Reviews on Recent Clinical Trials - Volume 1, Issue 3, 2006

I am pleased to begin my tenure as Editor-in-Chief with this issue of Reviews on Recent Clinical Trials. This journal publishes frontier reviews on recent clinical trials of major importance. The journal's aim is to publish the highest quality review articles in the field. Topics covered include important Phase I - IV clinical trial studies, clinical investigations at all stages of development, and therapeutics. It is our hope that this journal will be essential reading for all researchers and clinicians involved in drug therapy and clinical trials. The editorial board and publication team is committed to producing an outstanding journal. The implication of an immunologic phenomena in the pathogenesis psoriasis has led the research to explore new treatment options over the past few years [1]. The result has been the birth of biologic therapies, those drugs targeting the activity of T lymphocytes and cytokines responsible for the inflammatory nature of this disease. Singri et al. [2] recently defined four strategies that clarify the mechanism of action for the various biologic agents. These strategies include (1) reduction of pathogenic T cells, (2) inhibition of T-cell activation, (3) immune deviation (“deviation” of a TH1 immune response toward a greater TH2-type response through the involvement of these TH2-type cytokines), and (4) blocking the activity of inflammatory cytokines [2]. There are currently five biologic agents which are approved for psoriasis and/or psoriatic arthritis. The biologic agents include infliximab (strategy 4), etanercept (strategy 4), efalizumab (strategy 2), alefacept (strategy 1), and adalimumab (strategy 4) (Table). These therapies offer successful therapy of psoriasis, with a lack of organ toxicity seen with traditional systemic therapies, such as methotrexate and cyclosporine. However, long-term monitoring of these agents will be necessary to determine the potential risk for increased infection and malignancy in patients treated with them. In this issue, there are two reviews on biologic therapy in psoriasis. Vamvouris and Hadi [3] review the treatment of psoriasis with infliximab, and Fuchs and Hadi [4] review the treatment of psoriasis and psoriatic arthritis with etanercept. Psoriasis often has a devastating effect on those who are afflicted. The author John Updike devoted the chapter “At war with my skin” to psoriasis in Self-Consciousness. [5] He observed that psoriasis keeps you thinking: “Strategies of concealment ramify, and self-examination is endless.” The patient constantly invents new ways of hiding the symptoms. After an attack of measles in 1938, Updike noted that his psoriasis paraded “in all its flaming scabbiness from head to toe“ [6]. I am pleased to begin my tenure as Editor-in-Chief with this issue of Reviews on Recent Clinical Trials. This journal publishes frontier reviews on recent clinical trials of major importance. The journal's aim is to publish the highest quality review articles in the field. Topics covered include important Phase I - IV clinical trial studies, clinical investigations at all stages of development, and therapeutics. It is our hope that this journal will be essential reading for all researchers and clinicians involved in drug therapy and clinical trials. The editorial board and publication team is committed to producing an outstanding journal. The implication of an immunologic phenomena in the pathogenesis psoriasis has led the research to explore new treatment options over the past few years [1]. The result has been the birth of biologic therapies, those drugs targeting the activity of T lymphocytes and cytokines responsible for the inflammatory nature of this disease. Singri et al. [2] recently defined four strategies that clarify the mechanism of action for the various biologic agents. These strategies include (1) reduction of pathogenic T cells, (2) inhibition of T-cell activation, (3) immune deviation (“deviation” of a TH1 immune response toward a greater TH2-type response through the involvement of these TH2-type cytokines), and (4) blocking the activity of inflammatory cytokines [2]. There are currently five biologic agents which are approved for psoriasis and/or psoriatic arthritis. The biologic agents include infliximab (strategy 4), etanercept (strategy 4), efalizumab (strategy 2), alefacept (strategy 1), and adalimumab (strategy 4) (Table). These therapies offer successful therapy of psoriasis, with a lack of organ toxicity seen with traditional systemic therapies, such as methotrexate and cyclosporine. However, long-term monitoring of these agents will be necessary to determine the potential risk for increased infection and malignancy in patients treated with them. In this issue, there are two reviews on biologic therapy in psoriasis. Vamvouris and Hadi [3] review the treatment of psoriasis with infliximab, and Fuchs and Hadi [4] review the treatment of psoriasis and psoriatic arthritis with etanercept. Psoriasis often has a devastating effect on those who are afflicted. The author John Updike devoted the chapter “At war with my skin” to psoriasis in Self-Consciousness. [5] He observed that psoriasis keeps you thinking: “Strategies of concealment ramify, and self-examination is endless.” The patient constantly invents new ways of hiding the symptoms. After an attack of measles in 1938, Updike noted that his psoriasis paraded “in all its flaming scabbiness from head to toe“ [6]. I am pleased to begin my tenure as Editor-in-Chief with this issue of Reviews on Recent Clinical Trials. This journal publishes frontier reviews on recent clinical trials of major importance. The journal's aim is to publish the highest quality review articles in the field. Topics covered include important Phase I - IV clinical trial studies, clinical investigations at all stages of development, and