About Phenoxodiol
Frequently asked questions
Clinical Trials
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Interim Results of a Phase Ib/IIa Study of Oral Phenoxodiol in Patients
with Late-stage, Hormone-Refractory Prostate Cancer
Robert Davies1, Mark Frydenberg2, Alastair Tulloch3, Graham Kelly4
1. Sir Charles Gairdner Hospital, Perth, Australia;
2. Monash Medical Centre, Melbourne, Australia;
3. St John of God Hospital, Perth, Australia;
4. Marshall Edwards, Inc.
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Rationale
Objectives
Methods
Demographics
Results
Conclusions
RATIONALE
Phenoxodiol (PXD) is a small-molecule, signal transduction regulator that induces apoptosis in tumor cells via both the extrinsic and intrinsic apoptosis pathways. A primary effect of PXD is down-regulation of expression of the anti-apoptotic proteins, c-FLIP and XIAP (Fig. 1). PXD potently synergizes in vitro and in vivo the cytotoxic effects of standard chemotoxic drugs, and restores sensitivity to such drugs in chemo-resistant tumor cells, including human prostate cancer cells.
This study was conducted as a preliminary step in the use of PXD in combinational therapy in men with late-stage, hormone-refractory prostate cancer.
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Fig. 1. FLIP and XIAP. Targets of PXD in tumor cells
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OBJECTIVES
The primary objectives were:
- to establish the safety profile of oral PXD
- to establish the pharmacokinetic profile of oral PXD
- to confirm a biological effect of oral PXD on PSA levels
- to identify a suitable dose of PXD to take
into a Phase II combinational study
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METHODS
Subjects: Twenty-four (24) patients with late-stage, hormone-refractory prostate cancer.
Treatment: PXD was administered orally, 8-hourly. Three treatment cycles of 21 days of treatment followed by 7 days without treatment. Repeated treatment cycles until disease progression.
Inter-patient dose escalation of PXD (20, 80, 200, and 400 mg per dose), with 6 patients per dose stratum.
Toxicity: Scored according to NCI criteria.
PSA Response: Measured at 3 and 6 months
| progression - |
PSA >25% higher than baseline |
| stabilization - |
PSA within 25% of baseline |
| response - |
PSA at least 25% below baseline (further\
divided into 25-50% decline and 50-75% decline) |
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DEMOGRAPHICS
No. of patients: 24
Age: range 56-85 years (mean 72.1)
Gleason Score: range 7-9 (mean 8.1)
Baseline PSA (ng/mL): range 1.4 - 118 (mean 59.5)
Anti-androgen therapy: 22/24 (during study) |
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RESULTS
Toxicity:
No drug-associated toxicities or intolerances were observed or reported.
There were 4 serious adverse events, none considered to be associated with PXD therapy.
Pharmacokinetics:
Plasma PXD was almost completely (99.5%) conjugated as the glucuronide and/or sulfate salts.
Steady-state plasma PXD levels were (mean of 3 treatment cycles): 2.0, 6.7, 11.8 and 19.9 ug/mL for the 20, 80, 200 and 400 mg dose strata respectively.
PSA outcome:
Data summarized in Table 1. After three treatment cycles (3 months), PSA levels progressed in 12 patients, were stabilized in 6 patients, and declined in 6 patients. There was a trend towards a dose-response effect, with 2/6 patients in the 400 mg dose stratum showing a > 50% decline. |
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Table 1: PSA response at 3 months
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CONCLUSIONS
1. PXD (oral dosage formulation) was well tolerated by patients with late-stage prostate cancer, with no evidence of toxicity or intolerances when dosages of 200 mg were given t.i.d. for periods up to 40 weeks, or dosages of 400 mg t.i.d. for 14 weeks.
2. PXD given on an 8-hourly basis achieved steady-state blood levels with no evidence of accumulation over periods up to 40 weeks.
3. A dose-response effect of PXD on PSA levels was found, with 6/12 men treated with higher dosages of PXD (200 and 400 mg) showing a decline in PSA levels.
These results justify conducting a new study in which PXD will be used in combination with standard taxane or platinum chemotherapy in men with late-stage, hormone-refractory prostate cancer.
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