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Program Overview
About Elesclomol
Elesclomol is a novel, injectable, drug candidate that kills cancer
cells by elevating oxidative stress levels beyond a breaking point, triggering
programmed cell death. In preclinical models elesclomol showed killing of a
broad range of cancer cell types at high doses, and an ability to enhance the
efficacy of certain chemotherapy agents, with minimal additional toxicity, at
moderate doses. In a recent 21-center, double-blind, randomized, controlled
Phase 2b clinical trial in 81 patients with metastatic melanoma, elesclomol in
combination with paclitaxel met the primary endpoint – doubling the median time
patients survived without their disease progressing – compared to paclitaxel
alone (p= 0.035). Elesclomol is currently enrolling patients in the SYMMETRY
trial - a 630-patient, pivotal, confirmatory Phase 3 clinical trial in
metastatic melanoma, which has the same design as the Phase 2b trial. Results
are expected in early 2009. Phase 2 trials in other indications, and in
combination with other agents, are planned.
Elesclomol Mechanism of Action
Elesclomol acts through a novel mechanism of action with broad and exciting
potential as a new category of anti-cancer therapy. In a series of in vitro
and in vivo experiments, elesclomol has been shown to rapidly cause an
increase in oxidative stress – the level of reactive oxygen species (ROS) –
inside cancer cells. This increase in ROS is observed through measuring
levels of individual reactive oxygen species, such as hydrogen peroxide,
directly; or through measuring the increased expression of genes that are
induced by the presence of high levels of ROS, including stress proteins such
as heat shock protein 70 (Hsp70).
The prolonged elevation of ROS inside cancer cells induced by elesclomol causes
the cell to exceed a critical breaking point and undergo programmed cell death,
or apoptosis. The triggering of the mitochondrial apoptosis pathway is observed
within the first six hours of applying elesclomol, as shown below:
Cancer cells operate at a much higher intrinsic level of ROS than normal cells,
and have a greatly reduced anti-oxidant capacity compared to normal cells. This
leaves them more vulnerable to an agent such as elesclomol that elevates
oxidative stress. In similar experiments at similar doses, elesclomol has been
found to have little to no impact on normal cells.
This mechanism therefore represents a novel anti-cancer strategy – a novel way
of differentiating, and selectively killing, cancer cells vs. normal cells. It
is this differentiation that we believe has led to the high therapeutic index -
strong anti-tumor activity with favorable safety profile - seen in our
preclinical models.
The potent anti-tumor activity and high therapeutic index are promising
indicators of the exciting potential for this mechanism category in
treating a broad range of cancer types.
About Melanoma
Melanoma, the most deadly form of skin cancer, arises from melanocytes, the
pigment producing cells of the skin. According to the American Cancer Society,
the incidence of melanoma in the United States was 62,000 in 2006, and was the
cause of 8,000 deaths. While melanoma accounts for approximately five percent
of all skin cancers, it causes about 75% of all skin cancer-related deaths. If
diagnosed and surgically removed while localized in the outermost skin layer,
melanoma is potentially curable; however, for patients with deeper lesions or
metastatic disease, the prognosis is poor, with limited available treatments
and an expected survival of only six to nine months. The incidence of melanoma
has increased more rapidly than any other cancer during the past ten years.
According to a Datamonitor report, despite R&D efforts to improve disease
prognosis, little progress has been made over the past three decades. Due to
melanoma’s cutaneous location and its high metastatic potential, the management
of melanoma remains a major clinical challenge. Stage IV patients are burdened
with a very poor prognosis, with five-year survival rates of between 6.7% and
18.8%, depending on the site of metastasis.
A recent Datamonitor report also stated that current treatment for advanced
stage melanoma yields response rates of approximately 20% or less, indicating
that the disease is poorly served by currently available therapy. In addition,
most of the drugs administered to patients are associated with a high degree of
toxicity, in many cases reducing patient quality of life. The study quotes a
key opinion leader, who states that "Both for stage III and IV patients, the
lack of effective therapy that is able to control the progression of metastatic
disease [and] that offers some sort of symptom benefit for patients is arguably
the greatest unmet need. We do not have a therapy that alters the natural
history of melanoma and improves overall survival for patients".
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Visit The Billy
Foundation
to view statistics on melanoma.
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For more information, visit the
melanoma section of the Cancer Institute’s website.
Presentations
References
Oxidative Stress and Cancer
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B Ramanathan et al: Resistance to Paclitaxel is Proportional to Cellular
Total Antioxidant Capacity, Cancer Research 65: (18), September 2005,
8455-8460.
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Fruehauf, JP, Meyskens, FL: Reactive Oxygen Species: A Breath of Life or Death?
Clinical Cancer Research; 13(3) February 2007, 789-794.
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Gastpar, R., Gehrmann, M., et.al.: Heat shock protein 70 surface-positive tumor
exosomes stimulate migratory and cytolytic activity of natural killer cells.
Cancer Res, 2005; 65 (12).
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Massa, C., et.al.: Enhanced efficacy of tumor cell vaccines transfected with
secretable hsp70. Cancer Res, 2004; 64:1502-1508.
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Noessner, E., et.al.: Tumor-derived heat shock protein 70 peptide complexes are
cross-presented by human dendritic cells. J of Immunology, 2002; 169:5424-5432.
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Pelicano, H et al: ROS stress in cancer cells and therapeutic implications,
Drug Resistance Updates 7 (2004) 97-110.
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Schmitt, E., et.al.: Intracellular and extracellular functions of heat shock
proteins: repercussions in cancer therapy. J of Leukocyte Biology, 2007; Vol 81
(published as DOI 10.1189/jlb.0306167, Aug 2006).
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Schumacker, PT: Reactive oxygen species in cancer cells: Live by the sword, die
by the sword, Cancer Cell, September 2006, 175-176.
Melanoma – Review Articles
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Balch, CM et al, Final Version of the American Joint Committee on Cancer
Staging System for Cutaneous Melanoma, Journal of Clinical Oncology, Vol. 19,
No. 16, 2001, 3635-3648.
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Korn E, et al: Meta-Analysis of Phase II Cooperative Group Trials in Metastatic
Stage IV Melanoma to Determine Progression-Free and Overall Survival Benchmarks
for Future Phase II Trials. J Clin Oncol 2008; 26(4):527-534.
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NCCN, Melanoma Guidelines V. III, September 2005.
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Tarhini, A., Agarwala, S.: Cutaneous melanoma; available therapy for metastatic
disease. Dermatologic therapy, 2006; 19: 19-25.
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Thompson, JF et al,: Cutaneous Melanoma, The Lancet, 2005, Vol 365, 687-701.
Melanoma – Historical Clinical Trials
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Click here for
references on historical clinical trials.
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