Background
Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1‐3) inhibitor with significant activity in patients with advanced or metastatic urothelial ...carcinoma bearing FGFR3 alterations. Given the distinct biologic characteristics of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB), the authors examined whether infigratinib had varying activity in these settings.
Methods
Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions. Comprehensive genomic profiling was performed on formalin‐fixed, paraffin‐embedded tissues. Blood was collected for cell‐free DNA analysis using a 600‐gene panel. Patients received infigratinib at a dose of 125 mg orally daily (3 weeks on/1 week off) until disease progression or intolerable toxicity occurred. The overall response rate (ORR; partial response PR plus complete response CR) and disease control rate (DCR; CR plus PR plus stable disease SD) were characterized.
Results
A total of 67 patients were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. In 8 patients with UTUC, 1 CR and 3 PRs were observed (ORR, 50%); the remaining patients achieved a best response of SD (DCR, 100%). In patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%). Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3‐TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%).
Conclusions
Differences in the cumulative genomic profile were observed between patients with UTUC and those with UCB in the current FGFR3‐restricted experience, underscoring the distinct biology of these diseases. These results support a planned phase 3 adjuvant study predominantly performed in this population.
Infigratinib demonstrates activity in patients with metastatic urothelial carcinoma (UC) bearing fibroblast growth factor receptor 3 (FGFR3) mutations and/or fusions, with particular activity noted in patients with upper tract UC (UTUC). Key differences in FGFR3 alterations are noted between UTUC and UC of the bladder in the genomically selected patients in the current study.
Does Urinary Bisphenol-A Change after Bariatric Surgery? Dambkowski, Carl L.; Garcia, Luis; Leva, Natalia ...
Journal of the American College of Surgeons,
August 2018, 2018-08-00, 20180801, Letnik:
227, Številka:
2
Journal Article
Recenzirano
One of the world's highest volume chemicals is bisphenol-A (BPA), an organic compound with a high solubility in fat. An emerging body of literature has suggested a link between BPA, obesity, and ...insulin resistance. The study aim was to determine if surgical weight loss is associated with changes in BPA levels.
Demographic, preoperative, and 3-, 6-, and 12-month postoperative urine and laboratory data were prospectively collected on 22 bariatric surgery patients at a single academic institution. Laboratory values included hemoglobin A1C, fasting insulin, and fasting glucose. Demographic, preoperative and postoperative data, and urinary BPA levels were compared using Student's t-tests and simple regression analyses using GraphPad Prisim6 software.
Patients were predominantly privately insured (86%), female (83%), and white (68%). Urinary BPA excretion was negatively correlated with weight at 6 months (r = −0.47, p = 0.029) and 12 months (r = −0.65, p = 0.006). The average weight before surgery was 274 pounds. Average preoperative BPA excretion was 2.4 ng/mL (SD = 1.0 ng/mL) in patients lighter than average weight and 1.3 ng/mL (SD = 0.7 ng/mL) in patients heavier than average weight (p = 0.006). Average BPA excretion at 12 months was 2.5 ng/mL (SD = 2.2 ng/mL) among lighter patients and 0.58 ng/mL (SD = 0.4 ng/mL) among heavier patients (p = 0.05). Follow-up included 18 patients at 3 months, 22 patients at 6 months, and 16 patients at 12 months. Higher urinary excretion of BPA preoperatively correlated with lower 6-month patient weight (r = −0.557, p = 0.025). Higher preoperative fasting insulin correlated significantly with reduced BPA excretion at 6 months postoperatively (r = −0.5366, p = 0.032).
Excretion of BPA increases as bariatric surgery patients lose weight. Heavier patients with insulin resistance may store more BPA in adipose tissue and therefore excrete less BPA.
As medical and surgical interventions to support premature infants have evolved, the need for long-term vascular access in extremely low birth weight infants has increased. The classic approach to ...Broviac(®) (C.R. Bard, Covington, GA) catheter placement in very small neonates has been through an open surgical cutdown technique. Ultrasound guidance has emerged as a potentially beneficial method for obtaining central venous access in children and is being applied to smaller and smaller infants. This case series reports the feasibility of using ultrasound-guided percutaneous vein access to obtain a long-term central venous line in three extremely low birth weight infants who all weighed less than 850 g at the time of line placement.
