Università Cattolica del Sacro Cuore

Divisione di Ginecologia OncologicaDipartimento per la Tutela della Salute

della Donna e della Vita NascentePoliclinico GemelliSede di Roma

Centro di Ricerca e Formazione ad Alta Tecnologia

nelle Scienze BiomedicheDipartimento di Oncologia

Sede di Campobasso

INNOVAZIONI TERAPEUTICHE IN INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICAONCOLOGIA MEDICA

Cagliari 24 Giugno 2005Cagliari 24 Giugno 2005

DOXORUBICINA LIPOSOMIALE PEGILATA:DOXORUBICINA LIPOSOMIALE PEGILATA:ESPERIENZE CLINICHEESPERIENZE CLINICHE

Giovanni ScambiaGiovanni Scambia

Chemotherapy Issues

Results of Chemotherapy in Advanced Ovarian Cancer• Overall response rate 75-80%• Clinical complete response 50-75%• Surgical complete response 25-50%• Disease-free interval 18-24 mo• Median survival 28-56 mo• % Five-year survival 15-30%

Open problems in ovarian cancer treatment

Role of IDS and NACTLaparoscopyLymphadenectomy

SurgerySurgery

Role of Taxanes in 1st line CTNew drugsNew combinations (doublets, triplets)Consolidation therapy Role of “high dose”Prediction of responseBiological therapy

MedicalTherapyMedicalTherapy

NEWNEW

“CLASSICAL DRUGS:“CLASSICAL DRUGS: -- Platinum Platinum AnalogsAnalogs-- TaxaneTaxane derivativesderivatives-- AnthracyclinesAnthracyclines

FORMULATIONS :FORMULATIONS : Liposome TechnologyLiposome Technology

MECHANISM BASED COMBINATIONS: MECHANISM BASED COMBINATIONS: e.g. e.g. TopoisomeraseTopoisomeraseI / II inhibitorsI / II inhibitors

MECHANISM BASED SCHEDULES:MECHANISM BASED SCHEDULES: weekly weekly TaxanesTaxanes, CTX, etc., CTX, etc.

-- AdriamycinAdriamycin ((CaelyxCaelyx®)®)-- CisplatinCisplatin (SP077)(SP077)-- PaclitaxelPaclitaxel

30-49 Study DesignRANDOMIZATION

RRAANNDDOOMMIIZZAATTIIOONN

Topotecan 1.5 mg/m2/day for5 consecutive days, q 21 d

TopotecanTopotecan 1.5 mg/m1.5 mg/m22/day /day forfor5 5 consecutive daysconsecutive days, q 21 d, q 21 d

Liposomal doxorubicin50 mg/m2 q 28 d

Liposomal doxorubicinLiposomal doxorubicin50 mg/m50 mg/m22 q 28 dq 28 d

Enrollment• Recurrent epithelial

ovarian cancer• 474 patients• 104 US and international

sites Endpoints• Primary

– Time to progression• Secondary

– Overall survival – Response rate– Toxicity

Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.

Baseline Disease Characteristics

Liposomaldoxorubicin

(n=239)

Liposomaldoxorubicin

(n=239)Topotecan

(n=235)

Platinum-sensitive (%) 46 47

Platinum-refractory (%) 54 53

Bulky disease (%)Present 46 47Absent 54 53

Baseline lesionsMedian (cm2, range) 20 (1–441) 20 (1–296)

Platinum-sensitive (%) 46 47

Platinum-refractory (%) 54 53

Bulky disease (%)Present 46 47Absent 54 53

Baseline lesionsMedian (cm2, range) 20 (1–441) 20 (1–296)

Topotecan(n=235)

Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.

