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Background and Aims: Mobile Stroke Units (MSU) have been shown to reduce time to treatment and improve patient outcomes.There is an opportunity to improve the efficacy of stroke reperfusion treatment provided by MSUs. In the MSU environment, tenecteplase (TNK) offers practical benefits as it is administered as a single bolus rather than a one-hour infusion like alteplase (tPA). In the present study, we test the hypothesis that treatment with TNK in the MSU results in superior reperfusion on hospital arrival compared with tPA. Method(s): The Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation Trial in the Ambulance (Mobile Stroke Unit- TASTE-A) is a PROBE, phase II superiority RCT of TNK (0.25mg/kg) versus tPA (0.9mg/ kg) for patients presenting within 4.5 hours of symptom onset to the Melbourne MSU. The primary outcome is the volume of the perfusion lesion post treatment, on computed tomography perfusion imaging performed on arrival at the receiving hospital ED, adjusted for pre-treatment NIHSS and time from initiation of MSU treatment to ED imaging. Secondary outcomes include time for MSU arrival to treatment, NIHSS change from MSU to ED assessments and 90 day modified Rankin Score. Result(s): The trial was conducted on one MSU in Melbourne Australia which transferred enrolled patients to one of five participating hospitals. The last patient was recruited on November 16, 2021 after recruitment of the prespecified adaptive sample size of 104 patients, and the final results will be presented at the conference. Conclusion(s): To be Determined.

Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. Immune checkpoint inhibition (ICI) with PD/PD1 inhibitors (PD1i) yield high response rates in some lymphomas; though single agent PD1i yields a disappointing ORR of 10% in heavily pre-treated DLBCL, some responses are durable. RT stimulates anti-tumour immunity through several mechanisms and may enhance response to ICI. Concurrent ICI & RT is synergistic in preclinical studies & solid tumours, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumour antigen release and overcome clonal variation between disease sites to further augment the immune response. A dose-response relationship between RT and antigen release has yet to be established. This phase I dose escalation study aims to determine the safety profile of RT in combination with durvalumab, an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL and FL. Study Design and Methods: RaDD (NCT03610061) is a phase I dose escalation study to determine the safety profile of escalating dose and number of sites of RT in combination with durvalumab in relapsed/refractory (RR) DLBCL & FL. Eligible patients (pts) have received >= 1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplant (auto-SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic-SCT or chronic steroid use are excluded. RT dose and site escalation proceeds according to a 3+3 design with 6 dose levels (cohorts 1-6). Treatment comprises external beam RT to target site(s) daily for 5 days (Cohorts 1-5); Cohort 6 receives a further 5 daily fractions (max 30Gy). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until disease progression. Pts can continue until a second radiological progression if clinical benefit is ongoing. The dose limiting toxicity period is 28 days from start of RT. The primary endpoint is the toxi

Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. PD1/PDL1 inhibitors yield high response rates in some lymphomas, but single agent therapy in heavily pre-treated pts are disappointing. RT stimulates anti-tumor immunity through several mechanisms and may enhance response to immune checkpoint inhibition (ICI). Concurrent ICI & RT is synergistic in preclinical studies & solid tumors, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumor antigen release and overcome clonal variation between disease sites to further augment the immune response. Method(s): RaDD (NCT03610061) is a phase I, 3+3 dose escalation study to determine the safety profile of escalating dose & number of sites of RT in combination with Durvalumab (anti-PD-L1 antibody) in RR DLBCL & FL. Eligible pts (i.e. >=1 prior therapy, ineligible for auto-SCT, no contraindication to PDL1i) receive 5 fractions of external beam RT to target site(s). 5 RT dose & site levels are included (dose range 2.5Gy-20Gy to 1-3 sites). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until confirmed disease progression. The DLT period is 28 days from start of RT. Primary endpoint is the recommended phase two dose (RP2D) of RT in combination with durvalumab. Secondary endpoints include response rates, PFS & OS. Correlative studies will examine the tumour-immune system interaction; an exploratory PET substudy with novel tracers for durvalumab (89Zr-Durvalumab) & CD8+ T cells (89Zr -Df-IAB22M2C) will also be performed. Projected enrollment for determination of maximum tolerated dose (MTD) & RP2D is 6-30 pts pending toxicity. Recruitment will continue to 36 pts for secondary endpoint analysis. 9 pts are enrolled across cohorts 1-3 to date.

Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. Immune checkpoint inhibition (ICI) with PD/PD1 inhibitors (PD1i) yield high response rates in some lymphomas; though single agent PD1i yields a disappointing ORR of 10% in heavily pre-treated DLBCL, some responses are durable. RT stimulates anti-tumour immunity through several mechanisms and may enhance response to ICI. Concurrent ICI & RT is synergistic in preclinical studies & solid tumours, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumour antigen release and overcome clonal variation between disease sites to further augment the immune response. A dose-response relationship between RT and antigen release has yet to be established. This phase I dose escalation study aims to determine the safety profile of RT in combination with durvalumab, an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL and FL. Study Design and Methods: RaDD (NCT03610061) is a phase I dose escalation study to determine the safety profile of escalating dose and number of sites of RT in combination with durvalumab in relapsed/refractory (RR) DLBCL & FL. Eligible patients (pts) have received >= 1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplant (auto-SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic-SCT or chronic steroid use are excluded. RT dose and site escalation proceeds according to a 3+3 design with 6 dose levels (cohorts 1-6). Treatment comprises external beam RT to target site(s) daily for 5 days (Cohorts 1-5); Cohort 6 receives a further 5 daily fractions (max 30Gy). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until disease progression. Pts can continue until a second radiological progression if clinical benefit is ongoing. The dose limiting toxicity period is 28 days from start of RT. The primary endpoint is the toxi

Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. PD1/PDL1 inhibitors yield high response rates in some lymphomas, but single agent therapy in heavily pre-treated pts are disappointing. RT stimulates anti-tumor immunity through several mechanisms and may enhance response to immune checkpoint inhibition (ICI). Concurrent ICI & RT is synergistic in preclinical studies & solid tumors, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumor antigen release and overcome clonal variation between disease sites to further augment the immune response. Method(s): RaDD (NCT03610061) is a phase I, 3+3 dose escalation study to determine the safety profile of escalating dose & number of sites of RT in combination with Durvalumab (anti-PD-L1 antibody) in RR DLBCL & FL. Eligible pts (i.e. >=1 prior therapy, ineligible for auto-SCT, no contraindication to PDL1i) receive 5 fractions of external beam RT to target site(s). 5 RT dose & site levels are included (dose range 2.5Gy-20Gy to 1-3 sites). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until confirmed disease progression. The DLT period is 28 days from start of RT. Primary endpoint is the recommended phase two dose (RP2D) of RT in combination with durvalumab. Secondary endpoints include response rates, PFS & OS. Correlative studies will examine the tumour-immune system interaction; an exploratory PET substudy with novel tracers for durvalumab (89Zr-Durvalumab) & CD8+ T cells (89Zr -Df-IAB22M2C) will also be performed. Projected enrollment for determination of maximum tolerated dose (MTD) & RP2D is 6-30 pts pending toxicity. Recruitment will continue to 36 pts for secondary endpoint analysis. 9 pts are enrolled across cohorts 1-3 to date.

Background and Aims: Our large international RCT of early rehabilitation (AVERT), provided evidence that early high intensity training interferes with stroke recovery (The Lancet, 2015), and that most patients may be responsive to therapy if the right dose is provided. (Neurology 2016). The aim of AVERT DOSE is to define the optimal early training regimens for people with mild and moderate ischaemic stroke. Method(s): Multi-Arm, Multi-Stage, Covariate-Adjusted, Response- Adaptive, randomised trial in two specified stroke severity strata. (Mild: NIHSS 0-7; Moderate: NIHSS 8-16). Patients are randomised to one of four mobility training regimens in each strata (including a pre-specified reference group), and the intervention is delivered for up to 14 days. Inclusion criteria: Ischaemic stroke within 48 hours, >=18 years. Exclusion criteria: Severe stroke, medically unwell, no evident mobility problems. We will recruit 2,700 patients from 8 countries. Primary Outcome: Identification of the intervention regimen that results in fewer disabled patients (mRS 0-2) at 3 months post-stroke. Blinded assessments will occur at 3 and 6 months. An adaptive sample size re-estimation provides 80% power to detect a 10% absolute treatment effect or larger compared to the pre-specified reference group, with a significance threshold of p=0.025 per stratum. Analyses will be intention-to-treat. Result(s): Australian National Mutual Acceptance HREC approval for Australia has been received. International collaborations, site selection and development of an online database are underway. Conclusion(s): AVERT DOSE will provide information about the dose and timing of early rehabilitation after ischaemic stroke onset. The results will be generalisable globally.

