Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
METHODS TO POTENTIATE INTRAVENOUS
ESTRAMUSTINE PHOSPHATE
This application claims priority to U. S. Provisional Application serial No.
60/079.542. which was filed on March 27. 1998.
BA KGROUND OF THE INVENTION
Field of the lnven~,on:
The present invention relates to the use of estramustine phosphate, a non-
nitrogen mustard carbamate derivative of estradiol-17b-phosphate. as a high
dose
infusion. The present invention further relates to methods to potentiate
intravenously
administered estramustine phosphate and to methods for treating cancer by
intravenously administering estramustine phosphate.
Discussion of the Back~Qund:
Cytotoxic effects have been shown to be due to the intact estramustine
molecule (Hartley-Asp, 1982). Tissue culture studies have shown that
estramustine
(EM) is an anti-mitotic agent. causing a dose-dependent blocking of tumor cell
division in the metaphase (Hartley-Asp, 1984). Metaphase arrest is known to be
caused by an interference of drugs with the microtubule structure that forms
the
2U mitotic spindle. It has been shown, with the help of immunohistochemistry.
that dose-
dependent disturbances of interphase microtubules occur in cultured human
prostatic
cells (Mareel 1988. Dahllof 1993). Treatment with EM in vitro inhibited the
assembly
of microtubules composed of only tubulin demonstrating a direct interaction
with
tubulin (Dahllof 1993). In addition. an interaction with microtubule
associated
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proteins (MAPS) has been demonstrated (Steams 1988). MAPS are high~molecular
weight proteins that are believed to be important in stabilizing microtubules.
That EM
exhibits the mechanism of action of an anti-mitotic agent has been confirmed
in vivo
( Eklov. 1992).
Estramustine phosphate is thus an anti-mitotic agent currently used in the
treatment of advanced adenocarcinoma of the prostate. As a single agent. its
activity
in hormone-refractory prostate cancer is comparable to that of several other
cytotoxic
agents that have been studied in a series of mufti-institutional. randomized
trials by
the National Prostatic Cancer Project (Murphy. 1983). While the drug is
usually
administered orally at a dose of 10-1 ~ mgikg/day. it is approved for
intravenous
administration in several countries. However. estramustine phosphate when
administered intravenously has been used at dosages and according to a
schedule
paralleling the oral administration for the drug, i.e. at recommended dosages
of 300-
600 mg daily given intravenously and usually repetitively over for several
consecutive
days. This is then followed by orally administered drug.
In the published material. details from about X00 patients who have been
treated with the intravenous formulation initially which was then followed by
oral
treatment can be found. Induction schedules employing 300-600 mg intravenous
daily
for 7-21 days. followed by daily oral doses. were typical in these studies.
The drug
30 was administered as a slow intravenous injection or as a bolus at 30U
mg/day. and
thrombophlebitis and local irritation at the peripheral intravenous injection
sites were
considered major limitations of drug administration requiring the
establishment of
central line administration in many patients or discontinuation of treatment.
At 450
mg/day. Nagel and Kolln ( 1977) stated that this led to so "severe
Lastrointestinal
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problems that 300 mgidav was taken as the maximum intravenous daily-dose." In
a
compilation, by Andersson et al. of 245 patients receiving: 300-600 mg /day
for 2ldays
followed by the same dose once or twice weekly for 2 months, 20% of the
patients
exhibited thrombophlebitis. 17% exhibited gastrointestinal problems and 9%
exhibited liver disturbances. Toxicities resulting from such repetitive dosing
schedules often require drug discontinuation (Lundgren. I 9951. Maier ( 1990),
administered daily intravenous doses of 900 mg/day for 7-10 days, followed by
oral
therapy, without reporting phlebitis but severe liver problems did occur in 11
of 18
patients (61%) with one death due to toxic Liver failure.
