SUCCSS AND FAILUR OF ANTI-CANCR DRUG

DVLOPMNT SINC 2010

PHA F266

PRM PRAKASH SINGH

2015A5PS862H

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 ACKNOWLDGMNT

Th Projct opportunity I had was a grat chanc for larning. I am gratful

for having a chanc to work with profssor who guided m throughout this
projct.
I would lik to xprss my dpst apprciation to all thos who providd m
th possibility to complt this rport. A spcial gratitud to our had of
dpartmnt, Dr. D Sriram, who gav m th opportunity to do th projct.
I hartily thank my projct in-charg, Dr. Balaram Ghosh for his guidanc
and suggstions till th compltion of my projct work by providing all th
ncssary information for dvloping a good projct. It wasnt possibl for
m to complt this projct without his suggstions and ncouragmnt.
A spcial thanks, gos to my collagus Shubhank, Mrityunjay, Srividya and
Pooja for thir valuabl suggstions. It is my radiant sntimnt to plac on
rcord our bst rgards and dpst sns of gratitud to Dpak Singh for his
carful and prcious guidanc which wr xtrmly valuabl for my study
projct.

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 ABSTRACT

This main objctiv of this projct to covr thraputics (Nw chmical

ntity, combination, adjuvant) of cancr in diffrnt phass of clinical trials,
history of prvious trails and thir promiss.
Cancr can b known as disass of cllular malfunction, in which a group
of clls grow and rplicat uncontrollably by violating th normal rul of cll
division. Thr ar about 120 diffrnt typs of cancr but som of thm ar
mor gnral than othrs, in man cancr of lip, oral, stomach and lungs ar
mor common whr as in woman crvical, ovary and brast cancr.
Thr ar a fw factors which can lvat th chancs of gtting cancr, fw
of thm ar mutations (gaind or acquird at tims), tobacco itms, liquor
utilization or ar diffrnt cological factors, for xampl, UV light, X-bams,
chmicals, and infctions.
Now days, cancr is a major burdn for all th countris throughout th world.
ach yar, tns of millions of popl ar diagnosd with cancr worldwid,
and mor than half of th patints vntually di from it. It is th scond most
common disass in India with th mortality rat of about 682830 daths pr
yar.

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 TABL OF CONTNTS

Acknowldgmnt 02
Abstract 03

1. Introduction 05
1.1 Prvalnc of Cancr in India 07
1.2 Causs of Cancr 09
2. Thraputics of cancr in diffrnt Phass of Clinical
Trails and thir promiss.
2.1 Rubaraca in ovarian Cancr 11
2.2 Ispinsib in Brast Cancr 13
2.3 Dovitinib in Brast cancr 17

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1. Introduction:

Cancr can b known as disass of cllular malfunction, in which a group

of clls grow and rplicat uncontrollably by violating th normal rul of cll
division. Although cancr compriss of at last 100 diffrnt disass, all th
cancr clls shar on common important charactristics: thy ar abnormal
clls in which th procsss rgulating normal cll division ar disruptd.
That is, cancr dvlops from changs that caus normal clls to acquir
abnormal functions. Ths changs occurs mainly du to rsult of inhritd
mutations or ar inducd by various nvironmntal factors such as UV light,
X-rays, chmicals, tobacco products, and viruss.
Normally, human clls ar constantly subjctd to signal that dcid whthr
th cll should divid, diffrntiat into anothr cll or di. Whn cancr
dvlops, ths clls dvlops a dgr of autonomy from ths signals
rsulting in uncontrolld cll growth and prolifration. Ths abnormalitis
occurs du to mutation in protins ncoding gns that regulates cll division.
Th abnormal growth of tissues (called neoplasm), if it forms lumps or
growths, is commonly known as tumour. Tumours dosnt man that it is
cancr, it is broadly dividd in to two catgoris. Cancrous tumours ar
malignant which, which mans it can sprad into, or invad, narby tissues.
As this tumour grows, som of ths cancrous clls brak off and travl to
th othr parts of th body through blood, lymph systm and form nw
tumours far from original position. Th procss by which cancr clls sprad
to th othr parts of th body called as mtastasis.
In mtastasis cancr, all th clls hav sam nam and sam typs of cancr
as original, or primary cancr. For xampl, brast cancr that sprads to and
forms a mtastatic tumour in th lung is mtastatic brast cancr, not lung
cancr. Unlik malignant tumours, bnign tumours do not sprad into, or
invad, narby tissues. Bnign tumours ar somtims b quit larg. Whn
w rmovd it, usually it dont grow back, whras malignant tumours
somtims do.

