilimab treatment due to TRAEs. One death due to hemorrhagic shock occurred in cohort B-10. Among 44 patients who underwent at least one post-baseline tumor assessment, the ORR was 66.7% in cohort A-15, 68.8% in cohort A-10, 92.3% in cohort B-10, and 79.3% in cohorts A-10 and B-10 combined.
UNASSIGNED: Cadonilimab combined with standard therapy was acceptable, with encouraging antitumor activity in patients with R/M CC.

Thromboelastography is a quantitative test widely used to measure the efficiency of blood clotting. However, awaiting the results of maximum amplitude (MA) is necessary for determining the need for platelet- and fibrinogen-containing products. A more rapid prediction of MA could facilitate faster preparation and administration of blood transfusion products, thereby resulting in coagulation improvement. In this retrospective study, we hypothesized that early amplitude at 10 min (A10) could be a predictor of MA. Therefore, we investigated whether MA can be rapidly inferred from thromboelastographic 6 s (TEG6s) measurements and evaluated its correlation with A10. We extracted TEG6s measurements obtained in operating rooms and intensive care units of our hospital between January 2018 and December 2022. The correlation of MA with display items of TEG6s results, including reaction time, kinetics, α angle, activated clotting time, and A10, was evaluated. The relationship between citrated rapid TEG (CRT)-A10 and CRT-MA, as well as between citrated functional fibrinogen (CFF)-A10 and CFF-MA, were evaluated if A10 and MA showed a good correlation. The results showed good correlations between CRT-A10 and CRT-MA, as well as between CFF-A10 and CFF-MA. Therefore, evaluating A10 using TEG6s could predict MA.

Objective: The purpose of this study was to investigate the efficacy and safety of netupitant/palonosetron (NEPA) for the prevention of chemotherapy-induced nausea and vomiting (CINV) for hematopoietic cell transplantation (HCT) patients receiving BEAM therapy. Study Design: This phase II, prospective, intention-to-treat, single-center, single-arm study involved 43 adult patients who received NEPA and dexamethasone for the prevention of CINV due to BEAM conditioning chemotherapy. An interim analysis, performed after 13 patients, determined utility versus futility, and supported continuation to full enrollment. Descriptive statistics were used to report complete response (CR), complete protection, incidence of emesis, and administration of rescue agents. A Kaplan-Meier curve depicted time to first emesis and first rescue medication. Patients self-reported levels of daily nausea descriptively via a CINV Questionnaire. Results: By study end, 13 of 43 patients achieved a CR with an average of 10.6 emesis-free days (SD 0.95) over the 11-day observation period, with no emetic events in any patient during the acute/chemotherapy phase. Nausea was well-controlled throughout the acute therapy phase (Day 1-6) and increased during the delayed phase (Day 7-11) with a peak mean level of 2.79/10 at Day 10. Aside from lower grade (≤2), headaches, constipation, and diarrhea were the most widely reported adverse effects. Conclusion: The combination of NEPA and dexamethasone is safe and effective for the prevention of CINV in patients receiving BEAM conditioning therapy prior to HCT. The regimen demonstrated greater effectiveness in the acute phase versus the delayed phase, with low levels of nausea throughout the study period and complete emesis prevention during chemotherapy.

UNASSIGNED: To investigate topical nepafenac drops (TND) effect on retinal vasculature following uneventful phacoemulsification.
UNASSIGNED: 54 eyes were randomly assigned to G1: TND 3 days preoperatively and 1 month postoperatively; G2: TND for 1 month postoperatively; and G3 no TND (control). BCVA, macular OCTA were compared baseline, 1 week and 1 month.
UNASSIGNED: No statistically significant differences found between 3 groups in OCTA parameters during study visits. However, at 1 month (compared to baseline) there were a statistically significant increase in superficial capillary plexus (SCP) capillary vessel density (CVD) in G2 (p=0.036); increase in central foveal thickness (CFT) in G2 (p=0.011) and G3 (control) (p=0.001); and reduced number of patients with SCP disorganization in G2 (p=0.04). There were no significant correlation/association between most of OCTA parameters and final BCVA.
UNASSIGNED: TND use perioperative did not show any effect on retinal OCTA microvasculature and might affect macular edema by other mechanisms.

