"We are tremendously grateful to the hundreds of patients who have
elected to participate in the SYMMETRY trial as well as the physicians
and other healthcare professionals at over 150 sites in 15 countries who
have been and continue to be so critical to the successful completion of
this pivotal trial," said Dr.
“Today’s milestone represents a terrific achievement on the part of the
full SYMMETRY team – the Synta employees, physicians, nurses, healthcare
professionals and our partners around the world who came together to
enroll one of the largest pivotal trials for a new agent in this disease
so rapidly and effectively,” said Dr.
Elesclomol is being developed under a global collaboration agreement
Elesclomol is an investigational first-in-class oxidative stress inducer that triggers apoptosis (programmed cell death) in cancer cells. Cancer cells operate at high levels of reactive oxygen species, or oxidative stress. Elesclomol acts by increasing the level of oxidative stress in cancer cells even further, beyond sustainable levels, inducing apoptosis. This mechanism of action, called oxidative stress induction, represents a novel way of selectively targeting and killing cancer cells.
In a double-blind, randomized, controlled Phase 2b clinical trial in 81 patients with stage IV 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). The most common adverse events in the elesclomol plus paclitaxel group included fatigue, alopecia, constipation, nausea, hypoaesthesia, arthralgia, insomnia, diarrhea, and anemia.
A pivotal Phase 3 clinical trial of elesclomol in combination with paclitaxel in patients with stage IV metastatic melanoma (the SYMMETRY trial) has completed enrollment; a Phase 1/2 trial in hormone-refractory prostate cancer, in combination with docetaxel, is ongoing. Phase 2 trials in other indications, and in combination with other agents, are planned.
About the SYMMETRY Trial
The SYMMETRY trial, a double-blind, randomized, controlled study conducted at approximately 150 centers worldwide, has enrolled patients with stage IV metastatic melanoma who had not received prior chemotherapy but who may have already been treated with non-chemotherapeutic agents such as biologics. Patients have been randomized (1:1) to elesclomol (213 mg/m2) plus paclitaxel (80 mg/m2) or paclitaxel alone (80 mg/m2) and receive three weekly treatments followed by one week without treatment per each four week cycle. If tolerated, treatment continues until disease progression. The primary endpoint of the study is progression-free survival; overall survival and response rate are secondary endpoints. Progression and response are based on standard RECIST criteria, with scans assessed at a minimum of every eight weeks and independently reviewed at a central site.
The control arm treatment, the combination arm treatment, the doses, the schedule, and the primary endpoint are the same as in the prior Phase 2b trial. The SYMMETRY trial increases the total patient size from the prior trial and includes central review of radiology scans, stratification to ensure balance between treatment arms, and a no-crossover design for facilitating the assessment of overall survival.
The Phase 3 SYMMETRY trial completed the Special Protocol Assessment
process with the
Elesclomol has received Fast Track and Orphan Drug designation from the
Synta and GSK are working closely together to further the clinical development of elesclomol as well as prepare for the manufacture and commercial launch of elesclomol.
About Metastatic Melanoma
Melanoma, the most deadly form of skin cancer, arises from melanocytes,
the pigment producing cells of the skin.
About Oxidative Stress
Oxidative stress in cells is the presence of elevated levels of reactive oxygen species (ROS) such as oxygen radicals and hydrogen peroxide. ROS can be generated by many processes and stimuli, including ordinary cell metabolism, exposure to heat or radiation, or attack by bacteria or viruses. Because ROS can react chemically with different proteins and other elements of a cell, altering their normal function, prolonged exposure to elevated levels of ROS can cause serious damage to a cell. To protect against this damage, cells have natural defense mechanisms – anti-oxidant abilities – to clear excessive levels of ROS and to repair the disruption they cause.
Normal, non-cancer cells typically function at a low, steady-state level of oxidative stress. Their strong anti-oxidant capacity guards against prolonged, excessive levels of ROS. Cancer cells, however, typically operate at a much higher level of oxidative stress than normal cells, and have a greatly diminished anti-oxidant capacity. This diminished capacity to clear ROS leaves them vulnerable to further increases in oxidative stress. In particular, when ROS levels exceed a natural breaking point, continued survival of the cell becomes unsustainable. At levels of ROS above this breaking point, a switch inside the mitochondria is triggered that causes the cell to initiate programmed cell death, also known as apoptosis.
By elevating ROS, an oxidative stress inducer such as elesclomol exploits this difference between cancer cells and normal cells. Elesclomol has been observed to have little to no effect in vitro on most normal cells. In contrast, elesclomol has been observed to potently induce apoptosis in cancer cells. In preclinical models elesclomol showed potent anti-cancer activity against a broad range of cancer cell types, as well as an ability to enhance the efficacy of certain chemotherapy agents with minimal additional toxicity.
Oxidative stress induction represents a novel approach to treating cancer. It is distinct from chemotherapy, from "targeted" agents such as kinase inhibitors and antibodies, and from angiogenesis inhibitors in that OS inducers exploit a fundamentally different vulnerability of cancer cells – the elevated levels of reactive oxygen species.
For more on oxidative stress and cancer see for example J. Fruehauf et
Safe Harbor Statement
This media release may contain forward-looking statements about
Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125
MacDougall Biomedical Communications
Doug MacDougall, 781-235-3060