Anastassia Negrouk

Phase III Intergroup Study of Fludarabine Phosphate Compared With Cyclophosphamide, Vincristine, and Prednisone Chemotherapy in Newly Diagnosed Patients With Stage III and IV Low-Grade Malignant Non-Hodgkin's Lymphoma

PURPOSE To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkins lymphoma (NHL) patients in a phase III, multicenter study. PATIENTS AND METHODS Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m2 intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 1; and prednisone, 40 mg/m2 orally on days 1 through 5 every 4 weeks). Results Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients. CONCLUSION Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.

Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

Background The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. Settings The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. Results The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Interpretation Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Accelerating the Development and Validation of New Value-Based Diagnostics by Leveraging Biobanks

The challenges faced in developing value-based diagnostics has resulted in few of these tests reaching the clinic, leaving many treatment modalities without matching diagnostics to select patients for particular therapies. Many patients receive therapies from which they are unlikely to benefit, resulting in worse outcomes and wasted health care resources. The paucity of value-based diagnostics is a result of the scientific challenges in developing predictive markers, specifically: (1) complex biology, (2) a limited research infrastructure supporting diagnostic development, and (3) the lack of incentives for diagnostic developers to invest the necessary resources. Better access to biospecimens can address some of these challenges. Methodologies developed to evaluate biomarkers from biospecimens archived from patients enrolled in randomized clinical trials offer the greatest opportunity to develop and validate high-value molecular diagnostics. An alternative opportunity is to access high-quality biospecimens collected from large public and private longitudinal observational cohorts such as the UK Biobank, the US Million Veteran Program, the UK 100,000 Genomes Project, or the French E3N cohort. Value-based diagnostics can be developed to work in a range of samples including blood, serum, plasma, urine, and tumour tissue, and better access to these high-quality biospecimens with clinical data can facilitate biomarker research.

International clinical trials setting for rare cancers: organisational and regulatory constraints—the EORTC perspective

Rare diseases are a serious public health problem that presents unique challenges to many countries. There is no internationally accepted definition for rare diseases. Patients suffering from rare cancers often face challenges, including late or incorrect diagnoses, difficulties finding clinical expertise and accessing appropriate treatments, and uncertainty in clinical decision making, with difficult and rare access for these patients to clinical trials. Treatment choice is difficult as little information is available in the literature. In such situations, clinicians will base treatment decisions on retrospective data or case report series with a lower scientific level of evidence than that obtained from randomised controlled clinical trials. The only way forward is clinical trials organisation, but to perform it within rare indications we are always faced with many methodological, regulatory, and organisational challenges, besides stakeholders’ different views, which are not usually concurrent. The aims of the European Organisation for Research and Treatment of Cancer (EORTC) are to develop, conduct, coordinate, and stimulate translational and clinical research in Europe to improve the management of cancer and related problems by increasing survival but also patient quality of life. In particular, extensive and comprehensive research in the field of rare cancers is beyond the means of individual European hospitals and can be best accomplished through the multidisciplinary multinational efforts of basic scientists and clinicians. In this paper, we will present an overview of the clinical research scene for rare cancers and will try to propose possible steps to improve the current situation.

Clinical Trials, Data Protection and Patient Empowerment in the Era of the New EU Regulations

Cancer clinical trials and, in general, cancer clinical research by definition need a multi-modality approach. It is not enough to discover and register new drugs. To get cancer under control requires us to perform complex clinical studies that integrate drugs, companion diagnostics, new or improved surgical procedures and new radiotherapy approaches as well as, most importantly, to integrate all available information. This includes biological material and, of increasing importance, large amounts of data using big data technologies. To personalise treatment, genetic data are more and more frequently used. Therefore, the general approach is holistic. Legislators, on the other hand, work in a silo mentality; the needs of clinical research are poorly understood, and legislation focuses on either health care or the commercialisation of a product, and not on clinical research. In the last 2 years the EU has drafted several major regulations touching on clinical trials, in vitro diagnostics, medical devices and data protection, all of which will impact clinical research, although the silo mentality makes the overall framework inconsistent and potentially highly damaging to the EUs capacity to make rapid progress in the field of personalised medicine.

