Note: Descriptions are shown in the official language in which they were submitted.
WO 93/11770 ~ ~ 2 5 2 ~ 3 I"~JllS92/~6131
TREATMENT ~F COLOR~(~AL G9NCER
This in~ren~aon rela~es ~o a meth~ of treadng colorectal cancef in a
human afflicted therewith which comprises administenng to such human an :~
effec~ive amount of a compound of ~he water soluble camp~oth~ill analog elass,
such as topo~ecan.
The s~uctuIe of the DNA helix within eukaryotic cell~ ~poses
certain topol~gical pr~blems ~hat the cellular apparatus must s~lve in oqde~ to use i~s
~gene~c matelial as a templa~e. The separation of the I)NA s~ds is fundamelltal to
cellular processes such as DN~ ~eplication and ~ans~ip~ion. Since eukary~c :~
D~A is organi;~ed into ch~oina~n by chromosomal proteins, ~e ends are const~ained ~::
and the s~ands cann~t unwind without dle aid of enzymes ~hat alt~ topol~y. It has
long been recogniæd ~at the advancement of the ~sc~ip~ion ~ r~plic~tion
complex along the D~A hehx w~uld be ~aGilieated by a s~vel ~t: w~ich would ~ `
reheve the torsional s~ain genera~ed dllling ~lese processes.
: Topoisomerases are enzysnes that a~e capable of:alt~ring DP~A
topology in eukary~c cclls. They are cntical for imp~r~ant ccllular functions a~d
cell prolifera~ion. Thele ~e ~wo classes of t~poisomerases in eu'xaryotic cells, type I
and type II. : ~ :
2s Topoisom~rase I is a mvnomerac enzyme of ~pproxima~ly 100,(300:
molecular weight. The enzyme binds eo DNA and in~uc~: a ~ansient single-
s~d br~k, unwinds the double helix (or allows it to ~nwind), an~ subsequendy
reseals the br~ak before dissoeiadllg i~om the DNA strand. -~
Campto~hecin, a water-insoluble aLlcaloid produee~ by ~es ~;;
indigenous to China and Is~dia, and a ~ew othes congeness thereo~ the only class ~ ~:
of compounds known to ~hibit topoisomerase I.
- Camptotheein and other t~poisome~ase I inhibinng congeners have
not proven to ~e at~actiYe for clinical drug development as cytolytic agents because
of lack of clinical e~fieacy, unaccept3ble dose-limi~ng toxicity, unpredictable
t~xicity, poor aqu~us solubillty, and/or unacceptable shelf li~e stability. :~
The~ose, ~er~ is a need ~or topoisomerase I inhibitir~g ager~ts which
avoid the af~rementioned undesirable features of camptothecin and related
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WO 93/11770 ~ PC~/US92/06131
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topoisomerase I inhibi~ing congeners. Topotecan, or any compound of the water
soluble camp~othecin analog class, is a specifi~ inhibitor of DNA topoisomerase I
which fulfills such nced.
s This inven~ion relates to a method of ~a~ing eolorectal cancer in a
human afflicted therewith which comprises adminislterilag to such human an
e~c~ive am-ount of a compound of the water soluble camptothecin analog class. `
This inYen~ion also relates to a meth~d of ~aeating colore~tal cancer in
a human a~icted therewith which comprises administering to suclh human an
ef~ec~ive amount of ~opo~can.
~ ...
By ~he tenn "a compound of the water solub~ campto~hec~ analog
class" is meant any compound claimed in U.S. Paten~ Number 5~004,75~, filed
No~ember 2, 1988, in view of ~e No~ice of Allowability mailed October 12, 1990,
the entire disclosure of which is he~by inc~ ra~d by reference. The p~para~on
of any compound of dle w~ter soluble camptoth~io analog class (includin~
pha~naceu~cally acceptable salts, bydrates and solvates th~reof) as well as the
prepara~ion of o~al and parenteral phannaceu~al cnmposidon~ compr~sing a
compound ~f the wa~er soluble c~nptothecin arlalog class and an irler~
ph~aceudcally acceptable camer ~r diluent, is extensively desclibed in U.S.
