DGAP-News: Press Release: 4SC announces positive interim results from clinical Phase I/II trial with anti-cancer compound resminostat in colorectal cancer
(firmenpresse) - DGAP-News: 4SC AG / Key word(s): Miscellaneous
Press Release: 4SC announces positive interim results from clinical
Phase I/II trial with anti-cancer compound resminostat in colorectal
cancer
12.12.2012 / 07:30
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Press Release
4SC announces positive interim results from clinical Phase I/II trial with
anti-cancer compound resminostat in colorectal cancer
- Resminostat in combination with FOLFIRI chemotherapy clinically
investigated as a potential new therapy option for patients with
advanced colorectal cancer
- Trial objective for Phase I part of SHORE study achieved
- Safety and tolerability of the combined administration of resminostat
and FOLFIRI successfully proven
- Good pharmacokinetic profile of resminostat confirmed in combination
with FOLFIRI
- Initial signs for potential clinical treatment benefit: Combination
therapy administered for up to 33 weeks with observed stabilisation of
tumour disease
- Phase II part of study planned to start soon in 2013
Planegg-Martinsried, Germany, 12 December 2012 - 4SC AG (Frankfurt, Prime
Standard: VSC), a discovery and development company of targeted small
molecule drugs for autoimmune diseases and cancer, today published positive
interim results on safety, tolerability and pharmacokinetics from its
clinical Phase I/II SHORE study with the anti-cancer compound resminostat
in combination treatment with FOLFIRI chemotherapy in patients with
advanced colorectal cancer (CRC). The results successfully prove the safety
and tolerability of the combined administration of resminostat and FOLFIRI.
This marks the achievement of the goal for the first part of the study
(Phase I) and lays the foundations for commencing the study's Phase II
part, which will assess the clinical efficacy of the
resminostat-FOLFIRI-combination in advanced CRC patients. Furthermore, the
Phase I part of the study has already provided some initial encouraging
data concerning the possible clinical benefit of this new therapeutic
approach in this difficult-to-treat patient population. These data showed
that for some patients it was possible to administer the combination
therapy over a comparatively long period of time - to a maximum of 33 weeks
- while observing a stabilisation of the tumour disease.
In the randomised, multi-centre, two-arm Phase II part of the SHORE study,
planned to start soon in 2013, the combination therapy of resminostat with
the FOLFIRI treatment regime will be assessed against sole treatment with
FOLFIRI as a second-line treatment option for patients with advanced,
KRAS-mutant colorectal cancer (CRC). For this patient group, which
constitutes around 40% of all patients with advanced CRC, there is a high
medical need for new, additional therapy options.
In general, first-line therapy for advanced CRC patients consists of
chemotherapy (FOLFOX or FOLFIRI) in combination with the drug Avastin(R).
If, after a while, this therapy is no longer effective or tolerated - due
to the development of resistance or the occurrence of side effects, for
example - patients are switched over to second-line therapy. In
second-line, patients without a KRAS mutation have access to treatments
aiming at the inhibition of epidermal growth factor receptor (EGFR) such as
Erbitux(R) as a supplement to a further chemotherapy (FOLFIRI or FOLFOX).
However, CRC patients with a KRAS mutation in the EGFR pathway of their
tumours, generally do not benefit from anti-EGFR therapy and, therefore,
receive a chemotherapy such as FOLFIRI alone as second-line therapy. Thus,
for this KRAS-mutant CRC patient group there is a high medical need for
new, supplementary therapy options which may be safely combined as
second-line treatment with chemotherapy such as FOLFIRI to increase the
latter's effectiveness - such as potentially resminostat.
Results from the Phase I part of the SHORE study
In the Phase I part of the SHORE study, a dose escalation for a total of 15
CRC patients to date was carried out to assess the safety and tolerability
of a range of doses for resminostat up to 600 mg daily in combination with
FOLFIRI, a multi-component chemotherapy regime that includes e.g.
5-fluorouracil (5-FU) and irinotecan, so as to determine the best possible
dose for resminostat in combination with FOLFIRI. Pharmacokinetic
parameters for resminostat and for the FOLFIRI components were also
evaluated.
Resminostat proved to be generally safe and well-tolerated in all doses
tested up to a daily single dosage of 600 mg in combination with the
recommended standard dose from the FOLFIRI regime. Accordingly, as regards
combination therapy with FOLFIRI, the data confirmed the daily dosage of
600 mg already determined in earlier monotherapy and combination therapy
studies with resminostat. Observed side effects were generally mild to
moderate and occurred, as expected, primarily as gastrointestinal and
haematological effects. FOLFIRI's known side-effect profile did not change
as a result of the additional administration of resminostat. Furthermore,
the study confirmed the compound's favourable pharmacokinetic profile which
is, inter alia, reflected in the dose proportionality of resminostat blood
levels - as already observed in other studies with resminostat. No
pharmacological interactions were observed between resminostat and the
FOLFIRI components. The dosage of 600 mg for resminostat in combination
with FOLFIRI is already being considered as a potential therapeutic dose
for the Phase II part of the SHORE study.
