Synta Pharmaceuticals Announces Presentation of Preliminary Results of Phase 3 SYMMETRY Trial of Elesclomol in Metastatic Melanoma at ASCO 2009
A significant PFS improvement was achieved for patients with normal LDH, a pre-specified exploratory analysis
Mature survival data expected by end of 2009 or early 2010
“There is an enormous unmet need and lack of treatment options for patients with metastatic melanoma. It is disappointing to all of us that the primary endpoint of the SYMMETRY trial, progression free survival (PFS), while showing a trend towards benefit, did not achieve statistical significance in the full patient population, particularly given the positive results from the prior, double-blind, randomized, controlled Phase 2b trial,” said Dr. O’Day. “A statistically significant PFS improvement was achieved, however, in the normal LDH population, which constituted just over 2/3 of total evaluable patients in this trial. The preliminary safety analysis shows that both the combination and control arms were well tolerated with generally comparable adverse event profiles. The imbalance in deaths observed between the two arms to date cannot be explained by organ-specific toxicities attributable to elesclomol. More mature survival data will be needed to understand the safety profile more fully.”
SYMMETRY Primary Endpoint Preliminary Results
Database lock and final analysis for the primary endpoint of the trial,
PFS, are expected in Q3 2009. Preliminary results for PFS, in the full
intent-to-treat (ITT) population, consisting of the 621 patients who
were evaluable by
PFS, ITT population |
Elesclomol + Paclitaxel |
Paclitaxel |
Events | 170 | 192 |
Median (months; 95% C.I.) | 3.4 (2.6 – 3.6) | 1.9 (1.9 - 2.9) |
Hazard ratio (95% C.I., p-value) |
0.84 (0.64 – 1.04), p=0.111 |
These results show a trend towards improvement in PFS, which did not achieve statistical significance (p=0.111; stratified log-rank test).
Patients in the SYMMETRY trial were stratified prospectively for level of LDH (lactate dehydrogenase), a known prognostic factor in melanoma; M-grade (degree of disease metastasis); and prior treatment history. Results of pre-specified exploratory analyses with respect to these variables showed a correlation between activity of elesclomol and level of LDH:
PFS, ITT population, |
Elesclomol + Paclitaxel |
Paclitaxel |
Events | 99 | 124 |
Median (months; 95% C.I.) | 3.7 (3.5 – 5.4) | 2.1 (1.9 – 3.5) |
Hazard ratio (95% C.I., p-value) |
0.72 (0.55 – 0.94), p=0.015 |
PFS, ITT population, |
Elesclomol + Paclitaxel |
Paclitaxel |
Events | 71 | 68 |
Median (months; 95% C.I.) | 1.8 (1.7 – 2.0) | 1.9 (1.8 - 2.5) |
Hazard ratio (95% C.I., p-value) |
1.11 (0.78 – 1.59), p=0.556 |
Medians are calculated using Kaplan-Meier methodology. Cox proportional hazards modeling was used to generate hazard ratios. Normal LDH was defined as less than 1x ULN (the upper limit of normal, 234 U/L); elevated LDH was defined as greater than or equal to 1x ULN and less than 2x ULN. Patients with LDH greater than 2x ULN were excluded from the trial.
“We were disappointed that the primary endpoint in the Phase 3 SYMMETRY
trial was not achieved,” said
“I want to thank the patients, their families, and all the healthcare
professionals around the world who worked so closely with us to conduct
this trial with such a high level of quality, efficiency, and attention
to detail,” said
Additional Preliminary Results
Adverse events of all NCI CTC Grades 1-4 occurring in >10% of patients were, in the ELPAC vs PAC alone arm respectively, alopecia (40% vs 40%), fatigue (39% vs 38%), nausea (31% vs 25%), diarrhea (25% vs 22%) and constipation (18% vs 18%), cough (15% vs 13%), headache (14% vs 14%), asthenia (13% vs 9%), rash (13% vs 11%), peripheral neuropathy (13% vs 12%), vomiting (12% vs 9%), and pyrexia (10% vs 7%).
Moderate to severe adverse events, those of NCI CTC Grade 3-4, were, in the ELPAC vs PAC alone arm respectively, fatigue (3.6% vs <1%), peripheral neuropathy (2% vs 1.3%), alopecia (1.6% vs 1.9%), vomiting (1.3% vs 1.3%), diarrhea (1.3% vs 0%); nausea, headache and asthenia (<1% vs <1%); and constipation, cough, rash and pyrexia (<1% vs 0%).
Overall Survival (OS) data are not yet mature; measures of significance of the relative mortality risk between the two arms are still evolving. No organ specific toxicities have been identified which would explain the imbalance in deaths observed in the interim DMC analysis. Survival data are expected to mature by end of 2009 or early 2010.
Although no patients are currently receiving study treatment, patients are continuing to be followed for assessment of survival.
The complete oral presentation will be available at the
SYMMETRY Trial Design
The SYMMETRY trial 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. The blinded,
randomized, controlled study, conducted at approximately 160 centers in
15 countries. Patients were randomized (1:1) to elesclomol (213 mg/m2)
plus paclitaxel (80 mg/m2) or paclitaxel alone (80 mg/m2)
and receive three weekly treatments and one week without treatment per
each four week cycle. If tolerated, treatment continued until disease
progression. Patients were stratified according to LDH levels, M-grade
status and prior treatment history. Responses were assessed using
standard RECIST criteria at baseline and at a minimum every other cycle,
with radiology scans being assessed by independent, blinded, reviewers
at a central site. The primary endpoint of the study was
progression-free survival; overall survival and tumor response rate were
secondary endpoints. The trial enrolled a total of 651 patients and 621
patients were evaluable as of
About Elesclomol
Elesclomol is a 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 is believed to act 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.
In
About Oxidative Stress
Elesclomol increases the generation of reactive oxygen species (ROS) such as oxygen radicals in cells. These ROS cause signaling leading to an increase in pro-apoptotic factors, a decrease in anti-apoptotic factors, and ultimately to the initiation of programmed cell death via the mitochondrial apoptosis pathway. By elevating ROS and altering the balance of apoptotic signaling factors, elesclomol sensitizes cancer cells to conventional anti-cancer agents that cause cell death through the mitochondrial apoptosis pathway.
Normal, non-cancer cells typically have very low levels of ROS and have a high antioxidant capacity. In contrast, cancer cells generally have much higher levels of ROS and exist in a state of oxidative stress, leaving them vulnerable to any further increases in ROS.
About Metastatic Melanoma
Melanoma, the most deadly form of skin cancer, arises from melanocytes,
the pigment-producing cells of the skin. According to the
About
Safe Harbor Statement
This media release may contain forward-looking statements about
Source:
Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7979
or
Synta
Pharmaceuticals Corp.
Aurora Krause, 781-541-7125