Phase I/II study protocol to assess safety and efficacy of adoptive cell therapy with anti-PD-1 plus low-dose pegylated-interferon-alpha in patients with metastatic melanoma refractory to standard of care treatments: the ACTME trial.

INTRODUCTION: Treatment with anti-PD-1 immunotherapy does not lead to long-lasting clinical responses in approximately 60% of patients with metastatic melanoma. These refractory patients, however, can still respond to treatment with tumour infiltrating lymphocytes (TIL) and interferon-alpha (IFNa). A combination of TIL, pegylated-interferon-alpha (PEG-IFNa) and anti-PD-1 is expected to provide a safe, feasible and effective therapy for patients with metastatic melanoma, who are refractory to standard of care treatment options. METHODS AND ANALYSIS: Patients are treated in two phases. In phase I, the safety of the combination TIL and anti-PD-1 is assessed (cohort 1) according to CTCAE 4.03 criteria. Subsequently, the safety of cotreatment with PEG-IFNa is tested in cohort 2. The efficacy will be evaluated in the second phase of the trial. Efficacy is evaluated according to RECIST 1.1 and immune-related response criteria. Clinical and immunological parameters will be evaluated for their relation with clinical responsiveness. ETHICS AND DISSEMINATION: Ethical approval of the trial was obtained from the Central Committee on Research Involving Human Subjects in the Netherlands. The trial results will be shared with the scientific community at (inter)national conferences and by publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03638375; Pre-results.

Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison.

BACKGROUND: The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke. Modelling studies suggest that urgent use of existing preventive treatments could reduce the risk by 80-90%, but in the absence of evidence many health-care systems make little provision. Our aim was to determine the effect of more rapid treatment after TIA and minor stroke in patients who are not admitted direct to hospital. METHODS: We did a prospective before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to March 31, 2007) study of the effect on process of care and outcome of more urgent assessment and immediate treatment in clinic, rather than subsequent initiation in primary care, in all patients with TIA or minor stroke not admitted direct to hospital. The study was nested within a rigorous population-based incidence study of all TIA and stroke (Oxford Vascular Study; OXVASC), such that case ascertainment, investigation, and follow-up were complete and identical in both periods. The primary outcome was the risk of stroke within 90 days of first seeking medical attention, with independent blinded (to study period) audit of all events. FINDINGS: Of the 1278 patients in OXVASC who presented with TIA or stroke (634 in phase 1 and 644 in phase 2), 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not referred to secondary care. 95% (n=591) of all outpatient referrals were to the study clinic. Baseline characteristics and delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic fell from 3 (IQR 2-5) days in phase 1 to less than 1 (0-3) day in phase 2 (p<0.0001), and median delay to first prescription of treatment fell from 20 (8-53) days to 1 (0-3) day (p<0.0001). The 90-day risk of recurrent stroke in the patients referred to the study clinic was 10.3% (32/310 patients) in phase 1 and 2.1% (6/281 patients) in phase 2 (adjusted hazard ratio 0.20, 95% CI 0.08-0.49; p=0.0001); there was no significant change in risk in patients treated elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of intracerebral haemorrhage or other bleeding. INTERPRETATION: Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results have immediate implications for service provision and public education about TIA and minor stroke.