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Thr ar about mor than 100 typs of cancr. Typs of cancrs ar usually
nams for th organ or tissues whr's th cancr form. For xampl, brain
cancr starts in clls of brain, and lung cancr starts in clls of lungs.
Som of th xampls of cancr diffrnt typs of cancr that bgan in
spcific typs of clls:
Carcinoma: It is typ of cancr which includs all thos in colon, lungs,
brast, prostat and pancras. Hnc, it is th most common typ of cancr
and formd by pithlial clls.

Sarcoma: Sarcoma ar typ of cancr that found in bon and soft tissu,
including muscl, fat, lymph vssl, nrvs, blood vssl, and tissu
around joints.
Lukamia: It is found in blood forming tissu of bon marrow. It dos
not form any solid tumours. Instad, thy lads to production of abnormal
whit blood clls which ar unabl to carry sufficint amount of oxygn,
control blding, or fight infction.

Lymphoma: It bgins in T clls and B clls (lymphocyts). In lymphoma,

abnormal lymphocyts builds in lymph nods and lymph vssl, as wll as
th othr parts of th body. It is of two typs, Hodgkin lymphoma and Non-
Hodgkin lymphoma.

Thr ar four normal rgulatory gns that ar principal targts of gntic

damag:
1. Proto-oncogns (it acclrats growth of clls)
2. Tumour Supprssr gns (inhibits growth of clls)
3. Gns that regulates Programmd Cll Dath (Apoptosis)
4. DNA rpair gns

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1.1 Prvalnc of Cancr in India
Cancr is th scond most common disass in India with th mortality rat
of about 682830 daths pr yar. According to Intrnational Agncy for
Rsarch on Cancr (IARC), In India 1.1 million (Dc 2013) nw cancr
cass wr stimatd, indicating India is contributing to 7.8% of th global
cancr burdn, with 8.33% of global cancr daths. In India, th fiv most
common cancrs in both sxs wr cancrs of th brast (144,937; 14.3%),
crvix utri (122,844; 12.1%), lip-oral (77,003; 7.6), lung (70,275; 6.9%) and
colorctal (64,332; 6.3%), comprising 47.2% of th 28 cancrs rportd.
Furthr, dath du to ths fiv cancrs ar 302,124.

Fig 2: Yar wis Cancr Prvalnc in India (copyright: Rsarch Gat)

Th fiv most occurring cancr in mals and womn:

Mn Womn
1 Lip, Oral (11.3%) Brst (27%)
2 Lungs (11.3%) Crvix (22.9%)
3 Stomach (9.1%) Colorctum (5.1%)
4 Colorctum (7.7%) Ovary (5.0%)
5 Pharynx (6.6%) Lip, Oral, Cavity (4.3%)

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Thr ar about 180,670 daths occurrd in mn du to ths top most fiv
cancr , with fiv-yar prvalnc as 235,840 whras in womn, dath du
to ths cancr (top 5) wr amountd to 193,664, with th fiv-yar
prvalnc as 833,106.