Safeguarding the future of independent, academic clinical cancer research in Europe for the benefit of patients

Cancer is a complex disease that is constantly evolving. It is now the most common cause of death in Europe after cardiovascular diseases. There are inequalities among European countries, potentially unsustainable healthcare systems impacting quality of cancer care and increasing number of patients with cancer with rare conditions. Clinical and translational research are the backbone in establishing scientific advances as novel treatments and advancing progress to the benefit of patients. Commercially sponsored clinical trials are responsible for developing new medicines that can treat various disease areas, including cancer. It is important to note, however, that these clinical trials only assess the viability of compounds that are chosen by a commercial entity that funds the entire process. By their design and focus, these trials need to fulfil commercial interests and market expectations, which do not always coincide with patients’ needs. As soon or even before novel treatments and compounds obtain formal market authorisation, academia will take these existing and new medicines to further conduct research in order to optimise their use, develop new combinations and with a strong focus on the patients and their needs. Established standard of care most commonly relies on clinical cancer research stemming from non-commercial entities, cooperative groups or academic clinical research. This article provides a consensus on the definition of academic research, illustrates its added value and suggests and calls to European Union institutions to support this type of research for the benefit of patients.

Collaboration between EORTC and JCOG-how to accelerate global clinical research partnership.

&NA; The demand for international collaboration in cancer clinical trials has grown stronger to maximize efficiency, avoid duplication of effort and to achieve effective implementation of research results into medical practice. Infrastructures that could facilitate intercontinental collaboration not only between Europe and United States but also between Europe and Asia are urgently needed. The European Organisation for Research and Treatment of Cancer, one of the major cancer clinical research infrastructure in Europe, initiated collaboration with the Japan Clinical Oncology Group, the largest cancer research cooperative group in Japan. Their first pilot trial on unresectable colorectal liver metastasis will commence on fourth quarter of 2016. With similar goals and strategies as well as with similar structures, the two research organizations have a great potential for efficient collaboration that could deliver faster and global therapeutic improvement to cancer patients. However, international collaboration requires careful and structured approach to harmonize activities to ensure success. This article focuses on specific intercontinental differences and the necessary requirements to ensure a successful partnership between European Organisation for Research and Treatment of Cancer and Japan Clinical Oncology Group. This could serve as a model to build more global international academic trials between the East and the West.

Clinical research for rare cancers: is it a reality in the global regulatory landscape? The international rare cancer initiative

Introduction: Rare cancers together account for about 22% of new cancer diagnoses each year, which is more than any single common cancer. They constitute a serious public health problem with distinctive challenges. Compared with common cancers, less is known about their etiology and molecular pathology, and therapeutic options are mostly poorly evidence based with outcomes that are on average inferior to those of more common cancers. There is, therefore, a pressing need for well-organized clinical research to address these deficiencies. The International rare cancer initiative (IRCI) was formed in 2011 with the aim of stimulating and facilitating the development of international clinical trials for patients with rare cancers, and so helping to establish better, more evidence-based treatments. As of October 2013, 8 clinical trials are in design, in set up or recruiting, in seven rare cancer types, giving IRCI a good understanding of the current research conditions for rare cancer. Areas covered: This paper sets the scene of clinical research in rare cancers and presents an overview of organizational, methodological, regulatory and financial challenges facing researchers in this field. It also proposes possible steps to improve the research environment for the future. Expert opinion: Based on our observations, we believe that measures should be taken to improve the integration of research across international boundaries, to improve the funding of academic research and to better integrate the research capacity of industry with the public sector for the greater benefits of patients and society.

Making Change Happen in Health

Integrating personalised medicine into Europes healthcare systems will undoubtedly need to draw upon diverse talents via a multi-stakeholder approach taking expertise from academia, industry, healthcare organisations, government, policymakers and, of course, patient groups. It will also need a long-term budget commitment geared towards stimulating research and innovation in order to succeed. The role of HTA also needs to be boosted, while EU engagement in health needs to increase, not decrease, and requires a long-term strategy to provide a structure, a framework, and a consensus. Health equals wealth and the authors argue here that investment in research and innovation, alongside laws and rules that are fit-for-purpose and reflect the swiftly changing world of medicine, are vital. Europe needs to grasp these points at every level for the benefit of the millions of potential patients spread across the soon-to-be 27 Member States.