Transcript template

NOT THE TAXANES
Chemotherapy
Joyce O’Shaughnessy, MD
Baylor-Sammons Cancer Center
US Oncology
Dallas, TX
Do Patients Benefit from Salvage
Chemotherapy?
 No demonstrated survival improvement with salvage




chemotherapy
No demonstrated superiority yet of one agent or
regimen
No overall advantage of combination chemotherapy
compared with sequential single agents
Several studies do show correlation between ORR
and symtom control and QOL
Patient preferences and chemotherapy toxicity profile
are important
Cardoso F, et al Ann Oncol 13:197, 2002
McLachlan SA, et al Breast Cancer Res Treat 54:213, 1999
Not Anthracyclines and Taxanes
Chemotherapies with Value
 Capecitabine
 Vinorelbine
 Gemcitabine
 Pegylated Liposomal Doxorubicin
 Pemetrexed
 Irinotecan
 Epothilones, Nanoparticle Paclitaxel
Enzymatic activation of Capecitabine
Intestine
Capecitabine
Liver
Tumour
Capecitabine
CE
5'-DFCR
5'-DFCR
CyD
CyD
5'-DFUR
5'-DFUR
Thymidine
phosphorylase (TP)
5-FU
5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;
CyD = cytidine deaminase; CE = carboxylesterase
Capecitabine
in taxane-pretreated MBC
 Capecitabine monotherapy has been evaluated in
taxane-pretreated MBC in four separate trials in 500
patients
– pivotal US trial (n=163)
1
– confirmatory US/French trial (n=75)
– German trial (n=136)
– French trial (n=126)
2
3
4
1Blum
JL et al. J Clin Oncol 1999;17:485–93
JL et al. Cancer 2001;92:1759–68
3Reichardt P et al. Eur J Cancer 2001;37(Suppl. 6):S191 (Abst 699)
4Fumoleau P et al. Breast Cancer Res Treat 2001;69:285 (Abst 435)
2Blum
Pivotal US trial in
paclitaxel-pretreated MBC
 Large, multicenter trial (n=163*)
 Patients were pretreated with
–
–
–
–
prior paclitaxel
prior anthracyclines
prior 5-FU
prior agents (mean)
100%
91%
82%
4.7
 Therapy
– capecitabine 1,250mg/m twice daily for
14 days, followed by a 7-day rest period
2
*One patient withdrew before receiving treatment
Blum JL et al. J Clin Oncol 1999;17:485–93
Pivotal US trial: capecitabinein
paclitaxel-pretreated MBC
 Rate of disease control: 63%
– 20% confirmed tumor response rate
– 43% stable disease (median 4 months)
 Palliation: durable pain reduction
in 47% of patients with considerable pain at
baseline
 Median TTP: 3.0 months
 Median survival: 11.6 months1
Survival updated in Blum JL et al. Eur J Cancer 2001;37(Suppl. 6):S190 (Abst 693)
1
Capecitabine: probability of survival with
response or disease stabilization
Estimated probability
1.0
Responder
Stable disease
Progressive disease
0.8
0.6
0.4
0.2
5.3
0.0
0
4
15.0
8
12
16.6
16
20
Time (months)
24
28
32
36
Blum JL et al. Eur J Cancer 2001;37(Suppl. 6):S190 (Abst 693)
Capecitabine in heavily pretreated MBC:
prior chemotherapy
US
US/French* German* French*
(n=163)
(n=75)
(n=136) (n=126)
Taxanes (%)
Paclitaxel
100
73
49
21
Docetaxel
0
47
46
84
Anthracyclines (%)
91
96
93
96
5-FU (%)
82
N/A
N/A
90
*Some patients had previously received both paclitaxel and docetaxel
Capecitabine in taxane-pretreated MBC
Disease control
No. of
CR + PR (CR + PR + SD)
patients
(%)
(%)
Median
response
duration
(months)
Median
TTP
(months)
Median
survival
(months)
1621
20