Fig 3: Cancr prvalnc in fiv mtropolitan citis of India (copyright: Rsarch Gat)

Statistics (about India):

In vry 8 minuts, on womn dis du to crvical cancr
Du to tobacco rlatd disass about 2500 prson di vryday
Smoking accounts for 1 in 5 daths in mn whras in womn it
accounts for 1 in 20 daths
Cancr of oral and lungs in mals and crvix and brast in womn
accounts of about 50% of total daths du to cancr (2010)

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1.2 Causs of Cancr
Cancr is nothing but abnormal and uncontrollably division of clls by
violating th normal ruls of cll division. In our body can dvlop anywhr
sinc our body is mad up of millions of clls. Many cancr sms to dvlop
without any apparnt rason. Howvr, crtain risk factors ar known to
incras th chanc, according to World Halth Organisation (WHO) th
most common risk factors for cancr includs:
Tobacco: It is considrd as on of th lading caus of cancr. Tobacco
us causs many typ of cancr including, cancr of mouth, throat, bladdr,
kidny, osophagus and pancras.

Alcohol: Drinking of alcohol can incras th chancs of gtting cancr,

and chancs incras with th lvl of alcohol consumption. Cancr
mouth, throat, osophagus, larynx (voic box), livr, and brast can happn
du to alcohol.
Ditary factors, including insufficint fruit and vgtabl intak: Th
xact mchanism by which fruits and vitamins dcrass risk of gtting
cancr is not fully undrstood. Ths foods ar rich in vitamins and
chmicals, and also contains antioxidants.

Chronic infctions: Popl with prsistnt infction with hpatitis B virus

(HBV), hpatitis C virus (HCV) hav an incrasd risk of dvloping
cancr of livr whras Hlicobactr pylori incras th risk of stomach
cancr.

xposur to radiation: Radiation can caus mutation in DNA, which can

Finally lads to cancr. xposur to nuclar matrial and UV light
incrass our risk skin cancr.

Physical inactivity: Ovrwight and obsity causs th body to produc

mor amount of insulin, strogn and crtain growth factors that has dirct
rlation with cancr growth and progrssion. Physical activitis hlps us
in rducing inflammation and improvs immun systm function.

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 TABACOO

AG ALCOHAL

Causs
IMMUNIO
SUPPROSION of FOOD
CANTAMINANTS

Cancr

DIT AND
NITRITUATIO RADIATION
N

MDICINAL
DRUGS

Fig 1: Causs of Cancr

Gnrally cancr is not dvlopd by a singl factor. Most of th cass it has

bn found that cancr is combination of svral factors (lik ag, dit, stat
of immun systm, xposur to radiation, hrditary tc.). Ag is also
considr as a risk factor for cancr. As th ag incrass, chancs of gtting
cancr also incrass.

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2. Thraputics of Cancr in diffrnt Phass of
Clinical Trials
2.1 Rubaraca:
It is a drug which can b usd to trat woman having ovarian cancr, which
is causd du to BRCA gn mutation, mutation in BRCA gn may b
gntic or can b acquird and patint should alrady rciv prvious
tratmnt with 2 or mor chmothrapy mdicin for thir cancr. Nausa,
vomiting, tirdnss, low platlt count in th blood, stomach pain and
shortnss of brath ar common sid ffcts associatd with it.

Fig2:Rucaparib Camsylat (copyright @ slidshar)

Mchanisms of Action of Drug:

Poly (ADP-ribos) polymras (PARP) nzyms (mainly PARP-1, PARP-2,
and PARP-3) plays a crucial rol DNA rpair and in prvnting cancr.
rucaparib basically inhibits th PARP nzym within th cancrous clls
which alrady contains having BRCA mutation. By blocking th PARP
nzym, thr would not b DNA rpair in cancrous clls, and it finally lads
to cll dath.
Clinical Studis:
Th studis of Rubarca was conductd among th patint of various rac and
ag, having progrssd BRCA mutant ovarian growth and dosag is givn
twic vry day until disas got wors or patints dvlopd an unaccptabl
sid ffct. . It was conductd in USA, Canada, urop and Isral. Advantags
ar masurd in just thos patints in which th tumor siz diminishd by 30
prcnt.