therapeutics. It is our hope that this journal will be essential reading for all researchers and clinicians involved in drug therapy and clinical trials. The editorial board and publication team is committed to producing an outstanding journal. The implication of an immunologic phenomena in the pathogenesis psoriasis has led the research to explore new treatment options over the past few years [1]. The result has been the birth of biologic therapies, those drugs targeting the activity of T lymphocytes and cytokines responsible for the inflammatory nature of this disease. Singri et al. [2] recently defined four strategies that clarify the mechanism of action for the various biologic agents. These strategies include (1) reduction of pathogenic T cells, (2) inhibition of T-cell activation, (3) immune deviation (“deviation” of a TH1 immune response toward a greater TH2-type response through the involvement of these TH2-type cytokines), and (4) blocking the activity of inflammatory cytokines [2]. There are currently five biologic agents which are approved for psoriasis and/or psoriatic arthritis. The biologic agents include infliximab (strategy 4), etanercept (strategy 4), efalizumab (strategy 2), alefacept (strategy 1), and adalimumab (strategy 4) (Table). These therapies offer successful therapy of psoriasis, with a lack of organ toxicity seen with traditional systemic therapies, such as methotrexate and cyclosporine. However, long-term monitoring of these agents will be necessary to determine the potential risk for increased infection and malignancy in patients treated with them. In this issue, there are two reviews on biologic therapy in psoriasis. Vamvouris and Hadi [3] review the treatment of psoriasis with infliximab, and Fuchs and Hadi [4] review the treatment of psoriasis and psoriatic arthritis with etanercept. Psoriasis often has a devastating effect on those who are afflicted. The author John Updike devoted the chapter “At war with my skin” to psoriasis in Self-Consciousness. [5] He observed that psoriasis keeps you thinking: “Strategies of concealment ramify, and self-examination is endless.” The patient constantly invents new ways of hiding the symptoms. After an attack of measles in 1938, Updike noted that his psoriasis paraded “in all its flaming scabbiness from head to toe“ [6]. I am pleased to begin my tenure as Editor-in-Chief with this issue of Reviews on Recent Clinical Trials. This journal publishes frontier reviews on recent clinical trials of major importance. The journal's aim is to publish the highest quality review articles in the field. Topics covered include important Phase I - IV clinical trial studies, clinical investigations at all stages of development, and therapeutics. It is our hope that this journal will be essential reading for all researchers and clinicians involved in drug therapy and clinical trials. The editorial board and publication team is committed to producing an outstanding journal. The implication of an immunologic phenomena in the pathogenesis psoriasis has led the research to explore new treatment options over the past few years [1]. The result has been the birth of biologic therapies, those drugs targeting the activity of T lymphocytes and cytokines responsible for the inflammatory nature of this disease. Singri et al. [2] recently defined four strategies that clarify the mechanism of action for the various biologic agents. These strategies include (1) reduction of pathogenic T cells, (2) inhibition of T-cell activation, (3) immune deviation (“deviation” of a TH1 immune response toward a greater TH2-type response through the involvement of these TH2-type cytokines), and (4) blocking the activity of inflammatory cytokines [2]. There are currently five biologic agents which are approved for psoriasis and/or psoriatic arthritis. The biologic agents include infliximab (strategy 4), etanercept (strategy 4), efalizumab (strategy 2), alefacept (strategy 1), and adalimumab (strategy 4) (Table). These therapies offer successful therapy of psoriasis, with a lack of organ toxicity seen with traditional systemic therapies, such as methotrexate and cyclosporine. However, long-term monitoring of these agents will be necessary to determine the potential risk for increased infection and malignancy in patients treated with them. In this issue, there are two reviews on biologic therapy in psoriasis. Vamvouris and Hadi [3] review the treatment of psoriasis with infliximab, and Fuchs and Hadi [4] review the treatment of psoriasis and psoriatic arthritis with etanercept. Psoriasis often has a devastating effect on those who are afflicted. The author John Updike devoted the chapter “At war with my skin” to psoriasis in Self-Consciousness. [5] He observed that psoriasis keeps you thinking: “Strategies of concealment ramify, and self-examination is endless.” The patient constantly invents new ways of hiding the symptoms. After an attack of measles in 1938, Updike noted that his psoriasis paraded “in all its flaming scabbiness from head to toe” [6]. The novel biologic therapies have been of benefit in improving the lives of many and, as progress continues in this area, they will hopefully continue to ease the burden of many more. [1] Tutrone WD, Kagen MH, Barbagallo J, Weinberg JM. Biologic therapy for psoriasis: a brief history, II. Cutis 2001; 68:367-72. [2] Singri P, West DP, Gordon KB. Biologic therapy for psoriasis: the new therapeutic frontier. Arch Dermatol 2002; 138:657-63. [3] Vamvouris T, Hadi, S. A review of the treatment of psoriasis with infliximab. Rev Recent Clin Trials 2006; 1: 201-205. [4] Fuchs BS, Hadi S. Use of etanercept in the treatment of psoriasis and psoriatic arthritis. Rev Recent Clin Trials 2006; 1:259-263. [5] Updike J. Self-Consciousness. New York, NY: Alfred A. Knopf 1989. [6] Updike J. Odd Jobs: Essays and Criticism. New York, NY: Alfred A. Knopf 1991.

