Controlled backfill in oncology dose-finding trials

The use of backfill in early phase dose-finding trials is a relatively recent practice. It consists of assigning patients to dose levels below the level where the study is at. The main reason for backfilling is to collect additional pharmacokinetic, pharmacodynamic and response data, in order to assess whether a plateau may exist on the dose-efficacy curve. This is a possibility in oncology with molecularly targeted agents or immunotherapy. Recommending for further study a dose level lower than the maximum tolerated dose could be supported in such situations. How to best allocate backfill patients to dose levels is not yet established. In this paper we propose to randomise backfill patients below the dose level where the study is at. A refinement of this would be to stop backfilling to lower dose levels when these show insufficient efficacy compared to higher levels, starting at dose level 1 and repeating this process sequentially. At study completion, data from all patients (both backfill patients and dose-finding patients) is used to estimate the dose-response curve. The fit from a change point model is compared to the fit of a monotonic model to identify a potential plateau. Using simulations, we show that this approach can identify the plateau on the dose-response curve when such a plateau exists, allowing the recommendation of a dose level lower than the maximum tolerated dose for future studies. This contribution provides a methodological framework for backfilling, from the perspective of both design and analysis in early phase oncology trials

Deep-sea archaeology in the Exclusive Economic Zone of Cyprus

Cyprus is currently undergoing something of a hydrocarbon explorations boom in its Exclusive Economic Zone (EEZ) with multiple companies undertaking survey work in deep waters and reporting the accidental discovery of Underwater Cultural Heritage (UCH) sites. This is a double-edged sword, as while the oil and gas industry funds and undertakes the majority of deep-sea explorations in which these new discoveries are made, the datasets disclosed to the relevant authorities remain largely confidential and inaccessible for further academic studies. This thesis provides a rare insight into how the oil and gas industry generates geophysical and Remotely Operated Vehicle (ROV) video-photography datasets and highlights that datasets are primarily produced for industry purposes and thus lack the appropriate recording strategies for the adequate documentation and thereby preservation by recorded of accidental UCH discoveries. In the absence of national standards specifying how UCH discoveries should be adequately surveyed and reported when discovered during oil and gas operations, the main contribution of this thesis is the proposal of a robust set of minimum professional by-standards that can be specified by national heritage agencies to oil and gas companies operating in the deep waters of the EEZ. These derive from the analysis of ROV video-photography, side-scan-sonar (SSS), multibeam-bathymetry-echosounder (MBES) and backscatter datasets submitted by fourteen oil and gas contractors operating in the deep waters of Cyprus, for a period of roughly a decade (2011 to 2021). The observations emerging from these datasets are worked to different levels of surveying with the associated by-standards presented therein pertaining to how offshore oil and gas contractors/subcontractors may best adapt marine geophysical surveys and their data outputs to incorporate elements of maritime archaeological surveying. These guidelines intend to promote the best practical solutions at a technical and operational level and are concerned with the effective detection, survey, in situ and by recorded preservation, reporting, data-submission and archiving of output datasets and UCH discoveries made in the EEZ of Cyprus during the course of deep-water oil and gas explorations.</p