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BACKGROUND: Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in â¼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumors cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors. PATIENTS AND METHODS: In this first-in-human, multicenter, open-label, phase 1 study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally (once [QD] or twice [BID] daily) continuously in 28-day cycle. Primary objectives were safety and tolerability assessed by dose-limiting toxicities (DLTs) and determination of the maximum-tolerated dose (MTD); secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. RESULTS: As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg QD or 600 mg BID. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). DLTs were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The MTD was determined to be 1200 mg QD. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-evaluable patients treated at the active and tolerable doses of 800 mg QD, 1200 mg QD, or 600 mg BID (n=42), objective response rate (ORR) was 21.4% (95% CI: 10.3-36.8). Responses were observed across eight different tumor types, including squamous/nonsquamous non-small cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating-tumor DNA [ctDNA] clearance) were observed. CONCLUSIONS: AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on ORR and ctDNA clearance.
RESUMEN
PURPOSE: The aim of this study is to evaluate the role of ureteric stents in relieving obstruction and improvement of kidney function in patients with obstructive uropathy. MATERIALS AND METHODS: This study involved 138 patients with obstructive uropathy with age ranged from 2 months to 73 years. Patients classified into two groups: Group (I): Includes 57 patients (41.3%), ureteric stents fixed to them; and Group (II): Includes 81 patients (58.6%) managed by other treatment modalities. All patients underwent clinical assessment, Laboratory and radiologic investigations: At presentation and postoperative. These included: Complete urine analysis, urine culture and sensitivity, serum creatinine, serum urea nitrogen, serum uric acid, serum sodium (Na), serum potassium (K), Fasting blood glucose level and blood picture and plain X-ray (KUB), abdominal ultrasonography (US), diuretic renography and retrograde pyelography. RESULTS: Renal glomerular filtration rate (GFR) was used as an indicator for improvement of renal function after fixation of ureteric stent. In group I: 56 (71.8%) kidneys showed significant recovery compared to 61 kidneys (66.3%). In group II, there is statistically significant relation between renal perfusion and renal recovery (P < 0.004), statistically significant relation between parenchymal thickness and recovery in both groups (P < 0.0002), statistically significant relation between degree of corticomedullary differentiation and recovery (P < 0.0003) and statistically significant relationship between hemoglobin levels at presentation and the recoverability (P < 0.002). CONCLUSION: The predictors of renal recoverability revealed that ureteral stents alone can help in regaining renal function and significant improvement of clinical condition in patients with obstructive uropathy.