Investigational Anti-Cancer Drug Phenoxodiol Produces Response and Restores Chemo-Sensitivity In Four Studies
March 31 2004 - 9:00AM
PR Newswire (US)
Investigational Anti-Cancer Drug Phenoxodiol Produces Response and
Restores Chemo-Sensitivity In Four Studies Late-breaking Phase 2
Prostate Cancer Study Data Included at AACR ORLANDO, Fla., March 31
/PRNewswire-FirstCall/ -- Data presented at the 95th Annual Meeting
of the American Association for Cancer Research (AACR) in Orlando,
Florida, confirms that phenoxodiol is on track in its development
as a first-line therapy for early-stage cancers and as a
chemo-sensitizing agent for late-stage cancers. Phenoxodiol, a
XIAP-inhibitor, is an anti-cancer drug being developed by Marshall
Edwards, Inc., . The data presented concerned clinical studies
conducted at U.S. and Australian hospitals, and pre-clinical
studies conducted atU.S. research institutions. Interim Results of
Phase 1b/2a Data Shows Dose-Related Response Late breaking data
from a Phase 1b/2a clinical trial in late-stage prostate cancer
patients supports the strategy of targeting this cancer type.
Twenty-four patients with malignant prostate cancer and rising
prostate specific antigen (PSA) levels (mean 60 ng/mL at start of
study) were treated with phenoxodiol (oral dosage formulation) 3
times daily, for 3 weeks each month up to a maximum of 6 months.
Patients received 1 of 4 different dosages - 20, 80, 200 or 400 mg.
There were 6 patients per dose stratum. This first trial of oral
phenoxodiol was designed to confirm that the dosage form was
biologically active. Activity was determined on the basis of PSA
levels in the blood. PSA, a protein normally secreted by the
prostate, is a marker commonly used to detect the presence of
prostate cancer. Although not an absolute predictor of prostate
cancer, it is generally accepted that as prostate cancer develops,
a greater amount of PSA is released into the blood stream.
Objective tumor response was not an aim of this study. Interim
results indicate that oral phenoxodiol is biologically active as
evidenced by a dose-dependent effect on serum PSA level. When the
12 patients treated with the 2 highest dosages (200 and 400 mg)
were tested after 3 months of therapy, 2 showed stabilization of
their PSA levels, while 6 (50%) showed a decrease in PSA levels.
Two of these 6 responders showed a decline in PSA levels of greater
than 75%. No toxicity was reported. The clinical study was
conducted in Australia by Dr. Robert Davies of Sir Charles Gairdner
Hospital in Perth, Professor Alastair Tulloch of St John of God
Hospital, Perth, and Dr. Mark Frydenberg of Monash Medical Centre,
Melbourne. Co-investigator Dr. Davies said, "Late-stage prostate
cancer is notoriously unresponsive to anti-cancer therapies, so to
see this degree of response to phenoxodiol confirms our confidence
in this investigational drug." He also said, "While the results of
this study suggest that phenoxodiol may be having a significant
anti-cancer effect in its own right in prostate cancer, we believe
that it has the potential to provide even greater benefit when used
in combination with other drugs." Dr. Graham Kelly, Executive
Chairman of Marshall Edwards, Inc., said, "These data justify
moving to the next step, which is a larger trial to test for
objective tumor response to both phenoxodiol alone and in
combination with chemotherapy, in men with late stage prostate
cancer." Yale University Study Shows Monotherapy Response in
Advanced Ovarian Cancer The second set of clinical trial data
discussed at the conference concerned the intravenous dosage
formulation of phenoxodiol. This was a Phase 2 study of monotherapy
phenoxodiol in 40 patients with late-stage, unresponsive, recurrent
ovarian cancer. On average, these patients had undergone 5
different chemotherapy regimens, and all patients failed to respond
to salvage therapy. The patients were treated with phenoxodiol in
an attempt to determine whether phenoxodiol had any anti-tumor
effect in such late-stage tumors, and if so, to identify the
appropriate dosage to be used in a follow-up study where it would
be used in combination with standard chemotoxic drugs. Intravenous
phenoxodiol was administered on 2 consecutive days per week;
patients were randomized to 4 dose levels - 1, 3, 10 and 20 mg/kg.
