The Brave New World of clinical cancer research: Adaptive biomarker-driven trials integrating clinical practice with clinical research.
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ABSTRACT:
SUBMITTER: Berry DA
PROVIDER: S-EPMC4516171 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe Biomarker Strategy Design has been proposed for trials assessing the value of a biomarker in guiding treatment in oncology. In such trials, patients are randomised to either receive the standard chemotherapy treatment or a biomarker-directed treatment arm, in which biomarker status is used to guide treatment.MethodsMotivated by a current trial, we consider an adaptive design in which two biomarkers are assessed. The trial is conducted in two stages. In the first stage, patients in the biomarker-guided arm are assessed using a standard and an alternative cheaper biomarker, with the standard biomarker guiding treatment. An analysis comparing biomarker results is then used to choose the biomarker to use for the remainder of the trial. The new biomarker is used if the results for the two biomarkers are sufficiently similar.ResultsWe show that in practical situations the first-stage results can be used to adapt the trial without type I error rate inflation. We also show that there can be considerable cost gains with only a small loss in power in the case where the alternative biomarker is highly concordant with the standard one.ConclusionsAdaptive designs have an important role in reducing the cost and increasing the clinical utility of trials evaluating biomarker-guided treatment strategies.
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Project description:Clinical trials with adaptive designs use data that accumulate during the course of the study to modify study elements in a prespecified manner. The goal is to provide flexibility such that a trial can serve as a definitive test of its primary hypothesis, preferably in a shorter time period, involving fewer human subjects, and at lower cost. Elements that may be modified include the sample size, end points, eligible population, randomization ratio, and interventions. Accumulating data used to drive these modifications include the outcomes, subject enrollment (including factors associated with the outcomes), and information about the application of the interventions. This review discusses the types of adaptive designs for clinical trials, emphasizing their advantages and limitations in comparison with conventional designs, and opportunities for applying these designs to healthcare epidemiology research, including studies of interventions to prevent healthcare-associated infections, combat antimicrobial resistance, and improve antimicrobial stewardship.
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Project description:Adaptive designs have the potential to improve efficiency in the evaluation of new medical treatments in comparison to traditional fixed sample size designs. However, they are still not widely used in practice in clinical research. Little research has been conducted to investigate what adaptive designs are being undertaken. This review highlights the current state of registered adaptive designs and their characteristics. The review looked at phase II, II/III and III trials registered on ClinicalTrials.gov from 29 February 2000 to 1 June 2014, supplemented with trials from the National Institute for Health Research register and known adaptive trials. A range of adaptive design search terms were applied to the trials extracted from each database. Characteristics of the adaptive designs were then recorded including funder, therapeutic area and type of adaptation. The results in the paper suggest that the use of adaptive designs has increased. They seem to be most often used in phase II trials and in oncology. In phase III trials, the most popular form of adaptation is the group sequential design. The review failed to capture all trials with adaptive designs, which suggests that the reporting of adaptive designs, such as in clinical trials registers, needs much improving. We recommend that clinical trial registers should contain sections dedicated to the type and scope of the adaptation and that the term 'adaptive design' should be included in the trial title or at least in the brief summary or design sections.
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Project description:Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.
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