phenoxodiol

December 2007 update: A new phase II trial has recently opened (November 2007):

This trial is at Yale Cancer Center. There are two non-randomized arms and no prior chemotherapy is allowed. The Phenoxodiol is being tested as a monotherapy and is Oral.

Group A: patients whose cancer has worsened or spread after being on hormonal therapy and has not had any chemotherapy.

Group B: patients who have a rising PSA after surgery or radiotherapy for the prostate and do not have any spread to the bones or other organs.

Patients will receive Phenoxodiol (PXD) 400 mg every 8 hours daily for 28 consecutive days (1 cycle). Treatment outcome will be evaluated after three cycles (12 weeks) of PXD treatment (immediately prior to cycle 4). Patients with progression of disease will be taken off study. Responding and stable disease patients will remain on study for a total of 12 cycles(approximately 12 months).

December 2006 update: new clinical trials for hrpca have not started. There is a phase I trial at the Cleveland Clinic for refractory solid tumors which would probably include hrpca patients (the NCI identifier is NCT00022295 at Clinicaltrials.gov. A phase III trial for Ovarian Cancer has begun at 60 sites around the world.

Marshall Edwards, Inc. (MEI), a subsidiary of the Australian pharmaceutical company,
Novogen, Ltd., is developing a class of drugs called multiple signal transduction
regulators (MSTRs). MEI is developing a number of drugs based on MSTRs that they
ultimately hope will be effective against a range of different cancer types.
Phenoxodiol is the first of these drugs and it is being developed by MEI for

• early-stage prostate cancer
• late-stage, hormone-refractory prostate cancer
• early stage cervical and vaginal cancer
• chemo-resistant and chemo-refractory ovarian cancer
• renal cancer.

Of interest here, of course, is the application to hormone-refractory prostate cancer
patients (HRPCa).

Phenoxodiol is a broad-spectrum anti-cancer drug that induces cancer cell death through inhibition of anti-apoptotic proteins including XIAP and FLIPshort. The mechanism of action of phenoxodiol suggests its potential to be used both as a monotherapy and in combination with standard anti-cancer drugs where it acts to enhance the efficacy of those drugs in chemo-sensitive patients and to restore sensitivity to those drugs in chemo-resistant patients. For example, patients who have failed taxanes might again respond to a taxane when taken with phenoxodiol.
Since Phenoxodiol is an investigational drug, it is not yet approved by the US FDA and
hence is not marketed in the US.

MSTRs offer the promise of therapies that can reach the very heart of the cancer process and correct it, and do so with little or no effect on healthy, non-cancer cells.
The technology stems from recent advances in understanding the underlying
mechanisms that allow cancer cells to persist in the body and to multiply.
Breakthroughs in the fields of genomics and molecular biology have now revealed that
cancer cells become established because they are able to override some key decision-
making processes within the cell. This decision-making concerns such fundamental
matters as whether to survive or to die, and whether to multiply or not.

• By overriding the survival/death decision-making process, cancer cells live forever,

• By overriding the growth/non-growth decision-making process, cancer cells grow in an unregulated manner.

Up until now, the focus of anti-cancer drug development has been on dealing with the
consequences of this process - that is, trying to block the cancer cell's ability to multiply or to survive. The other approach to halting the growth of cancer cells is to restore the normal decision-making processes. Although there are other drugs that have differentiation properties, none of them has shown a significant benefit to hormone-refractory prostate cancer patients. Drugs such as retinoids, vitamin D, peroxisome-proliferator-activated receptor gamma (PPARgamma) ligands, and, the histone deacetylase (HDAC) inhibitors have been studied for use against prostate cancer.

In the late 1990s, Novogen scientists discovered a group of plant chemicals that are
involved in regulating the same primitive decision-making processes such as
survival/death and growth/non-growth in plant cells. These chemicals are known as
isoflavonoids - these are plants signal transduction regulators. This family of plant chemicals was found to have the ability to regulate the same fundamental decision-making processes in human cells, and more importantly, were able to restore the normal decision-making processes in human cancer cells. Exposing human cancer cells to this family of drugs, results in the previously suppressed decision-making processes being restored. The result is that the cancer cell immediately stops multiplying and then dies.