Pa~ent Number 5,004,758. I he same ex~ensive des~ription îs found in European
Patent Applicadon Number B8311366.4, pu~lished orl June 21, 1989 as Publica~on :
Number EP 0 321 122, the entire disclnsure of which is hereby incoIporated by
refer~nce. lP~fe~r~ compounds of the water soluble camp~oth~in analog class ~:
2s include those compounds of the fonnula:
R
X~
;~
wherem:
a~ X is hydroxy and R is ~imedlylammoniummedlyl;
b3 X is hydroxy and R is N-methylpiperazinylmethyl; ~:
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-- 3
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-dlimethylaminoe~yloxymethyl;
f) X is hyd~oxy and R is cycl~propylaminomethyl;
S g) X is hyd~xy and R is m~rpholinomethyl;
h) ~f is hydr~xy and R is aminomethyl; and
i) X is hydroxy and R is cyanomethyl; and
j) X is hydroxy and R is dimethylaminome~hyl.
Topo~ecan is t~e most prefe~ compound of the water soluble
camptothecin a~alog class. By the te~m "topotecan" as used he~ein is anean~ ~he ::~
compound oi~ the f~mula~
C H3 ;
~3 ~
~ E ~
~SO : ,'`'
(S3-9-dimethyl~ninomethyl-l~hydroxycamp~o~ecin
and any pharmaceu~cally accep~able salt, hydrate or sol~rate the~ Topotecan's ~ .,
chemical naIIIc is (S)- l O~(dimethylan~ino)methylJ-4-e~hyl~,9-diKydloxy- lH~
pyrano[3',4:6,7]in~olizino[I,2-b]quint)lo;le-3,14(4~I,12H~)~dione.
Topotecan is wate~-soIuble by ~rirtue of the preænce vf the basic side~
chain a~ posi~on 9 wh~ch f~s sa~ts with a~cids. Prefe~ed salt ~orms of ~opotecan:: ~:
inclllde the hyd~ochl~ide salt, acetate salt and me~anesulfonic acid salt. A alkali
metal salt fonn of the carboxylate fonned on a~ iDe hyd~lysis:o~ the E-ring
lactone of topo~ecan would also yield a soluble salt, such as the sodium salt.
lhe pr~paration of topote6an ~including pharmaceu~cally acccp~able ~;:
salts, hydrates and solvates thereof) as well ~ the prepara~on of ~ and par~nteral ~: ~
pharmaceu~ical compositions comprising topotecan and an inert, pha~naceu~ally : :
acceptable ca~r or diluent~ i~ ex tensively descn~ed in U.S. Pa~ent Number ~
5~004,75~. The same extensive d~ rip~on is ~und in European Paterlt Applic~on
Number 883 l 1366.4, published on ~unc 21 j~ 1989 as Publicadon Numlber 3~P O 321 `;
1~2. :
'~,,
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WO 93/1~770 2 1 2 ~ 2 9 3 P~/US92/06131
This invention relates ts) a method of trea~ing colorectal cancer in a
human afflicted therewi~h which comprises a~ninistering to such human an
effec~ve amount of a compound of the water soluble camptothecin analog class.
One preferred aspect c>f thi~. inven~ion relates to a method of trea~ing colorectal
S cancer in a human afflicted therewith which comprises ~dministering ~o such human
an ef~ctive amount of topotecar1.
By the term "colorectal cancer" as used herein is mean~
adenocarcinoma of the colon andl~r rectum.
By the term "trea~ng colo~ectal cancer" as used herein is meant the
10 inhibition of the growth of col~rectal cancer cells. l~eferably such ~eatment a Iso
leads to tile Tegression of tum~r growth9 i.e.~ the decrease in size of a measurable ~:
tumor. Most preferab}y, such trea~nent leads to the comple~e regression of dle
tumor. Most preferably such therapy is ini~iated p~omptly af~er surgical albla~ion of
visible col~rectal cancer.