63
7.9
3.0
11.6
742
26
57
8.3
3.2
12.2
1363
15
62
7.4
3.3
10.4
1264
25
54
5.0
4.6
15.2*
*Preliminary results
1
Blum JL et al. Eur J Cancer 2001;37:S190 (Abst 693)
2
Blum JL et al. Cancer 2001;92:1759–68
3
Reichardt P et al. Eur J Cancer 2001;37(Suppl. 6):S191 (Abst 699)
4
Updated from Fumoleau P et al. Breast Cancer Res Treat 2001;69:285 (Abst 435)
Capecitabine monotherapy safety profile
 2% of patients experienced a grade 4
treatment-related adverse event
 Most frequent grade 3/4 treatment-related
adverse events were
– hand-foot syndrome
15%
– diarrhea
12%
– stomatitis
5%
– nausea
5%
 No hair loss
 No treatment-related deaths
capecitabine monotherapy:
myelosuppression (n=498)
20
Grade 3
Patients (%)
16
Grade 4
12
8
4
0
Leukopenia
Neutropenia
*Recorded as grade 3/4 laboratory adverse events
Anemia
Thrombocytopenia
Rationale for capecitabine in combination:
TP upregulation
(mg/kg)
Paclitaxel 100
Docetaxel
15
Vinblastine
3
Vindesine
5
Mitomycin C
5
Doxorubicin
7.5
Cisplatin
10
*
*
*
*
*
Cyclophosphamide 200
Gemcitabine
90
Vinorelbine
12
*
*
†
0
*p<0.05
†
p value not available
1
2
3
4
5
6
7
8
TP upregulation (x control activity)
9
10
Ishitsuka H. Invest New Drugs 2000;18:343–54
Sawada N et al. Proc Am Assoc Cancer Res 2002;43:1088 (Abst 5388)
Potential mechanisms underlying
Capecitabine plus Docetaxel synergy
Docetaxel
TP
upregulation
Bcl-2
1
2
downregulation
Capecitabine
1Sawada
2Fujimoto-Ouchi
N et al. Clin Cancer Res 1998;4:1013–9
K et al. Proc Am Assoc Cancer Res 2001 (Abst 463)
Capecitabine plus Docetaxel: overall
survival*
Capecitabine/docetaxel
Docetaxel
Estimated probability
1.0
0.8
Hazard ratio = 0.775
0.6
Log-rank
p=0.0126
0.4
0.2
11.5
0
0
2
4
6
8
10
14.5
12
14
16
Time (months)
*Minimum follow-up of 15 months
18
20
22
24
26
28
Post-study Therapies in the XT Study
Cytotoxic Agents Used in Post-Study
Chemotheray
Impact of First-line Post-study Chemotherapy on
Outcome in Patients in the Docetaxel Alone Arm
 Capecitabine vs any other agents as 1st line post-study
chemotherapy
 Hazard ratio = 0.5 (p=0.0046): patients treated with
capecitabine had a 50% decreased risk of dying
 Median survival = 21 months for capecitabine-treated
patients vs 12.3 months for other patients
 Vinorelbine-containing regimen vs other agents as 1st line
post-study chemotherapy (except for capecitabine)
 Hazard ratio = 1 (p=0.94): simiar risk of dying
 Median survival = 13.5 months for patients treated with
vinorelbine-containing regimen vs other agents
Capecitabine plus Vinorelbine: feasible
and active in a 21-day regimen
Lebanese German Korean
phase II
phase 2I phase II
1
3
(n=30)
(n=14)
(n=24)
Capecitabine
825
1,000
1,250
25
25
25
2
(mg/m twice daily days 1–14)
2
Vinorelbine (mg/m days 1,8)
Response rate (%)
61
56
53
(no. evaluated)
(23)
(9)
(19)
 Safety profile: neutropenia and gastrointestinal side effects are
dose limiting
 German regimen: randomized, phase III trial (vs XT) is under
discussion
1Ghosn
M et al. Proc Am Soc Clin Oncol 2002;21:42b (Abst 1978)
A et al. Proc Am Soc Clin Oncol 2001;20:58b (Abst 1979)
3Ahn J-H et al. Proc Am Soc Clin Oncol 2002;21:55b (Abst 2030)
2Welt
