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The inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34+ cell maintenance, and that it recapitulates aspects of BM injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation, as well as BM recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and BM-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that BM chips containing cells from patients with the rare genetic disorder Shwachman–Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil maturation abnormality. As an in vitro model of haematopoietic dysfunction, the BM chip may serve as a human-specific alternative to animal testing for the study of BM pathophysiology. A vascularized human bone-marrow-on-a-chip improves the maintenance of patient-derived CD34+ cells, and recapitulates clinically relevant aspects of bone marrow injury as well as key haematopoietic defects of patients with a rare genetic disorder.

Aim: The skeletal muscle Cl− channels, the ClC-1 channels, stabilize the resting membrane potential and dampen muscle fibre excitability. This study explored whether ClC-1 inhibition can recover nerve-stimulated force in isolated muscle under conditions of compromised neuromuscular transmission akin to disorders of myasthenia gravis and Lambert–Eaton syndrome. Methods: Nerve-muscle preparations were isolated from rats. Preparations were exposed to pre-or post-synaptic inhibitors (ω-agatoxin, elevated extracellular Mg2+, α-bungarotoxin or tubocurarine). The potential of ClC-1 inhibition (9-AC or reduced extracellular Cl−) to recover nerve-stimulated force under these conditions was assessed. Results: ClC-1 inhibition recovered force in both slow-twitch soleus and fast-twitch EDL muscles exposed to 0.2 µmol/L tubocurarine or 3.5 mmol/L Mg2+. Similarly, ClC-1 inhibition recovered force in soleus muscles exposed to α-bungarotoxin or ω-agatoxin. Moreover, the concentrations of tubocurarine and Mg2+ required for reducing force to 50% rose from 0.14 ± 0.02 µmol/L and 4.2 ± 0.2 mmol/L in control muscles to 0.45 ± 0.03 µmol/L and 4.7 ± 0.3 mmol/L in muscles with 9-AC respectively (P + channels (4-AP) relieve symptoms in myasthenia gravis and Lambert–Eaton syndrome, respectively. Neostigmine and 9-AC additively increased the tubocurarine concentration required to reduce nerve-stimulated force to 50% (0.56 ± 0.05 µmol/L with 9-AC and neostigmine) and, similarly, 4-AP and 9-AC additively increased the Mg2+ concentration required to reduce nerve-stimulated force to 50% (6.5 ± 0.2 mmol/L with 9-AC and 4-AP). Conclusion: This study shows that ClC-1 inhibition can improve neuromuscular function in pharmacological models of compromised neuromuscular transmission.

We note that intussusception was likely associated with severe acute respiratory syndrome coronavirus-2 infection in 2 infants in Wuhan and London. The intussusception was reduced by enemas in Wuhan; the outcome was fatal. The intussusception was not reduced by enemas in London and required surgery; the outcome was favorable.

Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles of 14Carbon-isotope (14C)-labelled vistusertib were characterised in this open-label phase I patient study. Four patients with advanced solid malignancies received a single oral solution dose of 14C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed. 14C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (Tmax) 90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~ 78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an N-methylamide circulate at low concentrations [each

Aims This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. Methods Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3e/TCR modulation on circulating T lymphocytes). Results Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. Conclusions Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.

Low 25-OH serum vitamin D (VitD) is pervasive in older adults and linked to functional decline and progression of frailty. We have previously shown that chronic VitD insufficiency in “middle-aged” mice results in impaired anaerobic exercise capacity, decreased lean mass, and increased adiposity. Here, we examine if VitD insufficiency results in similar deficits and greater frailty progression in old-aged (24 to 28 months of age) mice. Similar to what we report in younger mice, older mice exhibit a rapid and sustained response in serum 25-OH VitD levels to differential supplementation, including insufficient (125 IU/kg chow), sufficient (1000 IU/kg chow), and hypersufficient (8000 IU/kg chow) groups. During the 4-month time course, mice were assessed for body composition (DEXA), physical performance, and frailty using a Fried physical phenotype-based assessment tool. The 125 IU mice exhibited worse grip strength (p = 0.002) and inverted grip hang time (p = 0.003) at endpoint and the 8000 IU mice transiently displayed greater rotarod performance after 3 months (p = 0.012), yet other aspects including treadmill performance and gait speed were unaffected. However, 125 and 1000 IU mice exhibited greater frailty compared to baseline (p = 0.001 and p = 0.038, respectively), whereas 8000 IU mice did not (p = 0.341). These data indicate targeting higher serum 25-OH vitamin D levels may attenuate frailty progression during aging.