1~ By the term "administenng" is meant pa~enteral or oral
adminis~a~ion. By "parenteral" is meant intravenous, subcutaneous and
intramuscular adminis~ra~ion.
}3y the term "ef~ective amoullt ~f a cornpound of the water soluble
camp~othecin analog class" and "ef~cti~e amoun~ of topotecan" as used he~ein is
20 meant 2 COl;lISe of ~herapy which will result ~ ~eati-ag colo~ctal cance~. It will be
appr~iated ~hat the actual preferred course of therapy will vary a~co~ding to~
~, the mode of adminis~ation, the paracular formula~ion of a compound of dle
water soluble camp~othecin analog class (such as top~tecan) being utilized, the
mode of adminisl:ra~ion and ~he pardclllar h~st being ~ea~ed. The ~p~mal course of
~5 th~apy for a given set of conditions can ~ asce~ned by those skilled in the art
using conventional course ~ ~herapy dete~nination tests in view of the inf~rma~on
set out herein, as well as the inf~rmai~on outlined in U.S. Patellt Nurnber 5,0~,758.
The same in~orma~ion is found in Eu~pean Patent Applica~ioll Num~r
883l l366~4, published on June 2l, l989 as Publicaaon Number ~P 0 321 l22.
For parenteral adminis~a~ion of a compound of the water soluble
campto~hecin analog class, the course of therapy generally employed is ~rom abs)ut
0.5 to about 25.~ mg/m2 of body sur~ace area per day for a~ut on~ to about five
eonseeu~ive days. More pr~erably9 the course of ~erapy employed is from about
l.0 ao about 2.5 mglm2 of ~y su~facç area per day fo~ about ~lve conse~u~ve -
days. Most p~efe~ably, the c~urse of ther~py employed is fr~m about l.~ to about 2
mg/m~ of body surface area per d~y for about five consecu~ve days. Prefçrably, the
SU~TITUT~ S~EET - ~
WO 93/11770 2 12 5 2 9 3 PCT/US92J06131
course of therapy is repeated at least once at about a seven day to about a twenty-
eight day interval (from the date of initia~ion of therapy) depending upon thc ini~al
dosing schedule and the patient's reco~ery of no~mal ~issues. Most preferably~ ~he ~:
course of therapy con~nues to be repeated based on tumor response.
s P~efera~ly, ~he parenteral adminis~a~srl will be by short ~e.g., 30
minute) or prolonged te.g., 24 hour) in~avenous infusi~n. ~lore p~eferably, the
topotecan will be adT~inistered by a 30 minute in~venous infusion.
At ~is ame, it is believed tha~ the m t pre~e~red course c~f par*nteral
therapy to be employed with topotecan for a p~e~ously non-~eated or lightly ;:~
0 pretreated patient is an initial ~ourse of ther~py of 1.~ mg of topo~anJm~ of body
surface area pe~ day administeT~d by short in~aYen~us ;nfusion f~r Sve consecudve :
days. When the patient has recovered sufficiendy ~m the drug-rela~d e~ects o~ ::
this ini~ial course, an ad~inonal course ~ therapy of 2.0 mg of t~potec~/m2 ~f
body sur~ace area per day is adminis~ered by short intravenous inPusion f~r fivelS consecu~ive days, to be rep~ated based Oll tumor res~nse.
Ae ~is dme, it iS belieYed that dle most p~ d cou~se o~pa~ente~ ~:~
therapy to be employed with ~opotccan ~o$ a heavily pretreated pahent is ~n in~al ;
course of therapy of 1.0 mg of topotecaI-Jm of body sur~ace area pe~ day
administered by sh~rt intravellvus in~usion for fi~e cDnsecll~ve days. When ~e -~
patient has recovered suffil~ielltly ~m the drug-l~lated e~fects of thîs inidal course, :
an additional course of therapy of 1.5 mg ~ topotecan/m of body surface ~a per
day is administered by shore intravenous infi~sion for five consecutive days, sud
course of therapy to be repeated based on tum~r response.