Background: In 2015, we completed the landmark, international RCTof early rehabilitation, A Very Early Rehabilitation Trial (AVERT). We found that very early high intensity mobility training interferes with stroke recovery (The Lancet, 2015) and that most patients may be responsive to therapy if the right dose can be found (Neurology 2016). Aim(s): The aim of this study (AVERT DOSE) is to define the optimal early intervention regimens for people with mild and moderate stroke severity. Method(s): We will use a multi-arm, multi-stage, dose-finding, Covariate-Adjusted Response-Adaptive (CARA) randomised clinical trial in two specified (mild and moderate) stroke severity strata. We will test three separate rehabilitation intervention regimens in each strata against a pre-specified reference group to identify the intervention regimen that results in fewer disabled patients at 3 months post stroke (mRS 0-2). A sample size of 2,700 patients will allow us to independently observe pre-specified effects in these two strata with power 80% and significance threshold of p=0.025. All analyses will be intention-to-treat. Patients will be recruited using our existing and emerging trial networks in Australia, New Zealand, Singapore, Malaysia, India, Taiwan, Ireland and United Kingdom. Result(s): The trial protocol has been submitted to ethics for multi-site National Mutual Acceptance. Site selection is underway. Universal trial number: U1111-1221-2442 Discussion: AVERT DOSE will establish a clear, definitive, early intervention protocol that will ensure that stroke patients receive best evidence care, both in Australia and other developed nations as well as in developing health service systems.

QUESTIONS: Among older people receiving inpatient rehabilitation, does additional supervised physical activity lead to faster self-selected gait speed at discharge? Does additional supervised physical activity lead to better mobility, function and quality of life at discharge and 6 months following discharge? DESIGN: Multi-centre, parallel-group, randomised controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis. PARTICIPANTS: Older people (age>60years) from two Australian hospitals undergoing rehabilitation to improve mobility. INTERVENTION: Participants received multidisciplinary care, including physiotherapy. During hospital rehabilitation, the experimental group (n=99) spent additional time daily performing physical activities that emphasised upright mobility tasks; the control group (n=99) spent equal time participating in social activities. OUTCOME MEASURES: Self-selected gait speed was the primary outcome at discharge and a secondary outcome at the 6-month follow-up. Timed Up and Go, De Morton Mobility Index, Functional Independence Measure and quality of life were secondary outcomes at discharge and tertiary outcomes at the 6-month follow-up. RESULT(S): The experimental group received a median of 20 additional minutes per day (IQR 15.0 to 22.5) of upright activities for a median of 16.5days (IQR 10.0 to 25.0). Gait speed did not differ between groups at discharge. Mean gait speed was 0.51m/s (SD 0.29) in the experimental group and 0.56m/s (SD 0.28) in the control group (effect size -0.06m/s, 95% CI -0.12 to 0.01, p=0.096). No significant differences were detected in other secondary measures. CONCLUSION(S): While substantial gains in mobility were achieved by older people receiving inpatient rehabilitation, additional physical activity sessions did not lead to better walking outcomes at discharge or 6 months. TRIAL REGISTRATION: ACTRN12613000884707. [Said CM, Morris ME, McGinley JL, Szoeke C, Workman B, Liew D, Hill KD

Background: DLBCL presenting with both CNS and systemic disease at first diagnosis is rare. Such patients are excluded from clinical trials; thus, the optimal treatment is unknown and outcomes are poorly described. Aim(s): To describe treatment outcomes of patients with synchronous CNS and systemic DLBCL at first diagnosis. Method(s):Multicentre retrospective international study (6 Australian & UK sites). Cases were identified from clinical and pharmacy records. Eligible patients had histologically proven DLBCL, with radiological, histological, or CSF evidence of synchronous systemic & CNS disease, treated with combination chemotherapy and rituximab. Patients with relapsed disease were excluded. Primary Endpoint: OS. Secondary endpoints: CR rate, PFS, toxicity. P values of <0.05 were considered significant. Result(s): Of 59 patients, 71% were male and the median age was 66yrs (range 17-86). 45 (76%) had NCCN-IPI >=4. Median number of extranodal sites outside the CNS was 2 (range 0-8). 10% were double-hit by FISH, and 35% of those with data available were double-expressors of MYC and BCL2 protein. CNS disease was leptomeningeal only in 24 (41%); 35 (59%) had parenchymal disease, 8 (14%) had both. 34 (58%) received systemic therapy (predominantly R-CHOP, n=31) plus a CNS-directed treatment (group A). 25 (42%) underwent intensified MTX and/or Ara-C containing therapy: hyper-CVAD n=14, CODOX-M/IVAC n=10, DHAC=1 (group B). CNS-directed therapy in group A included: IV HD-MTX in 19 (56%), HDMTX+ Ara-C in 2 (6%), intrathecal therapy (IT) only in 10 (29%), radiotherapy (RT) only in 2 (6%). Specific CNS therapy was omitted in one patient due to early PD. Additional consolidative therapy included CNS RT in 18 (31%) (whole brain in 8, site-specific in 10), and autologous SCT in CR1 in 8 (13%) using BEAM (n=4) or BCNU+thiotepa (n=4) conditioning. All SCT patients were from group B. 23 (39%) required dose reductions and 23 (39%) required early cessation of therapy. Treatment-rela

QUESTIONS: Among older people receiving inpatient rehabilitation, does additional supervised physical activity lead to faster self-selected gait speed at discharge? Does additional supervised physical activity lead to better mobility, function and quality of life at discharge and 6 months following discharge? DESIGN: Multi-centre, parallel-group, randomised controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis. PARTICIPANTS: Older people (age>60years) from two Australian hospitals undergoing rehabilitation to improve mobility. INTERVENTION: Participants received multidisciplinary care, including physiotherapy. During hospital rehabilitation, the experimental group (n=99) spent additional time daily performing physical activities that emphasised upright mobility tasks; the control group (n=99) spent equal time participating in social activities. OUTCOME MEASURES: Self-selected gait speed was the primary outcome at discharge and a secondary outcome at the 6-month follow-up. Timed Up and Go, De Morton Mobility Index, Functional Independence Measure and quality of life were secondary outcomes at discharge and tertiary outcomes at the 6-month follow-up. RESULT(S): The experimental group received a median of 20 additional minutes per day (IQR 15.0 to 22.5) of upright activities for a median of 16.5days (IQR 10.0 to 25.0). Gait speed did not differ between groups at discharge. Mean gait speed was 0.51m/s (SD 0.29) in the experimental group and 0.56m/s (SD 0.28) in the control group (effect size -0.06m/s, 95% CI -0.12 to 0.01, p=0.096). No significant differences were detected in other secondary measures. CONCLUSION(S): While substantial gains in mobility were achieved by older people receiving inpatient rehabilitation, additional physical activity sessions did not lead to better walking outcomes at discharge or 6 months. TRIAL REGISTRATION: ACTRN12613000884707. [Said CM, Morris ME, McGinley JL, Szoeke C, Workman B, Liew D, Hill KD

Background and Aims: Our large international RCT of early rehabilitation (AVERT), provided evidence that early high intensity training interferes with stroke recovery (The Lancet, 2015), and that most patients may be responsive to therapy if the right dose is provided. (Neurology 2016). The aim of AVERT DOSE is to define the optimal early training regimens for people with mild and moderate ischaemic stroke. Method(s): Multi-Arm, Multi-Stage, Covariate-Adjusted, Response- Adaptive, randomised trial in two specified stroke severity strata. (Mild: NIHSS 0-7; Moderate: NIHSS 8-16). Patients are randomised to one of four mobility training regimens in each strata (including a pre-specified reference group), and the intervention is delivered for up to 14 days. Inclusion criteria: Ischaemic stroke within 48 hours, >=18 years. Exclusion criteria: Severe stroke, medically unwell, no evident mobility problems. We will recruit 2,700 patients from 8 countries. Primary Outcome: Identification of the intervention regimen that results in fewer disabled patients (mRS 0-2) at 3 months post-stroke. Blinded assessments will occur at 3 and 6 months. An adaptive sample size re-estimation provides 80% power to detect a 10% absolute treatment effect or larger compared to the pre-specified reference group, with a significance threshold of p=0.025 per stratum. Analyses will be intention-to-treat. Result(s): Australian National Mutual Acceptance HREC approval for Australia has been received. International collaborations, site selection and development of an online database are underway. Conclusion(s): AVERT DOSE will provide information about the dose and timing of early rehabilitation after ischaemic stroke onset. The results will be generalisable globally.