Purpose:Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery.Patients and Methods:Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Results:Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified.Conclusions:This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Multiple variations of oesophageal atresia (OA) have been described. We present two cases of a new variant of OA (‘Type Y’) where the fistula enters the trachea in a Y-shaped configuration. Awareness of this is important. Bronchoscopy will reveal a single fistula opening and therefore there will initially be no suspicion of anatomical variation. It may be that only one bifurcation of the ‘Y’ fistula is patent which poses a risk of incomplete fistula closure.

Understanding human bone marrow (BM) pathophysiology in the context of myelotoxic stress induced by drugs, radiation, or genetic mutations is of critical importance in clinical medicine. However, study of these dynamic cellular responses is hampered by the inaccessibility of living BMin vivo. Here, we describe a vascularized human Bone Marrow-on-a-Chip (BM Chip) microfluidic culture device for modeling bone marrow function and disease states. The BM Chip is comprised of a fluidic channel filled with a fibrin gel in which patient-derived CD34+ cells and bone marrow-derived stromal cells (BMSCs) are co-cultured, which is separated by a porous membrane from a parallel fluidic channel lined by human vascular endothelium. When perfused with culture medium through the vascular channel, the BM Chip maintains human CD34+ cells and supports differentiation and maturation of multiple blood cell lineages over 1 month in culture. Moreover, it recapitulates human myeloerythroid injury responses to drugs and gamma radiation exposure, as well as key hematopoietic abnormalities found in patients with the genetic disorder, Shwachman-Diamond Syndrome (SDS). These data establish the BM Chip as a new humanin vitromodel with broad potential utility for studies of BM dysfunction.

Background: Aurora kinases (AurK) represent potential targets for anticancer therapy in hematological malignancies and solid tumors. AurK B inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of AurKB, when given as 2-4hr IV on days 1 and 4, offers a prolonged drug exposure in vivo, mimicking the AZD1152 7-day continuous IV infusion. This is an update on the first-in-man dose-escalation study of AZD2811NP in pts with relapsed/refractory AML/MDS or treatment-naïve patients (pts) not eligible for intensive induction therapy (NCT03217838). The primary objectives are to determine the Maximum Tolerated Dose (MTD) and safety profile of AZD2811NP monotherapy and in combination with azacitidine. The secondary objectives are to evaluate the pharmacokinetic (PK) profile, Biologically Effective Dose (BED), and preliminary efficacy (CR, CRi, PR, 6 month OS). Methods: Pts received a 2-hour IV infusion on Day 1 and 4 of each 28-day cycle (Cy) for doses up to 600mg, extending to a 4 h IV infusion for dosages > 600 mg. In the ongoing dose escalation, 3-6 pts have been sequentially enrolled in cohorts ranging from 100 mg to 800 mg per infusion (Day 1 & 4), i.e. from 200 mg to 1,600 mg per cycle in monotherapy setting, according to a modified continuous reassessment method (mCRM) dose escalation design. AZD2811NP was also combined with azacitidine (75 mg day 1 to 7 or the 5-2-2 schedule) starting at an AZD2811NP dose of 400 mg D1 and D4 every 4 weeks. Study treatment was continued until disease progression, intolerability, or when discontinuation criteria were met. Results: Currently, 30 pts have enrolled of which 29 pts (12 females and 17 males) received study treatment in 5 monotherapy cohorts and 2 azacitidine combination cohorts, with ages ranging from 53 to 85 years. Nineteen pts had relapsed/refractory AML, 9 pts had MDS and 1pt had MDS/MPN. Monotherapy cohort 5 (800 mg D1 & D4) and combination cohort 4c (600mg D1 & D4 + Azacitidine) are currently enrolling. Of the 19 pts in monotherapy cohorts 1-5, 18 pts discontinued (due to consent withdrawal [2], early disease related deaths [2], other reason [1], or completed follow up [13; 11 pts after Cy1, 2 pts after Cy2]) and 1 pt is still on therapy. Nine pts were treated in combination with azacitidine, and of these, 3 pts are still on therapy and 6 pts have discontinued AZD2811NP (due to death [1], consent withdrawal [2], or completed follow up [3; 2 pts after Cy2, 1 pt after Cy4]). Adverse events that occurred in ≥ 20% of pts were mainly myelotoxicity, nausea and fatigue. One dose-limiting toxicity (DLT) has been observed in the monotherapy arm (esophageal infection) and one DLT in the combination setting (late neutropenia recovery). Two deaths were due to the underlying disease and 1 due to a serious adverse event of Gr 5 sepsis not related to study drug. AZD2811 total and released blood PK exposure appears broadly dose proportional with a terminal t1/2 of ~ 30-50 hours. Released blood PK exposure is ~ 1% of total PK exposure. Conclusion: AZD2811NP is documented to be well tolerated at doses up to 600 mg on Day 1 & 4 every 28 days in monotherapy setting and up to 400 mg (D1 & 4) in combination with azacitidine. The monotherapy and combination therapy dose escalations are ongoing. Updated results including preliminary efficacy data will be presented. Additional dose finding and expansion cohorts of AZD2811NP in combination with venetoclax are planned. Disclosures Atallah: Pfizer: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy. Yang:AstraZeneca: Research Funding; Agios: Consultancy. Eghtedar:Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Verastem Oncology: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Borthakur:Merck: Research Funding; Oncoceutics: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Eisai: Research Funding; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding. Charlton:AstraZeneca: Employment; GSK: Equity Ownership. MacDonald:AstraZeneca: Employment, Equity Ownership. Korzeniowska:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment, Equity Ownership. Strickland:Sarah Cannon Development Innovations: Employment. Overend:AstraZeneca: Employment, Equity Ownership. Adelman:AstraZeneca: Employment, Equity Ownership. Fabbri:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment, Equity Ownership. Pease:AstraZeneca: Employment, Equity Ownership. Cosaert:AstraZeneca: Employment. OffLabel Disclosure: AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of Aurora Kinase B (AurKB), is an investigational agent in clinical trials for human cancers including AML/MDS.

