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This phase 1 first-in-human study evaluated the safety, tolerability, and pharmacokinetics of MK-1088, a novel, small-molecule dual inhibitor of adenosine A2A and A2B receptors. Healthy adult participants were enrolled in two panels (n = 8 each) and randomly assigned to receive MK-1088 (n = 6) or placebo (n = 2) orally in each of five treatment periods. Participants in panel A received single ascending doses of MK-1088 at 1, 10, 50, and 150 mg or placebo in a fasted or fed (50 mg only) state. Participants in panel B received MK-1088 at 3, 25, 100, and 224 mg or placebo in a fasted state. Primary objectives were to evaluate safety, tolerability, and plasma pharmacokinetics following a single dose of MK-1088. The secondary objective was to evaluate the effects of a high-fat meal on pharmacokinetics. All participants (n = 16) completed the study (median age: 33 years [range: 20-43]; all were male). Treatment-related adverse events (AEs) occurred in 1 of 6 (17%), 4 of 6 (67%), 4 of 6 (67%), and 2 of 6 (33%) participants after receiving MK-1088 at 3, 25, 100, and 224 mg, respectively. No serious AEs or deaths due to any cause occurred. MK-1088 was rapidly absorbed after a single dose; half-life was ~ 11 h in the 100-224 mg dose range. The target concentration at 12 h (> 0.3 µM) was exceeded at the 50-mg dose level. MK-1088 plasma pharmacokinetics increased dose proportionately. A high-fat meal did not significantly affect pharmacokinetics at the 50-mg dose. MK-1088 was well tolerated and demonstrated dose-proportional pharmacokinetic properties that were not affected by a high-fat meal.
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PURPOSE: Intestinal-type adenocarcinoma (ITAC) is a rare sinonasal malignancy. Curative treatment requires multidisciplinary approach, with surgical options consist of the endonasal endoscopic approach (EEA) and external surgery (EXTS). Here, we provide the post-operative and survival results from a single-center long-term follow-up. METHODS: We report long-term follow-up of 92 ITAC cases treated between 1998 and 2018, treated with EEA (n = 40) or EXTS (n = 52). Survival estimates, post-operative complications and duration of hospitalization were compared between surgical modalities. RESULTS: Baseline characteristics were similar. A higher number of T4b tumors (16%), and subsequently more tumoral invasion (39%), was present in patients undergoing EXTS compared to EEA (3% and 18%, respectively). No difference in Barnes histology subtypes was noticed. Patients undergoing EEA had a shorter post-operative hospitalization stay versus EXTS (4 versus 7 days). Use of EEA was associated to improved disease-specific survival (DSS; 11.4 versus 4.4 years; HREEA = 0.53), especially for patients with T3-4a tumors (11.4 versus 3.0 years; HREEA = 0.41). Patients with T3-4 stage, tumoral invasion, positive surgical margins, mucinous or mixed histology, and prolonged post-operative hospital stay showed poor local relapse-free, disease-free, overall, and DSS. CONCLUSIONS: Long-term follow-up in locally advanced ITAC demonstrates that resection by EEA is correlated with improved DSS compared to EXTS, especially for T3-4 tumors. No significant differences between both treatment modalities was observed regarding per- and post-operative complications, although hospitalization in patients undergoing EEA was shorter than for patients treated with EXTS. These results confirm that EEA should remain the preferred surgical procedure in operable cases of sinonasal ITAC.