Capecitabine plus bevacizamab:
ongoing phase III trial
 Bevacizumab is a recombinant, humanised
monoclonal antibody to vascular endothelial growth
factor (VEGF)
 Active in patients with previously treated MBC
1
 Recruitment (~400 patients) for a randomised,
phase III trial in taxane-pretreated MBC is ongoing
– capecitabine monotherapy versus capecitabine
2
plus bevacizamab
1Cobleigh
2Details
MA et al. Breast Cancer Res Treat 2001;69:301 (Abst 520)
provided on US National Cancer Institute Clinical Trials Database
(URL http://www.cancer.gov/clinical_trials/)
Ongoing phase I/II trials investigating
capecitabine in all-oral combinations
 capecitabine continuously +1oral cyclophosphamide
(New Zealand and Australia)
2
– MTD: capecitabine 666mg/m 2 twice daily, d1–28 +
cyclophosphamide 125mg/m d1–14, q28d
– additional2 patients are being treated with 2capecitabine
666mg/m + cyclophosphamide 100mg/m
 capecitabine + oral idarubicin (Edinburgh, UK)
 capecitabine
+ oral idarubicin/cyclophosphamide
2
(China)
 capecitabine + oral vinorelbine (Milan, Italy)
1Findlay
2Chan
MP et al. Proc Am Soc Clin Oncol 2002;21:85b (Abst 2151)
S-C et al. Proc Am Soc Clin Oncol 2002;21:53b (Abst 2023)
Single-Agent Vinorelbine: Salvage Therapy
in Anthracycline or Taxane Resistant MBC
Author
N
CR (%) OR (%)
(eval)
ANTHRACYCLINE-REFRACTORY
*Jones (A)
Degardin (A)
84
100
5
1
16
16
MRD
(weeks)
MST
(months)
1-y
Survival
32
21
8.2
21.9
36%
-
(responders)
Jara (A)
27
4
26
21
ANTHRACYCLINE AND TAXANE-REFRACTORY
-
-
McGuirt
(A/T)
Livingston(A/T)
247
-
12
23
-
-
40
5
25
-
8
16%
Zelek (T)
30
-
20
-
-
-
Overall
528
1-5 %
8-21.9 mo
16-36 %
*Pivotal trial submitted to FDA 1994
A=Anthracycline-resistant; T=Taxane-resistant
12-26 % 21-32 wk
Vinorelbine versus Melphalan in
Anthracycline-Pretreated MBC
 Vinorelbine 30 mg/m2 weekly versus Melphalan
25 mg/m2 every 4 weeks
 183 pts 2:1 randomization
 Measurable or evaluable allowed
 Objective response or SD: 46% versus 28%
 TTP: 12 versus 8 weeks; p<.001
 OS: 35 versus 31 weeks; p=0.034
 No difference QOL, cancer-related symptoms
Jones SE, et al J Clin Oncol 13:2567, 1995
Gemcitabine: Phase II Studies
Study
Dose
No. Pts
Overall RR
Carmichael, 95
800 mg/m2 – D1, 8, 15 q28
40
25%
Possinger, 99
1000 mg/m2 – D1, 8, 15 q28
42
14%
Akrivakis, 95
1000 mg/m2 – D1, 8, 15 q28
14
30%
Blockstein, 96
1200 mg/m2 – D1, 8, 15 q28
35
37%
Spielmann, 97
1200 mg/m2 – D1, 8, 15 q28
43
28%
Brodowicz, 98
1250 mg/m2 – D1, 8, 15 q28
24
13%
Gerson, 00
1250 mg/m2 – D1, 8, 15 q28
19
42%
Schmid, 99
250 mg/m2 over 6 hours – D1, 8, 15
20
25%
Dose/Schedule in MBC with
Gemcitabine and Vinorelbine
Study
Dose (mg/m2)
Previous Chemotherapy
Gokmen
G1200 days 1, 8
V30 days 1,8
q21d
7 pt (32%) third line
13 pt (59%) second line
Gokmen E. PASCO 2000.a427
Haider
G 1000 days 1,15, 21
V40 days 1, 21
G-CSF 5mcg/kg/d
45 pt untreated for MBC
15 pt had one prior regimen
Haider K, Breast Cancer Research and Treatment 1999;55:203-211
Moser
Moser PASCO 2001.a1973
G1200 days 1, 8
V25 days 1, 8
q21d
25 pt first line
13 pt second line
11 pt second line with taxane
Efficacy in MBC with
Gemcitabine and Vinorelbine
Patients
(eval.)