Abstract
BACKGROUND: Germline mutations in fibroblast growth factor receptor (FGFR) genes 1-3 can cause skeletal dysplasias and craniosynostoses. Achondroplasia (ACH), the most common form of ...disproportionate short stature, is caused primarily by an autosomal dominant G380R substitution in FGFR3 Horton WA et al. Lancet 2007. Infigratinib (BGJ398), a potent and selective FGFR1-3 tyrosine kinase inhibitor (TKI), demonstrated preclinical efficacy at low doses in an ACH mouse model Demuynck et al. 2019; Komla-Ebri et al. 2016. The objective of this analysis is to evaluate the dose dependency and toxicity profiles of FGFR-selective TKIs like infigratinib in preclinical skeletal dysplasia models. Methods: A review of the literature was performed to investigate non-clinical data from studies of infigratinib and other FGFR-selective TKIs relevant to FGFR-driven skeletal dysplasias. Major databases (e.g., PubMed, Medline NLM Catalog) were searched for relevant articles from the past 10 years and conference archives (e.g., ENDO, ESPE, ISDS, ASHG, ASBMR) for relevant abstracts from the past 5 years. Full text was included where possible. Key words included in the searches were based on the following: achondroplasia, FGFR inhibition, infigratinib, BGJ398, tyrosine kinase inhibitor. Results: Of the 683 publications identified, 10 relevant articles and 2 abstracts were selected for review. Due to direct relevance, 2 additional articles were included, bringing the total to 14 publications. Key results from studies of infigratinib, the most commonly identified TKI, included: FGFR3 IC50 1.0 nM, FGFR3-K650E IC50 4.9 nM. In vitro data showed inhibition of FGFR1-3 activity at concentrations of 5 to 100 nM, including reversal of established growth arrest in chondrocytes at 7 nM. In vivo studies revealed dose-dependent improvements in foramen magnum and long bone length in Fgfr3Y367C/+ mice at doses of 0.2-2 mg/kg/day. No studies reported a survival disadvantage and one showed a significant survival advantage for infigratinib-treated ACH mice. In relation to other FGFR TKIs, one study showed that AZD4547 decreased survival in mice treated at doses of 1x106 to 2x106 nM, and another showed limb malformation in chicken embryos treated with PD173074 at doses of 1x106 to 50x106 nM. While one study suggested toxicity with infigratinib and other FGFR-selective TKIs, the results were not produced at pharmacologically relevant doses for ACH nor were they replicated in the literature. Furthermore, in vivo studies reporting treatment in mice with low doses of infigratinib did not result in any of the abnormal findings observed in this study. Conclusions: Recent studies indicate preclinical efficacy of infigratinib, including a survival advantage in Fgfr3Y367C/+ mice. Given the totality of evidence, low-dose infigratinib appears to be a potentially safe option for further development in children with ACH.
Abstract
Background: ACH, the most common non-lethal form of skeletal dysplasia, is characterized by defective endochondral ossification resulting from gain-of-function mutations in the fibroblast ...growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Current treatment options are non-targeted, ineffective, or painful interventions aimed at preventing or treating complications. Infigratinib is an orally bioavailable and selective FGFR1-3 tyrosine kinase inhibitor in development for FGFR-related conditions. In vitro data with infigratinib showed inhibition of FGFR1-3 activity with reversal of established growth arrest in chondrocytes. In vivo studies revealed dose-dependent improvements in foramen magnum and long bone length in Fgfr3Y367C/+ mice following treatment with infigratinib. Methods: PROPEL2 is a prospective, phase 2, open-label study of infigratinib in children with ACH. Children 3-11 years of age with ACH who have completed at least 6 months of observation in the observational PROPEL study are eligible to participate. PROPEL2 consists of dose escalation with an extended treatment phase, designed as dose finding, followed by a dose-expansion phase to confirm the selected dose and to provide evidence of efficacy. The primary endpoints of the dose-escalation/extended treatment phase are treatment-emergent adverse events and change from baseline in annualized growth velocity. Subjects (n=40) will be enrolled in ascending dose cohorts of approximately 10 subjects/cohort (4 cohorts planned) and treated for 6 months at their assigned dose, continuing for an additional 12 months with dose modifications as required. Up to 20 new subjects will be enrolled in the dose-expansion phase and receive infigratinib (mini-tablets, administered orally once daily) for 12 months. Secondary objectives include: safety/tolerability of infigratinib; changes from baseline in anthropometric parameters, including body proportions; and the pharmacokinetic/pharmacodynamic profile of infigratinib. An exploratory objective is evaluation of changes in ACH disease burden. Current Status: PROPEL2 is currently enrolling - the first subject was entered in July 2020. The planned total enrollment is 60 children with ACH (n=40 in the dose-escalation/extended treatment phase; n=20 in the dose-expansion phase). Following completion of PROPEL2, subjects have the opportunity to enroll in an open-label long-term extension study to assess the safety and efficacy of long-term administration of infigratinib in children with ACH.