BACKGROUND: The non-inferiority of dexamethasone (DEX) on day 1, with or without low-dose DEX on days 2 and 3, combined with oral NEPA (netupitant/palonosetron), compared with the guideline-consistent use of DEX was demonstrated in cisplatin. Here, we complete the analysis by assessing the impact of emesis on daily lives of patients receiving DEX-sparing regimens using the Functional Living Index-Emesis (FLIE).
METHODS: Chemotherapy-naïve patients undergoing cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized to receive either 1) no further DEX (DEX1), 2) oral DEX (4 mg daily) on days 2-3 (DEX3), or 3) DEX (4 mg twice daily) on days 2-4 (DEX4; control). Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included the FLIE nausea domain, vomiting domain, and overall combined domain scores, as well as the proportion of patients with no impact on daily life (NIDL; overall score > 108). This was a protocol-planned analysis.
RESULTS: In the DEX1 group, no significant differences were observed in the FLIE nausea score (48.9 [±1.8; SE] vs. 53.7 [±1.5]), vomiting score (56.6 [±1.4] vs. 58.7 [±0.8]) and overall score (105.6 [±2.8] vs.112.4 [±1.9]) versus DEX4 control; similar results were observed in the DEX3 group for nausea score (49.6 [±1.7]), vomiting score (58.2 [±1]) and overall score (107.8 [±2.4]) versus control. There were no significant between-group differences in the proportion of patients reporting NIDL.
CONCLUSIONS: Reducing DEX, when administered with NEPA, does not seem to adversely impact the daily functioning in patients undergoing cisplatin.
BACKGROUND: ClinicalTrials.gov NCT04201769 . Registration date: 17/12/2019 - Retrospectively registered.

Oncogenic drivers in solid tumors include aberrant activation of mesenchymal epithelial transition factor (MET) and AXL.
This study investigated the safety and antitumor activity of glesatinib, a multitargeted receptor tyrosine kinase inhibitor that inhibits MET and AXL at clinically relevant doses, in combination with erlotinib or docetaxel.
The phase I portion of this open-label, multicenter study included two parallel arms in which ascending doses of oral glesatinib (starting dose 96 mg/m2) were administered with erlotinib or docetaxel (starting doses 100 mg once daily and 50 mg/m2, respectively) using a modified 3 + 3 design. Maximum tolerated dose (MTD) was based on dose-limiting toxicities (DLTs) during the first 21-day treatment cycle. Enrollment focused on patients with solid tumor types typically associated with MET aberration and/or AXL overexpression. The primary objective was to determine the safety profile of the treatment combinations. Antitumor activity and pharmacokinetics (PK) were also assessed.
Ten dose levels of glesatinib across three glycolate formulations (unmicronized, micronized, or micronized version 2 [V2] tablets) available during the course of the study were investigated in 14 dose-escalation cohorts (n = 126). MTDs of unmicronized glesatinib plus erlotinib or docetaxel, and micronized glesatinib plus erlotinib were not reached. Micronized glesatinib 96 mg/m2 plus docetaxel exceeded the MTD. Further dosing focused on glesatinib micronized V2: maximum administered dose (MAD) was 700 mg twice daily with erlotinib 150 mg once daily or docetaxel 75 mg/m2 every 3 weeks. DLTs, acceptable at lower glesatinib (micronized V2) dose levels, occurred in two of five and two of six patients at the MADs of glesatinib + erlotinib and glesatinib + docetaxel, respectively. Across all cohorts, the most frequent treatment-related adverse events were diarrhea (glesatinib + erlotinib: 84.1%; glesatinib + docetaxel: 45.6%), fatigue (46.4%, 70.4%), and nausea (30.4%, 35.1%). The objective response rate was 1.8% and 12.0% in all glesatinib + erlotinib and glesatinib + docetaxel cohorts, respectively.
The safety profile of glesatinib plus erlotinib or docetaxel was acceptable and there were no PK interactions. MADs of glesatinib 700 mg twice daily (micronized V2) with erlotinib 150 mg once daily or docetaxel 75 mg/m2 every 3 weeks exceeded the MTD by a small margin. Modest signals of efficacy were observed with these treatment combinations in non-genetically selected patients with advanced solid tumors.
ClinicalTrials.gov NCT00975767; 11 September 2009.

OBJECTIVE: To assess the safety and efficacy of 0.1% nepafenac versus 0.09% bromfenac eye drops in controlling inflammation after neodymium yttrium-aluminum-garnet (YAG) laser peripheral iridotomy (LPI).
METHODS: Single-masked, single-center, randomized controlled trial.
METHODS: One hundred and sixty eyes of patients with primary angle-closure suspect (PACS) and primary angle closure (PAC) undergoing bilateral LPI.
METHODS: Patients were randomized in a 1:1 ratio to receive 0.1% nepafenac thrice daily or 0.09% bromfenac eye drops twice daily for 2 weeks after neodymium YAG LPI. Assessment was performed by masked investigators at 2 weeks after LPI. A Glaucoma Symptom Scale (GSS) questionnaire was administered both at baseline and 2 weeks after LPI. Subjective comfort scores to the study medications were assessed on the basis of a Likert scale at 2 weeks after LPI. In patients with bilateral PACS or PAC, the right eye was analyzed, and in asymmetrical disease (i.e., when one eye had PACS and the other eye had PAC), the eye with PAC was analyzed.
METHODS: The primary outcome (end point) was uncontrolled inflammation, defined as symptomatic inflammation within 1 week after LPI, the presence of anterior chamber cells at 2 weeks, or rebound inflammation after medication discontinuation. The secondary outcome was patient-reported comfort levels with study medications based on the GSS and Likert scale.
RESULTS: At 2 weeks after LPI, 7 patients (6 with PACS and 1 with PAC) in the nepafenac group and 2 patients with PACS in the bromfenac group achieved the primary end point, without a difference between the medication groups (P = 0.09). Post-LPI burning, smarting, and stinging was more common in the bromfenac group (P = 0.01), which also had a higher comfort score on the Likert scale (P = 0.004). The need for repeat LPI was comparable (10.0% in the nepafenac group vs. 15.4% in the bromfenac group; P = 0.22). A multivariate analysis revealed that a greater number of laser shots was associated with the need for repeat LPI (odds ratio, 1.05; 95% confidence interval, 1.00-1.10; P = 0.04).
CONCLUSIONS: Topical 0.09% bromfenac is noninferior to 0.1% nepafenac in controlling inflammation after LPI in eyes with PACS and PAC. Nepafenac may be associated with higher patient-reported comfort.

