WASHINGTON, DC - November 22, 2004. Phenoxodiol, a synthetic anticancer drug analog of genistein, belongs to a new class of anti-cancer drugs known as Multiple Signal Transduction Regulators (MSTRs). It is the first of this new class of anti-cancer drug to be tested in cancer patients.
Phenoxodiol has been tested so far primarily on patients with ovarian cancer but is being developed by a division of the pharmaceutical company Novogen as a "broad-spectrum anti-cancer drug, able to stop the growth of a wide range of human cancers."
Marshall Edwards, Inc., today released results of a small-scale clinical study of phenoxodiol in patients with hormone-refractory prostate cancer (HRPC).
The results, presented November 19 to the American Association of Cancer Research (AACR) conference on Basic, Translational and Clinical Advances in Prostate Cancer, held in Bonita Springs, Florida, showed that phenoxodiol has what company spokesman describe as a "potent ability to slow down the rate of cancer progression as evidenced by PSA levels and clinical status."
The type of Phenoxodiol developed for hormone refractory prostate cancer is an oral formulation. The company aims to gain approval for this formulation both as a first-line chemotherapy, and as a second-line chemotherapy for patients who have failed to respond to docetaxel.
Phenoxodiol is an investigational drug and has not been approved for marketing by FDA. Under U.S. law, a new drug cannot be marketed until it has been investigated in clinical trials and approved by the FDA as being safe and effective for the intended use.
About the study
The Phase Ib/IIa clinical study was conducted in two Australian hospitals. Nineteen men with HRPC were treated with phenoxodiol daily for 3 weeks each month for 6 months. All men had advanced, metastatic disease, and entered the trial with rising PSA levels.
The study focused on (a) the safety and tolerability of phenoxodiol in men with HRPC, (b) the ability to maintain a steady-state of phenoxodiol in the blood, and (c) the effect of phenoxodiol on PSA levels and disease progression. The overall purpose was to find out whether phenoxodiol has a clinical benefit that would justify conducting a large-scale study to determine its ability to reduce tumor progression. Another purpose was to determine an appropriate dosage of phenoxodiol to be used in such a study.
Patients received one of four different dosages of phenoxodiol -- 20, 80, 200 or 400 mg each 8 hours. Four to 6 patients were enrolled per dose level. Treatment continued for 6 months or until disease progression. Patients who were considered to have derived a clinical benefit from phenoxodiol after 6 months of therapy were continued on 200 mg phenoxodiol until disease progression.
About the results
Phenoxodiol produced a dose-response effect in terms of disease progression and PSA levels, with the 20 mg dose producing no discernible effect, the 80 mg dose an intermediate effect, and the 200 and 400 mg doses producing a marked effect.
The clinical effect of phenoxodiol was measured in two standard ways -- (i) the proportion of patients at 6 months who had shown disease progression (determined on the basis of time to PSA levels being greater than 25% higher than base-line and/or on the basis of clinical determination), and (ii) PSA response (greater than 50% fall in PSA level compared to base-line for at least 4 weeks' duration).
Increasing doses of phenoxodiol resulted in a progressive and marked increase in the time taken for the disease to progress. In the 20 and 80 mg dose groups, all patients had shown disease progression by the end of the study, with average times to progression of 10 and 17 weeks, respectively. However, in the 200 and 400 mg dose groups, 2 of 4 and 3 of 4 patients respectively had no evidence of disease progression at 6 months. The PSA levels in these 5 patients without disease progression at 6 months were at or below baseline levels.
A PSA response generally is regarded as indicative of tumor response. Two of four patients in the 200 mg dose group, and 3 of 4 patients in the 400 mg dose group showed a PSA response, which taken together with the disease progression data suggests that phenoxodiol monotherapy is exerting a significant anti-tumor effect in these late-stage, hormone-refractory cancers.
Phenoxodiol was well tolerated in all patients, with no toxicities being reported, including at dosages of 400 mg administered for 6 months, followed by 200 mg for up to a further 18 months.
The 8-hourly dosing schedule also proved effective at providing steady-state plasma levels of phenoxodiol with no long-term accumulation of drug at any of the four dosages.
Professor Graham Kelly PhD, Chairman, Marshall Edwards, Inc., who presented the data at the conference on behalf of the investigators, said, "These results give us optimism that with phenoxodiol we can slow the rate of tumor progression to the point where we can make a real difference to the survival of men with such advanced cancer. Current therapies offer only modest extensions of life to about half of patients with HRPC, but at the cost of significant toxicity to most men receiving the treatment. Our aim with phenoxodiol is to deliver meaningful prolongation of life in a significant number of patients, with little or no toxicity."
A Phase IIb/IIIa multi-center, international, clinical trial known as the COMPACT (Comparison of Phenoxodiol Against Conventional Therapy) Study in men with HRPC using a phenoxodiol dosage of 400 mg currently is being established.
About prostate cancer
Prostate cancer is one of the most common types of cancer among American men. According to the American Cancer Society, over 230,000 American men will be diagnosed with prostate cancer in 2004, and approximately 29,900 American men will die from the disease. Prostate cancer is strongly associated with the male sex hormone, testosterone, and most early cases of prostate cancer respond for some time to hormonal therapy that blocks the ability of testosterone to stimulate the cancer. However, the majority of cases of prostate cancer eventually become independent of testosterone, at which time they are known as hormone-refractory prostate cancer (HRPC). The cancer at this stage typically is metastatic, with a patient survival time typically in the range of 1 to 2 years.
The FDA recently approved the combination of docetaxel (Taxotere ™) and prednisone for the treatment of HRPC. That combination produces a PSA response in 45% of patients, although the tumor response rate is only 12% and the overall increase in survival in all patients is 10 weeks (from an average of 16.4 months to an average of 18.9 months).1,2
Phenoxodiol is an investigational product designed to block the key pro-survival signaling messenger, sphingosine-1-phosphate. As a consequence of this, the prostate cancer cell is both blocked from dividing or increasing in number (cytostasis) and induced to undergo apoptosis or programmed cell-death (cytotoxicity). Phenoxodiol is believed to target the cell membrane enzyme, tNADH oxidase, which regulates the production of sphingosine-1-phosphate. The restriction of tNADH oxidase to cancer cells accounts for the highly selective effect of phenoxodiol on cancer cells.
About Marshall Edwards, Inc.
Phenoxodiol, an isoflavonoid ring structure, is being developed by Marshall Edwards, Inc., (Nasdaq: MSHL - LSE AIM:MSH) which has licensed rights to bring phenoxodiol to market globally from Novogen Limited, an Australian biotechnology company based in Sydney, Australia (Nasdaq: NVGN - ASX: NRT).
1. Tannock IF, et al. (2004) New Eng J Med 351, 1502-1512.
2. Petrylak DP, et al. (2004) New Eng J Med 351, 1513-1520.
Search PUBMED for abstracts about this drug -- enter phenoxodiol
Clinical trials of phenoxodiol, recruiting:
Ohio: Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio, 44195, United States; Recruiting Ronald M. Bukowski, MD 216-444-6825
1) Connecticut: Yale Comprehensive Cancer Center, New Haven, Connecticut, 06520-8028, United States; Recruiting Renee Luongo 203-737-5225
2) Australia, Victoria Royal Women's Hospital, Carlton, Victoria, 3053, Australia; Recruiting Michael A. Quinn, MD 61-3-9221-5188
More information on phenoxodiol and on Marshall Edwards can be found at www.marshalledwardsinc.com.
This article edited by J. Strax, last updated November 26, 2004