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Reviews
on Recent Clinical Trials
ISSN: 1574-8871
Reviews on Recent Clinical Trials
Volume 1, Number 3, September 2006
Contents
Editorial Pp. 183
Nelarabine- A New Purine Analog in the Treatment of Hematologic
Malignancies Pp. 185-192
Sophie Curbo and Anna Karlsson
[Abstract] [Purchase
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Anti-Interleukin-6 Receptor Antibody Treatment
in Inflammatory Autoimmune Diseases Pp. 193-200
Changhai Ding and Graeme Jones
[Abstract] [Purchase
Issue/Articles]
A Review of the Treatment of Psoriasis with Infliximab
Pp. 201-205
Theodora Vamvouris and Suhail Hadi
[Abstract] [Purchase
Issue/Articles]
The ‘Arimidex’, Tamoxifen, Alone or
in Combination (ATAC) Trial: A Step Forward in the Treatment
of Early Breast Cancer Pp. 207-215
Anthony Howell
[Abstract] [Purchase
Issue/Articles]
Bcl-2-Targeted Antisense Therapy (Oblimersen Sodium):
Towards Clinical Reality Pp. 217-235
João Nuno Moreira, Adriana Santos and
Sérgio Simões
[Abstract] [Purchase
Issue/Articles]
The Emerging Role of Aromatase Inhibitors in the
Adjuvant Management of Breast Cancer Pp. 237-249
Jean-Marc Nabholtz and Joseph Gligorov
[Abstract] [Purchase
Issue/Articles]
Clinical Trials in Children Pp. 251-258
F.J. Morales-Olivas and C. Morales-Carpi
[Abstract] [Purchase
Issue/Articles]
Use of Etanercept in the Treatment of Psoriasis
and Psoriatic Arthritis Pp. 259-263
Brian S. Fuchs and Suhail Hadi
[Abstract] [Purchase
Issue/Articles]
Current Status of Clinical Trials for Glioblastoma
Pp. 265-281
Michael L. Salgaller and Linda M. Liau
[Abstract] [Purchase
Issue/Articles]
Specific Active Immunotherapy of Cancer: Potential
and Perspectives Pp. 283-292
Roopa Srinivasan and Dennis E. Van Epps
[Abstract] [Purchase
Issue/Articles]
Current Management of Extracranial Carotid Artery
Disease Pp. 293-301
Rabih A. Chaer, Brian DeRubertis, Sheela Patel, Stephanie
C. Lin, Craig K. Kent and Peter L. Faries
[Abstract] [Purchase
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Abstracts
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Editorial
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.
References
[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.
Jeffrey M. Weinberg, MD
Director, Clinical Research Center
Department of Dermatology
St. Luke’s-Roosevelt Hospital Center
New York, NY 10025, USA
E-mail: jweinberg3@nyc.rr.com
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Nelarabine- A New Purine Analog in the
Treatment of Hematologic Malignancies
Sophie Curbo and Anna Karlsson
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 T-cell 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.
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Anti-Interleukin-6 Receptor Antibody Treatment
in Inflammatory Autoimmune Diseases
Changhai Ding and Graeme Jones
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 C-reactive 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.
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A Review of the Treatment of Psoriasis with Infliximab
Theodora Vamvouris and Suhail Hadi
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.
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The ‘Arimidex’, Tamoxifen, Alone or
in Combination (ATAC) Trial: A Step Forward in the Treatment
of Early Breast Cancer
Anthony Howell
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.
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Bcl-2-Targeted Antisense Therapy (Oblimersen Sodium):
Towards Clinical Reality
João Nuno Moreira, Adriana Santos and
Sérgio Simões
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.
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The Emerging Role of Aromatase Inhibitors in the
Adjuvant Management of Breast Cancer
Jean-Marc Nabholtz and Joseph Gligorov
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.
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Clinical Trials in Children
F.J. Morales-Olivas and C. Morales-Carpi
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.
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Use of Etanercept in the Treatment of Psoriasis
and Psoriatic Arthritis
Brian S. Fuchs and Suhail Hadi
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.
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Current Status of Clinical Trials for Glioblastoma
Michael L. Salgaller and Linda M. Liau
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.
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Specific Active Immunotherapy of Cancer: Potential
and Perspectives
Roopa Srinivasan and Dennis E. Van Epps
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®,
Rituxan™, Bexxar™) 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.
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Current Management of Extracranial Carotid Artery
Disease
Rabih A. Chaer, Brian DeRubertis, Sheela Patel, Stephanie
C. Lin, Craig K. Kent and Peter L. Faries
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.
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