TRAITEMENT DU CANCER COLORECTAL

TREATMENT OF COLORECTAL CANCER

Abrégé anglais

2125293 9311770 PCTABS00022
A method of treating colorectal 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.

Revendications

WO 93/11770 - 8 - PCT/US92/06131
CLAIMS
What is claimed is:
1. A method of treating colorectal cancer in a human afflicted
therewith which comprises administering to such human an effective amount of a
compound of the formula:
<IMG>
wherein:
a) X is hydroxy and R is trimethylammoniummethyl;
b) X is hydroxy and R is N-methylpiperazanylmethyl;
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;
i) X is hydroxy and R is cyanomethyl; or
j) X is hydroxy and R is dimethylaminomethyl.
2. The method of Claim 1 wherein the colorectal cancer is
adenocarcinoma of the colon.
3. The method of Claim 1 wherein the colorectal cancer is
adenocarcinoma of the rectum.
4. The method of Claim 1 wherein the administration is oral.
5. The method of Claim 1 wherein the administration is parenteral.
6. The method of Claim 5 wherein the course of therapy employed is
from about 0.5 to about 25.0 mg/m2 of body surface area per day for about one toabout five consecutive days.
7. The method of Claim 6 wherein the course of therapy employed is
from about 1.0 to about 2.5 mg/m2 of body surface area per day for about five
consecutive days.
8. The method of Claim 7 wherein the course of therapy employed is

WO 93/11770 - 9 - PCT/US92/06131
from about 1.5 to about 2 mg/m2 of body surface area per day for about five
consecutive days.
9. The method of Claim 6 wherein the course of therapy is repeated
at least once at about a seven day to about a twenty-eight day interval.
10. The method of Claim 7 wherein the course of therapy is repeated
at least once at about a seven day to about a twenty-eight day interval.
11. The method of Claim 8 wherein the course of therapy is repeated
at least once at about a seven day to about a twenty-eight day interval.
12. The method of Claim 4 wherein the administration is via short or
long intravenous infusion.
13. The method of Claim 12 wherein the administration is via a 30
minute intravenous infusion.
14. The method of Claim 12 wherein the administration is via a 24
hour intravenous infusion.
15. The method of Claim 5 wherein the course of therapy employed
is from about 1.0 to about 50.0 mg/m2 of body surface area per day for about one to
about five consecutive days.
16. The method of Claim 15 wherein the course of therapy employed
is from about 1.5 to about 5.0 mg/m2 of body surface area per day for about fiveconsecutive days.
17. The method of Claim 15 wherein the course of therapy is
repeated at least once at about a seven day to about a twenty-eight day interval.
18. The method of Claim 16 wherein the course of therapy is
repeated at least once at about a seven day to about a twenty-eight day interval.
19. The method of Claim 1 wherein the compound is topotecan.
20. The method of Claim 12 wherein the compound is topotecan.

Description

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
~S~19~TE S~EE~

~ 125293
WO 93/11770 ~ PC~/US92/06131
-- 2 -- .
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; ~:
S~T~TUTE SliET

~o 93/11770 2 1 2 ~ Z 9 3 P~r/US~2/06131
-- 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. :
'~,,
SU~ITUTE S~l~ET ~ ~

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:
~~ IT~ S'~ET ~

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. ~
,.'.;
.
S~B~T!TUTE S~EET ;