ORR
(%)
Gokmen 2000
22‡
45%
5.5
NR
Haider
1999
45*
15**
56%
40%
9.5
7.0
>14
12
Moser
2001
30
30%
NR
NR
‡ 77% previously
Median Median
TTPD Survival
(mos)
(mos)
treated
* untreated
** previously treated
Biweekly Gemcitabine and Vinorelbine
 50 pts MBC s/p anthracyclines and 50% with prior






taxane
GEM 1000 and VRL 25 mg/m2 every 2 wks
ORR 54% (8% CRs), mainly soft tissue/lung
Duration response/SD 4 to 9+ mos
No pt required dose reduction
Grade 1/2 neutropenia, asthenia
Biweekly GEM/VRL active in pretreated MBC
 Stathopoulas GP, et al. JCO 20:37, 2001
Dose/Schedule in MBC with
Gemcitabine and Cisplatin
Study
Dose (mg/m2)
G750 days 1, 8
Nagourney et al, JCO 2000 C30 days 1, 8
q21d
Nagourney
Chaudhry
Chaudhry PASCO
2000
Doroshow
Doroshow PASCO
2000
Previous Chemotherapy
Most heavily pretreated
Dose dependent on prior
regimen
( >2 regimen received
G 600mg)
(1st 12pt treated on q28d
schedule)
G1000 days 1, 8,15
C25 days 1, 8,15
q28d
all pt failed anthracyclines
all pt failed taxanes
G1000 days 2, 8
C25 days 1-4
q21d
31 heavily pretreated (>2
regimens)
24 minimally pretreated
(0-1regimens)
Efficacy in MBC with Gemcitabine and
Cisplatin
Patients
(eval.)
ORR
(%)
Nagourney
30
53
Chaudhry
28
39
NR
NR
Doroshow
23*
21**
26
43
NR
Not yet reached
* Heavily Pretreated
** Minimally Pretreated
NR = Not Reported
Median
TTPD
Median
Survival
23.5 wks
46 wks
Pegylated Liposomal Doxorubicin
 509 pts PLDox 50 mg/m2 every 4 weeks versus
Doxorubicin 60 mg/m2 every 3 weeks
 OS similar; 2 pts CHF with PLDox vs 12 with Dox
 31% ORR in 64 pts with 45-60 mg/m2 every 3 to 4
weeks (anthracycline-naïve)
 Phase I: PLDox 24 mg/m2
and Gemcitabine
800 mg/m2 D1, 8 q 21 days; 9/27 objective responses
 Phase I: PLDox 40 mg/m2
30 mg/m2 day 1, 15
and
Vinorelbine
Pegylated Liposomal Doxorubicin vs.
Standard Salvage Regimen for
Taxane-Pretreated Patients
PLDox 50 mg/m2 q 4wks
vs.
Vinorelbine 20 mg/m2 q wk
or
Mitomycin C 20 mg/m2 d1 IV, q 6wks
Vinblastine 5 mg/m2 d1,21 IV, q 6wks
301 patients evaluable for safety and efficacy
 85% chose Vinorelbine
Pegylated Liposomal Doxorubicin in
Taxane-Pretreated Patients
Eligible Patients
– Measurable disease
– Progressed on prior taxane-containing regimen
– Karnofsky Performance > 60%; LVEF > 50%
Actual Patients
• Prior treatment with an anthracycline
– 84% as adjuvant or for advanced disease
– 37% “anthracycline resistant”
(Progression on or within 6 months of
anthracycline)
• 37% progressed within 8 weeks of study entry
PLDox in Taxane-Pretreated Patients
Response Rates
PLDox
Comparator
101 (67%)
108 (72%)
Complete Response (CR)
Partial Response (PR)
Stable Disease (SD)
3%
10 %
44 %
3%
12 %
37 %
Progressive Disease (PD)
44 %
48 %
Evaluable for response
PLDox vs a Standard Salvage Regimen
After Taxane Failure
% Progression-Free Survival
•Progression-Free Survival
Hazard Ratio 1.26
p = 0.11
1.0
0.8
0.6
PLDox
0.4
0.3
Comparator
0.0
0
3
6
9
Months from Start of Treatment
12
PLDox vs. a Standard Salvage
Regimen After Taxane Failure
Overall Survival
% Overall Survival
1.0
.