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A total of 106 patints took part in th clinical trial of RUBARCA for
assuranc of adquacy, with th middl ag of 59 yars and majority
population participatd wr whit. Th rsults of th trail ar condnsd in
th tabl undrnath.
Fig 3: Baslin Dmographics by Sx and Rac (copyright @ FDA)

Bnfits:
Bnfits wr rcordd in patints, thos having partial or complt shrinkag
of tumour (at last tumour siz rducd by 30%).
Total no of Participants:

Objctiv Rspons Rat (95% CI) 54% (44, 64)

Complt Rspons 9%

Partial Rspons 45%

Mdian DOR in months (95% CI) 9.2 (6.6 ,11.6)

Promiss of Rubaraca towards ovrian cancr.

Rucaparib (Rubraca) dmonstrats promising action and a snsibl wllbing
profil in patints with rlapsd BRCA1/2- mutatd advanc ovarian growth.
It has additionally discovrd that it is poly ADP-ribos polymras (PARP)
inhibitor.

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2.2 Ispinsib in Brast Cancr
Thr is rsarch going on Ispinsib to know th bhaviour of Ispinsib with
brast cancr. In th tratmnt of locally advancd or mtastatic brast cancr
patints, ispinsib has dmonstratd sufficint clinical activity to procd to
th nxt stag of th Phas II clinical trial. Currntly it has compltd its Phas
2 clinical trials (Octobr 2017), whr w hav tstd it with Advancd or
Mtastatic Brast Cancr.

Fig: Structur of Ispinsib (sourc @ cyman chmicals)

Mchanisms of Action of Drug:

In brast cancr, w always try to targt microtubul, ssntial for cll cycl
progrssion through mitosis. Kinsin Spindl Protin (KSP), also known as
Hsg5, is a kinsin that plays a crucial rol in th construction of a bipolar
mitotic spindl. Ispinsib is th first potnt, xtrmly xplicit small-molcul
inhibitor of KSP that causs mitotic captur and growth inhibitor in many
human tumour cll lins.

It has bn shown that ispinsib changs th capability of KSP to bind to

microtubuls and inhibits its movmnt by prvnting th rlas of ADP
without prvnting th rlas of th KSP-ADP complx from th
microtubul. This typ of inhibition is consistnt with th physiological ffct
of ispinsib on clls, which is to prvnt KSP-drivn mitotic spindl pol
sparation.

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Clinical Studis of Phas 1:
This study was conductd in Unitd Kingdom, to dtrmin tolrability, and
safty of Ispinsib in Combination with Carboplatin. It was givn on ach 21-
Day Schdul popl having advancd solid tumours.
Ispinsib is dosd by 1-hour intravnous infusion and carboplatin is dosd by
30 minuts intravnous infusion at rgular intrvals (on th sam day). A
patint may kp on rciving tratmnt until this drug was bnficial for
thm.
Blood tsts was prformd at particular circumstancs to chck th masur
of th two mdications in thir body at particular circumstancs aftr th
mdication was givn.

ligibility critria

Sx/Gndr ligibl for Study All

Ags >= 18 (Adults)

Accpts Halthy Voluntrs No

Rsult of Phas 1:
Thr ar total of 24 patints wr tratd at 6 diffrnt dos lvls and among
thm th most common tumour wr brast (4) and prostat (7). In about 17
patints, th most common toxicitis wr fatigu (8), vomiting (8), anmia
(7) and thrombocytopnia (7).

It has bn found that Ispinsib doss singl agnt maximum tolratd dos
(MTD) whn combind with carboplatin AUC 6 hav an accptabl
tolrability profil and dmonstrat prliminary vidnc of anti-tumor
activity.

