80+ Month Overall Survival (HR = 0.63, Pvalue =
0.02) Discussed in the 285 Patient Sub-group Treated with
ThermoDox® plus Standardized Radiofrequency Ablation (sRFA)
Celsion Corporation (NASDAQ:CLSN) today announced publication of
the manuscript, “Phase III HEAT Study Adding Lyso-Thermosensitive
Liposomal Doxorubicin to Radiofrequency Ablation in Patients with
Unresectable Hepatocellular Carcinoma Lesions,” in Clinical Cancer
Research, a high impact, peer-reviewed medical journal. The article
reports on one of the largest controlled studies in hepatocellular
carcinoma (HCC). It provides a comprehensive review of
ThermoDox®, Celsion’s proprietary heat-activated liposomal
encapsulation of doxorubicin, for the treatment of primary liver
cancer, also known as hepatocellular carcinoma or HCC. The article
details learnings from the Company’s 701 patient HEAT Study and
includes results from computer simulation studies and includes
interesting findings from a post hoc subgroup analysis, all of
which are consistent with each other and which -- when examined
together -- suggest a clearer understanding of a key ThermoDox®
heat-based mechanism of action: the longer the target tissue is
heated, the greater the doxorubicin tissue concentration.
Additionally, the article explores a new hypothesis prompted by
these findings: ThermoDox, when used in combination with
Radiofrequency Ablation (RFA) standardized to a minimum dwell time
of 45 minutes (sRFA ≥ 45 min), may increase the overall survival
(OS) of patients with HCC. The lead author is Won Young Tak, M.D.,
Ph.D., Professor Internal Medicine, Gastroenterology &
Hepatology, Kyungpook National University Hospital Daegu, Republic
of Korea, and there are 22 HEAT Study co-authors along with
Nicholas Borys, M.D., Celsion’s senior vice president and chief
medical officer. The article is available online in the October
2017 issue of the journal, Clinical Cancer Research, at
http://clincancerres.aacrjournals.org/content/early/2017/10/10/1078-0432.CCR-16-2433.long.
To test and confirm the HEAT Study post hoc
subgroup analysis, Celsion is conducting the Phase III OPTIMA
Study, a global, pivotal, double-blind, placebo-controlled clinical
trial (Clinical Trials.gov NCT021126560). Developed in consultation
with leading primary liver cancer researchers, and statistical and
regulatory experts, and based on extensive analysis of prior
clinical and preclinical studies of ThermoDox® plus standardized
RFA, the OPTIMA Study is evaluating ThermoDox in combination with
RFA standardized to a minimum of 45 minutes across all
investigators and sites for treating lesions 3 to 7 centimeters,
versus standardized RFA alone.
Global interest in ThermoDox as a potential
treatment option for HCC was recently showcased in the Company
sponsored R&D Day held in New York City on October 12, 2017.
Lead OPTIMA Study clinical investigators representing various
geographical regions (Asia-Pacific and Europe) and multiple medical
disciplines (hepatology, interventional radiology and surgery)
presented their past and current experiences with ThermoDox for the
treatment of primary liver cancer. The final OS analysis
demonstrated that in a large, well bounded, subgroup of patients
(n=285 patients, 41% of the previous 701 patient HEAT Study),
treatment with a combination of ThermoDox and standardized RFA
provided an average 58% improvement in OS compared to standardized
RFA alone. The Hazard Ratio (HR) is 0.63 (95% CI 0.43 - 0.93) with
a p-value of 0.0198. In this large subgroup, median OS for
the ThermoDox plus standardized RFA group translates into a 25.4
month (more than 2.1 years) survival benefit over the standardized
RFA only group – totaling approximately 80 months (6-1/2 years,
which is considered a curative treatment for HCC) for the
ThermoDox® plus standardized RFA group versus 53 months for the
standardized RFA only group.
"There is clear evidence that the duration of
the RFA regimen is critical when treating patients with ThermoDox®,
and the totality of the data presented in the newly published
article in the peer reviewed journal, Clinical Cancer Research,
demonstrate that ThermoDox® plus standardized RFA has a strong
potential to serve as a curative therapy for patients with liver
cancer," said Professor Won Young Tak, M.D., Ph.D., lead
investigator in South Korea for the Company's HEAT and OPTIMA
studies. "The OPTIMA Study is designed to validate this approach in
an indication where there exists a strong unmet need for effective
treatment options."
