CA2125293A1 - Treatment of colorectal cancer - Google Patents
Treatment of colorectal cancerInfo
- Publication number
- CA2125293A1 CA2125293A1 CA002125293A CA2125293A CA2125293A1 CA 2125293 A1 CA2125293 A1 CA 2125293A1 CA 002125293 A CA002125293 A CA 002125293A CA 2125293 A CA2125293 A CA 2125293A CA 2125293 A1 CA2125293 A1 CA 2125293A1
- Authority
- CA
- Canada
- Prior art keywords
- course
- day
- therapy
- hydroxy
- repeated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Steroid Compounds (AREA)
Abstract
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.
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 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 - ~
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 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 - ~
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 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 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 ;
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 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 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 ;
Claims (20)
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:
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.
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 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80457091A | 1991-12-10 | 1991-12-10 | |
| US07/804,570 | 1991-12-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2125293A1 true CA2125293A1 (en) | 1993-06-24 |
Family
ID=25189304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002125293A Abandoned CA2125293A1 (en) | 1991-12-10 | 1992-07-24 | Treatment of colorectal cancer |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0661977A1 (en) |
| JP (1) | JPH07501818A (en) |
| AU (1) | AU2394392A (en) |
| CA (1) | CA2125293A1 (en) |
| MX (1) | MX9205766A (en) |
| PT (1) | PT100948A (en) |
| WO (1) | WO1993011770A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5552154A (en) | 1989-11-06 | 1996-09-03 | The Stehlin Foundation For Cancer Research | Method for treating cancer with water-insoluble s-camptothecin of the closed lactone ring form and derivatives thereof |
| EP1250926B1 (en) * | 1993-01-15 | 2008-03-12 | The Stehlin Foundation For Cancer Research | Use of a water-insoluble S-camptothecin with a closed lactone ring in the manufacture of a medicament for treatment of colon cancer |
| US6291425B1 (en) * | 1999-09-01 | 2001-09-18 | Guilford Pharmaceuticals Inc. | Compounds, methods and pharmaceutical compositions for treating cellular damage, such as neural or cardiovascular tissue damage |
| ES2371171B1 (en) * | 2010-06-08 | 2012-11-16 | Consejo Superior De Investigaciones Científicas (Csic) | CAMPTOTECHINE DERIVATIVES AS ANTITUMOR AGENTS. |
| CN102477042A (en) * | 2010-11-26 | 2012-05-30 | 复旦大学 | 10-hydroxyamptothecin derivative, and its preparation method and application |
| CN102659800B (en) * | 2012-05-11 | 2014-09-03 | 中国药科大学 | Hypoxia-activated antitumor compounds and application thereof |
| CN103113381B (en) * | 2013-02-26 | 2014-12-10 | 大连理工大学 | Serial water-soluble hydroxycamptothecine naphthenic amino alcohol derivative and preparation method and use thereof |
| WO2021173773A1 (en) | 2020-02-25 | 2021-09-02 | Mediboston, Inc. | Camptothecin derivatives and conjugates thereof |
| CN117462548A (en) * | 2023-03-09 | 2024-01-30 | 兰州大学 | Application of camptothecine derivatives in preparation of medicines for treating bladder cancer |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5004758A (en) * | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
| JPH0641161B2 (en) * | 1988-02-17 | 1994-06-01 | 積水化成品工業株式会社 | Method for producing styrene resin foam sheet and styrene resin foam sheet for thermoforming |
| JPH0768403B2 (en) * | 1988-12-15 | 1995-07-26 | 東洋エンジニアリング株式会社 | Method of manufacturing foam |
| JP2756366B2 (en) * | 1990-11-27 | 1998-05-25 | 松下電工株式会社 | Method for producing hydrophobic airgel |
-
1992
- 1992-07-24 JP JP5510863A patent/JPH07501818A/en active Pending
- 1992-07-24 WO PCT/US1992/006131 patent/WO1993011770A1/en not_active Application Discontinuation
- 1992-07-24 CA CA002125293A patent/CA2125293A1/en not_active Abandoned
- 1992-07-24 AU AU23943/92A patent/AU2394392A/en not_active Abandoned
- 1992-07-24 EP EP92916470A patent/EP0661977A1/en not_active Withdrawn
- 1992-10-08 MX MX9205766A patent/MX9205766A/en unknown
- 1992-10-09 PT PT100948A patent/PT100948A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| PT100948A (en) | 1994-01-31 |
| MX9205766A (en) | 1993-06-01 |
| EP0661977A1 (en) | 1995-07-12 |
| JPH07501818A (en) | 1995-02-23 |
| WO1993011770A1 (en) | 1993-06-24 |
| EP0661977A4 (en) | 1994-10-20 |
| AU2394392A (en) | 1993-07-19 |
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