Auswahl der wissenschaftlichen Literatur zum Thema „Innocare“

Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion. As a therapeutic target, its clinical significance has been well established in multiple subtypes of non-Hodgkin's lymphoma (NHL). Orelabrutinib (ICP-022) is a novel, potent irreversible BTK inhibitor with much improved target selectivity in comparison to Ibrutinib and Acalabrunitib, which leads to improved safety profiles. With a proprietary formulation, Orelabrutinib achieves high bioavailability comparing to other BTK inhibitors. Results of Phase I study (another presentation on Orelabrutinib) demonstrated favorable pharmacokinetic and pharmacodynamic properties for Orelabrutinib. Sustained BTK occupancy at 24 hr was achieved with daily dosing regimen. In this presentation, we will report results from clinical study of Orelabrutinib in Chinese patients with r/r CLL/SLL. This is an open-label, multicenter, Phase II study with objectives to evaluate its safety, tolerability and efficacy following oral daily administration. The primary endpoint was objective response rate (ORR). The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints. Response was assessed per 2008 IWCLL criteria with modification for PR with lymphocytosis (PR-L) (Cheson, Hallek 2012). This study is composed of two stages. The stage I was to assess the safety and tolerability of Orelabrutinib at 150 mg, QD in pts with r/r CLL/SLL, while the stage II was to evaluate its therapeutic benefits (N=80, 150 mg, QD). Total of 80 patients with r/r CLL (n=70)/SLL (n=10) were enrolled. As of 31 May 2019, 40 pts had completed six cycles of treatment (28 days/cycle). The Median follow-up was 6.3 months (range, 0.4-13.7 months). Safety: The most frequent (≥15%) any grade adverse events (AEs) of any cause were well characterized hematological toxicities: thrombocytopenia, neutropenia, and anemia; and respiratory system infections as well as purpura. No case of atrial fibrillation or secondary malignancy was reported. The most frequently (≥10%) reported ≥ Grade 3 AEs of any cause were neutropenia, thrombocytopenia, lung infection. Twenty-five pts experienced at least one serious AE. Of those, 13 were considered related to Orelabrutinib treatment, including platelet count decrease (3 pts), pneumonitis, pyrexia (2 pts each) and herpes zoster etc. (1 pt each). Efficacy: Of the 80 enrolled pts, seventy-eight pts were evaluable for response (by 31 of May 2019), the ORR was 88.5% (69/78). Among them, one patient was reported as CR, 39 pts were PR and 29 pts were PR-L. Stable disease was seen in 6/78 (7.7%). Total disease control rate is 96.2%. The median DOR was not reached, 6 months DOR rate was 89.8%. Subgroup analysis (age, disease stage, previous treatment, 17p deletion, 11q deletion, IGHV mutation) did not reveal significant differences. Conclusion: Orelabrutinib is safe and well tolerated. No significant adverse events like atrial fibrillation/flutter or secondary malignancies were reported. Orelabrutinib is efficacious to treat pts with r/r CLL/SLL. The improved safety, resulting from high target selectivity, and daily dosing regimen enable Orelabrutinib to be a valuable therapeutic choice both as monotherapy and likely in combination with other agents to treat B-cell malignancies. Disclosures Xu: Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhu:Beijing InnoCare Pharma Tech Co., Ltd: Employment.