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Adenocarcinoma , Neoplasias dos Seios Paranasais , Humanos , Masculino , Feminino , Neoplasias dos Seios Paranasais/cirurgia , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/mortalidade , Adenocarcinoma/cirurgia , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Pessoa de Meia-Idade , Idoso , Seguimentos , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Tempo de Internação/estatística & dados numéricos , Adulto , Endoscopia/métodos , Taxa de Sobrevida , Estadiamento de NeoplasiasRESUMO
Next to prostate-specific antigen, no biochemical biomarkers have been implemented to guide patient follow-up after primary therapy for localized prostate cancer (PCa). We evaluated the prognostic potential of urine N-glycome in terms of event-free survival (EFS) in patients undergoing primary therapy for PCa. The prognostic features of the urine N-glycosylation profile at diagnosis, assessed in 77 PCa patients, were determined in terms of EFS next to standard clinical parameters. The majority of patients were diagnosed with International Society of Urological Pathology grade ≤ 3 (82%) T1-2 tumors (79%) and without pelvic lymph node invasion (96%). The patients underwent active surveillance (14%), robot-assisted laparoscopic prostatectomy (48%), or external beam radiotherapy (37%). Decreased ratios of biantennary core-fucosylation were noted in patients who developed an event, which was linked to a shorter EFS in both the intention-to-treat cohort and all subcohort analyses. Combining the urine N-glycan biomarker with the D'Amico Risk Classification for PCa resulted in an improved nomogram for patient classification after primary therapy. The rate of urine N-glycan biantennary core-fucosylation, typically linked to more aggressive disease status, is lower in patients who eventually developed an event following primary therapy and subsequently in patients with a worse EFS. The combination of urine N-glycan biomarkers together with clinical parameters could, therefore, improve the post-therapy follow-up of patients with PCa.
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Background: Tyrosine kinase inhibitors (TKIs) are associated with kidney function deterioration. A shift is ongoing towards glomerular filtration rate (GFR) equations based on other protein markers, such as cystatin C (CSTC) and ß-trace protein (BTP). We evaluated various GFR equations for monitoring of kidney function in actively treated oncology patients. Methods: We monitored 110 patients receiving a TKI. Blood and urine were collected during therapy. Serum analysis included creatinine (Cr), CSTC and BTP; for consequent GFR determination. Urine was analysed for protein, albumin, immunoglobulin G, and α-1-microglobulin. A similar analysis was done in a patient subgroup receiving immune checkpoint inhibitors (ICI) as prior or subsequent line of therapy. Results: Cr remained constant during TKI treatment (P = 0.7753), whereas a significant decrease in CSTC (from week 2 onward, P < 0.0001) and BTP (at weeks 2 and 4, P = 0.0100) were noticed. Consequently, GFR estimations, using CSTC and/or BTP as a biochemical parameter, showed an apparent increase in GFR, whereas this was not observed for Cr-related GFR estimations. As a result, the GFR gap (ΔGFR) was significantly different from week 2 onward between Cr-based and CSTC-based GFR and between BTP-based and CSTC-based GFR. Glomerular damage was noticed with significant increase in urine protein-to-creatinine ratio, albumin-to-creatinine ratio and immunoglobulin G (all P < 0.0001). No change in α-1-microglobulin was seen. ICI treatment had no effect on Cr (P = 0.2262), CSTC (P = 0.7341), and BTP concentrations (P = 0.3592). Conclusion: GFR equations, in which CSTC is incorporated, fail to correctly estimate the GFR in oncology patients treated with TKIs. As TKI-treated patients show clear signs of glomerular injury, further assessment is needed on how to correctly monitor the kidney function in actively treated oncology patients.
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Desmopressin is a synthetic analogue of vasopressin and a selective vasopressin receptor 2 agonist. It was first synthesised in 1967 and utilised for its antidiuretic properties. It is also used in bleeding disorders to enhance clotting. Other potential uses of the drug have been reported. The present review aims to provide a broad overview of the literature on potential further uses of oral forms of desmopressin. Key therapeutic areas of interest were identified based on known physiological activities/targets of desmopressin or reports of an effect of desmopressin in the literature. The feasibility of adequate dosing with oral forms of the drug was also considered. Systematic literature searches were carried out using the silvi.ai software for the identified areas, and summaries of available papers were included in tables and discussed. The results of the searches showed that desmopressin has been investigated for its efficacy in a number of areas, including bleeding control, renal colic, the central nervous system and oncology. Evidence suggests that oral desmopressin may have the potential to be of clinical benefit for renal colic and bleeding control in particular. However, further research is needed to clarify its effect in these areas, including randomised controlled studies and studies specifically of oral formulations (and doses). Further research may also yield findings for cancer, cognition and overactive bladder.