Response data: all patientsResponse data: all patients

Percentage of patients (number)

Objective response (p=0.393)

Complete

Partial

Stable disease (p=0.67)

Liposomal Dox(n=239)

Topotecan(n=235)

20 (47)

4 (9)

16 (38)

32 (76)

17 (40)

5 (11)

12 (29)

40 (94)

Overall Survival: Intent-to-Treat Population

Liposomal doxorubicin (n=239)Liposomal doxorubicin (n=239)Topotecan (n=235)Topotecan (n=235)

P ro b

a bil i

tyP r

o ba b

il ity

0.50.5Hazard ratio=1.12; P=.341Hazard ratio=1.12; P=.341

Liposomal doxorubicin60 weeks

Liposomal doxorubicin60 weeks

Topotecan56.7 weeksTopotecan56.7 weeks

1.01.00.90.9

0.80.8

0.70.7

0.60.6

0.40.4

0.30.3

0.20.2

0.10.1

0.0

Days From Study Drug DosingDays From Study Drug Dosing

000.0

100100 200200 300300 400400 500500 600600 700700 800800 900900

Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.

Overall Survival: Platinum-Sensitive Patients

Liposomal doxorubicin (n=109)Liposomal doxorubicin (n=109)Topotecan (n=111)Topotecan (n=111)

P er c

e nta

g e o

f Pa t

ient

sP e

r ce n

tag e

of P

a tie

nts

1001009090

8080

7070

60605050

4040

3030

2020

1010

00

P=.008P=.008

Liposomal doxorubicin108 weeks

Liposomal doxorubicin108 weeks

Topotecan71.1 weeksTopotecan71.1 weeks

Weeks Since First DoseWeeks Since First Dose

00 2020 4040 6060 8080 100100 120120 140140

Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.

Overall Survival Advantagefor Pegylated Liposomal Doxorubicin

Compared to Topotecanin Recurrent Epithelial Ovarian Cancer

Gordon et al., ECCO 12 – Abstract 157

Gordon et al, Gynecol Oncol 2004

Comparison of adverse events in Comparison of adverse events in LiposomalLiposomal Doxorubicin and Doxorubicin and

topotecantopotecan groupgroup

0

400

800

1200

1600

Stomatitis

/Pharyn

gitis PPENau

sea/V

omitin

gDiar

rhoea

Anaem

ia

Throm

bocyto

penia

Neutro

penia

Sepsis

Fever

Num

ber

of a

dver

se e

vent

s

Liposomal Doxorubicin

Topotecan

Pivotal phase III trial: Pivotal phase III trial: Quality of life resultsQuality of life results

•• Measured using EORTC QLQMeasured using EORTC QLQ--C30C30

•• 9 scales, including function and symptoms9 scales, including function and symptoms

•• In 7 of 9 scales, In 7 of 9 scales, LiposomalLiposomal Doxorubicin Doxorubicin patients showed an improved or maintained patients showed an improved or maintained score compared to score compared to topotecantopotecan

•• Significant differences with QSignificant differences with Q--TWiSTTWiSTmethodology methodology

Total treatment cost per patient

Caelyx

Topotecan

Drug cost Administration cost Adverse event management cost

0 3,000 6,000 9,000 12,000 15,000Cost (Pounds sterling)

Total cost£9,945

Total cost£12,595

Conclusions 1SUPERIOR EFFICACY

Liposomal doxorubicin appears to confer a survival advantage for patients with advanced ovarian cancer:

• Median Overall Survival (general population):Caelyx vs Topotecan : 63 vs 60 weeksHR= 0.82 p=0.5

• Median Overall survival (platinum sensitive population):Caelyx vs Topotecan : 112 vs 77 weeksHR= 0.63 p=0.02

• Median Progression-free Survival (platinum-sensitive population):Caelyx vs Topotecan : 28.9 vs 23.3 weeksp=0.037

17

Conclusions 2

LiposomalLiposomal Doxorubicin: Doxorubicin:

•• Fewer adverse events than Fewer adverse events than topotecantopotecan

•• Patients required less Patients required less haematologichaematologicsupportsupport

•• Better Quality of LifeBetter Quality of Life

MITOMITO--33

Multicentric randomized Phase III trial of PLD versusGEM in relapsed ovarian cancer patients with