An important side benefit is that these drugs have no effect on the decision-making
processes within normal cells - if the cell is already behaving normally, then it is not
affected by these drugs. Novogen scientists have chemically modified these naturally-occurring plant isoflavonoids and made them more active and more suitable for human cells. The result is a large family of synthetic drugs that work at different parts of the cancer cell's decision- making processes. The main difference between normal cells and cancer cells is its sensitivity to apoptosis. In cancer cells, the ability for those cells to die via apoptosis is inactivated by a series of protein interactions in the cell. Phenoxodiol makes cancer cells sensitive to apoptosis via the two modes of actions detailed above, thus reversing the cancer process and transforming a cancer cell back into a normal cell that is programmed to die.

Not all cancers express death receptors which trigger apoptosis, thus up until now
phenoxodiol has been less effective against these types of cancers, with only one of its two mechanism of action (via the increased production of BAX) able to kill the cancer cell. Recently scientists at Marshall Edwards have discovered a method of rendering all cancer cells susceptible to phenoxodiol via both mechanisms of action.
Two commonly used chemotherapeutic drugs are cisplatin and gamma-interferon (Note:
these are not commonly used for hormone-refractory prostate cancer.) By combining
phenoxodiol with either cisplatin or gamma-interferon it is believed that all cancer cells
will be susceptible to phenoxodiol because cisplatin and gamma-interferon both increase the number of death receptors on the cell. With the death receptors now present on the cell surface, phenoxodiol can kill the cancer cell via both mechanisms, making it a much more potent anti-cancer compound. (Note: cisplatin is a harsh chemotherapy drug – in hrpca, carboplatin is used, although some protocols call for cisplatin.)

Marshall Edwards embarked on a series of clinical trials with Phenoxodiol being
administered in two forms:

2. Part B – phenoxodiol in combination with either cisplatin or gamma-interferon

“A new study shows that phenoxodiol significantly delays tumor progression in
men suffering from late-stage hormone refractory prostate cancer.”

November 17, 2005 - A new study presented at the International Conference on
Molecular Targets and Cancer Therapeutics in Philadelphia shows that phenoxodiol
significantly delays tumor progression in men suffering from late-stage hormone
refractory prostate cancer. The meeting was sponsored by the American Association of
Cancer Researchers (AACR), the National Cancer Institute (NCI), and the European
Organization for Research and Treatment of Cancer (EORTC).
The anti-tumor effect in this Phase Ib/lla trial was dose-dependent. The trial was
designed to end after 24 weeks of treatment, but had to be extended to the current 90 weeks because of the unexpected extended survival in some patients. Patients have
been able to remain on phenoxodiol for this extended time without any evidence of
toxicity.

Researchers administered various doses (20, 80, 200 and 400 mg) of phenoxodiol to
men with metastatic, hormone-refractory prostate cancer to establish what level of anti-cancer effect the oral dosage form of this drug would provide and whether there was a dose-dependent effect. The phenoxodiol was administered in monthly treatment cycles comprised of 3 doses daily for 21 consecutive days followed by 7 days without
treatment. The original plan was to treat patients for a maximum of 6 treatment cycles.
Except for anti-androgen therapy being continued in those who were receiving it pre-
trial, phenoxodiol was the only treatment. The age of the 26 subjects studied ranged
from 55 to 85, the Gleason score was mean 8.04 (range 6-9), and the mean baseline
PSA level was 56.3 pg/ml.