Background: In 2015, we completed the landmark, international RCTof early rehabilitation, A Very Early Rehabilitation Trial (AVERT). We found that very early high intensity mobility training interferes with stroke recovery (The Lancet, 2015) and that most patients may be responsive to therapy if the right dose can be found (Neurology 2016). Aim(s): The aim of this study (AVERT DOSE) is to define the optimal early intervention regimens for people with mild and moderate stroke severity. Method(s): We will use a multi-arm, multi-stage, dose-finding, Covariate-Adjusted Response-Adaptive (CARA) randomised clinical trial in two specified (mild and moderate) stroke severity strata. We will test three separate rehabilitation intervention regimens in each strata against a pre-specified reference group to identify the intervention regimen that results in fewer disabled patients at 3 months post stroke (mRS 0-2). A sample size of 2,700 patients will allow us to independently observe pre-specified effects in these two strata with power 80% and significance threshold of p=0.025. All analyses will be intention-to-treat. Patients will be recruited using our existing and emerging trial networks in Australia, New Zealand, Singapore, Malaysia, India, Taiwan, Ireland and United Kingdom. Result(s): The trial protocol has been submitted to ethics for multi-site National Mutual Acceptance. Site selection is underway. Universal trial number: U1111-1221-2442 Discussion: AVERT DOSE will establish a clear, definitive, early intervention protocol that will ensure that stroke patients receive best evidence care, both in Australia and other developed nations as well as in developing health service systems.

Background: DLBCL presenting with both CNS and systemic disease at first diagnosis is rare. Such patients are excluded from clinical trials; thus, the optimal treatment is unknown and outcomes are poorly described. Aim(s): To describe treatment outcomes of patients with synchronous CNS and systemic DLBCL at first diagnosis. Method(s):Multicentre retrospective international study (6 Australian & UK sites). Cases were identified from clinical and pharmacy records. Eligible patients had histologically proven DLBCL, with radiological, histological, or CSF evidence of synchronous systemic & CNS disease, treated with combination chemotherapy and rituximab. Patients with relapsed disease were excluded. Primary Endpoint: OS. Secondary endpoints: CR rate, PFS, toxicity. P values of <0.05 were considered significant. Result(s): Of 59 patients, 71% were male and the median age was 66yrs (range 17-86). 45 (76%) had NCCN-IPI >=4. Median number of extranodal sites outside the CNS was 2 (range 0-8). 10% were double-hit by FISH, and 35% of those with data available were double-expressors of MYC and BCL2 protein. CNS disease was leptomeningeal only in 24 (41%); 35 (59%) had parenchymal disease, 8 (14%) had both. 34 (58%) received systemic therapy (predominantly R-CHOP, n=31) plus a CNS-directed treatment (group A). 25 (42%) underwent intensified MTX and/or Ara-C containing therapy: hyper-CVAD n=14, CODOX-M/IVAC n=10, DHAC=1 (group B). CNS-directed therapy in group A included: IV HD-MTX in 19 (56%), HDMTX+ Ara-C in 2 (6%), intrathecal therapy (IT) only in 10 (29%), radiotherapy (RT) only in 2 (6%). Specific CNS therapy was omitted in one patient due to early PD. Additional consolidative therapy included CNS RT in 18 (31%) (whole brain in 8, site-specific in 10), and autologous SCT in CR1 in 8 (13%) using BEAM (n=4) or BCNU+thiotepa (n=4) conditioning. All SCT patients were from group B. 23 (39%) required dose reductions and 23 (39%) required early cessation of therapy. Treatment-rela

Background and Aims: In 2015, we completed the landmark, international RCTof early rehabilitation (The Lancet, 2015).We determined that too much training early interferes with stroke recovery and that most patients may be responsive to therapy if the right dose can be found (Neurology 2016). The aim of this study is to define the optimal early intervention regimens for people with mild and moderate stroke severity. Method(s): We will use a multi-arm, dose-finding, Covariate-Adjusted, Response-Adaptive (CARA) Randomised Clinical Trial (Figure 1) in two specified mild and moderate stroke severity strata. We will test three separate rehabilitation intervention regimens in each strata against a prespecified control to identify the intervention regimen that results in fewer disabled patients at 3 months post stroke (mRS 0-2). A sample size of 2,572 patients will allow us to independently observe pre-specified effects in these two strata with power 80% and significance threshold of p=0.025. All analyses will be intention-to-treat. Patients with mild to moderate stroke will be recruited using our global trials network in Australia, New Zealand, Singapore, Malaysia, India and United Kingdom. Result(s): The trial protocol is in final stages of development with site identification underway. Conclusion(s): AVERT-DOSE will establish clear, definitive, early intervention protocols, that will ensure that stroke patients receive best evidence care, both here and in developing health service systems.

Background: The comparison of outcomes between organisations treating stroke has potentially major practice and policy implications. The American Heart and Stroke Associations (AHA/ASA) published a joint statement (Stroke, 2014; 45:918-944), which provided an overview of statistical considerations for evaluation of hospital-level outcomes after stroke. It was recommended that multilevel random effect regression models that use random intercept terms to describe hospital-specific effects would overcome the failure to account for variation in case numbers across hospitals, and intra-hospital clustering effects. We introduce an alternative novel cross-evaluation approach to comparing hospital performance on stroke outcomes and compare this approach to the one recommended by AHA/ASA. Method(s): The novel cross-evaluation approach relies on generating a set of counterfactual outcomes by applying individual hospital-specific regression models to other hospitals' casemix data. For a given hospital, a ranking of all the participating hospitals in terms of their hypothetical performance on this hospital's casemix data is produced. Finally, a decision-analytic procedure that aggregates all individual hospital's rankings into a total group ranking is applied to provide an overall cross-evaluation rank for every included hospital. Result(s): The cross-evaluation approach is illustrated using data from 24 hospitals participating in the Australian Stroke Clinical Registry (2009-2013). Variables used: age at stroke, sex, type of stroke, ability to walk on admission and mortality status. There were 13,477 patients included (median age 77 years; 53% male; 63% ischaemic). Conclusion(s): We propose a novel method for comparing hospital performance on stroke outcomes using mortality as an illustration. Future work will use this approach for other stroke outcomes.

Background and Aims: In 2015, we completed the landmark, international RCTof early rehabilitation (The Lancet, 2015).We determined that too much training early interferes with stroke recovery and that most patients may be responsive to therapy if the right dose can be found (Neurology 2016). The aim of this study is to define the optimal early intervention regimens for people with mild and moderate stroke severity. Method(s): We will use a multi-arm, dose-finding, Covariate-Adjusted, Response-Adaptive (CARA) Randomised Clinical Trial (Figure 1) in two specified mild and moderate stroke severity strata. We will test three separate rehabilitation intervention regimens in each strata against a prespecified control to identify the intervention regimen that results in fewer disabled patients at 3 months post stroke (mRS 0-2). A sample size of 2,572 patients will allow us to independently observe pre-specified effects in these two strata with power 80% and significance threshold of p=0.025. All analyses will be intention-to-treat. Patients with mild to moderate stroke will be recruited using our global trials network in Australia, New Zealand, Singapore, Malaysia, India and United Kingdom. Result(s): The trial protocol is in final stages of development with site identification underway. Conclusion(s): AVERT-DOSE will establish clear, definitive, early intervention protocols, that will ensure that stroke patients receive best evidence care, both here and in developing health service systems.

Background: The comparison of outcomes between organisations treating stroke has potentially major practice and policy implications. The American Heart and Stroke Associations (AHA/ASA) published a joint statement (Stroke, 2014; 45:918-944), which provided an overview of statistical considerations for evaluation of hospital-level outcomes after stroke. It was recommended that multilevel random effect regression models that use random intercept terms to describe hospital-specific effects would overcome the failure to account for variation in case numbers across hospitals, and intra-hospital clustering effects. We introduce an alternative novel cross-evaluation approach to comparing hospital performance on stroke outcomes and compare this approach to the one recommended by AHA/ASA. Method(s): The novel cross-evaluation approach relies on generating a set of counterfactual outcomes by applying individual hospital-specific regression models to other hospitals' casemix data. For a given hospital, a ranking of all the participating hospitals in terms of their hypothetical performance on this hospital's casemix data is produced. Finally, a decision-analytic procedure that aggregates all individual hospital's rankings into a total group ranking is applied to provide an overall cross-evaluation rank for every included hospital. Result(s): The cross-evaluation approach is illustrated using data from 24 hospitals participating in the Australian Stroke Clinical Registry (2009-2013). Variables used: age at stroke, sex, type of stroke, ability to walk on admission and mortality status. There were 13,477 patients included (median age 77 years; 53% male; 63% ischaemic). Conclusion(s): We propose a novel method for comparing hospital performance on stroke outcomes using mortality as an illustration. Future work will use this approach for other stroke outcomes.