The state of the art thus typically utilized intravenous estramustine
phosphate
formulations as a single-agent method for initiating a long term oral
estramustine
therapy. Furthermore. intravenous administration of estramustine phosphate at
higher
dosages is generally considered prohibitive due to toxicity. It is neither
known nor
obvious to the art that single dose. high-dosage administration of
estramustine
1 ~ phosphate is feasible intravenously. While dosing up to 1200 mg/m1 have
been given
orally (Keren-Rosenberg, 10971, differences in drug metabolism and
bioavailability do
not permit extrapolation to the high dose intravenous formulation, with
relative
bioavailabilitv of estromustine after oral administration found to be onlv
44%.
(Gunnarsson, 1984), with the phosphate moiety dephosphorylated in the oral
?0 formulation in contrast to the intravenous formulation. Furthermore, it is
not known
in the art that intravenous estramustine phosphate can be used in
combinational
chemotherapy recimens, including the use of higher dose intravenous
estramustine
phosphate. Furthermore. it is not known to the art that intravenous
estramustine
phosphate has clinical utility for cancers other than for the prostate cancer
indication.
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In previous work, Dr. Beryl Hartley-Asp. a co-inventor of this invention. was
the tirst to recognize the synergistic potential of estramustine phosphate
va~ith other
cytotoxic agents. (Mareel 1988). In several experiments. it was demonstrated
that
prolonged exposure to estramustine was necessary to achieve potentiation.
i Consequently. daily dosing was deemed necessary leading to the use of the
URAL
preparation as previous data from the intravenous (IV) preparation suggested
that
achievement of constant high levels would not be clinically achievable with IV
dosing.
Additive and possibly synergistic antimicrotubule effects in cells in vi~rn
have
been shown for estramustine and many other cytotoxic agents, (Mareel 1988,
Speicher
1992. Pienta 1993, Batra,1996). 'Thus, the combination of estramustine
phosphate
with other drugs in humans has been carried out using ORAL administration of
estramustine phosphate. Phase II trials (Seidman, 1992. Hudes, 199?. Pienta.
1994,
Hudes, 1996) with Estramustine phosphate combined with vinblas~inc~. have been
carried out in hormone refractory prostate cancer. In these trials a ~0-75%
decrease in
prostate specific antigen was demonstrated among 88 patients. The most
frequent
toxicity was mild to moderate nausea. Of particular note is the 10.~°/~
(4/37)
incidence of significant cardiovascular toxicity including one deep venous
thrombosis
(DVT). one myocardial infarction. one episode of congestive heart failure. and
one
reversible neurologic event which required stopping therapy in these patients
and
which can be attributed to estramustine phosphate. In another Phase II trial
carried out
by Pienta et al ( 1994), estramustine phosphate (oral) was combined with
Etoposide.
Fifty two patients were evaluable: including ?U patients with soft tissue
disease. in
which 3 complete responses {CR) ( 1 ~%) and 6 partial responses (PR) ( 30%)
were
4
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observed. In 32 patients with bone metastases 8 patients improved (25%), and
12
patients were stable (38%). Overall 13 men (25%) had a 7~% decrease in
prostate
specific antigen, and 28 men f s~l%) had a 50% decrease. :~ Phase i-II study
of Taxol
(Hudes. 1992) and estramustine phosphate was carried out in seventeen patients
with
hormone refracton~ prostate cancer. Six patients had measurable disease and 3
of
these obtained a PR of ?+. 6. and 8 months. Prostate specific antigen (PSA)
decreased by >_ ~0% in X8.8%. Median duration of response was 7 months. Grade
3-
4 granulocytopenia and mucositis occurred in 2 patients. nausea c:rade 1-2
(70.5%)
and grade 3 in one patient. Edema was seen in 8 patients (47%1 and transient
hepatic
I 0 enzyme elevation of grade 1-3 in 6 patients (35.2%).
In a recent study, Petrylak et al., (1997), using escalating doses of
docetaxel
with estramustine phosphate given orally demonstrated an overall prostate
specific
antigen response rate of 62%. In patients with bidimensionally measurable
disease, 3
(43%) achieved a partial response in lymph nodes. and 1 achieved a minor
response in
l5 ischial mass. This demonstrates that combination treatment with ORAL
estramustine
phosphate is efficacious. However, combinations of intravenous estramustine
phosphate with these cytotoxic agents are not known to the art. Differences in
the
metabolism, particularly regarding the phosphate moiem. in the oral versus
intravenous estramustine phosphate formulations make combinational therapies
with
?U the intravenous formulation non-obvious.
In contrast to other anti-mitotic agents, the effect of estramustine phosphate
appears to be dependent on the presence of the estramustine binding protein
(EMBP)
(Eklov, 1996). This is found under normal conditions only in the prostate
(Forsgren.
1979, Flucher. 1989). I-lowever. a similar protein has also been identified in
many
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cancerous tissues, as well as prostate tumors. such as lung, breast glioma.
colon,
pancreas (Bjork.1991, Bergh 1988. Ekl6v 1996. Edgren 1996. Von Schoultz. 1994,
Bergenheim, 1993). This protein binds estra- and estro-mustine (EaM and EoM)
with
very high affinity and is thought to be responsible for the selective
retention of EoM in
the prostate tumor, where a ratio of I :6 to 1: I 1 plasma/tumor has been
found in
prostate cancer patients treated with estramustine phosphate oral and
intravenously,
respectively {Norlen 1988,Walz 1988). Recently, we have demonstrated a
correlation
between the levels of EMBP and the levels of EaM and EoM in human prostate
tumors after a single intravenous estramustine phosphate dose to patients
before
I 0 radical prostatectomy, indicating that EMBP could be the cause of drug
retention
( Walz. 1996).
BRIEF DESCRIPTION OF THE FI(;rURFS
A more complete appreciation of the invention and many of the attendant
advantages thereof will be readily obtained as the same become better
understood by
1 ~ reference to the following detailed description when considered in
connection with the
accompanying drawings, wherein:
Figure 1 illustrates the concentration of estramustine phosphate after a
single
intravenous dose of Estracyt (mean t SEM. N = 4 + 4 + 3) given at a dosage of
1000
mg (range 980-1070 mg), 1000 mgim=. and 1500 mgim=; and
20 Figure 2 illustrates the concentration of estromustine after a single
intravenous
dose of Estracyt (mean t SEM, n = 4 + 4 + 3) given at a dosage of 1000 mg
(range
980-1070 mg), 1000 rngim=, and 100 mgim'-.
6
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The present invention describes methods of potentiating the therapeutic use
and efficacy of intravenously administered estramustine phosphate. It provides
for the
intravenous administration of estramustine phosphate in dosages exceeding 1300
mg.
It also provides for intravenous administration of estramustine phosphate at
dosages
exceeding 9~0 mg/m= (milligrams per square meter of body surface area). It
further
provides for administration of high dose intravenous estramustine phosphate as
a
single dose, which may further be administered on a weekly or longer schedule.
The
present invention enables optimization of pharmacokinetics as to maximize
I 0 therapeutic advantage, and further enables use of intravenous estramustine
phosphate
in combination with other therapies. including other chemotherapies, providing
further
improved therapeutic benefit. The present invention enables use of intravenous
estramustine phosphate as therapy for multiple tumor types, including
prostate, breast.
lung, ovarian. colorectal, melanoma, pancreatic, and brain cancers.
I 5 Thus. one application of the present invention is to provide high dose
estramustine phosphate therapy intravenously. wherein the dose exceeds 950
mg/m=.
Another application is to provide a schedule of intravenous administration,
whereby that schedule enables optimization of pharmacokinetics of estramustine
phosphate and its metabolites at minimal toxicity, and further whereby said
30 optimization permits convenient and efficacious combination regimens of
therapy.
Thus. an application of the present invention permits the use of intravenous
estramustine phosphate in combination with other therapeutic regimens.
including
cytotoxic chemotherapy.
Another application of the present invention is to provide a method which
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increases binding saturation and prolongs binding duration of estramustine
phosphate
or its metabolites to estramustine binding protein or estramustine binding
protein-like
protein (EMBP).
Thereby, the present invention provides application to treatment of cancers
having EMBP, including but not limited to prostate, breast, lung, ovarian,
colorectal,
melanoma. pancreatic, and brain cancers, by intravenous administration.
Another application of the present invention is to provide a method of rapidly
relieving symptoms secondary to cancer, inclusive of but not limited to cancer-
induced pain and urinary obstruction.
Further, the present invention enables these applications for use of
intravenous
estramustine phosphate independent of the formulation. Thereby. the present
invention provides for the infusion of estramustine phosphate as free drug, as
protein-
bound drug, or as drug within liposomes.
Thereby, the present invention describes a formulation of estramustine
l5 phosphate wherein the estramustine phosphate is administered intravenously
in
conjunction with liposomes.
Thus, the method of the present invention in which doses above 900 mg/m-'
(generally greater than 1300 mg per dose) can be administered safely and
within an
effective schedule is extremely unexpected.
The present invention teaches the advantage of intravenous estrarnustine in
combination with other chemotherapy agents. The present invention further
teaches
the advantage of high dose intravenous estramustine in combination with other
chemotherapeutic a=ents.
We teach in this invention that intravenous estramustine phosphate may be
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used to treat tumors having elevated EMBP-like protein (herein referred to
simply as
EMBPI.
The novel and non-obvious applications of the present invention can be
recognized from a comparison of the pharmacokinetic data following oral
administration estramustine phosphate with that following high-dose
intravenous
administration of estramustine phosphate. 'The pharmacokinetic and toxicity
data
regarding high-dose intravenous estramustine phosphate is not known to the
art.
Dephosphorylation of estramustine phosphate to estramustine (EM), followed by
oxidation at the 17 position to estromustine i EoM), the estrone analogue of
EM. are
the major metabolic steps after administration of oral estramustine phosphate
in man.
Eo~M is the predominant metabolite found in plasma when estramustine phosphate
is
administered on the daily oral schedule. The relative bioavailability based on
estromustine is approximately 44%(Gunnarsson, 1984). After intravenous
administration estramustine phosphate is initially found in plasma but is
rapidly
1 ~ hydrolyzed to the same metabolites as are found after oral administration,
the major
metabolite being estromustine. Both estramustine and estromustine are further
metabolized by cleavage of the carbamic ester to yield approximately 15%
estradiol
and estrone, respectively (Gunnarsson, 1981. 1984). We have demonstrated an
unexpected prolonged availability of the major metabolite estromustine
following
?0 high-dose intravenous administration, which can lead to unexpected clinical
benefits.
Previous data from patients treated with a single intravenous dose of 300 mg
demonstrated that the elimination of estromustine had a half lives of 10-?U
hours. The
main route of elimination was metabolism of estromustine phosphate to
estramustine,
estromustine. esuadiol and estrone. The data of particular importance for the
etf cacy
c)
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of estramustine phosphate was the half lives of estramustine phosphate,
(Figure 1 ),
and the major cytotoxic metabolite estromustine {Figure ?). By application of
the
methods of this invention. we now demonstrate the novel finding that after a
single
high intravenous dose of estramustine phosphate at 100Umgim= it was found that
the
half life of estromustine was approximately 100 hours. (Figure ?). This
finding
further enables therapeutic applications of high-dose intravenous estramustine
phosphate.
DETAILED DESCRIPTION OF THE PREFERRED EM)~ODIMENTS
The present invention teaches the ability to administer estramustine phosphate
l () at doses above 9~0 mgim= (i.e., greater than 1300 mg).
The method of the present invention is performed as follows. In the preferred
method, estramustine phosphate is administered at a single infusion dosage
exceeding
950 rng/m-'. Intravenous administration is performed either through a central
or
peripheral intravenous route. During preparation of the intended drug, the
contents of
l ~ packaged estramustine phosphate intended for intravenous usage are
dissolved,
wherein the packaged contents may consist of but are not limited to a
lyophilized
powder of the meglumine salts in vials of estramustine phosphate, or similar
freeze-
dried estramustine phosphate which are first dissolved in sterile water such
as 5 ml
sterile water per 300 mg estramustine phosphate. or in ~'%~ dextrose in water
for
'_'0 intravenous administration. In the preferred method. ~°% dextrose
in water is used as
the diluent. In the preferred method. during preparation of the dissolved drug
the
preparation should not be shaken. but should be slowly inverted to mix. The
solution
is then given as an intravenous infusion with the preferred duration of
infusion time
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being 30 minutes to 3 hours, whereby infusion over 1-2 hours is a safe and
convenient
method. Saline solution may result in drug precipitation and thereby its use
is not
preferred in the infusion.
When estramustine phosphate is administered through a peripheral intravenous
route, it is preferred that a longer duration of infusion and greater total
infusional
volume be utilized to minimize vascular irritation. Alternatively, the
estramustine
phosphate solution can be mixed with various amounts but preferably 3-~% human
albumin or other plasma proteins including synthetic plasma proteins to
achieve
protein binding= of the estramustine phosphate and therefore minimize any
potential
vascular damage.
The invention may be further realized using other preparations or formulations
of estramustine phosphate. One particularly advantageous preparation of the
chemotherapeutic agent estramustine phosphate which enables infusion of
estramustine phosphate through either a peripheral or central vein. both at
high doses
and also doses less than 1300 mg. involves the infusion of estramustine
phosphate in
conjunction with liposomes (herein referred to as liposome encapsulated
estramustine
phosphate or liposomal estramustine). In one preferred method of preparing
liposomal estramustine, estramustine phosphate solution is first prepared in
the
manner described above and then injected into a vial containing empty
liposomes
?0 available as a lyophilized powder. Following adequate hydration of the
liposomes. the
vials are vortexed and sonicated, followed by infusion into the patient.
When estramustine phosphate is administered through a central venous route.
said administration may be performed through either a temporary or permanent
venous access device, including but not limited to a triple lumen catheter.
Hickman
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catheter. subclavian line, jugular line, or medi-port. Said administration may
be but is
not necessarily performed concomitant with anticoagulant therapy or with the
addition
of varying amounts but preferably 3-5% human albumin or other plasma proteins
or
liposomal estramustine to minimize any potential vascular damage in a given
patient.
While the dosage of estramustine phosphate in the present invention is greater
than 1300 mg, it is preferred that the patient be treated at a dose exceeding
950 mgim=.
Thereby. one preferred method is to administer a single intravenous dosage of
1000
mglm'-. Another preferred method is to administer a single intravenous dosage
of
1500 mg/rn=. Furthermore. a dosage of 2000 mgim= may be administered. However.
the invention is inclusive of other dosages above 950 mgirn= and the preferred
dosages
are not to imply limitation.
The most preferred schedule of estramustine phosphate administration in the
invention is a single infusion given once weekly to a maximal dose of 4000 mg
or
3500 mg/m'-. Another preferred schedule is administration of a single drug
infusion
once every two weeks. Another preferred schedule is administration of a single
drug.
infusion once even three weeks. Another preferred schedule is administration
of a
single drug infusion once every four weeks. Une schedule may be preferred over
another in consideration of schedules with other concomitant therapy. These
schedules may repeat in a serial or repetitive fashion.
?0 The invention described herein enables methods to prolong blood and/or
tissue
levels at high elevations for estramustine phosphate metabolites. including
estromustine. estramustine. estrone and estradiol. Thereby. enhanced
synergistic
interactions with other therapies is enabled, wherein such other therapies
include but
are not limited to chemotherapy, radiotherapy. monoclonal antibodies, and
biologic
12
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WO 99/49869 PCT/US99104275
therapies. The present invention provides maximization of therapeutic benefit
by
prolongation of elevated blood and tissue levels of estramustine phosphate and
its
metabolites. Thereby, maximization of therapeutic benefit is achieved wherein
estramustine phosphate is administered intravenously at dosages exceeding 950
s mg/m=, which are administered in combination with other cancer therapies.
inclusive
but not limited to radiotherapy, chemotherapy, monoclonal antibodies. and
biologic
therapies.
In the preferred method. therapeutic benefit is potentiated by administering
intravenous estramustinc phosphate at single dosages exceeding 9s0 mg/m=. with
I 0 other cytotoxic chemotherapies. In the preferred method said combination
is achieved
by administering intravenous estramustine phosphate within 3 days of the other
chemotherapeutic agents, preferably on the day of, or the day prior to
administration
of the other chemotherapeutic agents. A particularly preferred method is
achieved
when the other chemotherapeutic agents consist of anti-mitotic agents or anti-
1 ~ microtubule agents. inclusive of but not limited to taxanes, including
taxol and
taxotere. and agents including vinblastine. vincristine, etoposide. navelbine.
doxorubicin, irinotecan (CPT-11 ). and liposome encapsulated chemotherapeutic
agents. including; liposome encapsulated taxanes such as liposome encapsulated
paclitaxel. It may be further beneficial if a combination with a monoclonal
therapy is
30 utilized, that the monoclonal agent include a radionucleotide or an anti-
growth factor
agent.
Plasma or serum levels of estromustine are further sustained when
estramustine phosphate is administered intravenously as a single infusion at a
dosage
exceeding 950 mg/m-'. The infusion may optionally be repeated in a serial or
13
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repetitive manner to maintain elevated blood levels of the estromustine
phosphate
metabolites. Sustained levels of estramustine phosphate and its metabolites
thereby
enable sustained therapeutic benefit.
The present invention thereby provides a method to increase the binding
saturation of estramustine or its metabolites to estramustine binding protein
or like-
protein by administering estramustine phosphate intravenously at a single
infusion
dose exceeding 950 mg/m'-. Similarly, the binding duration of estramustine
phosphate
or its metabolites to estramustine binding protein or estramustine binding
protein-like
protein (EMBP) is increased in the invention by administering the drug at
intravenous
i 0 dosages exceeding 950 mg/m'-. Thereby, all cancers having either
estramustine
binding protein or estramustine binding protein like-protein may be treated by
intravenous estramustine phosphate. It is particularly preferred to treat
prostate cancer
in such manner. It is further preferred to treat breast cancer, melanoma, lung
cancer,
pancreatic cancer, colorectal cancer, ovarian cancer. and cancers of the brain
in such
1 ~ manner. It is particularly preferred that estramustine phosphate be
administered
intravenously wherein the single dosage exceeds 950 mg/m'- when treating
cancers
having either estramustine binding protein or estramustine binding protein
like-
protein, inclusive of but not limited to the group of cancers including
prostate cancer.
breast cancer, ovarian cancer, pancreatic cancer, melanoma. lung cancer, and
cancers
20 of the brain.
Said cancers may further be treated using liposomal estramustine. either as a
single agent or in combination with other chemotherapies. Said administrations
are
prei'erablv repeated in serial or repetitive fashion at schedules of the
invention, with or
wvthout combination of other therapies. Thus. said schedules may include
1 ~4
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combinational treatment of intravenous estramustine phosphate with other
chemotherapeutic therapies given on a once weekly, a once every two week, a
once
every three week. or a once every four week schedule, and variations therein.
It is particularly preferred that intravenously administered estramustine
s phosphate be administered in combination with other chemotherapeutic
cytotoxic
agents when used in the treatment of prostate cancer. breast cancer. melanoma,
lung
cancer, pancreatic cancer. colorectal cancer. ovarian. and cancers of the
brain. It is
further particularly preferred that intravenously administered estramustine
phosphate
be administered in combination with radiation when used in the treatment of
prostate
I t) cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer,
and cancers of
the brain. It is further preferred that in treating cancers having
estramustine binding
protein or estramustine binding protein like-protein, including prostate
cancer, breast
cancer, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer, and
cancers
of the brain, estramustine phosphate be administered at intravenous dosages
exceeding
I ~ 950 mg/m'- when used in combination with other cancer therapies.
The present invention enables both objective mid subjective therapeutic
benefit. Benefit achieved may relate to reduction of tumor size, improved
quality of
life, reduction of tumor obstruction, such as urinary obstruction, reduction
of cancer-
induced pain, improved survival. reduction in time to cancer recurrence, or
other
3U evidence of improvement. In particular, rapid objective or subjective
therapeutic
benefit is achieved by administering estramustine phosphate intravenously at a
dosage
exceeding 950 mg/m=, either as a single agent or preferably in combination
with other
cancer therapies. Thereby the invention enables rapid relief of cancer-induced
urinary
obstruction, and rapid relief of cancer-induced pain.
IS
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Other features of the invention will become apparent in the course of the
following descriptions of exemplar<l embodiments which are given for
illustration of
the invention and are not intended to be limiting thereof:
The following clinical cases are provided by way of example and not
i imitation.
Example 1: Two patients with advanced metastatic prostate cancer were
treated with estramustine phosphate intravenously given through a central
line. The
patients received an estramustine phosphate dosage of 2500 mg/m=. Estramustine
1 U phosphate was administered as a single infusion on a weekly schedule in a
repetitive
fashion. Each infusional dose was administered over a 90 minute infusion. The
infusions were well tolerated without serious toxicity and both patients
demonstrated
a response (reduction) in their prostate specific antigen (PSA).
Example 3: Three patients with advanced metastatic prostate cancer were
15 treated with estramustine phosphate administered intravenously through a
central line
at a dosage of 1000 mglm'-. Estramustine phosphate was administered as a
single
infusion on a weekly schedule in a repetitive fashion. Each infusionai dose
was
administered over a 30 minute infusion. The infusions were well tolerated with
several patients demonstrating PSA response.
?U Example 3: Three patients with advanced metastatic prostate cancer were
treated with estramustine phosphate administered intravenously through a
central line
16
CA 02295049 1999-12-22
WO 99!49869 PCT/US99/04275
at a dosage of 1 X00 mym=. Estramustine phosphate was administered as a single
infusion on a weekly schedule in a repetitive fashion. The infusional dose was
administered either over 3U minutes or over 1 hour. The infusions were well
tolerated
with one patient demonstrating a response in bulky tumor adenopathy.
Example 4.: 'I~hree patients with advanced metastatic prostate cancer were
treated with estramustine phosphate intravenously given through a central
line. The
patients received an estramustine phosphate dosage of 2000 mgim=. Estramustine
phosphate was administered as a single infusion on a weekly schedule in a
repetitive
fashion. Each infusional dose was administered over a 60 minute infusion. An
anti-
I 0 thrombotic agent was additionally administered for venous thrombosis
prophylaxis.
The estramustine phosphate infusions were welt tolerated without serious
toxicity, and
with evidence of PSA response.
REFERENCES
Andersson SB, Lundgren R, Svensson L: Gas chromatographic determination
1 s of four metabolites of estramustine phosphate on plasma. Acta Pharm Suec
19:1-10,
1982
Batra S. Karlsson R. Witt L: Potentiation by estramustine of the cytotoxic
effect of vinblastine and doxorubicin in prostatic tumor cells. Int J Cancer
68:1-6.
1996
?0 Bergenheim AT. Gunnarsson PO, Edman K. von Schoultz E. Hariz MI
Henriksson R: Uptake and retention of estramustine and the presence of
estramustine
binding protein in malignant brain tumors in humans. Br .1 Cancer 67:358-361,
1993
17
CA 02295049 1999-12-22
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Bergh J. Bjork P. Westlin J-E. Nilsson S: Expression of an Estra;nustine-
binding associated protein in human lung cancer cell lines. Cancer Res 48:46 i
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This application is based on Li. S. Provisional Application serial No.
60/079.542, which was filed on March'_7, 1998, which is incorporated herein by
reference in its entirety.
20 Obviously, numerous modifications and variations of the present invention
are
possible in fight of the above teachings. It is therefore to be understood
that. within
the scope of the appended claims, the im~ention may be practiced otherwise
than as
specifically described herein.
31