ABSTRACT
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment. Here, we show that futibatinib, an irreversible pan-FGFR inhibitor, inhibits the growth of RMS cell lines in vitro by inhibiting phosphorylation of FGFR4 and its downstream targets. Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. However, in RMS xenograft models, futibatinib monotherapy and combination treatment have limited efficacy in delaying tumor growth and prolonging survival. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.
ABSTRACT
AIM: To identify multi-disciplinary paediatric weight management services currently available in Australia and determine gaps in service provision for children and adolescents with obesity. METHODS: Surveys were distributed to 17 identified Australian multi-disciplinary paediatric weight management services. A representative from each service was asked to complete an online survey regarding service and patient characteristics, assessment and management practices, and professional development approaches. RESULTS: Representatives from 16 multi-disciplinary paediatric weight management services completed the survey. Fourteen services were based in major metropolitan cities and two in regional areas. Fourteen services provided care to pre-school aged children (0-4 years old), 15 to primary school aged children (5-12 years old) and 13 to high school aged children (13-18 years old). The number of patients seen per year per service ranged from 20 to 250 and duration of waiting lists ranged from 2 months to more than 12 months. CONCLUSIONS: The current availability and accessibility of multi-disciplinary paediatric weight management services is inadequate to service Australian children and adolescents with obesity, particularly those with severe obesity and those in rural and remote communities. To better address the issue of paediatric obesity, establishment of additional multi-disciplinary services, training for health-care professionals and monitoring of the provision of evidence-based care is urgently needed.
Subject(s)
Pediatric Obesity , Rural Population , Adolescent , Australia , Child , Child, Preschool , Health Services Accessibility , Humans , Infant , Infant, Newborn , Pediatric Obesity/therapy , Surveys and QuestionnairesABSTRACT
RO6870868 is an oral prodrug of the toll-like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first-in-human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200-2000 mg). Single oral doses were generally well-tolerated with a predictable safety profile associated with dose-dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half-life ranging 2-6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0-∞ ) increasing proportionally with dose. A pattern of dose and time-dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose-dependent manner with adequate safety and tolerability. Single-dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.
Subject(s)
Immunologic Factors/adverse effects , Toll-Like Receptor 7/antagonists & inhibitors , Administration, Oral , Adolescent , Adult , Aged , Area Under Curve , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Half-Life , Healthy Volunteers , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/immunology , Humans , Immunity, Innate/drug effects , Immunologic Factors/administration & dosage , Immunologic Factors/pharmacokinetics , Interferons/blood , Interferons/metabolism , Male , Middle Aged , Prodrugs/administration & dosage , Prodrugs/adverse effects , Prodrugs/pharmacokinetics , Signal Transduction/drug effects , Signal Transduction/immunology , Young AdultABSTRACT
To optimize treatment for children and adolescents with obesity and minimize attrition, consideration of parents' engagement and satisfaction with paediatric weight management services is crucial. The aim of this study was to conduct a mixed-methods evaluation of parental acceptability and satisfaction of available paediatric weight management services in New South Wale, Australia's most populous state. Parents/carers referred to one of six weight management services between March 2018 and July 2019 were invited to participate. The study involved: (a) surveys and one-on-one phone interviews to assess overall satisfaction, acceptability of service design and delivery, treatment expectations, and service accessibility, strengths, weaknesses and areas of improvement; (b) a survey to determine costs to families of attending the service; and (c) a survey assessing families' reasons for treatment non-attendance. N = 146 participants completed the survey to assess service satisfaction and acceptability and 37 of these also participated in phone interviews. Ninety-three per cent were satisfied with the overall care they received and patient weight loss/cessation of weight gain and improvement in the family's overall health were rated as the most valued changes. Content analysis of interviews highlighted participants' recognition of positive changes achieved during treatment and appreciation of the resources provided, and the encouraging/empathetic nature of staff. The most common reasons for treatment attrition were difficulty in accessing the weight management service and flexibility of appointment times. Findings from this study can be utilized in future planning and development of paediatric weight management services to facilitate integrated, responsive and effective care of children and adolescents with obesity.