In August 2017, the OPTIMA Study’s Independent
Data Monitoring Committee (IDMC), comprised of medical and
scientific experts who are responsible for reviewing and evaluating
patient safety and efficacy data, completed a planned interim
analysis of the first 50% of patients randomized in the trial as of
April 2017 and unanimously recommended that the OPTIMA Study
continue as planned based on the risk to benefit analysis by the
Committee. The OPTIMA Study to date has accumulated data within
acceptable safety parameters. The Company announced that enrollment
in the OPTIMA Study is approaching 70% of the 550 patients
necessary to ensure that its primary end point, overall survival,
can be evaluated with statistical significance. The statistical
plan for the OPTIMA Study calls for two interim efficacy analyses
by the IDMC. The Company currently projects full patient enrollment
by mid-2018 and the first pre-planned efficacy analysis after 118
overall survival events by the first quarter of 2019.
“There is an urgent need for new and better
treatment options for HCC, the third leading cause of cancer in the
world. We believe strongly that ThermoDox® may be an important new
approach for the treatment of HCC. We are now fully committed
to the OPTIMA Study and to learning more about how this combination
therapy of standardized RFA plus ThermoDox® may significantly
prolong the survival of, if not cure, patients suffering from this
extremely deadly cancer,” stated Michael H. Tardugno,
Celsion's chairman, president and chief executive officer, in
response to the article’s publication. “Supported with an
independent endorsement by the National Institutes of Health, the
OPTIMA Study and ThermoDox® may prove to be the most important
oncology research in a generation,” Mr. Tardugno added.
On November 29, 2016, the Company announced
results from an independent retrospective analysis conducted by the
National Institutes of Health on the intent-to-treat population of
the 701 patient HEAT Study of ThermoDox® plus optimized RFA for the
treatment of primary liver cancer. The NIH analysis, which
sought to evaluate the correlation between RFA burn time per tumor
volume (min/ml) and clinical outcome, concluded that increased RFA
“burn time” per tumor volume significantly improved overall
survival (OS) in patients with solitary lesions treated with RFA +
ThermoDox® compared to patients treated with RFA alone. The
NIH analysis included 437 patients with a single lesion from the
Company’s HEAT Study, the same patient population being treated in
the Company’s ongoing Phase III OPTIMA study. The NIH findings are
consistent with Celsion’s own analysis of the HEAT Study data,
which demonstrated that over a 3.5 year period, there was a
statistically significant survival benefit consistent with the HEAT
Study in patients treated with ThermoDox® plus optimized RFA over
the optimized RFA only group.
“We are highly focused on successfully executing
the ongoing OPTIMA study,” stated Nicholas Borys, Celsion’s chief
medical officer. “With independent confirmation by the NIH of the
relationship between RFA heating time and the significant impact
that it has on overall survival when combined with ThermoDox®,
OPTIMA Study investigators fully recognize the value of the
findings from the HEAT Study, reinforcing their interest and
support for our highly de-risked, ongoing global Phase III OPTIMA
Study, and to accomplishing our chief goal, the delivery of
ThermoDox® as a novel, first-line treatment to HCC patients
worldwide.”
About the OPTIMA Study
The Phase III OPTIMA Study is expected to enroll
up to 550 patients in up to 70 clinical sites in the United States,
Europe, China and Asia Pacific, and will evaluate ThermoDox® in
combination with optimized RFA, which will be standardized to a
minimum of 45 minutes across all investigators and clinical sites
for treating lesions three to seven centimeters, versus optimized
RFA alone. The primary endpoint for the trial is Overall Survival,
which is supported by post-hoc analysis of data from the Company's
701 patient HEAT Study, where optimized RFA has demonstrated the
potential to significantly improve survival when combined with
ThermoDox®. The statistical plan calls for two interim efficacy
analyses by an independent Data Monitoring Committee.
ThermoDox® has received U.S. FDA Fast Track
Designation and has been granted orphan drug designation for
primary liver cancer in both the U.S. and Europe. Further, the U.S.
