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Aim and objectives To determine the factors influencing nurses' decisions and capacity to reduce sedentary behaviour in hospital inpatients in sub-acute hospital settings. Background Sedentary behaviour in hospital inpatients is a complex issue that can be resistant to resolution. There is little research investigating factors influencing nurses' promotion of reduced levels of sedentary behaviour in sub-acute hospital settings. Design An explanatory sequential design was employed, comprising quantitative and qualitative phases. Methods An online survey was conducted with a convenience sample of 138 nurses from five Australian states. Logistic regression modelling identified demographic and behavioural characteristics of nurses who often encouraged patients to reduce their sedentary behaviour. In-depth interviews were conducted with 11 ward nurses and nurse managers, with the content subjected to thematic analysis. STROBE and GRAMMS checklists were employed. Results Nurses recognised their role in promoting reduced sedentary behaviour but faced a range of personal and organisational barriers in achieving this outcome for patients. Few nurses were aware of national physical activity and sedentary behaviour guidelines. Five themes emerged from interviews (nursing role, care challenges, expectations of advocates, teamwork and improving the experience). Overall, many nurses experienced a lack of agency in promoting reduced sedentary behaviour and cognitive dissonance in feeling unable to undertake this role. Conclusions The results of this study are significant in confirming that reducing sedentary behaviour in hospital inpatients is influenced by a range of complex and multi-level factors. There is a fundamental need for organisational and clinical leadership in building a culture and climate in which staff feel empowered to promote reduced sedentary behaviour in their patients. Relevance to clinical practice The results of this study highlight the importance of taking action to reduce sedentary behaviour in sub-acute hospital settings. A co-design approach to developing interventions in local health services is warranted.

11011 Background: Oncogenic mutations in KIT or PDGFRα drive > 85% of GIST. However, primary and acquired mutations in the activation loop of PDGFRα and KIT are not effectively treated by approved therapies. A phase 1 study (NCT02508532) was initiated in advanced GIST to assess the safety, PK and clinical activity of BLU-285, a potent, highly-selective oral inhibitor that targets KIT Exon 17 and PDGFRα D842 activation loop mutants. Methods: Adult patients (pts) with unresectable GIST, who had received ≥2 kinase inhibitors including imatinib or who had a primary PDGFRα D842 mutation regardless of prior therapy, were given BLU-285 once daily on a 4-week cycle following a 3+3 escalation design, which allowed additional accrual to dose levels demonstrated to be safe. Adverse events (AEs) per CTCAE v4.03, PK and plasma/tumor mutant DNA levels were assessed. Response was determined by RECIST 1.1 every 8 weeks. Results: At a 01JAN17 cutoff, 40 pts (21 PDGFRa/19 KIT) have been treated with BLU-285 at doses of 30-600 mg. Median number of prior kinase inhibitor regimens was 4.5 (2-12) KIT/2.5 (0-4) PDGFRα. RECIST 1.1 responses were seen across all dose levels for PDGFRα GIST and at higher dose levels for KIT GIST. Of 17 PDGFRα D842V pts with ≥1 radiographic assessment, 7 had confirmed PR (ORR 41%) and 10 had SD. Of 11 evaluable KIT pts treated at doses ≥ 135 mg, 2 had PR (1 confirmed; ORR 18%) and 5 SD. BLU-285 is rapidly absorbed (Tmax 2-8 h), exposure increases linearly with dose, and half-life is > 24 h supporting QD dosing. Most AEs were grade 1 or 2, most commonly nausea (48%), fatigue (45%), peripheral edema, periorbital edema, vomiting (30% each), diarrhea (25%), anemia, dizziness, and lacrimation (23% each). There were no grade 4 or 5 BLU-285-related AEs, dose limiting toxicities, or discontinuations. 29 pts (all 21 PDGFRα pts) remain on treatment (duration 1-14 mo). Updated results including MTD, ct-DNA and central radiographic assessments will be presented. Conclusions: Precision targeted therapy with BLU-285 demonstrates important clinical activity in pts with both PDGFRα- and KIT-mutant GIST that is resistant to available therapies. Clinical trial information: NCT02508532.