OBJECTIVE: To compare 0.1% nepafenac, a topical nonsteroidal anti-inflammatory drop, with 1% prednisolone acetate in controlling inflammation after neodymium:yttrium-aluminum-garnet laser peripheral iridotomy (LPI) in primary angle-closure suspects (PACS).
METHODS: Randomized controlled trial.
METHODS: One hundred fifty-two PACS undergoing bilateral LPI.
METHODS: Patients were randomized to 0.1% nepafenac or 1% prednisolone acetate eye drops in both eyes. Medications were given 4 times daily for 7 days, then twice daily for additional 7 days. Investigators were masked to the type of medication. Right eyes in patients with bilateral PACS and the PACS eye in asymmetrical disease (primary angle closure in fellow eye) were analyzed.
METHODS: Noninferior control of inflammation, defined as absence of cell in the anterior chamber at 2 weeks and absence of rebound iritis with medication discontinuation, was the primary outcome, whereas difference in the rise in intraocular pressure (IOP) was a secondary outcome.
RESULTS: Both groups were comparable in baseline characteristics, including IOP and total laser energy. Nepafenac was noninferior to prednisolone with regard to inflammation control, with 1 nepafenac-treated eye (1.3%) not meeting the primary end point because of 1+ anterior chamber cell at 2 weeks and 4 prednisolone-treated eyes (5.4%) failing to meet the primary end point because of rebound iritis (P < 0.001). A greater increase in IOP from baseline to 2 weeks was observed in the prednisolone group compared with the nepafenac group (+2.6 mmHg vs. +0.6 mmHg; P = 0.004), although at 4 weeks, IOP was not significantly different than baseline in either group (P > 0.05 for both). Two weeks after LPI, 3 nepafenac-treated eyes and 10 prednisolone-treated eyes demonstrated a 6- to 15-mmHg IOP elevation from baseline (P = 0.10), whereas 2 prednisolone-treated eyes and no nepafenac-treated eyes showed IOP elevation of more than 15 mmHg (P = 0.20). Four weeks after LPI, more prednisolone-treated eyes showed IOP elevation of 6 to 15 mmHg as compared with nepafenac-treated eyes (6 eyes vs. 1 eye; P = 0.04); no eyes showed IOP elevation of more than 15 mmHg.
CONCLUSIONS: Nepafenac was noninferior to prednisolone in controlling inflammation after LPI in PACS.

To compare, using laser flare meter (LFM), the efficacy of topical nepafenac 0.1, % and diclofenac 0.1% ophthalmic solution in the control of anterior chamber inflammation after uncomplicated cataract surgery.
Patients undergoing phacoemulsification for age-related cataract were recruited. Complete evaluation with visual acuity, slit-lamp examination, endothelial cell density, intraocular pressure, retinal tomography and anterior chamber flare evaluation was performed before surgery and 1, 15, 30 and 60 days after surgery. Patients were randomly assigned to receive topical diclofenac 0.1% 4 times a day for four weeks or nepafenac 0.1% 3 times a day for three weeks in addition to topical steroids and antibiotic.
64 (31 males, mean age 77.3 ± 5.9) patients were enrolled. Half of them were randomly assigned to group A (diclofenac 0.1%) and half to group B (nepafenac 0.1%). There was a statistically significant visual acuity improvement postoperatively in both groups, with no statistical difference between the groups. Intraocular pressure, corneal thickness, endothelial cells count and macular thickness parameters didn\'t significantly vary between before and after surgery. One-day after surgery, aqueous flare was significantly higher (22,27 ± 9,25 ph/ms in group A and 22,36 ± 7,47 in group B) than before surgery (14,59 ± 7,16 ph/ms in group A and 11,84 ± 4,44 in group B) in both groups, then declining in the first month and reaching preoperative levels again by 2 months in both groups. In group B, LFM values at 15 and 30 days after surgery were significantly lower (13,59 ± 4,80 and 14,07 ± 5,01) than in group A (17,00 ± 6,97 and 16,96 ± 6,13).
Nepafenac ensured a better inflammation control than diclofenac during the first month.