FDA has provided ThermoDox® with a 505(b)(2) registration
pathway. Subject to a successful trial, the OPTIMA Study has
been designed to support registration in all key primary liver
cancer markets. Celsion fully expects to submit registrational
applications in the USA, Europe and China. The Company believes
that applications will be accepted in South Korea, Taiwan and
Vietnam, three other large and important markets for ThermoDox®
subject to approval in Europe, China or the USA.
About ThermoDox®
Celsion’s most advanced program is a
heat-mediated, tumor-targeting drug delivery technology that
employs a novel heat-sensitive liposome engineered to address a
range of difficult-to-treat cancers. The first application of this
platform is ThermoDox®, a lyso-thermosensitive liposomal
doxorubicin (LTLD), whose novel mechanism of action delivers high
concentrations of doxorubicin to a region targeted with the
application of localized heat at 40°C, just above body temperature.
In one of its most advanced applications, ThermoDox®, when combined
with radiofrequency thermal ablation (RFA), has the potential to
address a range of cancers. For example, RFA in combination with
ThermoDox® has been shown to expand the “treatment zone” with a
margin of highly concentrated chemotherapy when treating individual
primary liver cancer lesions. The goal of this application is to
significantly improve efficacy.
Celsion’s LTLD technology leverages two
mechanisms of tumor biology to deliver higher concentrations of
drug directly to the tumor site. The first: Rapidly growing
tumors have leaky vasculature, which is permeable to liposomes and
enables their accumulation within tumors. Leaky vasculature
influences a number of factors within the tumor, including the
access of therapeutic agents to tumor cells. Administered
intravenously, LTLD is engineered to allow significant accumulation
of liposomes at the tumor site at the time of radiofrequency
ablation as these liposomes recirculate in the blood stream.
The second: When the tumor tissue is heated to a temperature of
40°C or greater, the heat-sensitive liposome rapidly changes
structure and the liposomal membrane selectively dissolves,
creating openings that release the chemotherapeutic agent directly
into the tumor and into the surrounding vasculature. Drug
concentration increases as a function of the accumulation of
liposomes at the tumor site, but only where the heat is present.
This method targets only the tumor and the area related to tumor
invasion, supporting precise drug targeting.
About Celsion
Corporation
Celsion is a fully-integrated oncology company
focused on developing a portfolio of innovative cancer treatments,
including directed chemotherapies, immunotherapies and RNA- or
DNA-based therapies. The Company's lead program is ThermoDox®, a
proprietary heat-activated liposomal encapsulation of doxorubicin,
currently in Phase III development for the treatment of primary
liver cancer and in Phase II development for the treatment of
recurrent chest wall breast cancer. The pipeline also
includes GEN-1, a DNA-based immunotherapy for the localized
treatment of ovarian and brain cancers. Celsion has two
platform technologies for the development of novel nucleic
acid-based immunotherapies and other anti-cancer DNA or RNA
therapies. For more information on Celsion, visit our
website: http://www.celsion.com. (CLSN-LTSL/ThermoDox® CLSN-Optima
Study/HCC)
Celsion wishes to inform readers that
forward-looking statements in this release are made pursuant to the
"safe harbor" provisions of the Private Securities Litigation
Reform Act of 1995. Readers are cautioned that such
forward-looking statements involve risks and uncertainties
including, without limitation, unforeseen changes in the course of
research and development activities and in clinical trials; the
uncertainties of and difficulties in analyzing interim clinical
data, particularly in small subgroups that are not statistically
significant; FDA and regulatory uncertainties and risks; the
significant expense, time, and risk of failure of conducting
clinical trials; the need for Celsion to evaluate its future
development plans; possible acquisitions or licenses of other
technologies, assets or businesses; possible actions by customers,
suppliers, competitors, regulatory authorities; and other risks
detailed from time to time in the Celsion's periodic reports and
prospectuses filed with the Securities and Exchange
Commission. Celsion assumes no obligation to update or
supplement forward-looking statements that become untrue because of
subsequent events, new information or otherwise.
Celsion Investor Contact
Jeffrey W. Church Sr. Vice President and CFO 609-482-2455
jchurch@celsion.com
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