In some patients in the Phase I part, it was possible to administer the
combination therapy for several months (to a maximum of 33 weeks) while
observing stabilisation of the tumour disease. This substantiates the
overall good tolerability and may also be considered as an initial
indicator for the clinical benefit of this new therapeutic approach.
To allow for further expansion of the range of treatment options within
this combination approach, a final, further dosage variant constituting the
twice-daily administration of resminostat is currently under evaluation.
This involves the clinical examination of a total daily dose of 800 mg of
resminostat, taken as two doses of 400 mg in the morning and evening.
The medical-scientific rationale of the combination therapy of the
epigenetically-active HDAC inhibitor resminostat - which can exert a
substantial influence on key gene expressions - with traditional
chemotherapy such as FOLFIRI, has been established on the basis of
preclinical trials. In these studies, resminostat combined with irinotecan,
a component of the FOLFIRI regime, inhibited tumour growth more effectively
than either substance when used as a monotherapy. It was also shown that
resminostat - due to its gene regulatory properties - decreases the
expression of the enzyme thymidylate synthase. This enzyme triggers
resistance mechanisms that target the compound 5-FU, which is an integral
part of FOLFIRI. Accordingly, resminostat may work to sensitise tumour
cells for treatment regimes containing 5-FU, such as FOLFIRI, as
resminostat can be used to combat resistances that tumours have developed
against 5-FU.
Dr Ulrich Dauer, Chief Executive Officer of 4SC, commented: 'We are pleased
that the good safety and tolerability profile shown by resminostat in
multiple Phase I and II studies has up to now also been confirmed incombination therapy with the FOLFIRI chemotherapy, and that we have already
been able to treat some patients with advanced CRC over a period of several
months with this new approach. We are particularly encouraged by the
disease stabilization observed in individual patients. From our
perspective, this constitutes a promising new therapeutic option for
potential use in combination with FOLFIRI whose clinical efficacy we will
now continue to evaluate next year in the randomised Phase II part of the
SHORE study. K-RAS mutant patients, who account for 40% of all CRC
patients, might particularly benefit from this additional therapeutic
option since they have no access to EGFR-based therapies such as Erbitux(R)
as a supplementary treatment to chemotherapeutics such as FOLFIRI in
second-line CRC therapy.'
Ends
About the design of the SHORE study
SHORE is a randomised, open-label, multi-centre, two-arm Phase I/II study
in approximately 70 patients that will evaluate the efficacy, safety and
pharmacokinetics of resminostat, in combination with FOLFIRI, a
chemotherapy regimen for the treatment of colorectal cancer, versus FOLFIRI
alone in the control arm. In the combination arm of the study patients will
be treated with the maximum tolerated dose of resminostat in combination
with FOLFIRI, which will be determined through an initial dose-escalation
phase (Phase I part), evaluating 200mg, 400mg, 600mg and 800mg of
reminostat together with FOLFIRI. In the combination arm resminostat will
be given orally over five consecutive days (days 1-5), followed by a nine
day (days 6-14) treatment free period resulting in treatment cycles of 14
days (5+9 scheme) each. FOLFIRI will be given on day three and four (days 3
and 4) of each of these 14 day treatment cycles. In both study arms,
treatment may continue until there is evidence of progressive disease or
the patient leaves the trial for other reasons. The study will be performed
at several centres in Germany.
The primary endpoint of the second part of the study (Phase II) is to
determine the progression free survival (PFS). The secondary endpoints
include progression free survival rate (PFSR) after eight weeks and every
eight weeks thereafter, the analysis of time-to-progression (TTP), overall
survival (OS), analysis of drug safety, tolerability, pharmacokinetics and
the investigation of biomarkers.
About colorectal cancer (CRC)
Colorectal cancer (CRC) is one of the most frequently diagnosed malignant
tumours of the digestive system. In Western countries, the number of cases
is steadily increasing and colorectal cancer is already the second leading
cause of death from cancers. Less than 7% of patients suffering from
advanced, metastasized colorectal cancer survive the first five years
following diagnosis of the disease.
The treatment of advanced colorectal cancer is usually based on
chemotherapy regimens, such as FOLFIRI and FOLFOX, in combination with
antibodies such as bevacizumab (Avastin(R)), cetuximab (Erbitux(R)) or
panitumumab (Vectibix(R)). These antibodies inhibit various growth factors
or receptors that are involved in the progress of the cancer disease.
Currently, these approaches focus on targeting the vascular endothelial
growth factor (VEGF), an angiogenic signalling protein, or on inhibiting
the epidermal growth factor receptor (EGFR). However, tumours can develop
tolerances to these drugs in the form of defence mechanisms that then
neutralise the efficacy of the medication. Such tolerances can be combated
effectively by utilising resminostat as part of combination therapy.
Resminostat's epigenetic mechanism enables it to re-sensitise tumours, thus
ensuring they remain treatable by other drugs.
Furthermore, for CRC patients with K-ras mutated tumours in particular,
there is a specific unmet medical need since therapy options that target
EGFR - such as cetuximab - cannot be utilised for such patients. As a
result, there is substantial medical and commercial potential for an
innovative therapeutic approach such as resminostat, even as a second-line
treatment option, e.g. in combination treatment with FOLFIRI. This patient
group accounts for approximately 40% of all metastatic colorectal cancer
patients.