P~r a~al administradon of a compound of the water soluble
2s camptothecin analog dass, the co~se ~ the~apy gen~rally employed is from about ::
1.0 to about S0.0 mgJm ~ body s~ace area per day ~or abou~ one to five
consecu~ive days. More preferably, the course of ~herapy employod is ~r~m about
1~5 to about 5.0 mg/m of body surface ~a per day for about five consecunve
days. Pre~erably, the course of therapy is repeated at least once at about a seven day
tO about a twenty-eight day interval (from the da~e of initi~on of ther~py)
depending upon ~he init~al ~sing schedule and the pa~ient's ~ecoves~ of no~mal
tissues. Most preferably~ the course of therapy conhnues ~o be repeated based ontumor response. ~
~1_ -'.
Topotecan is cu~endy unde2going Phase I clinical investiga~orl. The
~l~llowing ph~naceu~ical in~onna~on is being supplied to the clinicians:
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WO ~3/11770 ~1~ 5 2 9 3 PCr/lJS92tlK131
-- 6
HQW ~u~plied - As a vial containing S mg (of the base) with 100 mg
mannitol. The pH is adjusted lo 3.0 with HCl/Na(~H. Ly~philiæd powder is ligh~
yellow in color. Intact vials should be stored l~nder refrigeration (2-8 degreesCentigrade). ~;
S SoD~Iio~ n -When Ihe 5 mg vial is recorls~ituted with 2 ml
of Sterile Water for Injec~oll, USP, each ml will coatain 2.5 mg of topotecan as the
base and SO mg of mannitol, USP. Topoteean must not be diluted or mixed with
bufi~ered solutions because of solubility and stability consid~ations.
~ k~ - Shelf life sunfeillance of ~he intact vials is ongoing.
Because the single-use lyophilized dosage f~nn con~ s no andbacterial ~:
preserva~Yes, it is advised ~hat the recons~ituted solutiol~ be discarded eight hours
after initial entry into the vial. Fu~her dilutions of the recons~tuted solu~ion to
concen~a~ons ~ 0.0~ mg/ml and 0.1 mg.ml in 5% Dex~ose Injection, USP,
("D5W") or 0.9% ~odium Chlorid~ Injec~on, USP, ("NS") i~ plas~c bags s~ored at :
lS room temperatu~ yielded ~e following stability results:
20 ~Ç~ ~m~hE~ Q.~m~ ~.
:DSYV 0 1C,~.OO 100.00
9~.29 99.68
24 102.30 98. ~
01.9~ 97.~1
~S O 1~0.00 1~0.0
6 98.58 97.71 ~
24 96.~}1 98.30 :
48 102.03 98.3
T~po~an dilu~ed in saline (10 u~/ml or 500 ug/ml) or dex~ose (6.7
ug/ml or 330 ug/ml) is stable in a hang bag ~r 24 hours with at least 95% recovery.
~D~ - The treatment dose is to be diluted in a fimal volum~
of 150 m~ of Sodillm Chloride lnjec~ion, USP (with~u~ preser~atives3 and -
administere{l over a 3û minute period. The ~ea~nent d~se is to be kept under
refngeration and protec~ed ~rom ligh~ and it is ~o be used wi~lin 24 hours. :~
1~!~
One human pa~ien~ with adenoca~cinoma of the colon, who was
refract~ry to previous standard therapy ~or c~lon cancer, received a course of
TUT~ S~ET :~
wo 93/11770 ~ 1 2 5 2 9 3 P~/~U~92/06131
-- 7
therapy comprising intravenous administra~ion of 1.5 mg of topotecan/m2 of body
surface area by con~nuous iv in~usion over a 24 h~ur p~iod. This course of therapy
has been repeated weekly at l~ast four more ~mes to date, and ~t least a ~lfty percent
~50%) tumor size regression has been observed, and this regression has lasted at ::
s least four weeks. ~
,.'.;
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