A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors

Purpose

Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, platelet-derived growth factor receptor alpha (PDGFRα), and Rad51. Amuvatinib was investigated in a first-in-human, single-agent, phase I, accelerated titration, dose-escalation trial (clinicaltrials.gov identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed.

Methods

Twenty-two patients received amuvatinib dry powder capsules (DPC) from 100 to 1,500 mg daily in 28-day cycles. Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics were investigated.

Results

No dose-limiting toxicities were reported with amuvatinib DPC up to 1,500 mg/day, given as one or in divided doses, for 1–6 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment. Exposure levels were low and variable. One gastrointestinal stromal tumor (GIST) patient who previously failed imatinib and sunitinib had a 2–[18F]fluoro-2-deoxyglucose positron emission tomography response and clinical stable disease. A second GIST patient had decreased Rad51 expression in a skin punch biopsy on days 15 and 29.

Conclusions

Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFRα and in vivo activity in human xenograft models in mice. Amuvatinib is also active as a DNA repair protein Rad51 inhibitor following chemotherapy. In this study, the amuvatinib DPC formulation was well tolerated up to 1,500 mg/day. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into single-agent amuvatinib in refractory GIST.     

Posttraumatic Stress Disorder in Rural Primary Care: Improving Care for Mental Health Following Bioterrorism

CONTEXT: Recent bioterrorism attacks have highlighted the critical need for health care organizations to prepare for future threats. Yet, relatively little attention has been paid to the mental health needs of rural communities in the wake of such events. A critical aspect of bioterrorism is emphasis on generating fear and uncertainty, thereby contributing to increased needs for mental health care, particularly for posttraumatic stress disorder, which has been estimated to occur in 28% of terrorism survivors. PURPOSE: Prior experience with natural disasters suggests that first responders typically focus on immediate medical trauma or injury, leaving rural communities to struggle with the burden of unmet mental health needs both in the immediate aftermath and over the longer term. The purpose of the present article is to draw attention to the greater need to educate rural primary care providers who will be the frontline providers of mental health services following bioterrorism, given the limited availability of tertiary mental health care in rural communities. METHODS: We reviewed the literature related to bioterrorism events and mental health with an emphasis on rural communities. FINDINGS AND CONCLUSIONS: Public health agencies should work with rural primary care providers and mental health professionals to develop educational interventions focused on posttraumatic stress disorder and other mental disorders, as well as algorithms for assessment, referral, and treatment of post-event psychological disorders and somatic complaints to ensure the availability, continuity, and delivery of quality mental health care for rural residents following bioterrorism and other public health emergencies.     

Nortriptyline influences protein pathways involved in carbohydrate metabolism and actin-related processes in a rat gene-environment model of depression

Although most available antidepressants increase monoaminergic neurotransmission, their therapeutic efficacy is likely mediated by longer-term molecular adaptations. To investigate the molecular changes induced by chronic antidepressant treatment we analysed proteomic changes in rat pre-frontal/frontal cortex and hippocampus after nortriptyline (NT) administration. A wide-scale analysis of protein expression was performed on the Flinders Sensitive Line (FSL), a genetically-selected rat model of depression, and the control Flinders Resistant Line (FRL). The effect of NT treatment was examined in a gene-environment interaction model, applying maternal separation (MS) to both strains.In the forced swim test, FSL rats were significantly more immobile than FRL animals, whereas NT treatment reduced immobility time. MS alone did not modify immobility time, but it impaired the response to NT in the FSL strain.In the proteomic analysis, in FSL rats NT treatment chiefly modulated cytoskeleton proteins and carbohydrate metabolism. In the FRL strain, changes influenced protein polymerization and intracellular transport. After MS, NT treatment mainly affected proteins in nucleotide metabolism in FSL rats and synaptic transmission and neurite morphogenesis pathways in FRL rats. When the effects of NT treatment and MS were compared between strains, carbohydrate metabolic pathways were predominantly modulated.     

Clinical outcome of single-incision slings,excluding TVT-Secur,vs standard slings in the surgical management of stress incontinence: an updated systematic review and meta-analysis

