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Ovarian Cancer
Table 1: Phase I and II Clinical Studies
13mg/kg and the highest dose stratum was 58mg/kg. The dosages used and
duration of treatment are shown in Table 2. There were no drug-associated
Dose Stratum n PSA Decline* Patients with PD Time to Progression toxicities or intolerance in any dose strata with PXD. No evidence of tumor
(mg) by 6 Months** (Weeks)***
response was observed, and the study was terminated due to the inability of
20 6 0 6 35
the blood to deconjugate glucuronide or sulfate moieties of PXD. Combined
80 6 0 6 58
with the high level of susceptibility of PXD to conjugation, this made
200 5 1 2 70
hematological cancers an inappropriate clinical target for PXD.
400 8 2 3 86****
* Prostate-specific antigen (PSA) decline defined as a decrease in PSA level to at least 50% of
Clincal Study 3
baseline for at least one month.
** Disease progression (DP) defined as an increase in PSA levels of 25% compared with
In a phase IIa safety and efficacy study of the neoadjuvant use of oral PXD
baseline and/or deterioration in disease status as determined clinically or radiologically.
in women with a primary diagnosis of squamous cell carcinoma or
*** Time patient remained on phenoxodiol therapy; therapy stopped when patients showed
evidence of disease progression based on either PSA levels or evidence of new lesions.
adenocarcinoma of the cervix, vagina, or vulva, patients were treated with
**** Three patients remained on therapy at last follow-up.
PXD 50 (n=6), 200 (n=10), or 400mg (n=10) eight-hourly for 28
consecutive days on a neoadjuvant basis prior to surgical resection;
Table 2: Details of Phenoxodiol Therapy in Seven Patients with
26 patients completed treatment. Tumor response was assessed over the
Hematological Cancers
28-day treatment period by both a change in tumor burden using
the Response Evaluation Criteria in Solid Tumors (RECIST) and by
Patient Number Dosages (mg/kg/12 Hours) Duration of Therapy (Days)
01 16, 18, 26 51
histochemical evidence of a biological effect (e.g. apoptosis). No
02 16, 26, 36 43
incidences of PR have been recorded (against RECIST criteria), although
03 16, 26 29
many patients have shown a reduction in the sum longitudinal diameter
04 13, 23, 26, 36 47
of between 20 and 27%. Of the six patients treated with PXD 50mg, the
05 13, 18, 23, 26, 36 30 incidence of stabilized disease (SD) and disease progression (DP) was two
06 26, 36, 47, 58 15 and and four, respectively. Of the eight patients treated with PXD 200mg,
07 18, 26, 47 42
the incidence of SD and DP was eight and zero, respectively. The data for
the 400mg stratum have yet to be collected. This trend suggests an
NADHoxidase (tNOX), which is thought to be involved in the transfer of antitumor effect of PXD in this setting, a fact supported by histological
electrons from intracellular NADH to an extracellular acceptor via plasma evidence showing an increase in apoptotic index and decrease in mitotic
membrane ubiquinone.
13
index in the 200mg stratum. There was one
1
serious adverse event (SAE)
deemed definitely related to PXD: prolonged bleeding time in a patient on
Clinical Studies the 400mg arm. The data are currently being cleaned and will be available
There have been eight clinical studies in which patients have been treated for analysis shortly.
with oral PXD.
Clincal Study 4
Clinical Study 1 In a current phase Ib safety and efficacy study of PXD in combination
In the phase Ib/IIa safety and efficacy study of PXD in males with hormone- with cisplatin or carboplatin in patients with advanced or metastatic
refractory prostate cancer (HRPC) trial, 30 patients enrolled in a treatment cancer not suitable for surgery or radiotherapy, 25 patients were treated
cycle of 28 days where PXD was given every eight hours for 21 days at with a oral PXD in combination with cisplatin or carboplatin. The primary
dosages of 20, 80, 200, or 400mg and, prior to a protocol amendment, two objective of this study was to determine the recommended phase II dose
patients were enrolled at 360mg per dose. Patients received six treatment of PXD in combination with cisplatin or carboplatin. Patients were given
cycles (six months) or were treated until there was disease progression. At six oral PXD 50 (n=6), 100 (n=6), 400 (n=6), or 800mg (n=7) every eight
months, those patients considered by the principal investigator to be deriving hours daily for 10 consecutive days followed by 11 days of rest. In
a clinical benefit were continued on PXD therapy. addition, patients received either cisplatin 50mg/m
2
on days two and
nine of each 21-day cycle or carboplatin area under the curve (AUC)=5
Twenty-five evaluable patients with HRPC have been studied. Six patients on day three every 21 days. The dose-limiting toxicity (DLT) was diarrhea
were treated in 20 and 80mg dose strata, five at 200mg dose levels, and at the 800mg dose level and the maximum tolerated dose (MTD) was
eight at the 400mg dose level. There were no drug-associated toxicities or determined to be 400mg orally every eight hours. In this trial there were
intolerance in any dose strata for the six months of treatment. The four serious adverse events: two cases of diarrhea, one case of
eight-hourly dosing regimen resulted in steady-state plasma levels of drug ventricular arrhythmia, and one case of vomiting. All of these patients
with no accumulation over time. The mean steady-state PXD levels in the 20, also received cisplatin therapy. The data are being analyzed for this study
80, 200, and 400mg dose strata were 1.57, 8.14, 16.31, and 27.19µg/ml, and the report is being prepared.
respectively. The clinical outcomes of the study are summarized in Table 1.
Clincal Study 5
Clinical Study 2 In a phase II evaluation of PXD in combination with cisplatin or paclitaxel in
In a phase IIa evaluation of oral PXD in patients with hematological cancers, women with a history of platinum/taxane-refractory or -resistant epithelial
seven patients were evaluated with oral PXD every 12 hours over 42 days with ovarian, fallopian tube, or primary peritoneal cancers, patients with
an intended dose escalation every 14 days. The lowest dose stratum was recurrent (n=60) late-stage epithelial cancer are being treated with weekly
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