AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment: an update to the structured summary of a study protocol for a randomised platform trial letter

Background There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods/design AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. Discussion Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial registration EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183 19 February 2021 ISRCTN reference: 27106947

Capecitabine maintenance therapy after induction chemotherapy in newly diagnosed metastatic nasopharyngeal carcinoma: An open-label, randomized, controlled, phase trial.

6044 Background: Capecitabine maintenance therapy improves outcomes in various tumor types, but minimal data are available on the effect of capecitabine maintenance therapy in metastatic nasopharyngeal carcinoma (NPC). We aimed to investigate whether capecitabine maintenance therapy would prolong the progression-free survival (PFS) of newly diagnosed metastatic NPC, in comparison to best supportive care (BSC). Methods: This was an open-label, randomized, controlled, phase trial. Eligible patients for maintenance randomisation were aged 18-65 years old with newly diagnosed metastatic NPC at the Sun Yat-Sun University Cancer Center (SYSUCC), had completed 4 to 6 cycles of induction chemotherapy as per protocol and had achieved disease control to protocol treatment, including capecitabine. Patients were randomly assigned 1:1 to capecitabine maintenance (oral 1,250 mg/m2/day on days 1-14 every 21 days) for up to 24 months with BSC or BSC alone. The primary endpoint was PFS. The secondary endpoints included overall survival, duration of response, objective response rate and adverse effects. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02460419 and is ongoing and no longer recruiting new patients. Results: Between May 16th, 2015, and January 9th, 2020, 140 metastatic NPC patients were screened, and 104 eligible patients were randomly assigned to capecitabine maintenance plus BSC (n = 52) or BSC alone (n = 52). After a median follow-up of 33.1 months (IQR, 21.5-50.7 months), median PFS was 35.2 months in the capecitabine maintenance group and 9.1 months in the BSC group (HR: 0.426; 95%CI: 0.248-0.731, P = 0.001). The most commongrade 3 or 4 adverse events during maintenance therapy were hand-foot syndrome (10.0%), nausea/vomiting (6.0%), fatigue (4.0%), and mucositis (4.0%). Totally 37 deaths occurred during follow-up, 14 (26.9%) in the capecitabine maintenance group and 23 (44.2%) in the BSC group. Overall survival data was immature. No deaths in the capecitabine maintenance group were deemed treatment related. Conclusions: Capecitabine maintenance significantly improved PFS in patients with newly diagnosed metastatic NPC who achieved disease control after induction chemotherapy compared to BSC and exhibited low grade and manageable toxicities. Clinical trial information: NCT02460419.

AGILE: A Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 treatment: An update to the structured summary of a study protocol for a randomised platform trial letter

Background:There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods/Design:AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol.Discussion:Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tociluzimab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial registrations:EudraCT Number: 2020-001860-27 14th March 2020 ClinicalTrials.gov Identifier: NCT04746183ISRCTN reference: 27106947

Drug Development in Soft Tissue Sarcomas: Novel Targets and Recent Early Phase Trial Results

ABSTRACT Soft tissue sarcomas are a heterogeneous group of rare malignancies with few effective standard therapies. Our understanding of the underlying biology driving tumorigenesis in these mesenchymal tumors have led to a growth in drug development for soft tissue sarcomas. This review focuses on novel targets in soft tissue sarcomas, describes early clinical trial results of drugs directed at these targets, and discusses the data surrounding the use of these compounds in clinical practice and rationale for possible future US Food and Drug Administration approvals.

The HARMONIC trial: study protocol for a randomised controlled feasibility trial of Shaping Healthy Minds—a modular transdiagnostic intervention for mood, stressor-related and anxiety disorders in adults

IntroductionAnxiety, mood and trauma-related disorders are common, affecting up to 20% of adults. Many of these individuals will experience symptoms of more than one disorder as diagnostically defined. However, most psychological treatments focus on individual disorders and are less effective for those who experience comorbid disorders. The Healthy and Resilient Mind Programme: Building Blocks for Mental Wellbeing (HARMONIC) trial introduces a novel transdiagnostic intervention (Shaping Healthy Minds (SHM)), which synthesises several evidence-based treatment techniques to address the gap in effective interventions for people with complex and comorbid difficulties. This early phase trial aims to estimate the efficacy and feasibility of the transdiagnostic intervention in preparation for a later-phase randomised controlled trial, and to explore mechanisms of change.Methods/analysisWe outline a patient-level two-arm randomised controlled trial (HARMONIC) that comparesSHMto treatment-as-usual for individuals aged >18 years (n=50) with comorbid mood, anxiety, obsessive-compulsive or trauma/stressor disorders diagnoses, recruited from outpatient psychological services within the UK National Health Service (NHS). The co-primary outcomes will be 3-month follow-up scores on self-report measures of depressive symptoms, anxiety symptoms, and disability and functional impairment. Secondary outcomes include changes in symptoms linked to individual disorders. We will assess the feasibility and acceptability ofSHM, the utility of proposed outcome measures, and refine the treatment manuals in preparation for a later-phase trial.Ethics and disseminationThis trial protocol has been approved by the Health Research Authority of the NHS of the UK (East of England, Reference: 16/EE/0095). We anticipate that trial findings will inform future revisions of clinical guidelines for numerous forms of mood, anxiety and stressor-related disorders. Findings will be disseminated broadly via peer-reviewed empirical journal articles, conference presentations, clinical workshops and a trial website.Trial registrationNCT03143634; Pre-results.

The HARMONIC trial: Study protocol for a randomised controlled feasibility trial of Shaping Healthy Minds – a modular transdiagnostic intervention for mood, stress and anxiety disorders in adults

Introduction: Anxiety, mood and trauma-related disorders are common, affecting up to 20% of adults. Many of these individuals will experience symptoms of more than one disorder as diagnostically defined. However, most psychological treatments focus on individual disorders and are less effective for those who experience comorbid disorders. The HARMONIC trial introduces a novel transdiagnostic intervention (Shaping Healthy Minds), which synthesises several evidence-based treatment techniques to address the gap in effective interventions for people with complex and comorbid difficulties. This early-phase trial aims to estimate the efficacy and feasibility of the transdiagnostic intervention in preparation for a later-phase randomised controlled trial, and to explore mechanisms of change.Methods/Analysis: We outline a patient-level two-arm randomised controlled trial (HARMONIC) that compares Shaping Healthy Minds to treatment-as-usual (TAU) for individuals aged >18 years (N=50) with co-morbid mood, anxiety, obsessive-compulsive or trauma/stressor disorder diagnoses, recruited from outpatient psychological services within the UK National Health Service. The co-primary outcomes will be 3-month follow-up scores on self-report measures of depressive symptoms, anxiety symptoms, and disability and functional impairment. Secondary outcomes include changes in symptoms linked to individual disorders. We will assess the feasibility and acceptability of Shaping Healthy Minds, the utility of proposed outcome measures, and refine the treatment manuals in preparation for a later-phase trial. Ethics and dissemination: This trial protocol has been approved by the Health Research Authority of the National Health Service of the United Kingdom (East of England, Reference: 16/EE/0095). We anticipate that trial findings will inform future revisions of clinical guidelines for numerous forms of mood, anxiety, and stressor-related disorders. Findings will be disseminated broadly via peer-reviewed empirical journal articles, conference presentations, clinical workshops, and a trial website.