Platinum-free interval less than 12 months

PrimaryPrimary ObjectiveObjective: : Compare TTPCompare TTPSecondarySecondary objectiveobjective(s):(s):Compare OS RR, Compare OS RR, QoLQoL

CAELYX 40 mg/m2 q 4 wks

Gemcitabine 1000 mg/m2 d1,8,15 q 4 wks

RANDOMIZATION

N = 200

MITOMITO--22

Multicentric randomized two arms trial of 1nd

line CT in advanced ovarian cancer patientsMulticentric randomized two arms trial of 1nd

line CT in advanced ovarian cancer patients

Carboplatin plus Paclitaxelvs.

Carboplatin plus Liposomal Doxorubicin

CarboplatinCarboplatin plus plus PaclitaxelPaclitaxelvs.vs.

Carboplatin plus Liposomal Carboplatin plus Liposomal DoxorubicinDoxorubicin

Open problems in ovarian cancer treatment

Role of IDS and NACTLaparoscopyLymphadenectomy

SurgerySurgery

Role of Taxanes in 1st line CTNew drugsNew combinations (doublets, triplets)Consolidation therapy Role of “high dose”Prediction of responseBiological therapy

MedicalTherapyMedicalTherapy

The The CombinationCombination of of LiposomalLiposomalDoxorubicin (Cae) and Gemcitabine (Gem) Doxorubicin (Cae) and Gemcitabine (Gem)

is Active in Relapsed Ovarian is Active in Relapsed Ovarian CancerCancer::a a PhasePhase II II StudyStudy

G D’Agostino, M G D’Agostino, M LudovisiLudovisi, G , G FerrandinaFerrandina, D , D LorussoLorusso,,A Testa, P A Testa, P CarratoCarrato, MG Salerno, S , MG Salerno, S MancusoMancuso, G Scambia, G Scambia

BritishBritish Journal of Journal of CancerCancer, 2003, 2003

GemcitabineGemcitabine and and LiposomalLiposomal DoxorubicinDoxorubicin in the in the SalvageSalvage Treatment of Treatment of OvarianOvarian CancerCancer: : UpdateUpdate ResultsResults and Long and Long TermTerm SurvivalSurvival

GynecolGynecol OncolOncol, , in pressin press

G G FerrandinaFerrandina, I Paris, M , I Paris, M LudovisiLudovisi, G D’Agostino,, G D’Agostino,A Testa, D A Testa, D LorussoLorusso, M , M ZanghiZanghi, S , S PiscontiPisconti, G , G PezzellaPezzella,,

V Adamo, E V Adamo, E BredaBreda, G Scambia, G Scambia

RATIONALE RATIONALE •• A A synergisticsynergistic cytotoxiccytotoxic effecteffect hashas beenbeen observedobserved

in in humanhuman breastbreast cancercancer cellcell lineslines whenwhen GEM GEM waswas administeredadministered after after doxorubicindoxorubicin..

•• BothBoth LiposomalLiposomal DoxorubicinDoxorubicin and GEM and GEM havehaveshownshown activityactivity in in ovarianovarian cancercancer..

•• Because of their different mechanism of action, Because of their different mechanism of action, nonnon--cross resistancecross resistance is is conceivableconceivable..

•• The The nonnon--overlappingoverlapping toxicitytoxicity profilesprofiles of of LiposomalLiposomal DoxorubicinDoxorubicin and GEM and GEM furtherfurthersupportsupport the the potentialpotential interest of interest of thisthiscombinationcombination.. D’Agostino et al, 2001

Growth of Growth of cisplatincisplatin--resistant human ovarian cancer resistant human ovarian cancer xenograftsxenografts(A2780/CDDP) in control and in animals treated with (A2780/CDDP) in control and in animals treated with CaelixCaelix, ,

GemcitabineGemcitabine or combination of both drugsor combination of both drugs

1

10

100

1000

10000

0 20 40 60 80 100

Day of study

Med

ian

tum

or w

eigh

t (m

g)

Vehicle

Caelix 5 mg/kg/day (q7d x 3)