Treatment continued until patients showed disease progression.
Response to therapy was assessed on the basis of a fall in blood
levels of the ovarian tumor marker (CA125), shrinkage of the tumor
mass, or improved clinical status. Ten (25%) of the 40 patients had
responded when assessed after 6 weeks of treatment, although tumor
mass was not assessed at this time. In 6 of these patients, CA125
levels had fallen by an average 54%; in the other 4 patients,
rapidly rising CA125 levels before the trial commenced had stopped
rising (stabilization) at 6 weeks. At 3 months, 4 of these 10
patients showed stabilized CA125 levels. Almost all of these
responders were in the 2 lowest dosage groups, confirming
laboratory studies that showed a greater anti-tumor effect for
ovarian cancer at lower dosages for phenoxodiol. Phenoxodiol
Restores Chemo-Sensitivity in Patients With Advanced Ovarian Cancer
Relevant data, however, in terms of the company strategy of
developing phenoxodiol as a chemo-sensitizing agent for late-stage
cancers, came from the follow-up management ofthese patients.
Following completion of the phenoxodiol therapy because of disease
progression, a number of the patients were re-challenged with
standard chemotoxic drugs in order to test what effect phenoxodiol
therapy had on their sensitivity to standard anti-cancer drugs.
Because all patients had recurrent disease despite being heavily
treated with chemotherapy, a clinical response to further
chemotherapy was considered unlikely. In 10 patients who received
paclitaxel, 8 of the 10 responded withan immediate and marked
decline (average 64%) in their CA125 levels; the other 2 women
failed to respond and showed progressive disease. Five of the 10
women treated with paclitaxel were previously considered either
resistant or refractory to paclitaxel (that is, their disease
previously either had recurred within 6 months of paclitaxel
therapy, or continued to worsen despite paclitaxel therapy).
However, after treatment with phenoxodiol and subsequent treatment
with paclitaxel, 4 of these 5 patients showed a marked response in
their CA125 levels, and 3 remain alive after an average of 292
days. These patients have yet to be assessed radiographically to
determine the degree of objective tumor response. Dr. Thomas
Rutherford of the Yale University School of Medicine, and Principal
Investigator in the study, said, "we are excited that phenoxodiol
has been able to provide an effect in women whose disease has been
so heavily pre-treated and for whom we have run out of options".
"But we have always believed that the best way to use the drug was
as a chemo-sensitizer, restoring the cancer cell's susceptibility
to standard drugs once they have become resistant to those drugs,"
Rutherford added. "That is why this preliminary finding with
phenoxodiol and paclitaxel is so exciting. We have seen women
positively respond to paclitaxel after being pre-treated with
phenoxodiol despite their earlier resistance to paclitaxel." Dr.
Kelly said, "This trial represents the first stage of a two-part
program to develop phenoxodiol as a chemo-sensitizer in ovarian
cancer patients. The trial has been successful in helping us
identify an appropriate, well-tolerated dose of 3 milligrams per
kilogram." Laboratory Data From Yale Shows Phenoxodiol Restores
Chemo-Sensitivity to a Broad Range of Chemotherapy In a
pre-clinical study conducted by Yale University and reported on by
Gil Mor M.D., Associate Professor, Department of Obstetrics and
Gynecology, phenoxodiol was shown to restore sensitivity in ovarian
cancer cells not only to taxane drugs such as Taxotere(R)
(docetaxol), but also to platinum agents such as carboplatin.
Additionally, phenoxodiol in combination with gemcitabine had a
comparable response. Significantly, ovarian cancer cells
resistantto each of these cytotoxic drugs showed an over 100-fold
increase in their sensitivity to chemotherapy following
pre-treatment with phenoxodiol. Dr. Mor said, "What makes the
results of this laboratory study so significant is the confirmation
that phenoxodiol has the capacity to reverse chemo-resistance in
ovarian cancer patients". "Chemo-resistance is one of the greatest
problems we face in cancer therapy. Almost every patient with
advanced ovarian cancer ultimately becomes resistant to all
anti-cancer drugs. We believe that phenoxodiol is a tool to
overcome this problem so we can offer these patients renewed hope."