Abstract
Background: Achondroplasia (ACH) is the most common non-lethal skeletal dysplasia. Fibroblast growth factor receptor 3 (FGFR3) plays a crucial role in bone elongation, demonstrated by FGFR3 ...gain-of-function mutations in individuals with ACH and hypochondroplasia. Multiple therapeutic strategies have been considered for ACH, the most advanced is to employ an analog of C-type Natriuretic Peptide (CNP), which antagonizes the MAP kinase (MAPK) pathway. Here, we evaluated a therapeutic strategy that targets all pathways downstream of FGFR3 (e.g., STAT1), not just MAPK. We hypothesized that a very low dose of the oral selective FGFR1-3 tyrosine kinase inhibitor (TKI) infigratinib (BGJ398) would be able to improve defective bone elongation. We also hypothesized that infigratinib would have greater potency at lower concentrations in an ACH cell line than a CNP analog (e.g., vosoritide) given its effects on multiple downstream pathways. Methods: A mouse model (Fgfr3Y367C/+) mimicking ACH was treated with subcutaneous injections of infigratinib daily (0.2 or 0.5 mg/kg/day) or intermittently (1 mg/kg, every 3 days) for a treatment duration of 15 days (PND1-15). In vivo results were compared with vehicle-treated mutant mice. TAN 4-18-chondrocytes, a human chondrocyte line expressing a heterozygous Y373C FGFR3 mutation, were treated with multiple concentrations of infigratinib and vosoritide and MAPK levels were measured. Results: We observed a significant improvement of the upper (humerus +7%, ulna +11%) and lower (femur +11%, tibia +16%) limbs at 0.5 mg/kg/day, and improvement in the foramen magnum. The effect of infigratinib on bone elongation was reduced with a lower dose (0.2 mg/kg), confirming a dose-response relationship. With intermittent injections of infigratinib (1 mg/kg, every 3 days), gain of growth was significant for all the long bones (+7%) and the size of the foramen magnum was increased. Modification of the growth plate structure, displaying better organization, was also seen. In cell line data, compared with FGF18-treated TAN 4-18-chondrocytes, concentrations of 10-6M to 10-10M infigratinib led to statistically significant (p<0.05) improvements. With vosoritide treatment, a concentration of 10-4M led to statistically significant improvements compared with FGF18-treated chondrocytes (p<0.05), although this was not seen at 10-5M. Conclusions: Preclinical ACH mouse model data indicate that low, as well as intermittent, doses of infigratinib promote growth and can improve the foramen magnum. No apparent toxicity of infigratinib was observed, suggesting that TKI therapy has the potential to be a valuable and relevant option for children with ACH. Furthermore, cell line data indicate that infigratinib showed superior potency over a CNP analog, suggesting that inhibition of multiple FGFR3-related pathways vs MAPK inhibition alone may lead to increased efficacy.
Abstract
BACKGROUND: Achondroplasia (ACH) is the most common non-lethal form of skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births Horton et al. 2007; Waller et al. 2008. ...Children and adults with ACH have disproportionate short stature, with a final height of approximately 131 cm for males and 124 cm for females. They are prone to significant co-morbidities, including obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis and a propensity towards obesity. In some infants, narrowing of the foramen magnum may result in compression of the spinal cord with neurologic sequelae, requiring timely neurosurgical intervention. There are currently no approved therapies for the treatment of ACH in either the United States or the European Union, and management is generally supportive in nature. The PROPEL trial is a prospective, non-interventional study examining baseline growth parameters and health status in children with ACH being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1-3 inhibitor in development for achondroplasia. Methods: Children with ACH between the ages of 2.5 and 10 years are eligible for enrollment in this prospective, non-interventional trial to evaluate growth parameters and determine clinical status. Participants will be assessed at baseline, month 3, month 6, and every 6 months thereafter. The primary endpoint is annualized height growth velocity. Secondary endpoints include change from baseline in other growth parameters (including body proportionality); analysis of bone biomarkers (e.g., bone alkaline phosphatase, collagen X fragment); and the occurrence of medical events and surgical procedures. Participants will be enrolled in the study for a minimum of 6 months up to a maximum of 2 years before being considered for enrollment in a QED-sponsored phase 2/3 interventional trial. Current status: The PROPEL study is underway with the first patient enrolled in August 2019. Planned total enrollment is 200 children with ACH.
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