Additional consensus recommendations for conducting complex innovative trials of oncology agents: a post-pandemic perspective.

In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.

Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial.

BACKGROUND: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. METHODS: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. FINDINGS: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment-time interactions were -0·09 (95% CI -0·19 to 0·00) for namilumab and 0·06 (-0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. INTERPRETATION: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation-as measured by CRP concentration-in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19. FUNDING: Medical Research Council.

CATALYST trial protocol: a multicentre, open-label, phase II, multiarm trial for an early and accelerated evaluation of the potential treatments for COVID-19 in hospitalised adults.

INTRODUCTION: Severe SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, proinflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs. METHODS AND ANALYSIS: The CATALYST trial is a multiarm, open-label, multicentre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription PCR assay) and a C reactive protein (CRP) ≥40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment. ETHICS AND DISSEMINATION: The protocol was approved by the East Midlands-Nottingham 2 Research Ethics Committee (20/EM/0115) and given urgent public health status; initial approval was received on 5 May 2020, current protocol version (V.6.0) approval on 12 October 2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBERS: EudraCT2020-001684-89, ISRCTN40580903.

The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells, with increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL-6 may be preferable to IL-1 or TNF-α. We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease.

COVID-19 in children with haematological malignancies.

BACKGROUND: Children with cancer are not at increased risk of severe SARS-CoV-2 infection; however, adults with haematological malignancies have increased risk of severe infections compared with non-haematological malignancies. METHODS: We compared patients with haematological and non-haematological malignancies enrolled in the UK Paediatric Coronavirus Cancer Monitoring Project between 12 March 2020 and 16 February 2021. Children who received stem cell transplantation were excluded. RESULTS: Only 2/62 patients with haematological malignancy had severe/critical infections, with an OR of 0.5 for patients with haematological compared with non-haematological malignancies. INTERPRETATION: Children with haematological malignancies are at no greater risk of severe SARS-CoV-2 infection than those with non-haematological malignancies.

The Care of Children With Cancer During the COVID-19 Pandemic.

The COVID-19 pandemic has considerably changed health services for children with cancer worldwide by creating barriers throughout the care continuum. Reports available at this time suggest that asymptomatic and mild upper and lower respiratory tract syndromes are the most common presentation of COVID-19 in children with cancer. Nonetheless, severe cases of COVID-19 and deaths secondary to the infection have been reported. In addition to the direct effects of the severe acute respiratory syndrome coronavirus 2, children with cancer have suffered from the collateral consequences of the pandemic, including decreased access to diagnosis and cancer-directed therapy. The COVID-19 pandemic has presented unprecedented challenges to safe and effective care of children with cancer, including their enrollment in therapeutic clinical trials. Data from the Children's Oncology Group and Cancer Research U.K. Clinical Trials Unit show variability in the enrollment of children with cancer in clinical trials during the COVID-19 pandemic. However, the overall effects on outcomes for children with cancer undergoing care during the pandemic remain largely unknown. In this article, we review the current knowledge about the direct and collateral effects of the COVID-19 pandemic, including on clinical trial enrollment and operations.

The threat of the COVID-19 pandemic on reversing global life-saving gains in the survival of childhood cancer: a call for collaborative action from SIOP, IPSO, PROS, WCC, CCI, St Jude Global, UICC and WHPCA.

The COVID-19 pandemic poses an unprecedented health crisis in all socio-economic regions across the globe. While the pandemic has had a profound impact on access to and delivery of health care by all services, it has been particularly disruptive for the care of patients with life-threatening noncommunicable diseases (NCDs) such as the treatment of children and young people with cancer. The reduction in child mortality from preventable causes over the last 50 years has seen childhood cancer emerge as a major unmet health care need. Whilst survival rates of 85% have been achieved in high income countries, this has not yet been translated into similar outcomes for children with cancer in resource-limited settings where survival averages 30%. Launched in 2018, by the World Health Organization (WHO), the Global Initiative for Childhood Cancer (GICC) is a pivotal effort by the international community to achieve at least 60% survival for children with cancer by 2030. The WHO GICC is already making an impact in many countries but the disruption of cancer care during the COVID-19 pandemic threatens to set back this global effort to improve the outcome for children with cancer, wherever they may live. As representatives of the global community committed to fostering the goals of the GICC, we applaud the WHO response to the COVID-19 pandemic, in particular we support the WHO's call to ensure the needs of patients with life threatening NCDs including cancer are not compromised during the pandemic. Here, as collaborative partners in the GICC, we highlight specific areas of focus that need to be addressed to ensure the immediate care of children and adolescents with cancer is not disrupted during the pandemic; and measures to sustain the development of cancer care so the long-term goals of the GICC are not lost during this global health crisis.

The Global COVID-19 Observatory and Resource Center for Childhood Cancer: A response for the pediatric oncology community by SIOP and St. Jude Global.

The COVID-19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID-19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID-19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community.

Severity of COVID-19 in children with cancer: Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project.

BACKGROUND: Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. METHODS: Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. RESULTS: Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. CONCLUSIONS: Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment.

Pediatric cancer research: Surviving COVID-19.

A diverse panel of pediatric cancer advocates and experts, whose collective experience spans the continuum of international academic medicine, industry, government research, and cancer advocacy, recently discussed challenges for pediatric cancer research in the context of coronavirus disease 2019 (COVID-19). Specifically, this special report addresses the following focus areas: (a) the critical role that translational research has played in transforming pediatric cancer outcomes; (b) the current and potential future impact of COVID-19 on pediatric cancer research; (c) target areas of COVID-19 research that may have application in immunity, oncogenesis, and therapeutic discovery; and (d) future considerations and directions in maintaining pediatric cancer research during and after COVID-19.