GW506U78 or nelarabine (Glaxo-SmithKline) is a nucleoside analog that is rapidly converted by cells of lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate (araGTP). The triphosphate form of araG acts as a substrate for DNA polymerases and araG gets incorporated into the DNA, resulting in inhibition of DNA synthesis and subsequent cytotoxicity. It has been shown that nelarabine has activity as a single agent in patients with Tcell malignancies that have relapsed or are refractory to other therapy. The ongoing research on nelarabine has earned fast-track status from the U.S. Food and Drug Administration (FDA) for treatment of patients with T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma who have not responded to or whose disease has progressed during treatment with at least two standard regimens. It is likely that nelarabine will be a useful drug in the treatment of leukemic diseases in the future and therefore nelarabine is an interesting drug to study further. Here we present an overview of what is known about the mechanism of action of nelarabine and its status in clinical trials.

Tocilizumab (namely MRA), a humanized anti-interleukin (IL)-6 receptor monoclonal antibody, is under development by Roche for the treatment of inflammatory autoimmune diseases such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (JIA), adult-onset Still's disease, Castleman's disease and Crohn's disease. Tocilizumab has a long plasma half-life, so it can be administered intravenously biweekly or monthly. Phase I and II clinical trials showed that tocilizumab (2, 4, 5, 8 or 10 mg/kg) reduced disease activity significantly in a dose-dependent manner. Tocilizumab not only improved signs and symptoms, but also normalized inflammatory markers such as Creactive protein, erythrocyte sedimentation rate (ESR), fibrinogen and serum amyloid A, and reversed joint damage of RA. The efficacy of tocilizumab in the treatment of RA was at least as good as methotrexate. Tocilizumab was generally safe and well tolerated. Some adverse events such as significant rises in total cholesterol and triglyceride levels, liver function disorders, decreases in white blood cell counts, diarrhoea and infection were observed. In summary, preliminary clinical results suggest that tocilizumab is effective and generally well tolerated in the treatment of IL-6-related inflammatory autoimmune diseases. Like other anti-cytokine immunotherapies, caution and close monitoring for the adverse events, especially infection, are necessary in subsequent clinical trials.