Mantle cell lymphoma (MCL), a subtype of aggressive B-cell non-Hodgkin lymphoma (NHL), remains challenging with unsatisfied outcomes from standard therapy. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitors has been validated in multiple subtypes of NHL. Ibrutinib, the first BTK inhibitor, has been approved by FDA for the treatment of refractory and relapse (r/r) MCL. In spite of encouraging efficacy, clinically often referred adverse events such as diarrhea, bleeding and atrial fibrillation, respectively following ibrutinib treatment. It has been hypothesized that poor target selectivity (inhibitive effect on EGFR, TEC, BMX and others) may partially explain the occurrence of these adverse events. As such, there are focused efforts to develop new BTK inhibitor with high target selectivity aiming to improve the safety. Orelabrutinib (ICP-022) is a novel, potent irreversible BTK inhibitor with high selectivity for BTK vs other kinases including TEC- and EGFR-family members. Results from Phase I study demonstrated excellent safety/tolerability profiles as well as favorable pharmacokinetic and pharmacodynamic properties. Sustained BTK occupancy at 24 hr was achieved with once daily dosing regimen. In this presentation, we describe the clinical results of orelabrutinib in Chinese patients with r/r MCL. This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) and the duration of response (DOR) and safety were chosen as secondary endpoints. The stage I was designed for regimen selection (RP2D, N=20 for 100 mg, bid and 150 mg, qd each, respectively), while the stage II for efficacy at RP2D (N=86 150 mg, qd). Response was assessed per Lugano criteria (2014). Total of 106 pts with r/r MCL were enrolled. As of 31 May 2019, sixty-two pts had completed six cycles of treatment (28 days/cycle). The median duration of treatment was 197.5 days. Safety: A total of 106 pts were enrolled and treated at 22 centers in China. The most frequent (>15%) adverse events (AEs) of any cause were mostly hematological toxicities including thrombocytopenia and neutropenia; and respiratory system infections as well as rash. The frequently reported (>10%) grade 3 or higher AEs of any cause were thrombocytopenia (12.3%). No grade 2 or higher hemorrhage was reported. No treatment related grade 3 GI or cardio toxicity was observed. Of the 106 patients, twenty-five experienced serious AEs and 13 of them were treatment-related (primarily occurred as hematologic toxicities and / or infections). Efficacy: Forty patients, divided into two cohorts (n=20 each), were enrolled in stage I. The regimen, 150 mg, qd, was selected as RP2D based on a better ORR and the convenience of once daily dosing. All patients who were enrolled in the stage I continued their treatment. At the time of reporting (the 31 May 2019), 97 patients had response assessments. The response rate was assessed by traditional CT image technology. The ORR was 82.5% (80/97) for combining both regimens with the complete response rate (CR) 24.7% (24/97), partial responses 57.7% (56/97). Stable disease was seen in 9.3% (9/97). The total disease control rate is 91.8%. Six (6.2%) patients progressed by the first response assessment. The median duration of response rate (DOR) has not been reached. Conclusion: Orelabrutinib is safe and well tolerated with no reported treatment related grade 3 or higher GI toxicity, atrial fibrillation/flutter and severe bleeding in this study. Orelabrutinib is efficacious to treat patients with r/r MCL. The improved safety, resulting from high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as the potential of preferred therapeutic choice for B cell malignancy. Disclosures Lu: Beijing InnoCare Pharma Tech. Co., Ltd.: Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Employment.

Orelabrutinib (ICP-022) is a novel and highly selective irreversible BTK inhibitor. We previously reported that orelabrutinib had high bioavailability with ~100% BTK occupancy at 24 hours at 150 mg daily dosing regimen and demonstrated excellent safety and efficacy profiles at median follow-up of 8.7 months in a Phase I/II trial of refractory/relapsed (r/r) CLL/SLL (Chronic Lymphocytic Leukemia/Small Cell Leukemia). Here we present an updated analysis of efficacy and safety results from the clinical study of Orelabrutinib in Chinese patients with r/r CLL/SLL following extended treatment. This is an open-label, multicenter, phase II study with objectives to evaluate its safety and efficacy following an oral daily administration. The primary endpoint was objective response rate (ORR). The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints. Response was assessed per 2008 IWCLL criteria with modification for partial remission (PR) with lymphocytosis (PR-L) (Hallek 2012) or the Lugano Classification (Cheson, 2014) for CLL and SLL, respectively. Results: A total of 80 patients with r/r CLL (n=70)/SLL (n=10) were enrolled. Eligible patients had relapsed after or were refractory to ≥1 prior treatment with median age of 60.0 (range, 36.0-78.0 years). There are 70% of patients for Rai stage 3-4 disease, 22.5% for 17p13.1 deletion [del(17p)] and/or TP53 mutation, 41.3% for unmutated immunoglobulin heavy chain variable region (IGHV) and 23.8% for 11q22.3 deletion [del(11q)]. The median follow-up time was 14.3 months (range, 0.2-21.6 months), and the last patient completed a minimum of 12 cycles of orelabrutinib treatment. Efficacy: The efficacy results presented here were evaluated by IRC (Independent review committee). Following a minimum of 12 cycles treatment, the ORR (PR-L or above) was 91.3% (95% confidence interval [CI]: 82.80 ~ 96.41%) with 10.0% of patients having complete response (CR), 63.8% PR and 17.5% PR-L. Median time for achieving first response was 1.87 months (range, 1.84 - 1.94 months). The median DOR and PFS were not reached. The estimated 12-month DOR was 77.1% (95% CI: 62.50-86.60%), PFS 81.1% (95% CI: 70.53 - 88.13%) and OS 86.3% (95% CI: 76.55 - 92.14%). Patients with Del(17p) and/or TP53 mutation achieved 100% ORR. The ORR is 94.7% for Del(11q)) and 93.9% for unmutated IGHV. Comparing to the first analysis results of which the median follow-up was 8.7 months, the CR rate had increased from 3.8% to 10.0%, and 8 patients with PR-L had converted to a deeper response. So, orelabrutinib showed a significant higher CR rate comparing to other BTK inhibitors at a similar treatment period and we anticipate a further increase of CR rate with longer duration of treatment. Safety: Most adverse events (AEs) were mild to moderate, similar to the first reported safety profiles at median follow-up of 8.7 months. Extended follow-up analysis did not reveal new safety nor toxicity concerns. The most frequent adverse events (AEs) of any cause/any grade were well characterized as hematological toxicities: thrombocytopenia, neutropenia, and anemia; upper respiratory tract infection, pneumonia and hypokalemia. No case of atrial fibrillation nor secondary malignancy was reported, no patient was observed for ≥3 hypertension and only one patient had ≥3 grade diarrhea. Major hemorrhage was reported in 2 patients, one with intracranial hemorrhage (65-year-old male patient with more than 10 years hypertension) and the other with vitreous hemorrhage which were resulted from posterior vitreous detachment that was assessed as unlikely related to the treatment of orelabrutinib. Once again, it has been further confirmed that orelabrutinib has excellent safety profiles following extended treatment. Conclusion: This updated and extended study further confirms that orelabrutinib is efficacious in treating r/r CLL patients with a higher CR rate, durable response and improved safety profiles. As a highly selective BTK inhibitor with favorable pharmacokinetic and pharmacodynamic properties, orelabrutinib provides a favorable therapeutic choice for patients with r/r CLL/SLL and a potential best candidate for combination therapy. Disclosures Zhu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

Background: Bruton tyrosine kinase (BTK) is one of the key kinases implicated in the pathogenesis of multiple B cell malignancies. Orelabrutinib is a novel, highly selective and potent irreversible BTK inhibitor with minimal activities against other kinases (ITK, EGFR, ERBB2, etc.). As thus orelabrutinib may avoid off-target related adverse events and shall have improved safety profiles comparing to other BTK inhibitors. Here we present the safety profile of orelabrutinib analyzed based on data from 5 ongoing clinical studies in B cell malignancies (Table 1). Methods: Safety data of 266 patients (pts) from 5 ongoing orelabrutinib monotherapy studies were pooled and analyzed. All pts have been treated with at least one dose of oral orelabrutinib at ≥150 mg daily. The analysis includes the frequency and severity of adverse events (AEs), AEs of special interest, and AEs leading to treatment discontinuation or dose modifications. Results: Safety data were pooled from 266 pts with median age of 60 years (range 35.0-79.0, 69.2% males). The median duration of exposure was 11.0 months (range 0.2-22.0). The most common (occurring in ≥15% of pts) AEs were neutropenia (28.6%), thrombocytopenia (25.9%), Upper respiratory tract infection (24.4%), leukopenia (18.0%), anemia (16.2%) and rash (15.8%). Treatment related serious AEs (SAEs) were reported in 14.7% pts. The most common treatment related SAEs included thrombocytopenia (3.0%), lung infection (3.0%), pneumonitis (1.9%), anemia (1.1%) and lymphadentis (0.8%), The safety profiles were comparable in pts with various subtypes of B cell malignancies. It's noted that orelabrutinib has much less frequency of BTK off-target related adverse events, such as atrial fibrillation, diarrhea, major hemorrhage etc. Among all 266 pts, only one patient was reported with one episode of transient grade 1 atrial fibrillation, and no grade ≥3 atrial fibrillation was observed. Diarrhea of any grade was 7.1% and only one case (0.4%) was reported as grade 3. The major hemorrhage, defined as serious or ≥ G3 bleeding of any site, or central nervous system bleeding of any grade, was rarely observed; as only one case of cerebral hemorrhage, in 65-year-old male patient with more than 10 years hypertension was reported; the other three cases were subcutaneous hemorrhage, vitreous hemorrhage and vitreous hemorrhage/retinal hemorrhage. The later 2 cases of vitreous hemorrhage and/or retinal hemorrhage were resulted from posterior vitreous detachment and macular degeneration and both events were assessed as unlikely related to the treatment. Among 266 pts, the second primary malignancies were reported in only one pt with r/r MCL during orelabrutinib treatment. Grade ≥3 infection occurred in 41 pts (15.4%); most common infections were upper respiratory tract infection and lung infection. Most of the AEs were occurred during the early treatment, the frequency of the new event occurrence was significantly decreased during the later cycles. Dose reductions due to AEs occurred in 15 pts (5.6%), and treatment discontinuation due to AEs in 5.3% of pts with 2.3% related to orelabrutinib. Conclusions: Orelabrutinib shows excellent safety profiles and tolerability across various B-cell malignancies in long-term treatment. These data suggested orelabrutinib as a favorable treatment choice including the combinational therapy for B-cell malignancies. . Disclosures Zhu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

Background: In spite of years of effort, Mantle Cell Lymphoma (MCL) remains a clinical challenge. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitor has been validated with the approvals by FDA for the treatment of multiple subtypes of NHL including refractory and relapse (r/r) MCL. However, some serious adverse events (AEs) due to poor target selectivity (inhibition of EGFR, TEC, BMX and others), such as diarrhea, sever bleeding and atrial fibrillation, remain as challenges in clinic. Orelabrutinib is a novel, potent irreversible BTK inhibitor with high selectivity for BTK. Results of early clinical study showed that it has excellent safety/tolerability profiles and favorable pharmacokinetic/pharmacodynamic properties. Sustained ~100% BTK occupancy at 24 hours was achieved with once daily dosing regimen of 50 mg and above. In this presentation, we will report an updated analysis of orelabrutinib in Chinese patients with r/r MCL with minimum of 12 cycles of treatment. Aims: To evaluate the sustained efficacy and long-term safety of orelabrutinib in Chinese patients with r/r MCL. Methods: This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) assessed per Lugano criteria (2014). Safety and other efficacy (DOR, PFS, OS) evaluations were chosen as secondary endpoints. Results: A Total 106 patients, were enrolled in this study with median follow up time of 15.0 months. 79.2% of the patients were male and median age of 62.0 years old. Most patients were at advanced stage (73.6% were at stage IV and 20.8% were at stage III). According to per protocol analysis, 87 (87.9%) patients achieved ORR and 93.9% patients achieved disease control. The median duration of response (DOR) was not reached, the DOR rate at 12 months was 73.7%, as expected the median PFS and OS were not reached, the PFS and OS rates at 12-month were 70.8% and 88.7% respectively. Comparing to the results of previous analysis, the CR rate, by conventional CT method, increased to 27.4% and it was expected a higher rate of in depth response may occur with prolonged treatment. Further analysis showed orelabrutinib was efficacious in all subgroups (age, gender, status, stage, prior therapy, etc.). Orelabrutinib demonstrated excellent safety profile in r/r MCL patients. The frequently reported treatment related adverse events (TRAE) were primarily hematological toxicities including thrombocytopenia, neutropenia, leukopenia, and hypertension. The frequently reported grade 3 or higher AEs of any cause was thrombocytopenia . No treatment related ≥grade 3 GI and cardio toxicity, nor severe bleeding, were observed. Of the 106 patients, 32 experienced serious AEs; and 17 of them, mainly hematological toxicities and / or infections were treatment-related. Comparing to the safety data