Gemcitabine20 mg/kg/day (q3/4d x 4)

Caelix 5 mg/kg/day + Gemcitabine 20mg/kg/day Gemcitabine 20 mg/kg/day + Caelix 5mg/kg/day (24 h)

1

10

100

1000

10000

0 10 20 30 40 50

Day of study

Med

ian

tum

or w

eigh

t (m

g)

Vehicle

Caelix 2 mg/kg/day, q7d x 3

Gemcitabine 5 mg/kg/day q3/4d x 4

Caelix 2 mg/kg/day q7d x 3 +Gemcitabine 5 mg/kg/day q3/4d x 4

Gallo et al, 2004

ObjectivesObjectives of the of the studystudy

••To determine the activity of the CAE/GEM combinationTo determine the activity of the CAE/GEM combinationin recurrent ovarian cancer patients in terms of responsein recurrent ovarian cancer patients in terms of responserate and timerate and time--toto--progressionprogression

••To assess the hematological and nonTo assess the hematological and non--hematological hematological toxicity of this combination toxicity of this combination

PatientPatient CharacteristicsCharacteristics (n=111)(n=111)

CharacteristicsCharacteristics No.No. %%

PatientsPatients EvaluableEvaluable 106106 95.595.5

Median age (range)Median age (range) 57 (2557 (25--76)76)

ECOG Median Performance Status (ECOG Median Performance Status (rangerange)) 1 (01 (0--2)2)

PlatinumPlatinum//PaclitaxelPaclitaxel ResistantResistant 6666 59.559.5

No. of No. of priorprior chemotherapychemotherapy regimensregimens: 1 : 1 4141 36.936.9

22 4040 36.036.0

≥≥3 3 30 27.130 27.1

Best Best responseresponse toto the CAE/GEM the CAE/GEM combinationcombinationclassifiedclassified byby priorprior platinumplatinum sensivitysensivity

ResistantResistantN=36

SensitiveSensitiveN=31 N=31

Total Total N=67N=67N=36 ResponseResponse

%%No.No.%%No.No.%%No.No.

32.132.134349.79.74446.146.13030PDPD

34.034.0363636.636.6151532.332.32121SDSD

25.525.5272736.636.6151518.518.51212PRPR

8.58.59917.117.1773.13.122CRCR

34.034.053.753.7OVERALL OVERALL RRRR

21.621.6

ProgressionProgression FreeFree SurvivalSurvival in the in the OverallOverall SeriesSeriesand and AccordingAccording toto PlatinumPlatinum SensitivitySensitivity

20

40

60

80

100

0 12 24 36 48 60 72

Weeks

PFS(%)

OverallResistantSensitive

p=0.0021

FerrandinaFerrandina etet al, al, GynecolGynecol OncolOncol in pressin press

OverallOverall SurvivalSurvival in the in the OverallOverall SeriesSeriesand and AccordingAccording toto PlatinumPlatinum SensitivitySensitivity

20

40

60

80

100

0 24 48 72 96 120 144

OverallResistantSensitive

OS(%)

Weeks

p=0.0016

FerrandinaFerrandina etet al, al, GynecolGynecol OncolOncol in pressin press

OverallOverall SurvivalSurvival in GEM/PLD sensitive and GEM/PLD in GEM/PLD sensitive and GEM/PLD resistantresistantrecurrentrecurrent ovarianovarian cancercancer patientspatients accordingaccording toto initialinitial PlatinumPlatinum SensitivitySensitivity

20

40

60

80

100

0 24 48 72 96 120 144

ABCD

OS(%)

Weeks

A vs B p=0.019C vs D p=0.0019A vs C p=0.25B vs D p=0.045

A: A: PlatinumPlatinum Sensitive, GEM/PLD SensitiveSensitive, GEM/PLD SensitiveB: Platinum Sensitive, GEM/PLD B: Platinum Sensitive, GEM/PLD ResistantResistantC: C: PlatinumPlatinum ResistantResistant, GEM/PLD Sensitive, GEM/PLD SensitiveD: Platinum Resistant, GEM/PLD D: Platinum Resistant, GEM/PLD Resistant