Response to therapy in these patients was determined on the basis of PSA response (a
decline in PSA level compared to baseline of at least 50 percent), PSA doubling time
(time for the baseline PSA level to double), and time to progression (length of time that
patients remained on phenoxodiol based on PSA levels and clinical assessment).
"The two highest dosages of phenoxodiol provided a significant anti-tumor response in a disease that is normally unresponsive to treatment in its late stages," said Robert
Davies, MD, lead investigator of the study and urologist at Sir Charles Gairdner Hospital
in Perth, Australia. "We found that the PSA level, an indicator of the level of cancer,
decreased. We also saw a clinical response that was prolonged in some patients."
Combining the data from the two lowest dosages (12 patients) and the two highest
dosages (14 patients), the number of patients still on therapy after 6 months increased
from 1 out of 12 (8.5 percent) to 10 out of 14 (71.4 percent), and the mean time to
progression (length of time patients were deemed to be deriving a benefit from therapy) increased from 15 weeks to 47 weeks. This latter figure does not take into account four patients who remain on therapy after 42, 74, 82 and 90 weeks.
In terms of PSA levels, there were no PSA responses in the two lowest dosage groups,
but 3 of the 14 in the two highest dosage groups experienced a PSA level reduction of 50 percent or greater from baseline. The PSA doubling time increased from a mean 18
weeks to 43 weeks, not including the 3 of 14 patients who remain on phenoxodiol
therapy and whose PSA levels have yet to double. While it was not possible to measure
tumor size in this study, an increase in PSA doubling time is generally regarded as
reflecting a tumor response.

"The long-term anti-tumor effects and safety demonstrated in this study are very
encouraging developments," said Graham Kelly, PhD, Chairman of Marshall Edwards,
Inc.

A Californian oncologist who referred two patients to the trial agrees that the results are good news, and may impact the way prostate cancer is treated. "Phenoxodiol represents a unique new class drugs for men with prostate cancer," says Steven Tucker, MD, Director of Prostate and Genitourinary Oncology at The Angeles Clinic & Research Institute in Los Angeles. "If the clinical benefit seen in these refractory patients can be extended into an earlier disease state, we may be looking at a paradigm shift in the management of advanced prostate cancer." Professor Kelly said that the next stage of development of phenoxodiol for prostate cancer would be to use it in patients who have failed to respond to both hormone therapy and docetaxel therapy. "On the basis of this data, we would expect that phenoxodiol alone would offer these patients a significant survival benefit, but we also will be interested in testing the ability of phenoxodiol to restore sensitivity to docetaxel(1) in these end-stage patients," Professor Kelly added.

This next study will be conducted in the U.S. and is planned to commence enrollment in
2006.

Question: Is there any other way to get this drug other than signing up for a clinical
trial?

Answer: The best way is to sign up for one of the new clinical trials when they are
announced. Trying to get the drug on a compassionate use basis(2) may prove
impossible if the company does not have a large enough production to satisfy both the
quantity needed for clinical trials and for selected compassionate use individuals.

Answer: Maybe never. The only data so far is from a single study with very few patients. Data provided by multiple institutions, with a large number of patients often does not support FDA approval as shown by the recent failure of Xinlay to get approval. Furthermore, in January 2005, The US FDA granted “fast track” status for oral phenoxodiol for prostatic adenocarcinoma that is resistant to both hormonal and
cytotoxic chemotherapy. Under the FDA Modernization Act of 1997, designation as a
“fast track” product means that phenoxodiol is eligible for certain accelerated marketing
approval programs, although it does NOT ensure future regulatory approval. As this is
being written in January 2006, a year has gone by since that “fast track” status was
granted to phenoxodiol. However, clinical trials for HRPCA have not yet begun. A more
realistic guesstimate of availability would be for it to be sometime in 2007. Let’s hope it
is available much sooner.

Graham Kelly, Interim Results of a Phase Ib/IIa Study of Oral Phenoxodiol in Patients
with Late-Stage, Hormone-Refractory Prostate Cancer, AACR Annual Meeting 2004,
Abstract Number: LB-214

FOOTNOTES
1 – Most cases of prostate cancer are sensitive to male sex hormones (androgen), and
blocking of the effect of these hormones is a common therapeutic process. Ultimately,
however, most prostate cancers become insensitive to androgens, at which time the
tumor is referred to as being ‘hormone refractory.’ The approved anti-tumor therapy for
these patients is docetaxel (Taxotere®), which has been shown to provide a modest
extension of survival in some patients, before the tumors become docetaxel-refractory.
Hormone-refractory, docetaxel-refractory patients represent the end-stage of this
disease.

2 – “Compassionate Use Basis” is also called “Single Patient” or “Emergency IND”
directly with the FDA. See: http://www.fda.gov/cder/cancer/access.htm.