3098 Background: Aurora kinase B (AURKB) represents a potential target for therapy in solid and hematological malignancies. AURKB inhibitor AZD1152 (barasertib) was previously investigated in solid tumor pts in a phase I setting. AZD2811-nanoparticle (np) is a novel, encapsulated slow release AURKB inhibitor offering several advantages over AZD1152 (Ashton S et al., Sci Transl Med 2016). We report the completed dose-escalation safety, pharmacokinetics (PK), preliminary activity and defined maximum tolerated dose (MTD) of AZD2811-np in pts with advanced solid tumors (NCT02579226). Methods: Adult pts with advanced solid tumors received AZD2811-np IV on Day 1 (D1) and 4 (D4) Q4 week (wk) in six cohorts 15-200 mg/infusion without the use of g-csf in cycle 1. D1 Q4wk and Q3wk schedules were investigated up to 600 mg/infusion (including cohorts with mandatory g-csf prophylaxis on day 8). A standard 3+3 design was used. PK was assessed in cycle 1. Results: 50 pts were recruited into 12 cohorts. D1, D4 Q4wk schedule: 24 pts (15, 25,38, 50, 100 mg/infusion (n=3/cohort), 200 mg/infusion (n=9)). All cohorts were tolerated. Transient grade 4 neutropenia was observed in 7/9 pts at 200 mg/infusion, including 1 DLT (gr4 > 7 days) D1 Q4wk: 200 mg(n=3) was tolerated. D1 Q3wk: 23 pts were evaluated (200/400 mg (n=3,7), and 400/600/500 mg with mandatory g-csf (n=3/5/6)). 400 mg without g-csf was not tolerated (1 gr3 mucosal inflammation & 1 gr4 neutropenia > 7 days). 600 mg with g-csf was not tolerated (gr3 febrile neutropenia & gr3 fatigue). 25/50 pts experienced AE ≥gr 3 (21 considered AZD2811-np-related, 19 neutropenia-related, no deaths within-DLT period). AZD2811-np caused transient gr1/2 fatigue, nausea, diarrhoea and mucosal inflammation. AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours irrespective of schedule. Released AZD2811 concentrations ~1% of total. 14 pts (28%) had disease stabilisation. 1 prostate ca. pt had a confirmed partial response (PR) (continued tx to 451 days). Conclusions: The MTD for AZD2811-np is 500 mg D1 Q3wk. AZD2811-np is now being investigated in a small cell lung cancer expansion. Clinical trial information: NCT02579226.

The pressure algometer probe tip is usually held stationary and pressure is steadily increased from zero until a pressure pain threshold (PPT) is elicited. In order to explore the extent of surface markings of abnormally tender regions in more detail an improved method is proposed whereby the pressure algometer is not kept still. It is slid over the tissues at a predetermined downward pressure and velocity to produce compressive, tensile and shear stress within underlying tissues. It is moved over surrounding non-tender regions until it reaches the surface overlying an abnormally tender region where a PPT is evoked. The probe is removed immediately and the skin marked. When this is repeated from different directions, the boundary of the surface markings of a tender region will appear in corresponding detail. Provided that this ‘sliding pressure algometer’ produces sufficiently similar amounts of stress when applied on separate occasions, it can be used to monitor the progress of a condition or the effects of treatment. To reduce cost and increase availability, this pressure algometer may be made of a plastic syringe converted into a gas-tight chamber.