FerrandinaFerrandina etet al, al, GynecolGynecol OncolOncol in pressin pressResistant

HematologicalHematological ToxicityToxicity

3 2.73 2.79 8.19 8.1PlateletsPlatelets

10 9.010 9.022 19.822 19.8Neutrophils Neutrophils

2 1.82 1.88 7.28 7.2HemoglobinHemoglobin

No. pts %No. pts %No. pts %No. pts %

Grade 4Grade 4Grade 3Grade 3ToxicityToxicity

NonNon--hematologicalhematological ToxicityToxicity

0 00 04 3.64 3.6DiarrhoeaDiarrhoea

2 1.82 1.816 14.416 14.4Mucositis Mucositis

0 00 016 14.416 14.4PPEPPE

No. pts %No. pts %No. pts %No. pts %

Grade 4Grade 4Grade 3Grade 3ToxicityToxicity

ConclusionsConclusions

•• This is the first clinical study demonstrating that the This is the first clinical study demonstrating that the

combination of CAE/GEM combination is an effective regimen combination of CAE/GEM combination is an effective regimen

in recurrent/progressive ovarian cancer patients in recurrent/progressive ovarian cancer patients

•• The toxicity of this regimen was comparable to that reported byThe toxicity of this regimen was comparable to that reported by

either GEM or CAE when used as a singleeither GEM or CAE when used as a single--agent agent

•• The overall The overall 68.0% of clinical benefit (CR+PR+SD)68.0% of clinical benefit (CR+PR+SD) highlights the highlights the

potential of this combination regimen as a valid option fpotential of this combination regimen as a valid option for theor the

salvage treatment of ovarian cancer patientssalvage treatment of ovarian cancer patients

LIPOSOMAL DOXORUBICIN: COMPARATIVE STUDIESLIPOSOMAL DOXORUBICIN: COMPARATIVE STUDIES

Liposomal Doxorubicin mg/m2/w10 12.5 12.5 16

RESPONSE RATEHFS+STOMATITISNEUTROPENIA G3-G4

50

40

30

20

10

0

%

Muggia, 1997Israel, 2000Markman, 2000 Gordon, 2000

GEMCITABINE AND LIPOSOMAL DOXORUBICIN IN

RECURRENT/METASTATIC BREAST CARCINOMA: A PHASE II STUDY

V Adamo, G V Adamo, G FerrandinaFerrandina, M Spada, F , M Spada, F Ferrau’Ferrau’, G , G CondemiCondemi, , L Di L Di LulloLullo, D , D LorussoLorusso, R Rossello, C , R Rossello, C GaripoliGaripoli, G Scambia, G Scambia

ASCO, 2005ASCO, 2005

ObjectivesObjectives

PrimaryPrimaryResponse rateResponse rateSafetySafetyPFSPFS

SecondarySecondaryOverall Overall survivalsurvival

StudyStudy Design and Treatment ScheduleDesign and Treatment Schedule

TwoTwo stage design stage design assumingassuming thatthat the the combinationcombination willwillbebe of of relevancerelevance ifif the the truetrue responseresponse rate (Hrate (H00) ) isis lesslessthanthan 30%, 30%, whilewhile of interest of interest ifif the the truetrue responseresponse rate rate isis45% (H45% (H11) )

At At leastleast 10 10 responsesresponses in the first 27 in the first 27 patientspatients, are , are neededneeded in in orderorder toto proceedproceed toto the the secondsecond stepstep(up (up toto 81 81 patientspatients))

CaelyxCaelyx 25 mg/m25 mg/m22 d1d1

GemcitabineGemcitabine 800 mg/m800 mg/m22 d1,8 d1,8 q21q21

Patient CharacteristicsNo. (%)

Enrolled

28

28

Measurable disease

Age (median, range) 59, 37-76

Prior Adjuvant 13

DiseaseVisceral involvementNon visceral involvement

25 (89.2)3 (10.7)

