Phenoxodiol significantly delays tumor progression in men with late-stage, hormone-refractory prostate cancer, according to a presentation at the International Conference on Molecular Targets and Cancer Therapeutics. 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 the Phase Ib/IIa trial was dose-dependent. The trial was designed to end after 24 weeks of treatment, but was extended to 90 weeks because of the unexpected extended survival in some patients. 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 formulation provided and whether there was a dose-dependent effect.

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.

Phenoxodiol was the only treatment received by participants with the exception of patients who had been on anti-androgen therapy prior to enrollment. The age of the 26 subjects ranged from 55 to 85 years; mean Gleason score was 8.04 (range 6-9), and mean baseline prostate-specific antigen level was 56.3 pg/mL.

"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 prostate-specific antigen 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 prostate-specific antigen levels, there were no responses in the two lowest dosage groups, but 3 of 14 patients in the two highest dosage groups experienced a reduction in level of 50 percent or greater. Doubling time increased from a mean of 18 weeks to 43 weeks, not including the 3 of 14 patients who remained on phenoxodiol therapy and whose PSA levels have not yet doubled.

A California 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 of drugs for men with prostate cancer," said Steven Tucker, MD, Director of Prostate and Genitourinary Oncology at The Angeles Clinic & Research Institute in Los Angeles.

The next study, which will focus on patients who have failed to respond to hormone therapy and docetaxel therapy, will be conducted in the U.S. and is planned to commence enrollment in 2006.

Phenoxodiol targets the tumor cell’s cation excretion pump, with resulting disruption of cellular reduction-oxidation potential producing a range of biochemical effects including inhibition of phosphorylation of the key pro-survival sphingosine-1-phosphate and Akt signaling pathways. Inhibition of production of anti-apoptotic proteins including XIAP is a key biochemical outcome.

The mechanism of action of phenoxodiol suggests a 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 chemosensitive patients and to restore sensitivity to those drugs in chemoresistant patients. Phenoxodiol currently is undergoing clinical studies in the US and Australia.