Background and Aims: EXTEND is an ongoing randomised, doubleblind, placebo-controlled Phase III trial of intravenous alteplase vs. placebo among patients with ischemic stroke 4.5-9 hours from stroke onset or wake-up-stroke (WUS). There is uncertainty about clinical characteristic differences between patients from Australasia and Taiwan in these extended time windows. Objective(s): To determine the clinical characteristics among EXTEND randomised patients for Australasia and Taiwan. Method(s): Patients with ischemic stroke within 4.5-9 hours from stroke onset and WUS patients (time of WUS onset defined as the midpoint between time to sleep and awakening with the stroke symptoms) are eligible for enrolment. Patients must fulfil the advanced imagining criteria to ensure the presence of ischemic penumbra. Result(s): 165 patients (140 from Australasia, 25 from Taiwan) have been randomised to date. The median height of Australasian and Taiwanese patients were 165.0 cm (157.8, 175.0 cm) and 164 cm (158,169 p=0.38), and weight 80 kg (76.0,85.3 kg) and 63 kg (55.6, 70.5 kg p=0.002) respectively. For the Australasian and Taiwanese cohort the median age were 77yo (66, 82) and 73 (61, 78 p=0.04), the percentage of atrial fibrillation was 40% and 24% (p=0.22), hypertension 72% and 56% (p=0.14), history of transient ischemic attack 17.4% and 8.0% (p=0.14), hyperlipidemia 50.7% and 24% (p=0.15), diabetes 15.9% and 32% (p=0.01). Conclusion(s): Within the EXTEND cohort, Taiwanese patients are younger, have lower body weight and higher rate of diabetes.

Background and Aims: Background: Current clinical application of thrombolysis in stroke is limited by the 4.5hour time window and not applicable to patients with wake up stroke (WUS). Patient selection using advanced penumbral imaging criteria may allow extension of the therapeutic window. Objective(s): To test the hypothesis that perfusion-ischemic core mismatch can be used to select patients with favourable response to thrombolysis beyond conventional time windows. Method(s): Design: EXTEND is an investigator-initiated, phase III, randomised, double-blind, placebo controlled trial of intravenous alteplase vs placebo in patients with ischemic stroke 4.5-9 hours from stroke onset and WUS. Method(s): Patients with ischemic stroke within 4.5-9 hours from stroke onset and WUS patients, (WUS defined as the midpoint between time to sleep and awakening with the stroke symptoms less than 9 hours), are eligible for recruitment. Criteria for entry into the trial include perfusionischemic core mismatch using a perfusion threshold of Tmax more than 6 sec and a perfusion-ischemic core lesion volume ratio of more than 1.2 and absolute mismatch more than 10 mL. Ischemic core lesion volume must be less than 70 mL. This will be assessed using a fully automated software package (RAPID, Stanford University). Reperfusion/recanalization will be assessed at 24 hours. Safety endpoints include symptomatic intracerebral haemorrhage and death Results: Outcome measures: The primary endpoint is mRS 0-1 at 90 days. Secondary endpoints will include mRS ordinal analysis, reperfusion, recanalization, quality of life and depression scales. Conclusion(s): Trial status: Recruitment is underway in Australasia, Taiwan and Finland. As of January 2017,172 patients were randomised.

Background: EXTEND is an ongoing randomised, double-blind, placebocontrolled Phase III trial of intravenous alteplase vs. placebo among patients with ischemic stroke 4.5-9 hours from stroke onset or wakeup- stroke (WUS). There is uncertainty about the extent of salvageable tissue in this crucial time window and in WUS patients for exploring therapeutic options. Objective(s): To determine the penumbral mismatch and ischaemic core volumes in the EXTEND cohort. Method(s): Patients with ischemic stroke within 4.5-9 hours from stroke onset and WUS patients (time of WUS onset defined as the midpoint between time to sleep and awakening with the stroke symptoms) are eligible for enrolment. Criteria for trial entry include perfusion-ischemic core mismatch using a perfusion threshold of Tmax>6 sec and a perfusion: ischemic core lesion volume ratio of >1.2. Ischemic core must be <70 mL based on assessment by automated RAPID software on MR or CT platforms (Stanford). Result(s): 156 patients have been randomised to date with median age of 77.0 (IQR 66.0, 81.0 years), median admission NIHSS of 13.0 (8.0, 18.0) and 86 patients (55.0%) being female. The median volume of ischemic core was 11.0 ml (IQR 2.0, 31.3 ml), perfusion lesion was 72.0 ml (IQR 41.0, 118.0 ml), mismatch volume was 60.8 ml (IQR 36.6, 95.5 ml) and mismatch ratio was 6.7 (IQR 3.3, 18.0). Conclusion(s): Within the EXTEND cohort, there is a clinically significant amount of salvageable penumbral tissue within the 4.5-9 hr time window and WUS patients. Tissue salvage has the potential to lead to clinical improvement within this cohort and recruitment is ongoing.

Background and Aims: A very early intensive out-of-bed mobilisation (VEM) protocol after stroke compared to usual care was associated with a reduction in odds of a favourable outcome at 3 months. We report prespecified analyses to determine whether VEM post stroke results in better outcomes for patients at 12 months when compared to usual stroke unit care. Method(s): We performed a prospective, parallel group, assessor-blinded, multi-centre, clinical trial with the following inclusion criteria: admission within 24 hours of stroke and physiological parameters within pre-set limits. Treatment with rt-PA was allowed. Patients with severe premorbid disability and/or severe comorbidities were excluded. Patients were randomised to VEM or usual care. The intervention, delivered by a physiotherapy/ nurse team, started within 24 hours and continued for a maximum of 14 days. Analyses were intention-to-treat. Pre-specified adjusted analyses for 12 month outcomes included: (i) health related quality of life (HRQoL); (ii) favourable outcome mRS 0-2; (iii) deaths; and (iv) time to walking 50 metres unassisted. Result(s): From July 2006 to October 2014, 2104 patients were recruited from five countries. Patient demographics: age median (IQR): 72.5 (62.9- 80.3) years; NIHSS median (IQR): 7 (4-12); rt-PA treated 24.1%. Follow up was completed in 2052 patients (97.5%). No between group differences in: (i) HRQoL (adj median regression: >=0.036 (95% CI-0.045- 0.038, p=0.865); (ii) mRS 0-2 (aOR 0.84, 95% CI 0.68-1.03, p=0.089); (iii) deaths (aOR 1.29, 95% CI 0.96-1.72, p=0.088); (iv) or time to walking (aHR 1.02, 95%CI 0.94-1.13, p=0.553) were found. Conclusion(s): Early intensive mobilisation after stroke did not improve 12 month outcomes after stroke.

Background and Aims: Stroke risk-adjusted mortality rates (RAMR) are influenced by the methods used to adjust for potential confounders. To determine whether linking data from Admissions and Registry datasets provides a better explanation of variability in 30-day RAMR than using admission data alone. Method(s): Cohort design linking Australian Stroke Clinical Registry (AuSCR) data for patients from 2009 to 2013 in Queensland with hospital admissions and national death registrations. The Elixhauser Index, a validated method for measuring patient comorbidity, was derived from hospital admissions ICD-10 codes. Model A contained data including variables available in hospital admissions datasets (i.e. demographics, stroke type and the Elixhauser index). Model B included the variables contained in model A plus additional information from the AuSCR such as stroke severity and recurrent stroke. Generalised linear latent and mixed models were used to calculate 30-day RAMR. Models were compared using Bayesian information criterion (BIC) and the C-statistic: 95% confidence intervals (CI). Result(s): Of 2986 episodes of care, 363 patients (12%) died within 30 days of admission. RAMRs for hospitals ranged from 6% to 16%. According to the model fit statistics, Model B (BIC: 1581; C-statistic: 0.842; 95%CI: 0.82, 0.86) provided better explanation than Model A (BIC: 1900; C-statistic: 0.790; 95%CI: 0.77, 0.81). Both the magnitude of difference in BIC and statistically significantly different c-statistics indicate that Model B was strongly superior in explaining variability in 30-day RAMR. Conclusion(s): The addition of severity and recurrent stroke to mortality models provides a better explanation of variability in RAMR than risk adjustment available from administrative data alone.