The aim of the present paper was to assess and compare the long-term efficacy and safety of single-incision mini-slings (SIMSs), except tension-free vaginal tape (TVT)-Secur, with standard midurethral slings (SMUSs) for female stress urinary incontinence through an updated systematic review and meta-analysis of randomized controlled trials (RCTs) comparing these two surgical methods. A literature review of all RCTs comparing SIMSs (Mini-Arc, Contasure-Needleless, Ophira, Tissue Fixation System and Ajust), except TVT-Secur, with SMUSs was performed. The Medline, Embase, Scopus, Web of Science and Cochrane Controlled Trial Register databases were reviewed. We retrieved 29 RCTs (including a total of 2 986 patients) that compared SIMSs, except TVT-Secur, with SMUSs. Meta-analysis of long-term results showed no significant difference in the patient-reported cure rate (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.44–1.60); however, we found that SMUSs had a significantly superior objective cure rate (OR 0.68, 95% CI 0.47–0.99; P = 0.04). SIMSs were associated with a significantly shorter operation time, lower immediate postoperative pain based on a visual analogue scale score, lower intra-operative blood loss, and lower postoperative voiding dysfunction. The meta-analysis showed clear evidence of the superiority of SMUSs over SIMSs, except TVT-Secur, in terms of the objective cure rate, after long-term follow-up; however, SIMSs were superior with respect to immediate postoperative pain, intra-operative blood loss, and postoperative voiding dysfunction.     

Fe(III)(salophene)Cl], a potent iron salophene complex overcomes multiple drug resistance in lymphoma and leukemia cells

We demonstrate the cytotoxic potential of the Schiff base iron complex [Fe^III(salophene)Cl] in vitro and ex vivo and illustrate its ability to overcome multiple drug resistance in vincristine and daunorubicine resistant leukemic cells (Nalm-6). Treatment of lymphoma cells (BJAB) with [Fe^III(salophene)Cl] led to the exclusion of unspecific necrosis, a concentration-dependent inhibition of proliferation and a specific apoptotic cell death. We further detected a significant loss of the mitochondrial membrane potential in lymphoma cells and an up- and downregulation of various apoptosis relevant genes, respectively, indicating the involvement of the intrinsic mitochondrial pathway.     

Urinary tract infection caused by carbapenem-resistant K. pneumoniae and P. aeruginosa

There has been an increase in recent years of antimicrobial resistance of Gram negative bacilli (GNB). Carbapenems, the mainstay for the treatment of multidrug resistant GNB infections, are no longer always effective leaving treatment options limited. We present the case of patient with recurrent, complicated urinary tract infections. The current episode was caused by carbapenem-resistant K. pneumoniae and P. aeruginosa and carbapenem-susceptible, but MDR E. cloacae. Resistance to carbapenems of K. pneumoniae was conferred by the production of the class B metallo-beta-lactamase, VIM1. Infection control measures were implemented and following a 2-week course of treatment with colistin, the infection resolved and the patient was discharged. We discuss the changes in the epidemiology, the mechanisms involved and the means of detecting carbapenem resistance in GNB. We would also like to stress the role of infection control measures in limiting patient-to-patient spread of MDR organisms which, are of paramount importance in cases when few treatment options are left available.     

Systemic juvenile xanthogranuloma with multiple central nervous system lesions

Juvenile xanthogranulomatosis (JXG) is an uncommon histiocytic disorder that is usually benign and limited to the skin. The systemic form of JXG is rare and may be associated with severe morbidity and mortality especially in central nervous system (CNS) involvement. Here, we describe a six-year-old boy with disseminated skin lesions and neurological signs and symptoms. Diagnostic work up revealed multiple brain lesions. A skin biopsy and a stereotactic brain biopsy considered suggestive of systemic JXG. Treatment with prednisolone, vinblastine and methotrexate was successful with regression of skin and CNS lesions. The patient has been in remission for almost three years.     

Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers

Purpose

Amuvatinib is a multi-targeted tyrosine kinase inhibitor with activity that also disrupts DNA damage repair through suppression of homologous recombination protein Rad51. Amuvatinib dry-powder capsules (DPC) showed evidence of activity in early Phase 1 cancer studies but low systemic exposure. The purposes of the studies were to investigate the cause of low exposure, develop, and test an alternative formulation with improved exposure, and establish the dose to be tested in future studies in cancer patients.

Methods

Three studies were conducted in a total of 58 healthy subjects: a food-effect study using amuvatinib DPC, a single-dose pharmacokinetic study comparing amuvatinib DPC to a new lipid-suspension capsules (LSC), and a multiple-dose pharmacokinetic study using amuvatinib LSC.

Results

A high-fat meal administered with amuvatinib DPC increased the rate and extent of absorption compared to the Fasted state, a 183 and 118% increase in the mean C _max and AUC_0–∞ of amuvatinib, respectively. The single-dose pharmacokinetics of amuvatinib LSC resulted in an approximately two-third-fold increased exposure (AUC) compared with amuvatinib DPC. The multiple-dose pharmacokinetics of the amuvatinib LSC 300 mg administered every 8 h exhibited improved accumulation compared with the 12-h regimens and achieved presumed therapeutic level safely with no serious or severe adverse events reported. No subject discontinued treatment due to an adverse event.

Conclusion

Amuvatinib LSC, 300 mg every 8 h, is being studied in cancer patients based on the improved exposure and similar safety profile to amuvatinib DPC. A lipid-based formulation approach may be a useful tool for other low aqueous soluble compounds.