Background: Aggressive Systemic Mastocytosis (ASM) and the related disorders, SM with associated hematologic non-mast cell disorder (SM-AHNMD) and mast cell leukemia (MCL), are mast cell (MC) neoplasms that cause debilitating allergy symptoms, markedly impair organ function and decrease life expectancy. Although the oncogenic KIT D816V mutant is recognized as an important driver in about 95% of advanced SM (ASM, SM-AHNMD, MCL), no currently approved therapy effectively targets KIT D816V. A phase 1 study (NCT02561988) was initiated in advanced SM to assess the safety, PK, and preliminary clinical activity of BLU-285, a potent, highly-selective oral inhibitor designed to target KIT D816V (IC50 = 0.27 nM). Methods: Adult patients (pts) with ASM, SM-AHNMD or MCL per WHO diagnostic criteria were given BLU-285 once daily on a 4-week cycle following a 3+3 escalation design. Adverse events (AEs) per CTCAE, PK and biomarkers including serum tryptase, D816V mutant allele fraction in blood and bone marrow and co-occurring mutations (Illumina TruSight panel) were assessed. Liver and spleen size were measured serially via CT or MRI. All cases will undergo central pathology review to confirm SM diagnosis and subtype. Results: At a 21-JUL-2016 cutoff, 6 pts (5 ASM; 1 SM-CMML) have been treated with BLU-285 in 2 cohorts at doses of 30 and 60 mg/day. All pts had confirmed D816V mutation in blood and bone marrow and all pts had ≥ 1 co-occurring mutation(s) in bone marrow (range 4-9, most frequently TET2 (5), DNMT3A (4) and GATA1 (4)). All pts had MC-related organ damage as evidenced by ≥ 1 C-finding (bone marrow dysfunction with ≥ 1 cytopenia; hepatomegaly with impaired liver function, ascites and/or portal hypertension; osteolytic skeletal lesions; splenomegaly with hypersplenism; malabsorption with weight loss). The median number of C-findings was 1.5 (range 1-3). 4 pts had urticaria pigmentosa. Concomitant medications for MC-related symptoms included anti-histamines (5), corticosteroids (2), leukotriene receptor antagonist (2) and/or cromolyn (1). 2 pts had received prior anti-neoplastic therapy with pegylated interferon (1) or midostaurin (1). Although early in dose escalation, marked improvements in disease symptoms and burden were seen in all pts across both dose levels. This included symptomatic relief of allergy symptoms with decreased use of corticosteroids (2), improved urticaria pigmentosa (3 of 4), and increased albumin (5)/weight gain (6), indicative of diminished malabsorption. Objective decreases in mast cell burden were also observed including decline in peripheral blood and bone marrow KIT D816V DNA levels (6), decreased splenomegaly (3), tryptase decline (5), and decreased bone marrow MCs (2 of 2) (1 pt had bone marrow aspirate MCs decline from 30% at baseline to 3%; 1 pt had bone marrow biopsy MCs decline from 80% to 20%, both at C3D1). Tryptase decline appears to be dose related, with > 50% decrease in 1/3 patients in the 30 mg cohort and > 50% decrease in 3/3 patients in the 60 mg cohort. Updated diagnostic, biomarker, bone marrow and response data will be presented at the time of the meeting. An MTD has not been determined and dose escalation continues. BLU-285 was well tolerated with most AEs being CTCAE grade 1 and no grade ≥ 4 events. Grade 2 AEs included fatigue, dizziness, headache, rash, shingles, anemia, elevated GGT and thrombocytopenia (1 patient each). Grade 3 alkaline phosphatase elevation was observed in 3 patients and grade 3 back pain in 1 patient. All pts remain on treatment, with duration of therapy ranging from 2-5 cycles. Initial PK data show that BLU-285 is rapidly absorbed (Tmax 2-4 h), and half-life is > 19 h supporting once daily dosing. Mean steady-state AUC and Cmax at the 30 mg dose level were 1,845 ng*h/mL and 89 ng/mL, which are below the maximally active exposure in KIT D816-mutant xenograft models. Conclusion: Currently approved therapies do not effectively target KIT D816V, a key genomic-driver in approximately 95% of SM. BLU-285, a potent, highly-selective inhibitor of this mutant has been well tolerated and demonstrates clinical activity early in dose escalation with objective decreases in MC burden and improvements in MC-related organ damage in advanced SM. These encouraging phase 1 data support selective targeting of KIT D816V and further clinical testing of BLU-285 in SM. Disclosures Drummond: BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau. DeAngelo:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Ariad: Consultancy; Baxter: Consultancy; Celgene: Consultancy. Deininger:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Radia:Novartis: Honoraria; Pfizer: Honoraria. Hexner:Blueprint medicines: Membership on an entity's Board of Directors or advisory committees; novartis: Research Funding. Shi:Blueprint Medicines: Employment, Equity Ownership. Alvarez-Diez:Blueprint Medicines: Employment, Equity Ownership. Evans:Blueprint Medicines: Employment, Equity Ownership. Healy:Blueprint Medicines: Employment, Equity Ownership. Wolf:Blueprint Medicines: Employment, Equity Ownership.

Small cell lung cancer (SCLC) is an aggressive cancer characterized by several autocrine growth mechanisms including stem cell factor and its receptor c-Kit. In order to arrive at potentially new and novel therapy for SCLC, we have investigated the effects of the tyrosine kinase inhibitor, STI 571, on SCLC cell lines. It has been previously reported that STI 571 does not only inhibit cellular Abl tyrosine kinase activity but also the PDGF receptor and c-Kit tyrosine kinases at similar concentrations (approximately 0.1 microM). There is no expression of the PDGF-receptor, and the Abl kinase is not activated by SCLC, but over 70% of SCLC contain the c-Kit receptor. Utilizing this preliminary data, we have determined that three (NCI-H69, NCI-H146 and NCI-H209) of five (including NCI-H82 and NCI-H249) SCLC cell lines had detectable c-Kit receptors and were inhibited in growth and viability at concentrations 1 - 5 microM of STI 571 after 48 h of treatment. The SCLC cell lines, NCI-H69, NCI-H146 and NCI-H209, showed a dose-response (tested between 0.1 - 10 microM) inhibition of tyrosine phosphorylation of c-Kit as well as in vitro kinase activity (at 5 microM) of c-Kit in response to STI 571. STI 571 inhibited cell motility, as assessed by time-lapsed video microscopy, within 6 h of STI 571 treatment (5 microM). STI 571 also decreased intracellular levels of reactive oxygen species (ROS) by at least 60%, at a concentration (5 microM) that also inhibited cell growth. Cell cycle analysis of STI 571 responsive cells showed that cells were generally slowed in G2/M phase, but there was no arrest at G1/S. A downstream phosphorylation target of c-Kit, Akt, was not phosphorylated in response to stem cell factor in the presence of STI 571. These data imply that STI 571 inhibits growth of SCLC cells through a mechanism that involves inactivation of the tyrosine kinase c-Kit. The effectiveness of STI 571 in this study suggests this drug may be useful in a clinical trial, for patients with SCLC. Oncogene (2000) 19, 3521 - 3528

10005 Background: Ceritinib is a potent ALK inhibitor with durable efficacy in adult pts with ALK-translocated non-small cell lung cancer. This report describes the results of a phase I study (NCT0...