Background: Comparisons of stroke mortality rates between hospitals may vary widely depending on the covariates used in adjustment. We aimed to determine whether linkage between the Australian Stroke Clinical Registry (AuSCR) and hospital separations data provides better explanation for variability in 30-day risk-adjusted mortality rates (RAMR) than conventional separations data alone. Method(s): Cohort design using patient-level linkages between the AuSCR (2009-2013), national death registrations and state separations data (Vic, Qld, NSW, WA). Prior comorbidities (Elixhauser Index) were derived from ICD-10 diagnosis codes. Hospitals with 200+ episodes per year were included. Generalised linear latent and mixed models were used to calculate RAMR for each hospital.We compared Model A (demographics, prior comorbidities), Model B (demographics, stroke severity, recurrent stroke) and Model C (covariates contained in Models A+B) using Bayesian information criterion (BIC) and C-statistic. Smaller BIC indicates better fit and C-Statistics between 0.7-0.79 show acceptable and 0.8-0.89 show excellent discrimination. Result(s): Of 8,852 episodes of care from 17 eligible hospitals, 980 (11%) patients died within 30 days of admission. Hospital RAMRs ranged from 4% to 15%. According to fit statistics Models B (BIC: 4225; C-statistic, 0.822) and C (BIC: 4242; C-statistic, 0.829) provided a better explanation than Model A (BIC: 5399; C-statistic, 0.762) on the basis of lower BIC and higher C-statistic. Conclusion(s): Addition of stroke severity and recurrent stroke to mortality models provides a better explanation of variation in RAMR compared to risk adjustment based on separations data alone. Use of the AuSCR enables improved validity of inter-hospital RAMR comparisons.

Background and Aims: Background: EXTEND is an ongoing randomised, double-blind, placebo-controlled Phase III trial of intravenous alteplase vs. placebo among patients with ischemic stroke 4.5-9 hours from stroke onset or wake-up-stroke (WUS). There is uncertainty about the extent of salvageable tissue in this crucial time windows. Objective(s): To determine the penumbral mismatch and ischaemic core volumes in EXTEND WUS and non-WUS cohort. Method(s): Patients with ischemic stroke within 4.5-9 hours from stroke onset and WUS patients are eligible for enrolment. Criteria for trial entry include perfusion-ischemic core mismatch using a perfusion threshold of Tmax>6 sec and a perfusion:core lesion volume ratio of >1.2. Ischemic core must be <70 mL based on assessment by automated RAPID software on MR or CT platforms (Stanford). Result(s): 165 patients have been randomised to date with median age of 77.0 (IQR 65.0, 81.0 yrs), median admission NIHSS of 12.0 (8.0, 18.0). Compared to non WUS, 140 (66%) WUS patients had median NIHSS12.0 (8.0, 18.0) vs 10.0 (5.6, 16.0 p=0.07), ischemic core volume 19.0 ml (7.0, 37.6 ml) vs 11.0 ml (6.0, 24=7.2 ml p=0.17), perfusion deficit volume 82.0 ml (44.8, 124.8 ml) vs 59.5 ml (34.8, 118.0 ml p=0.22), mismatch ratio 5.2 ml (2.9, 10.5 ml) vs 5.0 (2.5, 16.4 p=0.9) and mismatch volume 60.8 ml (36.3, 102.3 ml) vs 51.0 ml (29.8 ml, 90.5 ml p=0.3). Conclusion(s): Within the EXTEND cohort, there is a clinically significant amount of salvageable penumbral tissue within the 4.5-9 hr time window and in WUS patients which has the potential to lead to clinical improvement if salvaged.

Background and Aims: EXTEND is an ongoing randomised, doubleblind, placebo-controlled Phase III trial of intravenous alteplase vs. placebo among patients with ischemic stroke 4.5-9 hours from stroke onset or wake-up-stroke (WUS). There is uncertainty about clinical characteristic differences between patients from Australasia and Taiwan in these extended time windows. Objective(s): To determine the clinical characteristics among EXTEND randomised patients for Australasia and Taiwan. Method(s): Patients with ischemic stroke within 4.5-9 hours from stroke onset and WUS patients (time of WUS onset defined as the midpoint between time to sleep and awakening with the stroke symptoms) are eligible for enrolment. Patients must fulfil the advanced imagining criteria to ensure the presence of ischemic penumbra. Result(s): 165 patients (140 from Australasia, 25 from Taiwan) have been randomised to date. The median height of Australasian and Taiwanese patients were 165.0 cm (157.8, 175.0 cm) and 164 cm (158,169 p=0.38), and weight 80 kg (76.0,85.3 kg) and 63 kg (55.6, 70.5 kg p=0.002) respectively. For the Australasian and Taiwanese cohort the median age were 77yo (66, 82) and 73 (61, 78 p=0.04), the percentage of atrial fibrillation was 40% and 24% (p=0.22), hypertension 72% and 56% (p=0.14), history of transient ischemic attack 17.4% and 8.0% (p=0.14), hyperlipidemia 50.7% and 24% (p=0.15), diabetes 15.9% and 32% (p=0.01). Conclusion(s): Within the EXTEND cohort, Taiwanese patients are younger, have lower body weight and higher rate of diabetes.

Background and Aims: Background: Current clinical application of thrombolysis in stroke is limited by the 4.5hour time window and not applicable to patients with wake up stroke (WUS). Patient selection using advanced penumbral imaging criteria may allow extension of the therapeutic window. Objective(s): To test the hypothesis that perfusion-ischemic core mismatch can be used to select patients with favourable response to thrombolysis beyond conventional time windows. Method(s): Design: EXTEND is an investigator-initiated, phase III, randomised, double-blind, placebo controlled trial of intravenous alteplase vs placebo in patients with ischemic stroke 4.5-9 hours from stroke onset and WUS. Method(s): Patients with ischemic stroke within 4.5-9 hours from stroke onset and WUS patients, (WUS defined as the midpoint between time to sleep and awakening with the stroke symptoms less than 9 hours), are eligible for recruitment. Criteria for entry into the trial include perfusionischemic core mismatch using a perfusion threshold of Tmax more than 6 sec and a perfusion-ischemic core lesion volume ratio of more than 1.2 and absolute mismatch more than 10 mL. Ischemic core lesion volume must be less than 70 mL. This will be assessed using a fully automated software package (RAPID, Stanford University). Reperfusion/recanalization will be assessed at 24 hours. Safety endpoints include symptomatic intracerebral haemorrhage and death Results: Outcome measures: The primary endpoint is mRS 0-1 at 90 days. Secondary endpoints will include mRS ordinal analysis, reperfusion, recanalization, quality of life and depression scales. Conclusion(s): Trial status: Recruitment is underway in Australasia, Taiwan and Finland. As of January 2017,172 patients were randomised.

Background: EXTEND is an ongoing randomised, double-blind, placebocontrolled Phase III trial of intravenous alteplase vs. placebo among patients with ischemic stroke 4.5-9 hours from stroke onset or wakeup- stroke (WUS). There is uncertainty about the extent of salvageable tissue in this crucial time window and in WUS patients for exploring therapeutic options. Objective(s): To determine the penumbral mismatch and ischaemic core volumes in the EXTEND cohort. Method(s): Patients with ischemic stroke within 4.5-9 hours from stroke onset and WUS patients (time of WUS onset defined as the midpoint between time to sleep and awakening with the stroke symptoms) are eligible for enrolment. Criteria for trial entry include perfusion-ischemic core mismatch using a perfusion threshold of Tmax>6 sec and a perfusion: ischemic core lesion volume ratio of >1.2. Ischemic core must be <70 mL based on assessment by automated RAPID software on MR or CT platforms (Stanford). Result(s): 156 patients have been randomised to date with median age of 77.0 (IQR 66.0, 81.0 years), median admission NIHSS of 13.0 (8.0, 18.0) and 86 patients (55.0%) being female. The median volume of ischemic core was 11.0 ml (IQR 2.0, 31.3 ml), perfusion lesion was 72.0 ml (IQR 41.0, 118.0 ml), mismatch volume was 60.8 ml (IQR 36.6, 95.5 ml) and mismatch ratio was 6.7 (IQR 3.3, 18.0). Conclusion(s): Within the EXTEND cohort, there is a clinically significant amount of salvageable penumbral tissue within the 4.5-9 hr time window and WUS patients. Tissue salvage has the potential to lead to clinical improvement within this cohort and recruitment is ongoing.