0.8
0.6
PLDox
0.4
Comparator
0.2
0.0
0
3
6
9
12
15
Months from Start of Treatment
18
The Non-Taxanes
 Capecitabine, Gemcitabine, Vinorelbine and
Pegylated Liposomal Doxorubicin are active
and generally well tolerated cytotoxics that
DON’T CAUSE ALOPECIA
 They are highly active in combination with the
taxanes or with each other
 We need comparative trials of non-taxane
doublets with taxane-based doublets
Pemetrexed
O
O
O
OH
O
OH
HN
H2 N
N
OH
N
N
H
O
Lometrexol
N
H
N
H2 N
N
N-[4-[2-(2-amino-3,4-dihydro-4oxo-7H-pyrrolo[2,3-d]pyrimidin-5-
N
OH
O
N
OH
N
Methotrexate
OH
O
H
N
O
yl)ethyl]benzoyl]-L-glutamic acid
O
N
H
NH2
Pemetrexed
O
O
O
H2N
OH
N
H
N
H
HN
O
HN
N
S
O
O
OH
N
Tomudex 
Taylor EC, et al. J Med Chem 35:4450-4454, 1992
Pemetrexed
Key Intracellular Folate Enzyme Targets
Pemetrexed
(multitargeted antifolate)
TS
dUMP
5,10-CH2-THF
10-CHO-THF
DNA
dTMP
DHF
NADPH
GARFT
PRPP
DHFR
THF
GAR
NADP+
fGAR
AMP, GMP
TS: thymidylate synthase
DHFR: dihydrofolate reductase
GARFT: glycinamide ribonucleotide
formyltransferase
DNA, RNA
Spielmann, Martin et al: Subset of patients with
prior anthracycline and taxanes, n=31.
Patient Characteristics
•
•
•
•
Pemetrexed 600 mg/m2 q3w (no vitamins suppl.)
Median Age 55 (30-75)
PS 0-1 99%
Sites of disease
• 90% visceral disease (lung and/or liver)
• 6% with bone metastasis
Spielmann, Martin et al. Clin Breast Ca 2:47-51, 2001
Spielmann, Martin et al: Efficacy Results
•
•
•
•
1 CR, 7 PR
6 SD > 4 months
Median duration of response
Median survival
26%
19%
5.4 months
12.8 months
Spielmann, Martin et al. Clin Breast Ca 2:47-51, 2001
Spielmann, Martin et al : Hematologic and Lab
Toxicity (CTC Grade, % patients, n= 31)
G1
Anemia
42
Leukopenia 13
Neutropenia 3
Platelets
32
ALT
35
G2
26
23
16
13
3
G3 G4
10 3
39 16
26 32
10 6
13 0
Spielmann, Martin et al. Clin Breast Ca 2:47-51,
2001
Spielmann, Martin et al : Non-lab Toxicity
(CTC Grade, % patients, n= 31)
G1
G2
G3
G4
Rash
23
26
6
0
Nausea
29
10
10
0
Vomiting
13
16
3
0
Stomatitis 19
16
10
0
Diarrhea
10
6
3
0
Infection
10
10
6
0
Spielmann, Martin et al. Clin Breast Ca 2:47-51,
2001
Llombart et al:
Patient Characteristics, n=45
•
•
•
•
•
N=45 (32 evaluable, 7 too early, 6 ineligible)
Pemetrexed 500 mg/m2 q3w (no vitamins suppl.)
Median Age
56 (31-72)
Median PS
0 (0-2)
Median # sites of disease 2 (1-6)
• 79% visceral disease (lung and/or liver)
• Prior # chemotherapy
2 (1-4)
Llombart et al. Breast Cancer Res Treatment 58(1): A526, 2000
(Poster)
Llombart et al : Efficacy Results
•
•
•
•
N=32 evaluable
0 CR, 6 PR
17 SD
Median survival
19%
53%
NA
Llombart et al. Breast Cancer Res Treatment 58(1): A526, 2000
(Poster)
Llombart et al : Hematologic and Lab Toxicity (CTC
Grade, % patients, n= 45)
G3 G4
Anemia
9 2
Neutropenia 30 19
Platelets
0 0
ALT/AST
5 0
Llombart et al. Breast Cancer Res Treatment 58(1): A526, 2000
(Poster)
Llombart et al : Non-lab Toxicity
(CTC Grade, % patients, n= 45)
G3
G4
Rash
9
0
Vomiting
2
0
Diarrhea
0
0
Infection
2
0
Llombart et al. Breast Cancer Res Treatment 58(1): A526, 2000
(Poster)
Pemetrexed Combinations in MBC
 Pemetrexed - Taxane
 Pemetrexed - Doxorubicin
 Pemetrexed - Gemcitabine
 Pemetrexed - Cyclophosphamide
DOWN WITH ALOPECIA !!!