of median follow up of 10.5 months, there was only a mild increase of adverse events rate after extended treatments; the safety profiles were essentially the same. These results suggested that safety events primarily occurred during early treatment and it appeared less eventful with orelabrutinib continue treatment. Conclusion: Orelabrutinib showed continuous efficacious in treating patients with r/r MCL. In addition, orelabrutinib is safe and well tolerated with no treatment related grade 3 or higher diarrhea, atrial fibrillation/flutter or severe bleeding in this study. Results of prolong treatment expected to produce a higher rate of in depth response without altering its safety profiles support orelabrutinib being a better selection for BTKi therapy. The improved safety as a resulting of high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as preferred therapeutic choice for B cell malignancy. Disclosures Zhang: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

4092 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR activities irreversibly by covalent binding. Preclinical data showed that gunagratinib overcomes the acquired resistance to the first-generation reversible FGFR inhibitors, e.g., infigratinib. ICP-CL-00301 is a phase I, first-in-human, clinical study which includes a dose escalation followed by dose expansion. The safety and tolerability as well as pharmacokinetics/pharmacodynamics (PK/PD) of gunagratinib were evaluated in patients with advanced solid tumors, and the preliminary anti-tumor activity was evaluated by RECIST1.1 in patients with FGF/FGFR gene aberrations. Methods: In the dose-escalation stage, patients with advanced solid tumors with or without FGF/FGFR alterations were treated with escalating doses (2, 4, 8, 10, 12, 14, 16 mg etc.) of gunagratinib once daily in 21-day cycles until disease progression or unacceptable toxicity. During the dose-expansion stage, patients with cholangiocarcinoma harboring FGFR2 gene fusion/translocation received the treatment of gunagratinib daily at 12 mg continuously. Results: As of February 2021, a total of 30 patients had received the treatment of gunagratinib. The median age of the treated patients was 55.0 (range: 28 to 75 years) with 56.7% male and ECOG performance status between 0-1. The maximum tolerated dose (MTD) had not been reached. The most common treatment-related adverse events (TRAEs) ( > 20%) included hyperphosphatemia, hypercalcemia, increased ALT or AST, diarrhea and hypertriglyceridemia. Hyperphosphatemia is a commonly reported AE from other trials targeting FGFR and here serves as a PD biomarker of FGFR inhibition. This PD biomarker was observed in 73.3% of the patients treated with gunagratinib at all dose levels and was consistently observed at doses of 8 mg QD and above. Hyperphosphatemia was well managed with oral phosphate binders when necessary. The plasma exposure increased proportionally to the oral dosage levels of gunagratinib. Among the 12 patients with FGF/FGFR gene aberrations who have completed at least one tumor assessment, the overall response rate (ORR) was 33.3%, including 1 patient (8.3%) of cholangiocarcinoma with complete response (CR) and 3 patients (25%) with partial response (PR). The disease control rate (DCR) was 91.7% (11 of 12 patients). Conclusions: Gunagratinib is safe and well-tolerated in patients with advanced solid tumors. Anti-tumor activity was demonstrated in patients with FGF/FGFR gene aberrations in multiple tumor types, including cholangiocarcinoma (NCT03758664). Better response is expected with the increase of treatment durations. Clinical trial information: NCT03758664.

A new innovative satellite mission, the Innovative CubeSat for Education (InnoCube), is addressed. The goal of the mission is to demonstrate “the wireless satellite”, which replaces the data harness by robust, high-speed, real-time, very short-range radio communications using the SKITH (SKIpTheHarness) technology. This will make InnoCube the first wireless satellite in history. Another technology demonstration is an experimental energy-storing satellite structure that was developed in the previous Wall#E project and might replace conventional battery technology in the future. As a further payload, the hardware for the concept of a software-based solution for receiving signals from Global Navigation Satellite Systems (GNSS) will be developed to enable precise position determination of the CubeSat. Aside from technical goals this work aims to be of use in the teaching of engineering skills and practical sustainable education of students, important technical and scientific publications, and the increase of university skills. This article gives an overview of the overall design of the InnoCube.

