Phenoxodiol Delays Progression in Hormone Refractory Prostate Cancer,
No side-effects, study says

"Designed to end after 24 weeks of treatment, the trial has been extended to 90 weeks so far 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 drug-related toxicity."

November 17, 2005. - Phenoxodiol is an oral drug designed to treat late-stage, chemo-resistant prostate, ovarian and renal cancers. Marshall Edwards, Inc., the company that makes phenoxodiol, has called it a synthetic analog (i.e. mimic) of genistein, which is a chemical found in soy.

Phenoxodiol is in clinical trials in the US and Australia to see if it has potential on its own (as a monotherapy) and in combination with standard anti-cancer drugs. For patients who are responding to a chemotherapy, the aim is to boost the overall response. For patients whose cancer has stopped responding to chemotherapies, the aim is to restore sensitivity to those drugs.

A study reported today at a conference in Philadelphia says the drug has benefit for patients with advanced hormone refractory prostate cancer and has no side-effects.

The anti-tumor effect in this Phase Ib/IIa trial was dose-dependent -- only patients receiving higher doses showed a good response.

The trial was designed to end after 24 weeks of treatment, but was 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 drug-related toxicity.

There were 4 serious adverse events during the trial, but according to the company none of these were connected with phenoxodiol. (One of the hazards of early stage clinical trials is that "non-drug related adverse events" may arise if patients are assigned to what turns out to be a weak or ineffective dose, leaving them in effect in a treatment gap that allows worsening of their cancer.)

At higher doses, 7 out of 10 patients got more than 6 months benefit

In this trial men with metastatic, hormone-refractory prostate cancer received various doses (20, 80, 200 and 400 mg) of phenoxodiol 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 men took phenoxodiol in monthly treatment cycles with 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 measured by
  • 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).

How it works

Cells, like water softeners, use ion exchange pumps. Phenoxodiol aims to bring about cancer cell suicide (apoptosis) and necrosis (decay) by targeting the tumor cell's cation (positive ion) excretion pump. If it works, this disrupts the cancer cells' redox potential by slowing signals along the sphingosine-1-phosphate and Akt signalimg pathways.

Sphingosine 1-phosphate (S1P) is a cell signaling molecule that helps cells, including cancer cells, to grow. Phenoxodial aims to tame tumor growth by disrupting signals from S1P and related molecule, Akt.

For a demo of the AKt signaling pathway visit BioCarta.

"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," says 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, Ph.D, Chairman of Marshall Edwards, Inc., the company which makes this drug.

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," says Dr. Tucker, who is also an Assistant Clinical Professor of Medicine at the UCLA School of Medicine.

Professor Kelly said that the next stage of development of phenoxodiol for prostate cancer would be to try it on patients who have failed to respond to both hormone therapy and docetaxel (Taxotere) 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 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.

These study results were presented November 17, 2005 in a poster session (.pdf download) at the International Conference on Molecular Targets and Cancer Therapeutics in Philadelphia. The meeting is 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).

Phenoxodiol is an investigational drug and, as such, is not marketed in the US.

More information about phenoxodiol can be found at http://www.phenoxodiol.com

by J. Strax November 17, 2005.

Information on this website is not intended as medical advice nor to be taken as such. Consult qualified physicians specializing in the treatment of prostate cancer. Neither the editors nor the publisher accepts any responsibility for the accuracy of the information or consequences from the use or misuse of the information contained on this web site.

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