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Clinical Studis of Phas 2:
Th sol motivation bhind stag 2 to dcid, impact on brast cancr, sid
ffcts, and pharmacodynamics of Ispinsib. This xamination was conductd
on diffrnt aras including Pnnsylvania, Blgium, Malaysia, Singapor and
th Unitd Kingdom, on th patints having Stag IIIB or Stag IV brast
cancr and thy ought to alrady gt anthracyclin and taxan tratmnt.

ligibility critria

Sx/Gndr ligibl for Study All

Ags >= 18 (Adults)

Accpts Halthy Voluntrs No

Ispinsib was administrd as a 1-hour infusion at a dos of 18 mg/m2 onc

vry 3 wks until disas progrssion. No objctiv rsponss wr sn.
Six patints (35%) had th bst rspons of stabl disas for a mdian
duration of 2.8 months. Disas progrssion was documntd in 9 (53%) aftr
1 or 2 cycls. ighty-ight prcnt of patints rcivd > or =90% of plannd
dos intnsity. Grad 3 non-hmatologic toxicitis includd dizzinss (1) and
blurrd vision (1). Thr was on pisod of fbril nutropnia, but no grad
3 or 4 biochmical advrs vnts.

Rsult of Phas 2:
Ispinsib can b safly administrd using th dos and schdul mployd,
with mild hmatologic and non-hmatologic toxicity. No objctiv rsponss
wr dtctd, and furthr dvlopmnt of singl-agnt ispinsib in malignant
mlanoma is not rcommndd.
Dspit th fact that KSP articulation givs off an imprssion of bing basic
in mlanoma, KSP may not b a rasonabl focus for its tratmnt.

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Promiss of Ispinsib against Brast Cancr:
It has bn found that Ispinsib that inhibits g5, in humans g5 is
accountabl for bipolar spindl formation during arly mitosis. If w inhibit
g5, thn thr wouldnt b formation of monoastral spindls, lading to
mitotic arrst that vntually causs apoptosis.
Thr is incrasing vidnc that g5 constituts a potntial drug targt for
th dvlopmnt of cancr chmothraputics. Th most advancd g5-
targting agnt is ispinsib, which xhibits potnt antitumor activity and it
compltd its clinical trials

2.3 Dovitinib in Brast cancr:

Brast cancr is th most common typ of cancr and th lading caus of
cancr daths in womn worldwid. In most countris, 3% to 12% of brast
cancrs ar advancd or mtastatic at diagnosis. Most brast cancrs ar
hormon rcptorpositiv (HR+), with 75% to 83% of brast cancrs
xprssing stragon rcptor (R)- and/or progstron rcptor. Likwis,
approximatly 86% to 87% of brast cancrs ar ngativ for ovrxprssion
of human pidrmal growth factor rcptor 2 (HR2). B that as it may, just
20% to 40% of patints rspond to first-lin tratmnt, and around on-
portion of rspondrs backslid insid 8 14 months. Most patints in th long
run dcras in light of th fact that at prsntly accssibl mdications ar
not advantagous. Scond-lin ndocrin tratmnt (.g., fulvstrant,
aromatas inhibitors, tamoxifn) is prscribd aftr backslid, but th
rspons is gnrally short-livd.

Fig: Structur of Dovitinib (Sourc@ Sllck Chmicals)