Background and Aims: A very early intensive out-of-bed mobilisation (VEM) protocol after stroke compared to usual care was associated with a reduction in odds of a favourable outcome at 3 months. We report prespecified analyses to determine whether VEM post stroke results in better outcomes for patients at 12 months when compared to usual stroke unit care. Method(s): We performed a prospective, parallel group, assessor-blinded, multi-centre, clinical trial with the following inclusion criteria: admission within 24 hours of stroke and physiological parameters within pre-set limits. Treatment with rt-PA was allowed. Patients with severe premorbid disability and/or severe comorbidities were excluded. Patients were randomised to VEM or usual care. The intervention, delivered by a physiotherapy/ nurse team, started within 24 hours and continued for a maximum of 14 days. Analyses were intention-to-treat. Pre-specified adjusted analyses for 12 month outcomes included: (i) health related quality of life (HRQoL); (ii) favourable outcome mRS 0-2; (iii) deaths; and (iv) time to walking 50 metres unassisted. Result(s): From July 2006 to October 2014, 2104 patients were recruited from five countries. Patient demographics: age median (IQR): 72.5 (62.9- 80.3) years; NIHSS median (IQR): 7 (4-12); rt-PA treated 24.1%. Follow up was completed in 2052 patients (97.5%). No between group differences in: (i) HRQoL (adj median regression: >=0.036 (95% CI-0.045- 0.038, p=0.865); (ii) mRS 0-2 (aOR 0.84, 95% CI 0.68-1.03, p=0.089); (iii) deaths (aOR 1.29, 95% CI 0.96-1.72, p=0.088); (iv) or time to walking (aHR 1.02, 95%CI 0.94-1.13, p=0.553) were found. Conclusion(s): Early intensive mobilisation after stroke did not improve 12 month outcomes after stroke.

Background and Aims: Stroke risk-adjusted mortality rates (RAMR) are influenced by the methods used to adjust for potential confounders. To determine whether linking data from Admissions and Registry datasets provides a better explanation of variability in 30-day RAMR than using admission data alone. Method(s): Cohort design linking Australian Stroke Clinical Registry (AuSCR) data for patients from 2009 to 2013 in Queensland with hospital admissions and national death registrations. The Elixhauser Index, a validated method for measuring patient comorbidity, was derived from hospital admissions ICD-10 codes. Model A contained data including variables available in hospital admissions datasets (i.e. demographics, stroke type and the Elixhauser index). Model B included the variables contained in model A plus additional information from the AuSCR such as stroke severity and recurrent stroke. Generalised linear latent and mixed models were used to calculate 30-day RAMR. Models were compared using Bayesian information criterion (BIC) and the C-statistic: 95% confidence intervals (CI). Result(s): Of 2986 episodes of care, 363 patients (12%) died within 30 days of admission. RAMRs for hospitals ranged from 6% to 16%. According to the model fit statistics, Model B (BIC: 1581; C-statistic: 0.842; 95%CI: 0.82, 0.86) provided better explanation than Model A (BIC: 1900; C-statistic: 0.790; 95%CI: 0.77, 0.81). Both the magnitude of difference in BIC and statistically significantly different c-statistics indicate that Model B was strongly superior in explaining variability in 30-day RAMR. Conclusion(s): The addition of severity and recurrent stroke to mortality models provides a better explanation of variability in RAMR than risk adjustment available from administrative data alone.

Background: Comparisons of stroke mortality rates between hospitals may vary widely depending on the covariates used in adjustment. We aimed to determine whether linkage between the Australian Stroke Clinical Registry (AuSCR) and hospital separations data provides better explanation for variability in 30-day risk-adjusted mortality rates (RAMR) than conventional separations data alone. Method(s): Cohort design using patient-level linkages between the AuSCR (2009-2013), national death registrations and state separations data (Vic, Qld, NSW, WA). Prior comorbidities (Elixhauser Index) were derived from ICD-10 diagnosis codes. Hospitals with 200+ episodes per year were included. Generalised linear latent and mixed models were used to calculate RAMR for each hospital.We compared Model A (demographics, prior comorbidities), Model B (demographics, stroke severity, recurrent stroke) and Model C (covariates contained in Models A+B) using Bayesian information criterion (BIC) and C-statistic. Smaller BIC indicates better fit and C-Statistics between 0.7-0.79 show acceptable and 0.8-0.89 show excellent discrimination. Result(s): Of 8,852 episodes of care from 17 eligible hospitals, 980 (11%) patients died within 30 days of admission. Hospital RAMRs ranged from 4% to 15%. According to fit statistics Models B (BIC: 4225; C-statistic, 0.822) and C (BIC: 4242; C-statistic, 0.829) provided a better explanation than Model A (BIC: 5399; C-statistic, 0.762) on the basis of lower BIC and higher C-statistic. Conclusion(s): Addition of stroke severity and recurrent stroke to mortality models provides a better explanation of variation in RAMR compared to risk adjustment based on separations data alone. Use of the AuSCR enables improved validity of inter-hospital RAMR comparisons.

Background and Aims: Background: EXTEND is an ongoing randomised, double-blind, placebo-controlled Phase III trial of intravenous alteplase vs. placebo among patients with ischemic stroke 4.5-9 hours from stroke onset or wake-up-stroke (WUS). There is uncertainty about the extent of salvageable tissue in this crucial time windows. Objective(s): To determine the penumbral mismatch and ischaemic core volumes in EXTEND WUS and non-WUS cohort. Method(s): Patients with ischemic stroke within 4.5-9 hours from stroke onset and WUS patients are eligible for enrolment. Criteria for trial entry include perfusion-ischemic core mismatch using a perfusion threshold of Tmax>6 sec and a perfusion:core lesion volume ratio of >1.2. Ischemic core must be <70 mL based on assessment by automated RAPID software on MR or CT platforms (Stanford). Result(s): 165 patients have been randomised to date with median age of 77.0 (IQR 65.0, 81.0 yrs), median admission NIHSS of 12.0 (8.0, 18.0). Compared to non WUS, 140 (66%) WUS patients had median NIHSS12.0 (8.0, 18.0) vs 10.0 (5.6, 16.0 p=0.07), ischemic core volume 19.0 ml (7.0, 37.6 ml) vs 11.0 ml (6.0, 24=7.2 ml p=0.17), perfusion deficit volume 82.0 ml (44.8, 124.8 ml) vs 59.5 ml (34.8, 118.0 ml p=0.22), mismatch ratio 5.2 ml (2.9, 10.5 ml) vs 5.0 (2.5, 16.4 p=0.9) and mismatch volume 60.8 ml (36.3, 102.3 ml) vs 51.0 ml (29.8 ml, 90.5 ml p=0.3). Conclusion(s): Within the EXTEND cohort, there is a clinically significant amount of salvageable penumbral tissue within the 4.5-9 hr time window and in WUS patients which has the potential to lead to clinical improvement if salvaged.

Background: Bendamustine +/- anti-CD20 antibody is a highly effective regimen for iNHL. Though initially favoured for its toxicity profile, subsequent analyses demonstrate profound and prolonged lymphopenia and the landmark phase III GALLIUM study showed a grade 3-5 infection rate of 20-26% in the bendamustine arms (Hiddemann JCO 2018). The relationship between severity and duration of lymphopenia and infection, and the role of antimicrobial prophylaxis (ppx), are not fully characterised. We performed a multicentre, retrospective analysis of bendamustine-treated iNHL patients (pts) to define the type and onset of infections, identify concomitant risk factors and evaluate the role of ppx. Method(s): iNHL pts aged >=18 yrs, treated with bendamustine +/- anti-CD20 in 1st-3rd line from 2011-2019, were identified from 9 Australian centres. HIV, prior transplant and long-term immunosuppression were excluded. Demographics, treatment, lymphocyte counts, infections and ppx were collected from baseline to 24 months post end of bendamustine treatment (EOT) or subsequent lymphoma therapy. Association between potential risk factors and infection was evaluated by logistic regression (odds ratio, OR) and negative binomial regression (incidence rate ratio, IRR) with Stata 16.1. Result(s): 302 pts were eligible. Baseline and treatment characteristics are summarised in Table 1. 252 infection episodes occurred across 134 pts (44%), equally divided between during therapy and after EOT (Figure 1A, Table 2). Infections on treatment occurred in 30% of pts (n=92) with 18% hospitalised (n = 54; n = 20 with febrile neutropenia (FN)) and dose delay /modification/ discontinuation in 11%. Late infections post EOT occurred in 23% of pts (n=70) with 11% hospitalised (n = 32; n = 12 with FN); infection post EOT was more common in pts on maintenance anti-CD20 (infection rate 49% v 16%, OR 5.1 p<0.001). Opportunistic infections (OI) occurred in 21 pts: VZV (n=9; 4 on treatment, 5 post EOT, 1 on ppx)