Hospital-acquired Infections (HAIs) surveillance, defined as the systematic collection of data related to a certain health event, is considered an essential dimension for a prevention HAI program to be effective. In recent years, new automated HAI surveillance methods have emerged with the wide adoption of electronic health records (EHR). Here we present the validation results against the gold standard of HAIs diagnosis of the InNoCBR system deployed in the Ourense University Hospital Complex (Spain). Acting as a totally autonomous system, InNoCBR achieves a HAI sensitivity of 70.83% and a specificity of 97.76%, with a positive predictive value of 77.24%. The kappa index for infection type classification is 0.67. Sensitivity varies depending on infection type, where bloodstream infection attains the best value (93.33%), whereas the respiratory infection could be improved the most (53.33%). Working as a semi-automatic system, InNoCBR reaches a high level of sensitivity (81.73%), specificity (99.47%), and a meritorious positive predictive value (94.33%).

Introduction: Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin's lymphoma. It is an incurable disease with frequent relapse from chemotherapies, targeted therapies, and cell therapies. Dysregulated expression of BCL-2 family members resulting in enhanced cell survival frequently occurs in many cancer types and often contributes to the development of therapeutic resistance. The BCL-2 inhibitor venetoclax has been shown to be effective in treating refractory/relapsed MCL patients. However, resistance often occurs and one of the underlying mechanisms of this resistance is the increased expression of other anti-apoptotic BCL-2 family members, such as BCL-XL and MCL-1. In this study, we assessed the in vitro and in vivo efficacy of a novel and highly potent BCL-2/XL dual inhibitor AZD4320 in preclinical models. Methods: Cell viability assay was tested after 72-hour treatment with AZD4320 in a panel of ibrutinib/venetoclax-sensitive and -resistant MCL cell lines by CellTiter-Glo (Promega). The assay was also done after a 24-hour treatment in primary PDX cells. Cell apoptosis assay was performed to determine if AZD4320 induces cell apoptosis in MCL cell lines. Furthermore, the in vivo efficacy of AZD4320 was assessed in a CAR-T resistant MCL patient-derived xenograft (PDX) model. Results: AZD4320 significantly inhibited cell proliferation in all tested MCL cell lines, including both ibrutinib/venetoclax-sensitive and -resistant cell lines. It had an IC50 value at a low nanomolar range between 0.59 nM to 18 nM. Consistently, AZD4320 was effective in targeting primary PDX cells ex vivo. AZD4320 induced cell apoptosis in a dose-dependent manner. AZD0466, the nanomedicine formulation of AZD4320 (30mg/kg, weekly, IV), dramatically inhibited tumor growth and prolonged mouse survival in an ibrutinib-CAR-T dual-resistant PDX mouse model. All mice tolerated the treatment dose without any body weight loss. Conclusion: The novel BCL-2/XL dual inhibitor AZD4320 demonstrated excellent anti-MCL activity in both ibrutinib/venetoclax-sensitive and -resistant MCL cells in vitro. This was further validated in vivo in a ibrutinib-CAR-T dual-resistant PDX model. These findings provide evidence that dual targeting of BCL-2 and BCL-XL by AZD4320 is promising as it may overcome therapeutic resistance in relapsed/refractory MCL. Disclosures Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cidado:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Wang:OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Loxo Oncology: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OncLive: Honoraria; Lu Daopei Medical Group: Honoraria; Acerta Pharma: Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Oncternal: Consultancy, Research Funding; Pulse Biosciences: Consultancy; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Beijing Medical Award Foundation: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Guidepoint Global: Consultancy; Targeted Oncology: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy.

