Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis.

Background: Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell-mediated diseases. Objective: This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis. Methods: In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks' blinded treatment, followed by 38 weeks' open-label treatment and 12 weeks' drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events. Results: The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (-54.4% vs -34.2% for part 1 and -59.0% vs -41.8% for part 2, P = .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2. Conclusion: Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.

Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies.

BACKGROUND: Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. METHODS: We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1-2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6-8 × 107 cells, or 1·8-2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. FINDINGS: Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3-4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. INTERPRETATION: These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. FUNDING: Servier.

Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.

BACKGROUND: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. METHODS: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28-3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3-39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4-21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64-0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5-51·3) in the ipilimumab group versus 34·8% (30·1-39·5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb.

The cost of unresectable stage III or stage IV melanoma in Italy.

BACKGROUND: In recent decades, melanoma incidence has been increasing in European countries; in 2006, there were approximately 60,000 cases leading to 13,000 deaths. Within Europe there is some geographical variation in the incidence of melanoma, with the highest rates reported in Scandinavia (15 cases per 100,000 inhabitants per year) and the lowest in the Mediterranean countries (5 to 7 cases per 100,000 inhabitants per year). METHODS: The present article is based on the information collected in the MELODY study (MELanoma treatment patterns and Outcomes among patients with unresectable stage III or stage IV Disease: a retrospective longitudinal survey).In that study, the medical charts of patients were reviewed to document current treatment patterns and to analyse information on patients, disease characteristics and healthcare resource utilization related to the treatment of advanced melanoma regarding patients who presented with a diagnosis of malignant melanoma (stage I to IV) at participating sites between 01 July, 2005 and 30 June, 2006. RESULTS: Summarizing, though the length of the follow-up period varies among sample patients, an amount of the yearly cost per patient can be estimated, dividing the average per patient total cost (€ 5.040) by the average follow-up duration (17.5 months) and reporting to one year; on these grounds, unresectable stage III or stage IV melanoma in Italy would cost € 3,456 per patient per year.