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Thr ar various mchanisms of ndocrin thrapy rsistanc hav bn
dpictd, including initiation of rcptor tyrosin kinass (.g., fibroblast
dvlopmnt factor rcptor [FGFR]) and thir downstram flagging
pathways (.g., phosphoinositid 3-kinas, and also nactmnt of th cyclin-
subordinat kinass 4 and 6 that manag cll cycl movmnt.
Abrrant rgulation of fibroblast growth factor (FGF) and FGFR signaling is
associatd with tumorignic activity , an incrasd risk of dvloping brast
cancr, and rsistanc to ndocrin thrapy. Amplifications in FGFR1 and
FGFR4 ar found in 9% to 10% and 10% of primary brast cancrs ovrall,
rspctiv. FGFR1 amplification is mor frquntly associatd with luminal
B cancr, whras FGFR4 amplification is mor common in HR+ tumors and
a subst of HR2+ tumors . FGFR2 amplification is prsnt in 4% of tripl-
ngativ brast cancrs. Ovrxprssion of FGFR family mmbrs is
associatd with poor prognosis, including rducd ovrall survival (OS),
disas-fr survival, and rlaps-fr survival. FGFR ovrxprssion is also
associatd with rsistanc to hormon thrapy and chmothrapy.
Mchanisms of Action of Drug:
Dovitinib (TKI258), a small-molcul inhibitor of FGFR1, FGFR2, and
FGFR3 and othr rcptor tyrosin kinass, has shown prclinical activity in
FGFR-xprssing brast cancr modls in vivo and in vitro. Dovitinib
inhibitd cll prolifration in FGFR-amplifid cll lins and showd
antitumor activity in FGFR-amplifid xnograft modls. In a phas II trial of
singl-agnt dovitinib, ncouraging clinical activity was obsrvd in patints
with HR+, HR2 FGF pathwayamplifid brast cancr.
Corrlativ studis btwn FGF pathway amplification markrs and
antitumor activity indicatd that dovitinib activity was highr in patints who
had FGF pathway amplification masurd by qPCR, particularly in thos who
had highr lvls of FGFR1 amplification (i.., at last six copis of FGFR1).
Th combination of fulvstrant and dovitinib could potntially ovrcom
rsistanc to ndocrin thrapy, thrby rducing th nd for cytotoxic
chmothrapy in rlapsd patints.

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Clinical Studis of Phas 1:
In Phas 1 clinical trial, Patints with first or scond glioblastoma (GBM)
rapparanc startd tratmnt with th maximal tolratd dos (500 mg/d, 5
days on/2 days off) wr usd. Thr ar 20 patints participatd in this
clinical trial.
Svnty-two advrs vnts (As) occurrd and 16.7 % of As wr
classifid as CTC grad 3 toxicity, mainly including hpatotoxicity and
hmatotoxicity. Only on out of six patints of th 300-mg cohort showd
grad 3 toxicity. Th PFS-6 rat was 16.7 %, and it was not associatd with
dtction of th FGFR-TACC gn fusion in th tumor.
Dovitinib is saf in patints with rcurrnt GBM and showd fficacy in only
som patints unslctd for targt xprssion. Th rcommndd phas II
dos of 300 mg would b substantially lowr than th rcntly stablishd
MTD in systmic cancr patints.

Clinical Studis of Phas 2:

Stag 2 was intndd to assss th viability and scurity of dovitinib in
combination with fulvstrant in postmnopausal womn with HR+, HR2
mtastatic brast malignancy who had confirmation of malady movmnt.
nlistd patints wr randomizd in a 1:1 proportion to gt dovitinib plus
fulvstrant or placbo plus fulvstrant.

ligibility critria

Sx/Gndr ligibl for Study patints had an COG prformanc

status of 0

Ags Mdian ag: 63 (rang 3882) yars

Wight Mdian wight: 66 kg

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All patints got fulvstrant 500 mg (intramuscular infusion onc at rgular
intrvals, with an xtra masurmnt 2 wks aftr th undrlying dosag)
and dovitinib (500 mg) or placbo orally following a wk aftr wk 5 days
on and 2 days off th schdul until dath, misfortun to dvlopmnt, illnss
movmnt, or assnt withdrawal.
Patints who did not discontinu study tratmnt owing to disas progrssion
or dath, or who wr not lost to follow-up or did not withdraw consnt, wr
assssd vry 8 wks for disas status, astrn Cooprativ Oncology
Group (COG) prformanc status, and patint-rportd outcoms until th
start of nw anticancr thrapy, disas progrssion, dath, loss to follow-up,
or consnt withdrawal. Survival follow-up was prformd vry 3 months
until dath, loss to follow-up, or consnt withdrawal for patints who
discontinud th tratmnt.
In this controlld invstigation of dovitinib in combination with fulvstrant in
postmnopausal patints with HR+, HR2 progrssd or mtastatic brast
malignancy that advancd amid or aftr arlir ndocrin tratmnt did not
rcogniz any nw wllbing discovris. Dovitinib in blnd with fulvstrant
indicatd promising clinical action in th FGF pathway nhancd subgroup.

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