Subject(s)
Parents/psychology , Patient Acceptance of Health Care/psychology , Patient Satisfaction , Pediatric Obesity/therapy , Weight Reduction Programs , Adolescent , Adult , Caregivers/psychology , Child , Child, Preschool , Female , Humans , Male , Middle Aged , New South Wales , Qualitative Research , Research DesignABSTRACT
BACKGROUND: While prophylactic human papillomavirus (HPV) vaccination exists, women are still developing cervical intraepithelial neoplasia (CIN) grade 2 or 3 for which an immunotherapeutic, non-surgical, approach may be effective. The primary aim was to assess the efficacy of tipapkinogen sovacivec (TS) vaccine in achieving histologic resolution of CIN2/3 associated with high risk (HR) HPV types. METHODS: Women 18â¯years and older who had confirmed CIN2/3 were enrolled in a randomized, double blind, placebo-controlled phase II trial and assigned to drug in a 2:1 ratio (vaccine:placebo). The primary endpoint occurred at month 6 when the excisional therapy was performed; cytology and HR HPV typing were performed at months 3, 6 and every six months through month 30. The safety population included all patients who received at least one dose of study drug. RESULTS: Of the 129 women randomized to vaccine and 63 to placebo, complete resolution was significantly higher in the vaccine group than placebo for CIN 2/3 regardless of the 13 HR HPV types assayed (24% vs. 10%, pâ¯<â¯0.05); as well as for only CIN 3 also regardless of HR HPV type (21% vs. 0%, pâ¯<â¯0.01). Irrespective of baseline HPV infection, viral DNA clearance was higher in the vaccine group compared to placebo (pâ¯<â¯0.01). The vaccine was well tolerated with the most common adverse events being injection site reactions. CONCLUSIONS: The TS vaccine provides histologic clearance of CIN 2/3 irrespective of HR HPV type in one third of subjects and is generally safe through 30â¯months.
Subject(s)
Papillomavirus Infections/virology , Papillomavirus Vaccines/therapeutic use , Uterine Cervical Dysplasia/therapy , Uterine Cervical Neoplasms/therapy , Adolescent , Adult , Double-Blind Method , Female , Follow-Up Studies , Genotype , Humans , Injection Site Reaction/etiology , Middle Aged , Papillomaviridae/genetics , Papillomavirus Infections/complications , Papillomavirus Vaccines/adverse effects , Prospective Studies , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Young Adult , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/virologyABSTRACT
HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a "3+3" design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m2/day for QD, and 210.7 mg/m2/day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD × 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non-small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor.This is a result from a first-in-human study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.
Subject(s)
Benzamides/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , HSP90 Heat-Shock Proteins/genetics , Pyrazoles/administration & dosage , Administration, Oral , Adult , Aged , Benzamides/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Female , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Humans , Japan , Male , Maximum Tolerated Dose , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/adverse effects , United KingdomABSTRACT
AIMS: To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed. METHODS: Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10-25 ng ml(-1) until week 8, and then 8-15 ng ml(-1) thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed. RESULTS: MPA exposure was 39-50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) microg ml(-1) h) and MPAG exposure was 25-52% higher (722 (607, 838) vs. 485 (402, 569) microg ml(-1) h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported. CONCLUSIONS: Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made.
Subject(s)
Cyclosporine/pharmacokinetics , Graft Rejection/metabolism , Graft Rejection/prevention & control , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , Sirolimus/pharmacokinetics , Adult , Aged , Cyclosporine/administration & dosage , Cyclosporine/adverse effects , Drug Therapy, Combination , Female , Graft Rejection/drug therapy , Humans , Leukopenia/chemically induced , Leukopenia/metabolism , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/adverse effects , Mycophenolic Acid/pharmacokinetics , Prospective Studies , Sirolimus/administration & dosage , Sirolimus/adverse effectsABSTRACT
PURPOSE: Irinotecan is a novel antineoplastic agent that works by inhibiting the enzyme, topoisomerase 1. Although not extensively studied in children, preclinical studies and several phase I trials indicate activity against a variety of relapsed solid tumors when administered on a protracted schedule. This report describes an institutional experience with irinotecan for the treatment of pediatric solid tumors. PATIENTS AND METHODS: Twenty-two heavily pretreated children with multiply relapsed tumors were treated with courses of irinotecan at 20 mg/m2 per day for 10 days [(every day x 5) x 2]. RESULTS: Of the 19 patients evaluable for response, four achieved an objective response, including two complete responses and one partial response among four patients with rhabdomyosarcoma and one additional patient with an undifferentiated sarcoma with rhabdomyoblastic features, and one patient with a fibrosarcoma had stable disease. Among three patients with non-Hodgkin lymphoma, one achieved a partial response and one had stable disease. Diarrhea was the most commonly observed toxicity. CONCLUSION: Irinotecan appears to have promising single-agent activity, particularly against rhabdomyosarcoma. with minimal hematopoietic toxicity, making it ideal for further evaluation in patients at high risk with newly diagnosed disease, particularly in combination with other active agents with nonoverlapping toxicities.