Safety and efficacy of trabectedin when administered in the inpatient versus outpatient setting: Clinical considerations for outpatient administration of trabectedin.

BACKGROUND: The results of the randomized, phase 3 ET743-SAR-3007 trial demonstrated that trabectedin had a significantly longer progression-free survival (PFS) compared with dacarbazine in patients with advanced leiomyosarcoma/liposarcoma after the failure of prior chemotherapy. Patients randomized to trabectedin received a 24-hour intravenous infusion either in an inpatient or outpatient setting. Herein, the authors reported the safety, efficacy, and patient-reported outcomes based on first infusion site of care. METHODS: Patients were randomized 2:1 to trabectedin (at a dose of 1.5 mg/m2 ) or dacarbazine (1 g/m2 over 20-120 minutes) with overall survival (OS) as the primary endpoint and PFS, time to disease progression, objective response rate, duration of response, safety, and patient-reported symptom scoring as secondary endpoints. The setting of the trabectedin infusion was based on institutional preference and categorized based on the setting of the first infusion. RESULTS: Of the 378 patients who were treated with trabectedin, 100 (27%) and 277 (73%), respectively, first received trabectedin in the inpatient and outpatient setting. No differences were observed with regard to PFS or OS based on site of care. The median PFS was 4.1 months versus 4.2 months (hazard ratio, 0.90; P = .49) for inpatients versus outpatients, respectively, and the median OS was 14.3 months versus 13.7 months (hazard ratio, 0.89; P = .40), respectively. Grade 3/4 adverse events (classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) were reported in 87 inpatients (87%) compared with 219 outpatients (79%); grade 3/4 serious adverse events were reported in 43 inpatients (43%) and 92 outpatients (33%). Extravasation occurred in 0 inpatients and 5 outpatients (2%), whereas the incidence of catheter-related complications was similar between groups (16% vs 15%). CONCLUSIONS: Although the majority of patients who were randomized to trabectedin received outpatient therapy, the outcomes of the current study suggested equivalent safety and efficacy in either setting.

Pirfenidone for diabetic nephropathy.

Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m²) whereas the mean eGFR decreased in the placebo group (-2.2 ± 4.8 ml/min per 1.73 m²; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 ± 6.7 ml/min per 1.73 m²). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.

Pirfenidone is renoprotective in diabetic kidney disease.

Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix. In mouse mesangial cells, PFD decreased TGF-beta promoter activity, reduced TGF-beta protein secretion, and inhibited TGF-beta-induced Smad2-phosphorylation, 3TP-lux promoter activity, and generation of reactive oxygen species. To explore the therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4 wk. PFD treatment significantly reduced mesangial matrix expansion and expression of renal matrix genes but did not affect albuminuria. Using liquid chromatography with subsequent electrospray ionization tandem mass spectrometry, we identified 21 proteins unique to PFD-treated diabetic kidneys. Analysis of gene ontology and protein-protein interactions of these proteins suggested that PFD may regulate RNA processing. Immunoblotting demonstrated that PFD promotes dosage-dependent dephosphorylation of eukaryotic initiation factor, potentially inhibiting translation of mRNA. In conclusion, PFD is renoprotective in diabetic kidney disease and may exert its antifibrotic effects, in part, via inhibiting RNA processing.

Stimulation of urinary TGF-beta and isoprostanes in response to hyperglycemia in humans.

TGF-beta and oxidant stress have been considered to play key roles in the pathogenesis of diabetic vascular complications; however, the stimulus for these factors in humans is not clear. The purpose of this in vivo study was to determine whether transient hyperglycemia in humans is sufficient to increase renal production of TGF-beta1 and urinary isoprostanes in normal humans. A hyperglycemic clamp procedure was performed on 13 healthy volunteers. An infusion of glucose was delivered to maintain the plasma glucose between 200 and 250 mg/dl for 120 min. Timed urine samples, collected on an overnight period before the study, at each void on completion of the procedure, and the following overnight, were assayed for TGF-beta1, F2-isoprostanes, and creatinine. Plasma samples were assayed for TGF-beta1 before and at timed intervals throughout hyperglycemia. Mean baseline TGF-beta1 in plasma was 4.57 +/- 0.22 ng/ml, and no change in plasma TGF-beta1 levels was detected throughout the hyperglycemia period. Baseline urine TGF-beta1 was 4.14 +/- 1.16 pg/mg creatinine. The fractional urine samples showed a sharp increase in TGF-beta1 excretion in the 12-h period after exposure to hyperglycemia, with a mean peak TGF-beta1 of 30.43 +/- 8.05 pg/mg (P = 0.002). TGF-beta1 excretion in the subsequent overnight urine sample was not different from baseline (4.62 +/- 1.21 pg/mg). Urinary isoprostanes increased from a baseline of 4.92 +/- 0.74 to 13.8 +/- 3.37 ng/mg creatinine. It is concluded that 120 min of hyperglycemia in normal humans is sufficient to induce an increase in renal TGF-beta1 and isoprostane production.

Transforming growth factor-beta: a clinical target for the treatment of diabetic nephropathy.

Diabetic nephropathy is continuing to rise in incidence, despite awareness of tight glycemic control and blood pressure. The identification that matrix accumulation is driven by transforming growth factor-beta (TGF-beta) has led to a concerted effort to apply antifibrotic strategies for this disorder. Recent studies have not only demonstrated the beneficial effects of blocking TGF-beta on matrix accumulation but have also found that blocking TGF-beta may have important hemodynamic effects that are relevant to diabetic complications. In this article, we review the latest knowledge regarding the role of TGF-beta in diabetic kidney disease and discuss available and novel therapeutic approaches. The role of a novel antifibrotic drug, pirfenidone, may have important clinical relevance to diabetic nephropathy.

TGF-beta-induced Ca(2+) influx involves the type III IP(3) receptor and regulates actin cytoskeleton.

Ca(2+) influx has been postulated to modulate the signaling pathway of transforming growth factor-beta (TGF-beta); however, the underlying mechanism and functional significance of TGF-beta-induced stimulation of Ca(2+) influx are unclear. We show here that TGF-beta stimulates Ca(2+) influx in mesangial cells without Ca(2+) release. The influx of Ca(2+) is prevented by pharmacological inhibitors of inositol 1,4,5-trisphosphate receptors (IP(3)R) as well as specific antibodies to type III IP(3)R (IP(3)RIII) but not to type I IP(3)R (IP(3)RI). TGF-beta enhances plasma membrane localization of IP(3)RIII, whereas the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA) preferentially translocates to the nucleus. Untreated mesangial cells exhibit actin filamentous protrusions on the cell surface, and treatment with TGF-beta dramatically reduces this pattern. The alterations in the actin cytoskeleton by TGF-beta are dependent on TGF-beta-induced Ca(2+) influx. These studies identify a novel pathway by which TGF-beta regulates Ca(2+) influx and induces cytoskeletal alterations.