Background: Although ~60% of patients with DLBCL are cured with frontline therapy, outcomes for those with relapsed/refractory disease remain poor. Tumour cells exploit immune checkpoint pathways, including the PD1/PDL1 axis, to evade and inhibit host anti-tumour immune responses. PD1/PDL1 expression and cytogenetic 9p24 alterations in some DLBCL subtypes provide additional rationale for PDL1 inhibition (PD-L1i) in DLBCL. Though single agent PD1i yields a disappointing ORR of 10-30% in heavily pre-treated DLBCL, some responses are durable.1 Radiotherapy (RT) is an established mechanism of stimulating anti-tumour immunity via increased circulating tumour antigen, immunogenic cell death and T-cell recruitment and activation in the tumour microenvironment. Synergy between concomitant immune checkpoint inhibition (ICI) and RT has been demonstrated in preclinical studies2 and solid tumours; a recent study in non-small cell lung cancer demonstrated an ORR of 36% with pembrolizumab + RT compared with 18% with pembrolizumab alone.3 RT hypofractionation appears critical to the abscopal effect when used with ICI,4 and concurrent RT and PD-L1i is more successful than sequential treatment.5 RT to multiple sites may broaden the spectrum of tumour antigen released and overcome clonal variation between disease sites; a dose-response relationship between RT and antigen release has yet to be established. This phase I study aims to determine the safety profile of escalating dose and number of sites of RT in combination with Durvalumab (MEDI4736), an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL, including primary refractory DLBCL and transformed follicular lymphoma. Study Design and Methods: RaDD (NCT03610061) includes eligible pts who have received >=1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplantation (SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic SCT or chronic steroid use are excluded. T

Background: The effectiveness of anti-tumour T and NK cells in malignancy is mitigated by the engagement of the immune check point pathway with PD-1/PDL-1 interaction.1,2 Immune manipulation with PD-1 inhibition, in combination with rituximab, can increase T cell anti-tumour effect and enhance NK cell antibody dependent cell cytotoxicity (ADCC), with this combination proving efficacious in rituximab-refractory follicular lymphoma (FL).3 The concept of 'priming' the immune system with nivolumab, a PD-1 inhibitor, prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in previously untreated FL is not described.4 We are conducting a phase II Simon's two stage study to assess the feasibility and safety of combination nivolumab and rituximab in these patients and present the pre-planned interim analysis results. Method(s): The 1st FLOR study (NCT03245021) is an ongoing open-label, multi-centre, phase 2 study of nivolumab and rituximab in patients with previously untreated stage III-IV grade 1-3A FL requiring systemic therapy. Eligible patients are ECOG <= 2 and do not require urgent debulking therapy. All patients receive induction nivolumab 240mg intravenously (IV) every 2 weeks for 4 cycles. Patients achieving complete response (CR) based on PET/CT Lugano criteria receive a further 4 cycles of 240mg IV nivolumab monotherapy then maintenance nivolumab 480mg IV every 4 weeks for 12 cycles. Patients achieving less than CR received 240mg nivolumab plus 375mg/m2 IV rituximab every 2 weeks for 4 cycles. Those achieving a response at the end of 8 cycles of nivolumab and rituximab continue maintenance nivolumab 480mg IV every 4 weeks for 12 cycles PLUS rituximab 375mg/m2 every 12 weeks for 8 cycles. PET/CT assessment is performed at baseline, after 4 cycles of nivolumab, after 8 cycles of nivolumab +/-rituximab and prior to maintenance cycle 6. The primary end point is safety, with a pre-planned analysis after the first 19 patients comple

Introduction: Standard of care immunochemotherapy in front-line (1L) follicular lymphoma (FL) is highly efficacious but not without significant toxicity. High rates of grade 3-5 adverse events (AEs), primarily infection and bone marrow suppression, are experienced in up to 75% of patients. A more tolerable but equally effective approach is required. PD-1 inhibition, in combination with rituximab (R), increases T cell anti-tumour effect & enhances NK cell antibody dependent cell cytotoxicity, with proven efficacy in relapsed FL. The concept of 'priming' the immune system with nivolumab (N) prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in 1L FL is not described. Method(s): '1st FLOR' (NCT03245021) is an open-label, multi-centre, phase 2, Simon's 2-stage study of N + R (N = 39). Key eligibility were stage III-IV grade 1-3A FL requiring 1L systemic therapy; ECOG <=2; adequate organ function. All patients (pts) receive induction N 240mg IV 2-weekly for 4 cycles. Pts with complete response (CR) receive 4 further cycles of 240mg IV N monotherapy then 12 cycles of maintenance N 480mg IV 4-weekly. Pts with 2 IV R 2-weekly for 4 cycles followed by maintenance N+R (N 480mg 4 weekly for 12 cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was >= G3 toxicity rate. Secondary EPs were response rate, overall toxicity, progression free survival (PFS) & overall survival (OS). Result(s): Between September 2017 to March 2020, 39 pts were enrolled. Baseline characteristics included median age of 54 (range: 28-79), stage IV disease in 67%, B Symptoms & bulk (>=7cm) in 23% each, intermediate-high risk FLIPI in 74%. The primary EP was met, with 16 pts (41%) having >=G3 toxicity at end of induction. Non-immune AEs were predominantly G1-2; most commonly infection (67%) & fatigue (64%). G3-4 Immune-related AEs were infrequent and included pancreatitis plus hepatitis (N = 1), pancreatitis alone (N = 1), rash (N = 1), transaminitis (N = 2)

Background: Standard of care immunochemotherapy in front-line (1L) follicular lymphoma (FL) is highly efficacious but not without significant toxicity. High rates of grade 3-5 adverse events (AEs), primarily infection and bone marrow suppression, are experienced in up to 75% of patients. A more tolerable but equally effective approach is required. PD-1 inhibition, in combination with rituximab (R), increases T cell anti-tumour effect & enhances NK cell antibody dependent cell cytotoxicity, with proven efficacy in relapsed FL. The concept of 'priming' the immune system with nivolumab (N) prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in 1L FL is not described. Method(s): '1 FLOR' (NCT03245021) is an openlabel, multi-centre, phase 2, Simon's 2-stage study of N + R (N = 39). Key eligibility were stage III-IV grade 1-3A FL requiring 1L systemic therapy; ECOG <=2; adequate organ function. All patients (pts) receive induction N 240mg IV 2-weekly for 4 cycles. Pts with complete response (CR) receive 4 further cycles of 240mg IV N monotherapy then 12 cycles of maintenance N 480mg IV 4-weekly. Pts with < CR had 240mg N plus 375mg/m2 IV R 2-weekly for 4 cycles followed by maintenance N+R (N 480mg 4 weekly for 12 cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was >= G3 toxicity rate during induction. Secondary EPs; response rate by Lugano response criteria, overall toxicity, PFS, OS. Result(s): Between September 2017 to March 2020, 39 pts were enrolled. Baseline characteristics included median age of 54 (range: 28-79). stage IV disease in 67%, B Symptoms & bulk (>=7cm) in 23% each, intermediate-high risk FLIPI in 74%. The primary EP was met, with only 16 pts (41%) having >=G3 toxicity at end of induction. Non-immune AEs were predominantly G1-2; most commonly infection (67%) & fatigue (64%). G3-4 Immunerelated AEs were infrequent and included pancreatitis plus hepatitis (N = 1), pancreatitis alone (N = 1), rash (N = 1), tr