Background: Aurora kinases represent potential targets for anticancer therapy in solid tumors and hematological malignancies. In a phase I/II study, the aurora B kinase inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811 nanoparticle is a novel, encapsulated slow-release inhibitor of Aurora kinase B offering several advantages compared with AZD1152, including prolonged drug release in vivo. AZD2811 nanoparticle mimics the AZD1152 7-day continuous infusion when given as a 2-hr infusion on Day 1 and 4, and resulted in increased efficacy and decreased toxicity in vivo. We report the first-in-man dose-escalation of AZD2811 nanoparticle in pts with relapsed AML/MDS or treatment-naïve patients not eligible for intensive induction therapy. The objectives were to determine the safety profile, MTD, PK, dosing schedule and preliminary efficacy of AZD2811 nanoparticle. Methods: Patients received a single 2-hour IV infusion on Day 1 and 4 of each 28-day cycle. Based on the previous experience with AZD1152 in the same patient population, the expected MTD is in a range of 1,200 mg per cycle. In the ongoing dose escalation, cohorts of 3-6 patients have been sequentially enrolled in 4 cohorts ranging from 100 mg to 600 mg per infusion on Day 1 and 4 every 28 days, i.e. from 200 mg to 1,200 mg per cycle. Patients were allowed to continue to receive AZD2811 until disease progression, tolerability, or discontinuation criteria have been met. The study uses a Bayesian adaptive design approach to dose escalation to improve the efficiency and precision of the MTD estimation compared to a traditional 3+3 design. Results: Currently, 10 pts with age ranges from 56 to 86 years have completed DLT assessment period for the first 3 cohorts. 9 patients had relapsed/refractory secondary AML/MDS after failure of hypomethylating agents and 1 patient had a relapsed, therapy-related AML. Cohort 4 (600 mg per infusion D1 and D4) is currently under evaluation. Of the 10 pts in cohorts 1-3, 7 pts discontinued due to disease progression, 1 discontinued due to subject decision/consent withdrawal, 1 discontinued due to physician decision, and 1 pt is active and ongoing. AEs assessed as related to AZD2811 that occurred in one or more patients were Grade 3/4 neutropenia/thrombocytopenia, Grade 3 anemia and Grade 1 fatigue, rash and stomatitis. Thus far, no DLTs and no fatal AEs related to AZD2811 have been observed. 2 deaths have been reported, 1 due to the underlying disease and 1 due to a Serious Adverse Event of Gr 5 Sepsis (not related to study drug). AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours. Conclusion: AZD2811 nanoparticle is safe and well tolerated at a dose up to 400 mg on Day 1 and 4 every 28-days. The monotherapy dose escalation is ongoing and updated results including preliminary efficacy data and supporting preclinical data will be presented. Additional dose finding and expansion cohorts of AZD2811 nanoparticle in combination with azacytidine and venetoclax are planned. Disclosures Atallah: Novartis: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Jazz: Consultancy; Pfizer: Consultancy. Charlton:AstraZeneca: Employment. MacDonald:AstraZeneca: Employment. Young:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment. Overend:AstraZeneca: Employment. Adelman:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment. Pease:AstraZeneca: Employment. Brugger:AstraZeneca: Employment.

2592Background: Aurora kinases represent potential targets for anticancer therapy in solid tumors and hematological malignancies. The aurora B kinase inhibitor AZD1152 (barasertib) has shown benefi...

Objective. Although infants living in the north of Canada have been reported to have one of the highest rates of hospital admission for bronchiolitis in the world, the economic effects of this condition have not been reported. Passive immunization against the Respiratory Syncytial Virus, the most common causative agent of infant bronchiolitis, is available. Methods. We tabulated transportation, in-hospital care and family accommodation costs for infants of less than 12 months of age residing in the Baffin Region of Nunavut aged who were admitted to Baffin Regional Hospital in Iqaluit, Nunavut, and the Children's Hospital of Eastern Ontario in Ottawa, Ontario, with a primary diagnosis of bronchiolitis or viral pneumonia, over a 36-month period, between April 1999 and March 2002. Results. One hundred fifty-nine infants were admitted a total of 210 times, with 196 admissions to Baffin Regional Hospital, and 14 to the Children's Hospital of Eastern Ontario, during the study period. The overall, annual, population-based admission rate for the Baffin Region of Nunavut was 197 admissions per thousand infants per year. Total costs were $2,997,373 ($2,357,747 for Baffin Regional Hospital, $639,625 for the Children's Hospital of Eastern Ontario). Overall average costs were $14,273 per admission, $12,029 for infants admitted to Baffin Regional Hospital and $45,688 for infants admitted to the Children's Hospital of Eastern Ontario. Conclusions. Infant bronchiolitis in the Baffin Region of Nunavut represents a significant burden on the territorial health care system. (Int J Circumpolar Health 2005; 64(1):38-45) Keywords: Baffin region, Bronchiolitis, cost, Inuit, Nunavut

