23 juli 2012: aanvullend op onderstaand artikel hebben we onderaan het abstract van dit gratis te lezen volledig studieverslag: Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer toegevoegd. Dit studie rapport beschrijft de werking van deze vorm van isoflavonen bij prostaatkanker: Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion. Opvallend dat deze vorm van bio-chemische isoflavonen zelfs werkt bij hormoonresistente prostaatkanker. Onderaan ook referentielijst toegevoegd.

21 november 2005: Met dank aan Gert die ons hierop wees.

Phenoxodiol, een biochemisch middel zorgt wanneer toegediend in hoge dosis 400 mg. - in fase I/II studie voor onverwacht significante positieve resultaten zonder enige bijwerkingen bij prostaatkankerpatienten met uitgezaaide en door resistentie onbehandelbare prostaatkanker. De 26 deelnemers waren in leeftijd 55 tot 85 jaar, met een gemiddelde Gleason score van 8.04 (range 6-9), en een gemiddelde basis PSA waarde van 56.3 pg/ml. bij aanvang van de studie. De 26 deelnemende zoals gezegd inmiddels onbehandelbare prostaatkankerpatiënten kregen in 4 groepen verdeeld verschillende doses (20, 80, 200 en 400 mg.) Phenoxodiol toegediend in maandelijks 21 dagen opeenvolgend en 3 x per dag gevolgd door een pauze van 7 dagen zonder behandeling. Alle patiënten kregen alleen Phenoxodiol toegediend en geen andere middelen of medicijnen. De bedoeling was een maximale studieduur van 6 behandelperiodes maar omdat de resultaten zo goed bleken bij met name de twee hoge dosesgroepen is voor deze twee groepen de studie verlengd.

Resultaten:

Vergelijking van onderzoeksgegevens van de twee laagst gedoseerde groepen (12 patiënten) met de twee hoogst gedoseerde groepen (14 patiënten) geeft aan dat het aantal patiënten dat na zes maanden nog steeds in behandeling bleek was gestegen van 1 uit 12 (8,5%) tot 10 uit 14 (71,4%). en de mediane tijd tot progressie van de ziekte (tijd waarin de patienten nog enig resultaat leken te hebben van de behandeling tot het moment waarop de behandeling niets meer leek te doen) steeg van 15 weken tot 47 weken Deze laatste gegevens zijn niet inclusief de patiënten die na de 6 maanden studietijd onder behandeling bleven na 47, 74, 82 en 90 weken. Dus de resultaten zijn eigenlijk nog veel beter.

In termen van PSA waarden, waren er geen PSA reacties in de twee laagst gedoseerde groepen maar 3 van de 14 in de twee hoogst gedoseerde groepen toonden een PSA verlaging van meer dan 50% t.o.v. de basiswaarden bij start van de behandeling. De tijd tot PSA verdubbeling steeg van gemiddeld 18 weken tot 43 weken, exclusief de gegevens van 3 van de 14 patienten die op een phenoxodiol behandeling bleven en welke PSA waarden de verdubbeling nog moeten bereiken. Ook hier zijn de resultaten dus nog veel beter dan officieel wordt aangegeven. Hoewel het onmogelijk was de tumorgrootte te meten in deze studie wordt in het algemeen aangenomen dat een verlenging van de tijd tot een PSA verdubbeling geassocieerd wordt met een positief effect op remming van de tumorgroei.

Hier het originele artikel over deze studie welke wel gekopieerd is van de producent van Phenoxodiol, dus lees het kritisch, maar desalniettemin o.i. interessant.

Bron: Website van Novogen

Phenoxodiol delays tumor progression in late stage hormone refractory prostate cancer

Long term Phase Ib/IIa study presented at AACR-NCI-EORTC meeting showed significant anti-tumor effects and no toxicity

Philadelphia - November 17, 2005 -- A new study presented today 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 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).

The anti-tumor effect in this Phase Ib/IIa 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," 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. Professor Kelly presented the data on behalf of the investigators in the 12:30 - 2:30 pm poster session on Thursday, November 17, at the AACR-NCI-EORTC meeting.

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 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 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. About Phenoxodiol

Phenoxodiol is being developed as a therapy for late-stage, chemo-resistant prostate, ovarian and renal cancers.

Phenoxodiol targets the tumor cell’s cation excretion pump, with the resulting disruption to the cell’s redox potential producing a range of biochemical effects including inhibition of phosphorylation of the key pro-survival sphingosine-1-phosphate and Akt signalling 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 chemo-sensitive patients and to restore sensitivity to those drugs in chemo-resistant patients. Phenoxodiol currently is undergoing clinical studies in the US and Australia.

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

Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer

BMC Clin Pharmacol. 2011; 11 : 1.

Published online 2011 February 3. doi: 10.1186/1472-6904-11-1

PMCID: PMC3045896

Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer

Jan B Howes,¹ Paul L de Souza,^2,⁴ Leanne West,³ Li Jiu Huang,³ and Laurence G Howes¹

Author information ► Article notes ► Copyright and License information ►

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Abstract

Background

Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer.

Methods

The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection.

Results

Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 ± 0.14 μg/ml after 0.87 ± 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h.

Conclusions

Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion.

Trial registration

Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000

Reference list for phenoxodiol

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