Patients afflicted with moderate to severe psoriasis experience a reduction in the quality of life. They not only suffer the aggravation associated with the pain, itchiness, and bleeding of the psoriatic lesions, but also experience a negative impact on their daily functions and social well-being. Unfortunately, traditional therapeutic measures have not been effective enough in treating individuals suffering from moderate to severe forms of psoriasis. Most of the conventional medications have produced at best only partial responses. However, the recent chimeric monoclonal TNF-α inhibiting antibody, infliximab, has been proven effective for the treatment of patients with moderate to severe psoriasis. Most patients treated with infliximab have shown rapid and remarkable improvement in the clinical manifestations of the disease. This article will closely examine the efficacy and safety of infliximab through the analysis of past case reports and clinical trials.

The ATAC trial is the first study to compare a third-generation aromatase inhibitor (AI), anastrozole, with tamoxifen for the adjuvant treatment of early breast cancer. Analyses at 33 and 47 months of median follow-up showed that anastrozole significantly prolonged disease-free survival (DFS) and time to recurrence (TTR), and reduced the incidence of contralateral breast cancer, compared with tamoxifen. Results of the Completed Treatment Analysis at 68 months of median follow-up confirmed the superiority of anastrozole over tamoxifen. The absolute difference in DFS between anastrozole and tamoxifen continued to increase beyond completion of treatment and early improvements in DFS and TTR have translated into a benefit in time to distant recurrence. Benefits of anastrozole over tamoxifen were maintained without a detrimental impact on quality of life. Mature safety data with extensive patient exposure indicate that overall, anastrozole has a favourable safety profile compared with tamoxifen. Importantly, a decrease in the odds ratio of cardiovascular events was observed with anastrozole compared with tamoxifen. The ATAC trial provides the most mature data of any AI trial and has enabled the evaluation of a full risk:benefit profile of anastrozole.

The identification of activated oncogenes, such as the bcl-2, in several types of cancer has made it possible to consider such genes as targets for antitumor therapy. Bcl-2 is an anti-apoptotic protein, whose overexpression is associated with chemotherapy resistant cancer, aggressive clinical course and poor survival. The development of novel targeted gene-silencing strategies, such as those based on the use of antisense oligonucleotides, represents a renewed hope in the treatment of cancer. Within this scope, this review covers the main pre-clinical aspects and the most recent clinical data obtained with Oblimersen sodium (Genta Inc.). Oblimersen is a 18-mer phosphorothioate antisense oligonucleotide designed to bind to the first six codons of the human bcl-2 mRNA. Phase I/II trials indicate that infusion of Oblimersen provides biologically relevant plasma levels that lead to downregulation of target Bcl-2 protein. Moreover, the use of Oblimersen in combination with chemotherapy in a variety of cancers has shown promising response rates with good tolerability. Randomized phase III trials are currently underway to evaluate whether the combined use of Oblimersen with standard treatment is superior to standard treatment alone in chronic lymphocytic leukaemia, malignant melanoma and multiple myeloma. Overall, the enhanced efficacy of anticancer treatments of this bcl-2-targeted antisense therapy represents a promising new apoptosis-modulating strategy.

Adjuvant hormonal therapy for patients with endocrine sensitive breast cancer has been dominated for several decades by the gold standard tamoxifen. Promising data on third generation aromatase inhibitors (AI), anastrozole, letrozole and exemestane, in metastatic setting led to the development of these agents in early breast cancer. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting remain discussed. Various approaches have been evaluated ranging from: 1. Front line 5 year use of AI instead of tamoxifen for newly diagnosed patients, to 2. Switching to AI after 2 or 3 years of tamoxifen for patients presently on tamoxifen (total of 5 years), or 3. Continuing with an AI after completion of 5 years of adjuvant tamoxifen. However, it is unclear today whether one of these AI strategies is superior to the other ones. The overall therapeutic index of AIs appears superior to that of tamoxifen with proven improved efficacy and better toxicity profile. AIs are all less toxic than tamoxifen in terms of thromboembolic disease and gynaecological complications while musculoskeletal disorders and joint pains are more frequent seen with AIs. This review will explore the results from the available adjuvant AIs trials and will define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.