A nanoparticle formulation of AZD2811, a selective aurora kinase B inhibitor, is currently under clinical development for the treatment of both haematological and solid tumour disease. AZD2811 is the active derivative of the prodrug Barasertib (AZD1152) which gave promising clinical activity in elderly AML patients delivered as a 7-day infusion (Kantarjian et al, Cancer, 119, 2611-2619, 2013). To address the limitations associated with the clinical utility of Barasertib and other cell cycle inhibitors in the clinic, AZD2811 has been incorporated into an AccurinTM nanoparticle using a pamoic acid ion pairing approach to optimise drug release rate (Song et al, Journal of Controlled Release, 229, 106-119, 2016), improve the drug exposure to tumour and reduce the duration of administration. A proof of principle formulation of AZD2811 as an AccurinTM nanoparticle established the principle that anti-tumour activity and improved therapeutic index could be achieved (Ashton et al, Science Translational Medicine, 325, 1-10, 2016). The clinical nanoparticle formulation of AZD2811 has been optimised for drug loading and release rate. In pre-clinical models, the clinical formulation can be used flexibly to optimise drug delivery for use in both haematological disease such as AML, or in solid tumour settings. Anti-tumour activity in solid tumours can be achieved at doses where bone marrow toxicity is reduced compared to Barasertib. In sensitive xenograft and PDX solid tumour models greater than 90% tumour regression is observed after a total dose of 50mg/kg with no tumour progression for greater than 40 days. In contrast, for AML, increasing the dose intensity by 2-4 fold leads to neutropenia and to complete tumour regression in a range of AML xenograft models for greater than 60 days. These data establish the concept that drug delivery using nanoparticles is able to resolve therapeutic index challenges, and is able to do so across different disease types. AZD2811 is currently in Phase 1 clinical trial (D6130C0000). The current pre-clinical and clinical data with this novel approach to inhibition of the cell cycle will be discussed. Citation Format: Susan Ashton, Nicholas Floch, Paula Taylor, Colin Howes, Doug Ferguson, Matthew Ling, Maureen Hattersley, Shenghua Wen, Kim Maratea, Adina Hughes, Sean Redmond, Wolfram Brugger, Simon Smith, Alexander MacDonald, Keith Parry, Howard Burris, Young-Ho Song, Jim Nolan, Elizabeth Pease, Simon T. Barry. Development of AZD2811, an aurora kinase B inhibitor, incorporated into an AccurinTM nanoparticle for use in haematological and solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 311. doi:10.1158/1538-7445.AM2017-311

TPS2608 Background: Aurora kinase B performs key roles in the regulation of the cell cycle and represents a potential target for anticancer therapy. AZD2811, formerly designated AZD1152 hydroxy-quinazoline pyrazole anilide (AZD1152 hQPA), is a potent and selective inhibitor of Aurora B kinase activity and has been incorporated into a polymer nanoparticle carrier for intravenous (IV) administration. The phosphate pro-drug of AZD2811, known as AZD1152 (barasertib), reached Phase II of clinical development as a continuous IV infusion. While promising efficacy was seen with barasertib in elderly acute myeloid leukaemia (AML) patients ( Kantarjian HG et al., Cancer 2013;119:2611-19), continuous intravenous drug delivery precluded subsequent development in this disease setting and there were limited clinical responses in solid tumour patients due to dose-limiting myelotoxicity. AZD2811 nanoparticle has been designed to overcome these issues. Methods: Patients with relapsed advanced solid malignancies with no standard treatments are eligible for the part A dose escalation. Primary endpoint is to determine the maximum tolerated dose of AZD2811 nanoparticle using a 3+3 design. Patients with refractory/relapsed small cell lung cancer (SCLC) will be eligible for the part B expansion, where the safety, PK and anti-tumour activity of AZD2811 nanoparticle will be assessed as monotherapy and in combination with chemotherapy. Study enrolment is ongoing. Clinical trial information: NCT02579226.