Can we create a highly effective
combination chemotherapy
regimen that does NOT cause
ALOPECIA?
Non-Alopecia Chemotherapy Agents
 Capecitabine
 Vinorelbine
 Gemcitabine
 Pegylated Liposomal Doxorubicin
 Pemetrexed
 Weekly Lower Dose Cisplatin
 Methotrexate
 5-Fluorouracil
 ? Lower Dose Weekly Docetaxel or Paclitaxel
Plea to the BCIRG
Demonstrate that a non-alopecia
combination chemotherapy
regimen is as effective (or more) as
AC/FAC/FEC for metastatic breast
cancer and TAKE IT INTO EARLY
STAGE BREAST CANCER
THANK YOU
Epothilone BMS-247550
O
S
OH
N
BMS-247550
HN
O
OH
O
 Topics
– Preclinical rationale for epothilone
– Initial Phase 2 results (ASCO 2002)
Taxane mimetics:
A second generation of tubulin polymerizing agents
Eleutherobin
Lindel et al ‘97
Ter Harr et al ‘96
O
Me
N
N
Epothilone
Discodermolide
O
Me
O
OMe
O OAc
O
Me
Me
Bollag et al ‘95
OH
OH
CH
O
sugar
CH
OH
CH H C
H C
3
Me
O
OH
3
3
3
OH
sidechain
CH
3
3
OH O
CH
H3 N
O
2
CH
3
O
S
N
OH
HO
O
O
OH
O
core
Polymerization of tubulin
0.15
Optical
Density
(350 mm)
Discodermolide
Epothilone B
Eleutherobin
Paclitaxel
No Compound Control
0.1
0.05
0
0
5
10
15
20
sec
Epothilone: Distinct binding to tubulin
Computer model of
beta-tubulin mutations
Taxane
Epothilone
Giannakakou et al. Proc. Natl. Acad. Sci. USA
2000, 97, 2904
Novel epothilone BMS-247550 overcomes
taxane resistance
Known mechanisms of
taxane resistance
– Increase drug efflux
• MDR
• MRP
– Tubulin alteration
• Mutation
7.3
18
16
HCT116
HCTVM46
(MDR)
BMS-247550
Paclitaxel
450
6.9
9.7
12.3
A2780
A2780Tax
(Tubulin
Mutation)
137
7.4
Pat-7
(Clinical)
0
150
100
200
300
400
Cytotoxicity (IC90 or IC50, nM)
Increasing resistance
500
Novel epothilone BMS-247550:
Activity against clinical taxane resistance

Taxane resistant Pat-21 breast cancer
TAXOL + Dexverapamil
(4 cycles)
ADR + CMF (10 cycles)
Pat-21
(Breast)
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Years
1.8
Control
Paclitaxel (36 mpk x5)
100
BMS-247550 (10 mpk x3)
Rx
Rx
10
40
50
60
2
Biopsied
1000
Median tumor weigh (mg)
0
70
80
Time post tumor implantation (days)
Initial Phase 2 results
using 50 mg/m2 over 1 hour (ASCO 2002)
Indication
Taxane-naive breast cancer
Taxane-refractory breast cancer
Hormone refractory prostate*
Platinum-pretreated NSCLC
PR / N
RR (%)
90% CI
12 / 19
2/8
11/ 12
4 / 28
63
25
92
14
44-79
9-54
70-98
7-28
* Phase I results, doses 35-40 mg/m2
• Phase I/II responses also observed in aggressive NHL,
colorectal, gastric, ovary, prostate, head and neck, cervical
cancer, GIST and melanoma
Novel epothilone BMS-247550:
Summary
O
S
OH
N
BMS-247550
HN
O
OH
O
– Microtubule stabilization is a clinically validated
biological target
– Epothilone (BMS-247550) is active in vitro and
in vivo against taxane-resistant tumor models
– Activity demonstrated in taxane-refractory patients in