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PURPOSE: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. RESULTS: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. CONCLUSIONS: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.
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Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Antígeno Prostático Específico , Meia-Vida , Resultado do Tratamento , Antineoplásicos/uso terapêutico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Linfócitos T/metabolismoRESUMO
The artemin-GFRα3 signaling pathway has been implicated in various painful conditions including migraine, cold allodynia, hyperalgesia, inflammatory bone pain, and mouse knees contain GFRα3-immunoreactive nerve endings. We developed high affinity mouse (REGN1967) and human (REGN5069) GFRα3-blocking monoclonal antibodies and, following in vivo evaluations in mouse models of chronic joint pain (osteoarthritic-like and inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) and safety trial of REGN5069 (NCT03645746) in healthy volunteers, and a phase 2 randomized placebo-controlled efficacy and safety trial of REGN5069 (NCT03956550) in patients with knee osteoarthritis (OA) pain. In three commonly used mouse models of chronic joint pain (destabilization of the medial meniscus, intra-articular monoiodoacetate, or Complete Freund's Adjuvant), REGN1967 and REGN5069 attenuated evoked behaviors including tactile allodynia and thermal hyperalgesia without discernably impacting joint pathology or inflammation, prompting us to further evaluate REGN5069 in humans. In the phase 1 study in healthy subjects, the safety profiles of single doses of REGN5069 up to 3000 mg (intravenous) or 600 mg (subcutaneous) were comparable to placebo; PK were consistent with a monoclonal antibody exhibiting target-mediated disposition. In the phase 2 study in patients with OA knee pain, two doses of REGN5069 (100 mg or 1000 mg intravenous every 4 weeks) for 8 weeks failed to achieve the 12-week primary and secondary efficacy endpoints relative to placebo. In addition to possible differences in GFRα3 biology between mice and humans, we highlight here differences in experimental parameters that could have contributed to a different profile of efficacy in mouse models versus human OA pain. Additional research is required to more fully evaluate any potential role of GFRα3 in human pain.
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Antecedentes: Cetuximab resulta efectivo en el carcinoma metastático o recurrente de células escamosas de cabeza y cuello, resistente al platino. Se investigó la eficacia de cetuximab más quimioterapia basada en platino como tratamiento de primera línea en pacientes con carcinoma metastático o recurrente de células escamosas de cabeza y cuello. Métodos: Se asignaron al azar 220 pacientes de 442 pacientes elegibles con carcinoma metastático o recurrente de células escamosas de cabeza y cuello sin tratamiento, para recibir cisplatino (a una dosis de 100mg por metro cuadrado de área de superficie corporal el día 1) o carboplatino (en un área por debajo de la curva de 5mg por mililitro por minuto, como infusión intravenosa de 1 hora el día 1) más fluorouracilo (a una dosis de 1000mg por metro cuadrado por día, durante 4 días) cada 3 semanas, por un máximo de 6 ciclos, y 222 pacientes para recibir la misma quimioterapia más cetuximab (a una dosis de 400mg por metro cuadrado en forma inicial, como infusión intravenosa de 2 horas, luego 250mg por metro cuadrado, como infusión intravenosa de 1 hora por semana) durante un máximo de 6 ciclos. Los pacientes con enfermedad estable que recibieron quimioterapia más cetuximab continuaron recibiendo cetuximab hasta la progresión de la enfermedad o hasta la aparición de efectos tóxicos inaceptables, lo que ocurriera primero. Resultados: El agregado de cetuximab a la quimioterapia basada en platino con fluorouracilo (platino-fluorouracilo) prolongó de manera significativa la mediana de la supervivencia global, de 7.4 meses en el grupo de quimioterapia sola a 10.1 meses en el grupo que recibía quimioterapia más cetuximab (índice de riesgo para muerte = 0.80; intervalo de confianza 95%: 0.64-0.99; p = 0.04). El agregado de cetuximab prolongó la mediana del tiempo de supervivencia libre de progresión de 3.3 meses a 5.6 meses (índice de riesgo para la progresión = 0.54; p < 0.001) y aumentó la tasa de respuesta de 20% a 36% (p < 0.001).