About Resminostat
Resminostat (4SC-201), 4SC's lead oncology compound, is an oral
pan-histone-deacetylase (HDAC) inhibitor with an innovative epigenetic
mechanism of action that potentially enables the compound to be deployed as
a novel, targeted tumour therapy for a broad spectrum of oncological
indications, both as a monotherapy and, in particular, in combination with
other cancer drugs. HDAC inhibitors have been shown to modify the chromatin
structure, which is the three-dimensional array of the genetic information
DNA, () in tumour cells. This may cause a cell differentiation and
eventually lead to the programmed cell death (apoptosis) of tumour cells.
Therefore HDAC inhibitors are considered to offer a mechanism of action
that has the particular potential to halt tumour progression and induce
tumour regression. Additionally, resminostat is also assumed to induce what
is known as tumour cell sensitisation to other anti-cancer compounds. This
process can suppress or reverse certain tolerance and resistance mechanisms
which tumour cells often develop against other cancer drugs. Supplementary
treatment with resminostat can be expected to restore or significantly
improve the efficacy of a previously administered cancer therapy which was
no longer effective; furthermore, combining resminostat and common cancer
drugs right from the very beginning can also be expected to effectively
enhance the success of such a treatment.
Resminostat is currently being investigated in a broad clinical Phase II
programme in the three indications liver cancer (hepatocellular carcinoma,
HCC), Hodgkin's Lymphoma (HL), and colorectal cancer (CRC). In the Phase II
SAPHIRE trial in patients with advanced Hodgkin's Lymphoma, resminostat in
monotherapy has demonstrated substantial anti-tumour activity, with an
overall response rate of 35.3% and a clinical benefit in 55.9% of the
patients in a heavily pre-treated patient population together with very
good safety and tolerability. In the Phase I/II SHORE study, which
evaluates resminostat in combination with the chemotherapeutic FOLFIRI
regimen as a second-line treatment of KRAS-mutant CRC patients, initial
results are expected in 2012. Furthermore, in the Phase II SHELTER study
resminostat is being evaluated as monotherapy and in combination with
sorafenib as a second-line treatment in advanced HCC after proven
radiological disease progression under first-line sorafenib therapy.
Patients receiving the resminostat/sorafenib combination therapy showed a
median overall survival of 8.0 months (as reported at the annual meeting of
the International Liver Cancer Association (ILCA) on 16 September 2012). As
presented at the ASCO annual meeting on 4 June 2012, the
resminostat/sorafenib combination therapy had shown a progression-free
survival rate (PFSR) after 12 weeks of 70.0% and a median PFS of 4.7
months. The primary study endpoint has been achieved ahead of schedule in
both the combination and the monotherapy group.
4SC is currently in discussions with regulatory agencies and potential
partners in order to prepare a pivotal clinical study programme for
resminostat in combination with sorafenib as a second-line treatment for
patients with advanced HCC who show tumour progression on first-line
treatment with sorafenib.
About 4SC
The Group managed by 4SC AG (ISIN DE0005753818) discovers and develops
targeted, small-molecule drugs for treating diseases with high unmet
medical needs in various autoimmune and cancer indications. These drugs are
intended to provide innovative treatment options that are more tolerable
and efficacious than existing therapies, and provide a better quality of
life. The Company's balanced pipeline comprises promising products that are
in various stages of clinical development. 4SC's aim is to generate future
growth and enhance its enterprise value by entering into partnerships with
leading pharmaceutical companies. Founded in 1997, 4SC had90 employees at
30 September 2012. 4SC AG has been listed on the Prime Standard of the
Frankfurt Stock Exchange since December 2005.
Legal Note
This document may contain projections or estimates relating to plans and
objectives relating to our future operations, products, or services; future
financial results; or assumptions underlying or relating to any such
statements; each of which constitutes a forward-looking statement subject
to risks and uncertainties, many of which are beyond our control. Actual
results could differ materially, depending on a number of factors.
For more information please visit www.4sc.com or contact:
4SC AG
Jochen Orlowski, Corporate Communications&Investor Relations
jochen.orlowski(at)4sc.com, Tel.: +49-89-7007-6366
MC Services
Mareike Mohr, Raimund Gabriel
mareike.mohr(at)mc-services.eu, Tel.: +49-89-2102-2840
raimund.gabriel(at)mc-services.eu, Tel.: +49-89-2102-2830
The Trout Group
Chad Rubin
Crubin(at)troutgroup.com, Tel.: +1 646-378-2947
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Language: English
Company: 4SC AG
Am Klopferspitz 19a
82152 Martinsried
Germany
Phone: +49 (0)89 7007 63-0
Fax: +49 (0)89 7007 63-29
E-mail: public(at)4sc.com
Internet: www.4sc.de
ISIN: DE0005753818
WKN: 575381
Listed: Regulierter Markt in Frankfurt (Prime Standard);
Freiverkehr in Berlin, Düsseldorf, München, Stuttgart
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