Randomized controlled clinical trials are felt by the medical community to provide the best evidence. Participation in trials involves the possibility of obtaining benefits but also of suffering some risks. Those risks are often considered unacceptable for children but if clinical trials are not conducted in children, clinicians are forced to extrapolate study data from adults. In 1968 H. Shirkey termed children “therapeutic orphans” because of the lack of adequately tested and labeled drugs available in appropriate formulations. Research involving children entails specific difficulties as the need to study children of different ages, the small number of children affected by certain diseases or ethical issues. This paper considers aspects of pediatric clinical pharmacology and children's responses to drugs. It also reviews some of the current situations in pediatric clinical trials, covering aspects such as: the benefits and risks of trial participation; the specificity of pediatric trial design; the ethical issues such as consent; the use of placebo or the participation of healthy children; and the current legal situation in Europe and in the USA.

Psoriasis and psoriatic arthritis are debilitating inflammatory immunemediated diseases which are chronic in nature and often require lifelong attention. Traditional therapies used to combat these diseases lack sufficient long-term efficacy and are associated with a number of toxicities. Failing to adequately satisfy both patients and physicians, traditional therapies have proven insufficient and have left few options. Etanercept is a tumor necrosis factor (TNF) antagonist that reduces elevated TNF levels by competitively binding to both TNF-α and TNF-β and inhibiting the proinflammatory cascade. Providing a valuable treatment option alone, etanercept can also be effectively administered in conjunction with traditional treatments. Etanercept is self administered by subcutaneous (SC) injection, making treatment less of a burden for patients by eliminating the need for frequent office visits and laboratory testing. Etanercept is approved in the US for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis.

Glioblastoma, the most highly aggressive and lethal form of brain cancer, has been a particular challenge to treat in terms of improving a patient's quality of life and outcome. Each of the current treatment options is limited due to factors intrinsic to the tumor's biology and the special microenvironment of its location within the brain. Surgical resection is limited by the non-circumscribed borders that can be detected. Radiation therapy has to contend with neurotoxicity to adjacent normal tissues. Chemotherapy is constrained by the blood-brain barrier, which is a very real constraint of systemic therapy - producing minimal benefit with substantial toxicity in order to administer therapeutic dosages. In part, such hurdles explain the reasons why survival has changed little over many decades of research in this field. The newest generation of treatments includes more effective cytotoxic agents, so-called targeted compounds, and biologics/immunotherapeutics. This article summarizes the preclinical proof-of-concept research and human studies involving some of the agents creating the most positive buzz in the medical community. The advantages and limitations of each are described.

Extensive research over the past two decades in tumor immunology has shown that immune reactivity to tumor antigens can restrict tumor growth and/or metastasis, especially when tumor burden is low. These observations in experimental models have been translated into clinical studies involving both active and passive forms of immunotherapies. While immune responses to specific tumor antigens can be detected in patients with various types of cancers, responses to any single antigen seldom correlate directly with a clinical response to tumors; however, some clinical regressions of solid tumors have been reported with certain types of cancer vaccines. While passive immunotherapies with antibody to tumor antigens (Avastin®, Herceptin®, Erbitux®, RituxanTM, BexxarTM) are being used to treat selected types of cancers, active immunotherapies may be better suited to potentially elicit a sustained immune response, particularly when administered in an adjuvant setting. This review covers the potential and issues with specific active immunotherapies (SAI) for the treatment of cancer.

Stroke is the third most common cause of death in the United States. There are approximately 700,000 strokes/year, eighty percent are ischemic, and 20-30% of ischemic strokes are secondary to carotid disease. Carotid stenosis is traditionally treated by carotid endarterectomy (CEA). Multicenter randomized controlled trials have shown that surgery significantly reduces the risk of ipsilateral stroke in patients with severe symptomatic and asymptomatic carotid stenosis. Endovascular techniques for treating carotid stenosis have been developed over recent years. Carotid angioplasty and stenting (CAS) with cerebral protection has become an alternative to CEA for high-surgical-risk patients and the procedure of choice for stenoses inaccessible by surgery. In this review we summarize the existing data regarding the traditional state of management of extracranial carotid artery stenosis, and compare these data to a critical analysis of the recent results of CAS.