NIH Laboratory Study Shows Phenoxodiol Kills Head and Neck Cancer
Cells In an additional pre-clinical study conducted by the NIH and
reported on at the conference, the means by which phenoxodiol was
able to stop head and neck cancer cells (squamous cell carcinomas),
from growing was described. Of particular relevance, however, was
the fact that phenoxodiol was able to stop the growth in the
laboratory of head and neck and salivary gland cancer cells that
were highly resistant to standard anti-cancer drugs. Mechanisms of
Action: Phenoxodiol Induces Apoptosis by Disrupting Intra-Cellular
Proteins Phenoxodiol has been developed as a highly selective
inducer of apoptosis in tumor cells that works by removing the
intra-cellular proteins (XIAP, c-FLIP) that play a major role in
ensuring the survival of cancer cells. Removal of these proteins
has the dual effect of rendering thecancer cell susceptible to the
body's normal defense mechanisms as well as making it more
sensitive to the cytotoxic effects of standard anti-cancer drugs.
The highly selective nature of phenoxodiol means that the drug has
no discernible adverse effects on non-tumor cells, and its ability
to enhance the killing effect of other chemotoxics is restricted to
tumor cells. Marshall Edwards, Inc., is developing phenoxodiol on
two broad therapeutic strategies. First, as a first-line therapy
for early-stage cancer (including prostate and cervical cancers)
where early detection is possible, and where the cancer is
particularly prone to the apoptotic effect of phenoxodiol alone.
Second, as a first-line therapy for late-stage cancers (including
prostate carcinoma and renal carcinoma) to improve the
responsiveness to standard chemotoxics in cancers that are
intrinsically poorly sensitive to such drugs, or as a second-line
therapy to restore responsiveness to standard chemotoxics in
cancers (including ovarian carcinoma) that have acquired resistance
to such drugs. Phenoxodiol has IND status within the U.S. and has
not yet been evaluated by the FDA for marketing approval.
Phenoxodiol, an investigational anti-cancer drug developed by
pharmaceutical company, Marshall Edwards, Inc. Marshall Edwards,
Inc., manages its international research and development programs
using the expertise and clinical research capabilities of
universities and hospitals in the U.S., Australia and Europe.
Marshall Edwards, Inc., has licensed rights to bring phenoxodiol to
market globally from its parent company, Novogen Limited.
(NASDAQ:NVGN). Novogen is developing a range of therapeutics across
the fields of oncology, cardiovascular disease and inflammatory
diseases basedon its phenolic drug technology platform. More
information on phenoxodiol and on the Novogen group of companies
can be found at http://www.marshalledwardsinc.com/ and
http://www.novogen.com/. Statements included in this press release
that are not historical in nature are "forward-looking statements"
within the meaning of the "safe harbor" provisions of the Private
Securities Litigation Reform Act of 1995. You should be aware that
our actual results could differ materially from those contained in
the forward-looking statements, which are based on management's
current expectations and are subject to a number of risks and
uncertainties, including, but not limited to, our failure to
successfully commercialize our product candidates; costs and delays
in the development and/or FDA approval, or the failure to obtain
such approval, of our product candidates; uncertainties in clinical
trial results; our inability to maintain or enter into, and the
risks resulting from our dependence upon, collaboration or
contractual arrangements necessary for the development,
manufacture, commercialization, marketing, sales and distribution
of any products; competitive factors; our inability to protect our
patents or proprietary rights and obtain necessary rights to third
party patents and intellectual property to operate our business;
our inability to operate our business without infringing the
patents and proprietary rights of others; general economic
conditions; the failure of any products to gain market acceptance;
our inability to obtain any additional required financing;
technological changes; government regulation; changes in industry
practice; and one-time events. We do not intend to update any of
these factors or to publicly announce the results of any revisions
to these forward-looking statements. Web site:
http://www.marshalledwardsinc.com http://www.novogen.com
DATASOURCE: Marshall Edwards, Inc. CONTACT: David Sheon, United
States: +1-202-518-6384, for Marshall Edwards, Inc.; or Christopher
Naughton of Marshall Edwards, Inc., Australia: +011-61-2-9878-0088
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