The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21

Why I Write

I write as a way of exploring issues I don\u27t understand: writing about something is my way of thinking about it. Mainly, the issues I don\u27t understand have to do with women. Why might a woman choose to become a bag-lady (Lilian\u27s Story)? Why do women stay in miserable marriages (Dreamhouse)? Why aren\u27t there more women in history books (joan Makes History)? Where does misogyny come from and what does it feel like (Dark Places)

Albion in Love

This is Albion Gidley Singer at the pen, a man with a weakness for a good fact. The first fact is always the hardest: you must begin somewhere, and such is the nature of this intractable universe that you must start with a thing admitted but undemonstrable. Myself, for example. I am a thing admitted, I close a drawer on my hand or slice my chin with my razor and admit myself to be, but it is a source of grief to me that I am undemonstrable, in spite of hands scarred by drawers, and blood spurting from my chin

The writer in a time of change

Kate Grenville discusses the transformative power of fiction. "A while ago I went to a lecture on geothermal power. Afterwards I got talking to the man sitting next to me, a retired professor of physics. When I told him I was a writer, his face lit up. A writer? Ah, you\u27re the people the planet needs! You must get the message out – it\u27s simple, just four words – coal is too cheap! Get that into every newspaper and magazine! Oh, well, I mumbled, I\u27m not that sort of writer. He peered at me. Uh, actually, I blurted out, I\u27m a fiction writer. His face fell. Fiction? You mean you write...novels? Coal is too cheap. That was the message that was going to save the planet, and I was not the person who was going to deliver it. My new acquaintance was right: as far as I know, the cheapness of coal has never been the subject of a novel. Stung by his dismissal, I toyed with the idea of writing the great coal-is-too-cheap novel..." Image: \u27Caught\u27, thorinside / flick

The Writing of The Secret River. The 2005 Herbert Blaiklock Memorial Lecture.

The Secret River won the Commonwealth Prize for Literature; the Christina Stead Prize for Fiction (the NSW Premier's Prize); the Community Relations Commission Prize; the Booksellers' Choice Award; the Fellowship of Australian Writers Prize and the Publishing Industry Book of the Year Award