Background: Bendamustine +/- anti-CD20 antibody is a highly effective regimen for iNHL. Though initially favoured for its toxicity profile, subsequent analyses demonstrate profound and prolonged lymphopenia and the landmark phase III GALLIUM study showed a grade 3-5 infection rate of 20-26% in the bendamustine arms (Hiddemann JCO 2018). The relationship between severity and duration of lymphopenia and infection, and the role of antimicrobial prophylaxis (ppx), are not fully characterised. We performed a multicentre, retrospective analysis of bendamustine-treated iNHL patients (pts) to define the type and onset of infections, identify concomitant risk factors and evaluate the role of ppx. Method(s): iNHL pts aged >=18 yrs, treated with bendamustine +/- anti-CD20 in 1st-3rd line from 2011-2019, were identified from 9 Australian centres. HIV, prior transplant and long-term immunosuppression were excluded. Demographics, treatment, lymphocyte counts, infections and ppx were collected from baseline to 24 months post end of bendamustine treatment (EOT) or subsequent lymphoma therapy. Association between potential risk factors and infection was evaluated by logistic regression (odds ratio, OR) and negative binomial regression (incidence rate ratio, IRR) with Stata 16.1. Result(s): 302 pts were eligible. Baseline and treatment characteristics are summarised in Table 1. 252 infection episodes occurred across 134 pts (44%), equally divided between during therapy and after EOT (Figure 1A, Table 2). Infections on treatment occurred in 30% of pts (n=92) with 18% hospitalised (n = 54; n = 20 with febrile neutropenia (FN)) and dose delay /modification/ discontinuation in 11%. Late infections post EOT occurred in 23% of pts (n=70) with 11% hospitalised (n = 32; n = 12 with FN); infection post EOT was more common in pts on maintenance anti-CD20 (infection rate 49% v 16%, OR 5.1 p<0.001). Opportunistic infections (OI) occurred in 21 pts: VZV (n=9; 4 on treatment, 5 post EOT, 1 on ppx)

Background: Although ~60% of patients with DLBCL are cured with frontline therapy, outcomes for those with relapsed/refractory disease remain poor. Tumour cells exploit immune checkpoint pathways, including the PD1/PDL1 axis, to evade and inhibit host anti-tumour immune responses. PD1/PDL1 expression and cytogenetic 9p24 alterations in some DLBCL subtypes provide additional rationale for PDL1 inhibition (PD-L1i) in DLBCL. Though single agent PD1i yields a disappointing ORR of 10-30% in heavily pre-treated DLBCL, some responses are durable.1 Radiotherapy (RT) is an established mechanism of stimulating anti-tumour immunity via increased circulating tumour antigen, immunogenic cell death and T-cell recruitment and activation in the tumour microenvironment. Synergy between concomitant immune checkpoint inhibition (ICI) and RT has been demonstrated in preclinical studies2 and solid tumours; a recent study in non-small cell lung cancer demonstrated an ORR of 36% with pembrolizumab + RT compared with 18% with pembrolizumab alone.3 RT hypofractionation appears critical to the abscopal effect when used with ICI,4 and concurrent RT and PD-L1i is more successful than sequential treatment.5 RT to multiple sites may broaden the spectrum of tumour antigen released and overcome clonal variation between disease sites; a dose-response relationship between RT and antigen release has yet to be established. This phase I study aims to determine the safety profile of escalating dose and number of sites of RT in combination with Durvalumab (MEDI4736), an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL, including primary refractory DLBCL and transformed follicular lymphoma. Study Design and Methods: RaDD (NCT03610061) includes eligible pts who have received >=1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplantation (SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic SCT or chronic steroid use are excluded. T

Background: The effectiveness of anti-tumour T and NK cells in malignancy is mitigated by the engagement of the immune check point pathway with PD-1/PDL-1 interaction.1,2 Immune manipulation with PD-1 inhibition, in combination with rituximab, can increase T cell anti-tumour effect and enhance NK cell antibody dependent cell cytotoxicity (ADCC), with this combination proving efficacious in rituximab-refractory follicular lymphoma (FL).3 The concept of 'priming' the immune system with nivolumab, a PD-1 inhibitor, prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in previously untreated FL is not described.4 We are conducting a phase II Simon's two stage study to assess the feasibility and safety of combination nivolumab and rituximab in these patients and present the pre-planned interim analysis results. Method(s): The 1st FLOR study (NCT03245021) is an ongoing open-label, multi-centre, phase 2 study of nivolumab and rituximab in patients with previously untreated stage III-IV grade 1-3A FL requiring systemic therapy. Eligible patients are ECOG <= 2 and do not require urgent debulking therapy. All patients receive induction nivolumab 240mg intravenously (IV) every 2 weeks for 4 cycles. Patients achieving complete response (CR) based on PET/CT Lugano criteria receive a further 4 cycles of 240mg IV nivolumab monotherapy then maintenance nivolumab 480mg IV every 4 weeks for 12 cycles. Patients achieving less than CR received 240mg nivolumab plus 375mg/m2 IV rituximab every 2 weeks for 4 cycles. Those achieving a response at the end of 8 cycles of nivolumab and rituximab continue maintenance nivolumab 480mg IV every 4 weeks for 12 cycles PLUS rituximab 375mg/m2 every 12 weeks for 8 cycles. PET/CT assessment is performed at baseline, after 4 cycles of nivolumab, after 8 cycles of nivolumab +/-rituximab and prior to maintenance cycle 6. The primary end point is safety, with a pre-planned analysis after the first 19 patients comple

Introduction: Standard of care immunochemotherapy in front-line (1L) follicular lymphoma (FL) is highly efficacious but not without significant toxicity. High rates of grade 3-5 adverse events (AEs), primarily infection and bone marrow suppression, are experienced in up to 75% of patients. A more tolerable but equally effective approach is required. PD-1 inhibition, in combination with rituximab (R), increases T cell anti-tumour effect & enhances NK cell antibody dependent cell cytotoxicity, with proven efficacy in relapsed FL. The concept of 'priming' the immune system with nivolumab (N) prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in 1L FL is not described. Method(s): '1st FLOR' (NCT03245021) is an open-label, multi-centre, phase 2, Simon's 2-stage study of N + R (N = 39). Key eligibility were stage III-IV grade 1-3A FL requiring 1L systemic therapy; ECOG <=2; adequate organ function. All patients (pts) receive induction N 240mg IV 2-weekly for 4 cycles. Pts with complete response (CR) receive 4 further cycles of 240mg IV N monotherapy then 12 cycles of maintenance N 480mg IV 4-weekly. Pts with 2 IV R 2-weekly for 4 cycles followed by maintenance N+R (N 480mg 4 weekly for 12 cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was >= G3 toxicity rate. Secondary EPs were response rate, overall toxicity, progression free survival (PFS) & overall survival (OS). Result(s): Between September 2017 to March 2020, 39 pts were enrolled. Baseline characteristics included median age of 54 (range: 28-79), stage IV disease in 67%, B Symptoms & bulk (>=7cm) in 23% each, intermediate-high risk FLIPI in 74%. The primary EP was met, with 16 pts (41%) having >=G3 toxicity at end of induction. Non-immune AEs were predominantly G1-2; most commonly infection (67%) & fatigue (64%). G3-4 Immune-related AEs were infrequent and included pancreatitis plus hepatitis (N = 1), pancreatitis alone (N = 1), rash (N = 1), transaminitis (N = 2)

Background: Standard of care immunochemotherapy in front-line (1L) follicular lymphoma (FL) is highly efficacious but not without significant toxicity. High rates of grade 3-5 adverse events (AEs), primarily infection and bone marrow suppression, are experienced in up to 75% of patients. A more tolerable but equally effective approach is required. PD-1 inhibition, in combination with rituximab (R), increases T cell anti-tumour effect & enhances NK cell antibody dependent cell cytotoxicity, with proven efficacy in relapsed FL. The concept of 'priming' the immune system with nivolumab (N) prior to tumour-directed therapy has rationale and evidence, but the safety of this approach in 1L FL is not described. Method(s): '1 FLOR' (NCT03245021) is an openlabel, multi-centre, phase 2, Simon's 2-stage study of N + R (N = 39). Key eligibility were stage III-IV grade 1-3A FL requiring 1L systemic therapy; ECOG <=2; adequate organ function. All patients (pts) receive induction N 240mg IV 2-weekly for 4 cycles. Pts with complete response (CR) receive 4 further cycles of 240mg IV N monotherapy then 12 cycles of maintenance N 480mg IV 4-weekly. Pts with < CR had 240mg N plus 375mg/m2 IV R 2-weekly for 4 cycles followed by maintenance N+R (N 480mg 4 weekly for 12 cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was >= G3 toxicity rate during induction. Secondary EPs; response rate by Lugano response criteria, overall toxicity, PFS, OS. Result(s): Between September 2017 to March 2020, 39 pts were enrolled. Baseline characteristics included median age of 54 (range: 28-79). stage IV disease in 67%, B Symptoms & bulk (>=7cm) in 23% each, intermediate-high risk FLIPI in 74%. The primary EP was met, with only 16 pts (41%) having >=G3 toxicity at end of induction. Non-immune AEs were predominantly G1-2; most commonly infection (67%) & fatigue (64%). G3-4 Immunerelated AEs were infrequent and included pancreatitis plus hepatitis (N = 1), pancreatitis alone (N = 1), rash (N = 1), tr