Phase I and II
– Phase 2 studies are in progress, in a broad program
via BMS and NCI
Enhanced Tumor Penetration of Paclitaxel by a
Novel Biological Nanotransporter Mechanism
ABI-007:
Nanoparticle
Paclitaxel
Overall Response
Patients, n (%)
Parameter
No. evaluable
Overall response
95% CI
Complete response
Partial response
ABI-007 175 mg/m2
N = 43
41
21 (51%)
[36 %– 67%]
3 (7%)
ABI-007 300 mg/m2
N = 63
59
36 (61%)
[49 %– 73%]
4 (7%)
18 (44%)
32 (54%)
Stable disease
15 (37%)
11 (19%)
Progressive disease
5 (12%)
12 (20%)
Response by Prior Therapy
Patients, N/N (%)
ABI-007
175 mg/m2
ABI-007
300 mg/m2
Anthracycline-naïve
95% CI
9/21 (43)
[22 – 64]
19/28 (68)
[51 – 85]
.08
Anthracycline-exposed
95% CI
12/20 (60)
[39 – 81]
17/31 (55)
[37 – 72]
NS
Adjuvant only anthracycline
95% CI
7/11 (64)
[35 – 92]
11/13 (85)
[65 – 104]
.24
Metastatic anthracycline
95% CI
5/9 (56)
[23 – 88]
6/18 (33)
[12 – 55]
NS
Parameter
P value
ABI-007 Activity in Patients Previously
Exposed to Taxol
Patients, n (%)
ABI-007
175 mg/m2
ABI-007
300 mg/m2
Prior taxane exposure
2
11
Patients evaluable
2
9
Overall response rate
Complete response (CR)
Partial response (PR)
0
0
0
2 (22)
1 (11)*
1 (11)§
Stable disease (SD)
2 (100)
4 (44)
CR + PR + SD
2 (100)
6 (67)
Parameter
*Patient achieving a complete response was heavily pretreated with FAC, radiotherapy,
Taxol 225 mg/m2 (second-line with Taxol resistance), doxil, and gemcitabine.
§Patient achieving a partial response was previously treated with Taxol 250 mg/m2
in the adjuvant setting.
Capecitabine plus Trastuzumab: at least
additive activity in a BC xenograft model
Control
capecitabine
trastuzumab
capecitabine + trastuzumab
Tumour volume (mm3)
1,000
800
600
BT474 xenograft
400
200
***
100
20
25
30
35
40
45
50
55
Days after inoculation
*p<0.05
Fujimoto-Ouchi KF et al. Cancer Chemother Pharmacol 2002;49:211–16
Capecitabine plus Trastuzumab is a feasible
combination: the German experience
 18 patients with anthracycline- and taxane-pretreated
HER2+ MBC received 21-day cycles of
– standard-dose trastuzumab, weekly
– capecitabine 1,125mg/m twice daily, days 1–14
2
 62% ORR in 13 patients
 Minimal side effects
 Additional phase II investigation is ongoing
Bangemann N et al. Ann Oncol 2000;11(Suppl. 4):143 (Abst 653P)
Summary of Single-Agent Vinorelbine
in MBC
Navelbine
CR
(%)
OR
(%)
MRD
MST
(weeks) (months)
First-Line
2-21
35-59
18-39
10-19
SecondLine
3-10
16-47
14-47
6-19
Salvage
1-5
12-26
21-32
8-21.9
Irinotecan in Metastatic Breast Cancer
 Randomized Phase II 100 mg/m2 weekly
4 on/2 off (A) versus 240 mg/m2 q 3 weeks (B)
 102 pts; 75% prior anthracyclines; 80% prior
taxane
 29% ORR (6/21)
 Grade 3/4 diarrhea 8 pts (A) and 5 pts (B)
 Grade 3/4 vomiting 2 pts (A) and 8 pts (B)
 Grade 4 neutropenia 6 pts (A) and 10 pts (B)
Perez EA, et al Proc ASCO 21, A206, 2002