Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in children and adolescents in Africa: A randomised, placebo-controlled, multicentre Phase II clinical trial

Background Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa. Methods and findings In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc. Conclusions The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU. Trial registration ClinicalTrials.gov NCT02564523.

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive after Treatment for Relapsed Follicular Lymphoma: Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study

Introduction The combination of rituximab & lenalidomide (R 2) is an established regimen for treatment of follicular lymphoma (FL), with efficacy reported in the first line and relapsed setting (Morchhauser NEJM 2018, Leonard JCO 2019). The inferior OS of patients who remain post-induction PET-CT positive (PET+ve) has also been demonstrated in both settings (Trotman Lancet Haem 2014, Lancet Oncol 2018, Ysebaert, ASH 2011). We sought to study the effect of R 2 in relapsed FL by examining its ability to convert to PET-negative (PET-ve) those patients who remain PET+ve after reinduction rituximab-chemotherapy. Methods This was a prospective, multicentre, Phase 2 study of patients with bulky Stage II, or Stage III-IV relapsed FL. Eligibility criteria were: at least stable disease on CT within 4-6 weeks of last cycle of re-induction rituximab-chemotherapy; ECOG ≤2; CrCL ³30mL/min; haemoglobin >80g/L, neutrophils >1.0 & platelets >75 x 10 9/L. Exclusion criteria were: histological transformation ≤12 months (mo); any interim-PET that was negative, and other malignancy ≤5 years. After enrolment pts underwent a centrally-reviewed PET within 8 weeks of D1 last cycle of re-induction rituximab-chemotherapy. Given the higher probability of further progression in the relapsed setting PET+ve was defined as a Deauville score (DS) 3-5. PET-ve patients were assigned rituximab maintenance q2mo for 2 years, and those remaining PET+ve were assigned R 2 to commence within 12 weeks. Lenalidomide schedule for R 2 pts was 10mg/d x 21 q28d, with dose modifications for tolerance, over a planned 2 years. Repeat PET scans were scheduled at 6 & 12 mo after starting R 2. The primary endpoint was the rate of conversion from postinduction PET+ve to PET-ve in evaluable patients 6 mo after commencing lenalidomide. Evaluable patients were defined as those receiving >63 days of Lenalidomide. Sample size calculations used a one-sided exact test for proportions, assuming a conversion rate of ³50% as worthy of further evaluation and ≤20% as unacceptable. Thus 16 evaluable patients were required to have 80% power with type I error of 5%. Secondary endpoints were PET conversion rates by baseline DS in the PET+ve, the toxicity & deliverability of R 2, and PFS & OS in both the PET+ve & PET-ve populations. Results Thirty-seven patients (pts) were recruited from Nov 2013 to Jan 2021 when the study was closed due to poor recruitment attributed to competing studies. Median (med) age was 67yrs (36-83); 58% male, med 2 (range 2-11) prior therapies incl. the recent rituximab-chemotherapy; FLIPI low risk (21%), intermediate risk (12%) high risk (67%). Eighteen of 37 (48.6%) pts were postinduction PET+ve. Med follow-up was 38 mo (0.8 - 76.4): 32 mo (0.8 - 76.4) in PET+ve and 42 mo (6.7 - 73.8) in PET-neg. Of the 18 PET+ve pts one was ineligible for R 2 due to reactivation of hepatitis B; 3 were not evaluable having not received >63 doses of lenalidomide due to progressive disease (PD). Thus 14/18 (78%) PET+ve pts were evaluable, of whom 5/14 (36%; 95% CI 11% - 61%) became PET-ve at 6-mo, thus not excluding a PET conversion rate of <20%, (p=0.14). If we had obtained full recruitment both additional pts would have had to convert to PET-neg to meet the primary endpoint. PET conversion occurred in 4/6 evaluable pts with DS 3 and 1/8 with DS 5. PD occurred in 14 pts: 11/17 PET+ve and 3/19 PET-ve. Med PFS was 30.8 mo (5.7-37.6) in the PET+ve and NR (95% CI 42.3-NR) in the PET-ve, p = 0.0001. Death occurred in 11/37 (30%): 7 from lymphoma (5 PET+ve), 1 other malignancy, 2 pneumonia, 1 aspergillosis. Med OS was 68.1 mo (9.6 - NR) in PET+ve and NR (95% CI 42.3 - NR) in PET-ve (p 0.059). Of the 17 PET+ve pts starting lenalidomide, deliverability was limited by both disease progression and AEs: 3 failed to receive 3 cycles, 6 pts received 4-6, and 8 pts 7-24 cycles. Mean number of lenalidomide doses was 213 (SD 188). At least one AE was reported in 16/17 (94%), most commonly neutropenia (n=10, 59%, Gd4 24%). At least one SAE occurred in 9/17 (53%): infections 2, malignancy 2, cardiac disorders 2, musculoskeletal 2, other causes 3 pts. Conclusion The high PET+ve rate of 49% (DS 3-5) after rituximab-chemotherapy for relapsed FL suggests the need for consolidation therapy. However, R 2 did not achieve a sufficiently high PET-conversion rate to justify further study. The inferior outcome of patients who remain PET+ve after treatment of relapse highlights the importance of investigating novel approaches in this setting. Figure 1 Figure 1. Disclosures Trotman: TAKEDA: Research Funding; beigene: Research Funding; roche: Research Funding; BMS: Research Funding; PCYC: Research Funding; JANSSEN: Research Funding. Gandhi: janssen: Research Funding; novartis: Honoraria. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam.