Note: Descriptions are shown in the official language in which they were submitted.
. WO92/1~70 210 4 ~ 4 9 PCT/US92/01029
TREATMENT OF ESOPHAGEAL CANCER
~ACKGROUND OF T~E INVFNTION
This invention relates to a method of treating
esophageal cancer in a human afflicted therewith which
comprises administering to such human an effective
amount of a compound of the water soluble camptothecin
analog class, such as topotecan.
The structure of the DNA helix within
eukaryotic cells imposes certain topological problems
lS that the cellular apparatus must solve in order to use
its genetic material as a template. The separation of
the DNA strands is fundamental to cellular processes
such as DNA replication and transcription. Since
eukaryotic DNA is organized into chromatin by
chromosomal proteins, the ends are constrained and the
strands cannot unwind without the aid of enzymes that
alter topology. It has long been recognized that the
advancement of the transcription or replication complex
along the DNA helix would be facilitated by a swivel
point which would relieve the torsional strain generated
during these processes.
Topoisomerases are enzymes that are capable of
aLtering DNA topology in eukaryotic cells. They are
critical for lmportant cellular functions and cell
proliferation. There are two classes of topoisomerases
in eukaryotic cells, type I and type II.
Topoisomerase I is a monomeric enzyme of
approximately 100,000 molecular weight. The enzyme
binds to DNA and introduces a transient single-strand
break, unwinds the double helix (or allows it to
unwind), and subsequently reseals the break before
dissociating from the DNA strand.
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Camptothecin, a water-insoluble alkaloid
produced by trees indigenous to China and India, and a
few other congeners thereof, are the only class of
compounds known to inhibit topoisomerase I.
Camptothecin and other topoisomerase I
inhibiting congeners have not proven to be attractive
for clinical drug development as cytolytic agents
because of lack of clinical efficacy, unacceptable dose-
limiting toxicity, unpredictable toxicity, poor aqueous
solubility, and/or unacceptable shelf life stability.
Therefore, there is a need for topoisomerase I
inhibiting agents which avoid the aforementioned
undesirable features of camptothecin and related
topoisomerase I inhibiting congeners. Topotecan, or any
compound of the water soluble camptothecin analog class,
is a specific inhibitor of DNA topoisomerase I which
fulfills such need.
~UM~ARY OF T~F. I~VENTION
This invention relates to a method of treating
esophageal cancer in a human afflicted therewith which
comprises administering to such human an effective
amount of a compound of the water soluble camptothecin -
analog class.
This invention also relates to a method of
treating esophageal cancer in a human afflicted
therewith which comprises administering to such human an
effective amount of topotecan.
DET~ILE~ DE$CRIPTION OF T~F. TNVF~NTTON
By the term "a compound of the water soluble
camptothecin analog class" is meant any compound claimed
in U.S. Patent Number 5,004,758, the entire disclosure
of which is hereby incorporated by reference. The
preparation of any compound of the water soluble
camptothecin analog class ~including pharmaceutically
acceptable salts, hydrates and solvates thereof) as well
as the preparation of oral and parenteral pharmaceutical
compositions comprising a compound of the water soluble
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camptothecin analog class and an inert, pharmaceutically
acceptable carrier or diluent, is extensively described
in U.S. Patent Number 5,009,758. The same extensive
description is found in European Patent Application
S Number 88311366.4, published on June 21, 1989 as
Publication Number EP 0 321 122, the entire disclosure
of which is hereby incorporated by reference. Preferred
compounds of the water soluble camptothecin analog class
include those compounds of the formula:
X~
.. . .
wherein:
a) X is hydroxy and R is
IS trimethylammoniummethyl;
b) X is hydroxy and R is N-
methylpiperazinylmethyl;
c) X is hydroxy and R is N-methylanilinomethyl;
d) X is hydroxy and R is cyclohexylaminomethyl;
e) X is hydroxy and R is N,N-
dimethylaminoethyloxymethyl;
f) X is hydroxy and R is
cyclopropylaminomethyl;
g) X is hydroxy and R is morpholinomethyl;
h) X is hydroxy and R is aminomethyl; and
i) X is hydroxy and R is cyanomethyl; and
j) X is hydroxy and R is dimethylaminomethyl
or any pharmaceutically acceptable salts, hydrates and
solvates thereof.
Topotecan is the most preferred compound of the
water soluble camptothecin analog class. By the term
"topotecan'` as used herein is meant the compound of the
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formula:
CH3
`CH3
D~
E o
(S)-9-dimethylaminomethyl-10-hydroxycamptothecin
and any pharmaceutically acceptable salt, hydrate or
solvate thereof. Topotecan's chemical name is (S)-
lO[(dimethylamino)methyl]-4-ethyl-9,9-dihydroxy-lH-
pyrano[3',9'.6,7~indolizino[1,2-b]quinolone-
10 3,19(4H,12H)-dione.
Topotecan is water-soluble by virtue of the
presence of the basic side-chain at position 9 which
foxms salts with acids. Preferred salt forms of
topotecan include the hydrochloride salt, acetate salt
and methanesulfonic acid salt. A alkali metal salt form
of the carboxylate formed on alkaline hydrolysis of the
E-ring lactone of topotecan would also yield a soluble
salt, such as the sodium salt.
The preparation of topotecan (including
pharmaceutically acceptable salts, hydrates and solvates
thereof) as well as the preparation of oral and
parenteral pharmaceutical compositions comprising
topotecan and an inert, pharmaceutically acceptable
carrier or diluent, is extensively described in ~.S.
Patent Number 5,009,758. The same extensive description
is found in ~uropean Patent Application Numbe-
88311366.9, published on June 21, 1989 as Publication
Number EP 0 321 122.
This invention relates to a method of treating
esophageal cancer in a human afflicted therewith which
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comprises administering to such human an effective
amount of a compound of the water soluble camptothecin
analog class. One preferred aspect of this invention
relates to a method of treating esophageal cancer in a
human afflicted therewith which comprises administering
to such human an effective amount of topotecan.
By the term "esophageal cancer" as used herein
is meant cancer of the esophagus.
By the term "treating esophageal cancer" as
used herein is meant the inhibition of the growth of
esophageal cancer cells. Preferably such treatment also
leads to the regression of tumor growth, i.e., the
decrease in size of a measurable tumor. Most
preferably, such treatment leads to the complete
regression of the tumor.
By the term "administering" is meant parenteral
or oral administration. By "parenteral" is meant
intravenous, subcutaneous and intramuscular
administration.
By the term "effective amount of a compound of
the water soluble camptothecin analog class" and
"effective amount of topotecan" as used herein is meant
a course of therapy which will result in treating
esophageal cancer. It will be appreciated that the
actual preferred course of therapy will vary according
to, ~ nter ~li~, the mode of administration, the
particular formulation of a compound of the water
soluble camptothecin analog class ~such as topotecan)
being utilized, the mode of administration and the
particular host being treated. The optimal course of
therapy for a given set of conditions can be ascertained
by those skilled in the art using conventional course of
therapy determination tests in view of the information
set out herein, as well as the information outlined in
U.S. Patent Number 5,009,758. The same information is
found in European Patent Application Number 88311366.4,
published on June 21, 1989 as Publication Number EP 0
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321 122.
For parenteral administration of a compound of
the water soluble camptothecin analog class, the course
of therapy generally employed is from about 0.5 to about
S 2S.0 mg/m of body surface area per day for about one to
about five consecutive days. More preferably, the
course of therapy employed is from about l.0 to about
2.5 mg/m2 of body surface area per day for about five
consecutive days. Most preferably, the course of
therapy employed is from about 1.5 to about 2 mg/m2 of
body surface area per day for about five consecutive
days. Preferably, the course of therapy is repeated at
least once at about a seven day to about- a twenty-eight
day interval (from the date of initiation of therapy)
depending upon the initial dosing schedule and the
patient's recovery of normal tissues. Most preferably,
the course of therapy continues to be repeated based on
tumor response.
Preferably, the parenteral administration will
be by short ~e.g., 30 minute) or prolonged (e.g., 24
hour) intravenous infusion. More preferably, the
topotecan will be administered by a 30 minute
intravenous infusion. -
At this time, it is believed tha. the most
preferred course of parenteral therapy to be employed
with topotecan for a previously non-treated or lightly
pretreated patient is an initial course of therapy of
1.5 mg of topotecanlm2 of body surface area per day
administered by short intravenous infusion for five -
consecutive days. When the patient has recovered
sufficiently from the drug-related effects of this
initial course, an additional course of therapy of 2.0
mg of topotecan/m2 of body surface area per day is
administered by short intravenous infusion for five
consecutive days, to be repeated based on tumor
response.
At this time, it is believed that the most
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preferred course of parenteral therapy to be employed
with topotecan for a heavily pretreated patient is an
initial course of therapy of l.0 mg of topotecan/m2 of
body surface area per day administered by short
S intravenous infusion for five consecutive days. When
the patient has recovered sufficiently from the drug-
related effects of this initial course, an additional
course of therapy of l.5 mg of topotecan/m2 of body
surface area per day is administered by short
intravenous infusion for five consecutive days, such
course of therapy to be repeated based on tumor
response.
For oral administration of a compound of the
water soluble camptothecin analog class, the course of
therapy generally employed is from about l.0 to about
50.0 mg/m2 of body surface area per day for about one to
five consecutive days. More preferably, the course of
therapy employed is from about l.5 to about 5.0 mg/m2 of
body surface area per day for about five consecutive
days. Preferably, the course of therapy is repeated at
least once at about a seven day to about a twenty-eight
day interval (from the date of initiation of therapy)
depending upon the initial dosing schedule and the
patient's recovery of normal tissues. Most preferably,
the course of therapy continues to be repeated based on
tumor response.
Clin;cal Pharmaceutical Tnformation
Topotecan is currently undergoing Phase I
clinical investigation. The following pharmaceutical
information is being supplied to the clinicians:
How supplied - As a vial containing 5 mg (of
the base) with l00 mg mannitol. The pH is adjusted to
3.0 with HCl/NaOH. Lyophilized powder is light yellow
in color. Intact vials should be stored unde
refrigeration (2-8 degrees Centigrade).
Solution Preparation -When the 5 mg vial is
reconstituted with 2 ml of Sterile Water for Injection,
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USP, each ml will contain 2.5 mg of topotecan as the
base and 50 mg of mannitol, USP. Topotecan must not be
diluted or mixed with buffered solutions because of
solubility and stability considerations.
Stability - Shelf life surveillance of the
intact vials is ongoing. Because the single-use
lyophilized dosage form contains no antibacterial
preservatives, it is advised that the reconstituted
solution be discarded eight hours after initial entry
into the vial. Futher dilutions of the reconstituted
solution to concentrations of 0.02 mg/ml and 0.1 mg.ml
in 5% Dextrose Injection, USP, ("D5W") or 0.9~ Sodium
Chloride In~ection, USP, ~"NS") in plastic bags stored
at room temperature yielded the following stability
results:
~cr~n~ase of Tn;tial Topotecan ~emain;ng in ~olution
~ons~n~rat i:on
20 Di luent T;me (hrs! 0.02 mg/ml 0.l mg/~l
D5W 0 100 . 00 100 . 00
6 99.29 99.68
29 102.30 98.16
48 101.98 97.91
NS 0 100.00 100.00
6 98.58 97.71
2q 96.01 98.30
48 102.03 98.35
Topotecan diluted in saline (10 ug~ml or 500 ~ -
ug/ml) or dextrose (6.7 ug/ml or 330 ug/ml) is stable in
3S a hang-bag for 24 hours with at least 95% recovery.
Treatment dose - The treatment dose is to be
diluted in a final volume of 150 ml of Sodium Chloride
In~ection, USP (without preservatives) and administered
over a 30 minute period. The treatment dose is to be
kept under refrigeration and protected from light and it
is to be used within 24 hours.
Util;ty
One human patient with metastatic esophageal
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cancer, who was refractory to at least one previous
chemotherapeutic regimen with a compound or compounds
other than a water soluble camptothecin analog, received
a course of therapy comprising intravenous
S administration of 1.5 mg of topotecan/m2 of body surface
area per day for five consecutive days. This course of
therapy was repeated at least two to three times at
twenty-eight day intervals (from the date of initiation
of therapy) for a total of at least three to four
treatments. Tumor size regression was evaluated by
physical measurement of the affected lymph nodes. Tumor
size regression was observed following the first course
of therapy of the above-outined treatment regimen. This
clinically significant response was maintained at least
through the third to fourth treatment.
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