Response RateNo. (%)

Evaluable 234 (17.4)Complete Response

6 (26.1)Partial ResponseOverall RR 10 (43.5)

11 (47.8)Stable DiseaseProgression Disease 2 (8.7)

Duration of Responseweeks, median (range) 9 (6-18)

Duration of Stable Diseaseweeks, median (range) 12 (9-21)

ConclusionsConclusions

The The combinationcombination CaelyxCaelyx/GEM /GEM providesprovidesencouragingencouraging resultsresults in in termsterms of of antitumorantitumor activityactivity

VeryVery favourablefavourable toxicitytoxicity profileprofile

The The secondsecond stepstep isis warrantedwarranted

PHASE II STUDY OF PEGYLATED LIPOSOMAL DOXORUBICIN IN

HEAVILY PRETREATED EPITHELIAL OVARIAN CANCER PATIENTS:

MAY A NEW TREATMENT SCHEDULEIMPROVE TOXICITY PROFILE ?

D Lorusso, A Naldini, A Testa, G D’Agostino, G Scambia, G Ferrandina.

Oncology, 2004

Assessable 37 100

Age (yrs) median 62

Platinum sensitive 20 54

Platinum resistant 17 46

Prior regimens

1 5 13

2 15 41

3 5 13

>3 12 32

Median number cycles 4 (2-11)

Mean cycle dose (mg/m2) 35 (33-35)

Mean cumulative dose/pt (mg/m2) 148.5 (70-385)

Assessable 37 100

Age (yrs) median 62

Platinum sensitive 20 54

Platinum resistant 17 46

Prior regimens

1 5 13

2 15 41

3 5 13

>3 12 32

Median number cycles 4 (2-11)

Mean cycle dose (mg/m2) 35 (33-35)

Mean cumulative dose/pt (mg/m2) 148.5 (70-385)

Patient characteristicsN.N. %%

Response RateResponse RateTotal Platinum Platinum

No (%) sensitive resistantNo (%) No (%)

CR - - -

PR 5 (13.5) 2 (10) 3 (19)

SD 18 (48.6) 11 (55) 7 (41.2)

PD 14 (38) 7 (35) 7 (35)

Time to Response 12.0 11.5 11.0(wks, median)

Time to Progression 28.8 29.2 27.0(wks, median)

Response Duration 22.8 23.0 22.0(wks, median)

SD Duration 17.6 18.0 16.8(wks, median)

Toxicity

PPE 4 (11.1%) 3 (8.3%) 1 (2.8%) -

Stomatitis 3 (8.1%) - - -

Nausea/vomiting 5 (13.5%) - - -

Asthenia 9 (24.3%) - - -

Hair loss 6 (16.2%) - - -Anaphylactic reaction 2 (5.4%) - - -Neutropenia 4 (11.1%) - 3 (8.3%) 1 (2.8%)

Anemia 10 (27.0) - - -

Thrombocytopenia 1 (2.8%) - - -

PPE 4 (11.1%) 3 (8.3%) 1 (2.8%) -

Stomatitis 3 (8.1%) - - -

Nausea/vomiting 5 (13.5%) - - -

Asthenia 9 (24.3%) - - -

Hair loss 6 (16.2%) - - -Anaphylactic reaction 2 (5.4%) - - -Neutropenia 4 (11.1%) - 3 (8.3%) 1 (2.8%)

Anemia 10 (27.0) - - -

Thrombocytopenia 1 (2.8%) - - -

G3G3 G4G4G1 G2

Conclusions• Encapsulating liposomal doxorubicin intopegylated liposomes has opened new and increased possibility of treatment in ovarian and breast cancer without a concomitant increase in toxicity either when the drug is used alone or aspart of a combination therapy.

• The ongoig studies will better define the roleof PLD in first line OC treatment.

•Different treatment schedules need to be explored in order to ameliorate PLD cutaneoustoxicity profile without affecting the efficacy.