Download Yale University School of Medicine, Department of

Phase Ib Study of Oral Phenoxodiol as Neo-Adjuvant Therapy in Squamous
Cell Carcinoma of the Cervix, Vagina or Vulva
1
Masoud Azodi ,
Michael
1
Kelly ,
Thomas
1
Rutherford ,
Peter
1
Schwartz ,
Lisa
1
Baker ,
Gil
1
Mor
and Graham
2
Kelly
Yale University School of Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Section of Gynecologic Oncology ,
2
Marshall Edwards, Inc.
RATIONALE
Phenoxodiol (PXD) is an inhibitor of
sphingosine-1-phosphate
and
Akt
phosphorylation. Its biological activity is
restricted to tumor cells as a result of its
primary molecular target being tumorspecific NADH oxidase (t-NOX), a regulator
of the plasma membrane quinone-quinol
cation pump. The primary biochemical
target of PXD is the sphingosine kinase-Akt
signaling pathway, resulting in induction of
apoptosis in cancer cells through blockage of
the phosphorylation of the anti-apoptotic
factors, XIAP and FLIPshort.
Phenoxodiol (PXD) is a novel anti-cancer
agent that is being developed in the oral
dosage form as a therapy for cervical cancer,
a second-line therapy for hormonerefractory, docetaxol-refractory prostate
cancer and as a chemo-sensitizer for
carboplatin in ovarian and renal carcinoma.
This study was conducted to evaluate the
toxicity of oral phenoxodiol and, in a
preliminary way, the efficacy of PXD (oral
dosage form) as a monotherapy in patients
with malignant squamous cell carcinoma
(SCC) or adenocarcinoma of the cervix,
vagina or vulva.
OBJECTIVES
•
•
The primary safety objective was to
assess the safety and tolerance to
phenoxodiol in this patient population.
The primary efficacy objective of the
study was to obtain evidence of the anticancer activity of phenoxodiol as a
monotherapy in patients with malignant
SCC or adenocarcinoma of the cervix,
vagina or vulva.
METHODS
Subjects: 16 women with SCC of the cervix
(7), vagina (1) or vulva (5).
Treatment: PXD was administered 8-hourly
for 21-28 days between diagnosis and
surgical resection; 6 women received 50 mg
PXD per dose, 10 received 200 mg per dose;
a further 10 are to be enrolled to receive 400
mg per dose.
Toxicity: Scored according to NCI criteria.
Clinical End-points: Tumors were assessed
for change in size (RECIST) and for mitotic
and apoptotic indices (not reported here).
DEMOGRAPHICS
No. of patients:
Table 2: Phenoxodiol levels
Table 1: MRI Tumor Size
16
Age (n=14): range 45-83 years (mean 64)
Histology (n=14): All Squamous
Patient
Number
01
02
03
04
05
06
11
12
13
14
15
16
18
19
Dose
50
50
50
50
50
50
200
200
200
200
200
200
200
200
Change in tumor
size (RECIST)
+ 8%
+ 7%
+ 34%
+ 13%
- 1%
unchanged
+ 8%
+ 16%
- 20%
unchanged
- 9%
- 2%
- 19%
+ 10%
Classification
SD
SD
DP
SD
SD
SD
SD
SD
SD
SD
SD
SD
SD
SD
50 mg dose: 5/6 patients had stable disease (RECIST
range = 1% reduction to 13% increase) and 1/6
showed progression at the time of surgical resection.
200 mg dose: 8/8 patients had stable disease at the
time of resection with the change in tumor size
ranging from a 16% increase to a 20% reduction.
Cervix 7, Vagina 1, Vulva 5, Not recorded 1
RESULTS - Pharmacokinetics
I:1
IB: 2
IIB:4
III: 5
IIIB: 1 IVA:1
RESULTS - Toxicity
Toxicity:
No drug-associated toxicities or intolerances
were observed or reported.
There was 1 serious adverse event of vaginal
bleeding post biopsy but was considered
unrelated to the drug.
Patient
Number
01
02
03
05
06
11
13
14
15
16
17
18
Dose
Plasma Free Plasma Total Tumour Tumour Total
(mg TDS)
(ng/mL)
(ng/mL)
Free (ng/g)
(ng/g)
50
0.9
4711.5
0
167.13
50
0.0
2968.0
0
571
50
2.0
16183.0
No sample
NS
50
1.8
3149.5
96.24
309.51
50
1.0
3036.0
No sample
NS
200
4.3
6684.0
39.1
248.12
200
2.6
6083.8
0
232.57
200
2.6
5129.9
23.59
360.39
200
4.1
11079.9
13.86
43.26
200
7.5
12803.3
0
973.31
200
8.7
9369.3
0
170.02
200
2.7
17411.9
70.91
393.18
RESULTS - Efficacy
Tumor site (n=14):
IFGO Stage (n=14):
1
USA ;
Plasma and tumor samples were taken and
analyzed for PXD levels after 4 weeks’ of treatment.
The results are shown in Table 2.
Tumor tissue showed considerably higher levels of
unconjugated (free) PXD compared to plasma.
CONCLUSIONS
PXD is present in cervical cancer tissue in the bio-active, unconjugated form,
at least in some individuals. This suggests that cervical cancer tissue may
contain the necessary deconjugating enzymes (glucuronidase, sulfatase) that
convert the conjugated form of the drug (the principal form of the drug in the
blood) to the bio-active free form, and that the free form of PXD then
accumulates in the tumor tissue.
The 28-day period of treatment in this study is a relatively short time to expect
to see any change in tumor burden in these patients. While no toxicity was
observed even in the 200 mg dose stratum, it is encouraging to see that all 8
patients in the 200 mg dose stratum showed no disease progression (based on
RECIST), while 2 of the patients showed a 19% and 20% reduction
respectively in the longest diameter of the target lesion.
The study continues with an evaluation of PXD at the higher dose stratum of
400 mg per dose, and further study of the tumor tissue for changes in mitotic
and apoptotic activities.