X-ray imaging was a very important detection that is used in many useful functionalities as in healthcare. It would be powerful and facilitate several functions if we could come up with a method that gives a better resolution when doing X-ray imaging. This will be done by using two different detectors, a commercial detector (Innocare) and a direct converting detector (Medipix3). These two detectors have different properties. In addition to these detectors, a radiation source that radiates with X-rays has been used and a line mask that provides the ability to read the resolution of the image. The use of these detectors will provide answers to the investigation of limitations that its detectors have.
Röntgenavbildning är en viktig upptäckt som används i bland annat vården. Det skulle underlätta flera användningsområden om en metod kunde tas fram som ger bättre upplösning på bilder vid avbildning. I detta arbete undersöks vad som kan bidra till att få den bästa upplösningen vid röntgenavbildning. I undersökningen kommer det att användas två olika detektorer, en kommersiell detektor (Innocare) och en direktkonverterande detektor (Medipix3). Dessa två detektorer har olika egenskaper. Utöver dessa detektorer har en strålkälla som strålar med röntgenstrålar använts och en linjemask som ger möjligheten att läsa av bildens upplösning. Användningen av dessa detektorer kommer att ge svar på utredningen av begränsningar som dess detektorer har.

Multiple breath washout (MBW) of inert gas for assessment of airway disease in children is an emerging technique. In many studies Lung Clearance Index (LCI), derived from multiple breath washout of SF6, is more able to detect early or mild lung disease than standard lung function measurements. It is also able to detect very early lung disease in progressive conditions such as Cystic Fibrosis (CF). Where infants born with this condition were thought to have minimal lung disease activity, LCI is higher in these children than healthy controls. Lack of available commercial devices has hampered expansion of this technique to centres other than specialist research teams. Innocor (Innovision, Dk), a photoacoustic mass spectrometer capable of performing multiple breath washout, was adapted within this research group for use in adults. This thesis describes the setup, adaptation and validation of Innocor for use in children. In 4 studies, healthy controls, children with asthma and children with CF were recruited to perform MBW. In one study, 29 healthy controls and 31 children with asthma were recruited. Healthy controls performed 1 set of washouts, establishing a normative range. Children with asthma performed measurements before and after bronchodilator. Results showed increased LCI in children with asthma even though they were clinically stable as defined by symptoms. LCI stayed high even following bronchodilator suggesting evidence of residual airway disease in well controlled asthmatics despite adequate symptom control. To investigate short term variability of MBW measurements, two other studies recruited 18 children with CF in each. They performed measurements before and after standard physiotherapy manoeuvres and during sitting and lying posture. LCI did not change significantly after airway clearance physiotherapy, compared with children who did no intervention. Variability was high in both groups however suggesting CF lung disease is a complex interaction of changing ventilation in adjacent lung units. Lying posture induced greater changes in lung function in children with CF than controls. LCI appears to be more sensitive to this change than standard lung function measurements (spirometry). In another study 32 children with CF were recruited to perform serial lung function measurements over 18 months. These were data collected as part of the UK Cystic Fibrosis Gene Therapy Consortium (CFGTC) clinical studies in preparation for planned gene therapy trials. LCI appears comparable to FEV1 and may be able to detect another aspect of airway disease. All initial studies were performed in older children (>5yrs). The basic Innocor device is unsuitable for testing of younger patients with low breath volume and high respiratory rate. In-house adaptations following detailed lung model experimentation led to a faster analyser response, potentially capable of MBW in younger children. The second part of this thesis concerns lab experiments and an in-vivo comparison with the current gold-standard MBW device, a respiratory mass spectrometer. 16 healthy volunteers and 9 children with CF were recruited. Ages ranged from 0.4 yrs to 49 yrs. Innocor values for lung volume estimation compared favourably with the mass spectrometer. No evidence of bias caused by Innocor error was seen, however intra-test variability was rather high, reducing the precision of the results. These studies indicate Innocor is a robust, simple to use device with potential as a commercial lung function system. Modifications were made to make it suitable for use in all ages. Further development will need to focus on the patient interface and software, which is the domain of the manufacturers. The experiments contained in this thesis are therefore of interest to the wider respiratory research community as well as manufacturers of MBW devices.