Transcript Targeting Microtubules: new drugs in the clinic

Integration of Treatment Advances into Clinical Practice:
Novel Microtubule-Targeting Agents in
Metastatic Breast Cancer
Linda T. Vahdat, MD
Medical Director, Breast Cancer Research Program
Weill Cornell Medical College
New York Presbyterian Hospital
New York, NY
Program Goals
• Review data on new anti-microtubule agents (nabpaclitaxel and ixabepilone)
– Background
– Mechanism of action
– Pharmacology
– Pre-clinical data
– Clinical data
Why Target Microtubules?
• Perform multiple basic cellular functions
• Fill the area from nucleus to plasma membrane
• At least 3 distinct binding sites for tubulin-targeting
drugs
• Disruption of microtubule cytoskeleton leads to mitotic
arrest and cell death
Microtubule Structure and Assembly
+
b
a
–
-
Slide courtesy of Dr. Paraskevi (Evi) Giannakakou
Mitosis and Microtubules
• Microtubules
– Make up the mitotic spindle
– Critical to separation of chromosomes in mitosis
Slide courtesy of Dr. Paraskevi (Evi) Giannakakou
Microtubule-Stabilizing Agents Derived
From Natural Products
Agent
Source
Latin Name
Pacific yew
Taxus brevifolia
Myxobacteria
Sorangium cellulosum
Discodermolide
Sponge
Discodermia dissoluta
Eleutherobin
Corals
Eleutherobin aurea
Sarcodictyins
Corals
Sarcodictyon roseum
Taccalonolide
Plant
Tacca plantagine/chantrieri
Paclitaxel
Epothilones
Laulimalide
Sponge
Fasciospongia rimosa
Cacospongia mycofijiensis
Partial Listing of Drugs That Target
Microtubules
• Vinca alkaloids
• Taxanes
• Epothilones
nab-paclitaxel
nab-paclitaxel
• Paclitaxel bound to albumin
• Advantages:
– No premeds
– Cremophor free
– Shorter infusion time
• Might make use of gp60-albumin mediated receptor
transport across endothelial cells
nab-platform Utilizes Endogenous Albumin Pathways of Endothelial
Transcytosis (gp60) and Intratumoral Binding of SPARC
Albumin-Bound Drug
Tumor
endothelial cell
gp60 receptor
Red Blood cell
Gp60 Receptor
Albumin-drug
complex
TUMOR
BLOOD
VESSEL
gp60/Alb-drug complex
Caveolae
TUMOR
SPARC on Tumor
INTERSTITIUM cell surface
Alb-drug complex
transcytosed by gp60
Surface SPARC bound to
Alb-drug complex
SPARC
Internalized
SPARC/Alb-drug
complex
Tumor
cells
Albumin-Drug Accumulation
A Pharmacokinetic Comparison of
nab-paclitaxel and Paclitaxel
PK Comparison-linearity
Total Paclitaxel
nab-paclitaxel: 30 min infusion
Linear, predictable PK
Dose
Cmax
(mg/m2)
%δ
135
175
CL
(ng*hr/ml)
%δ
(L/h/m2)
%δ
---- 3071 ----
8604
----
15.9
----
30 5202 70
15048
75
11.6
25
(ng/ml)
%δ
AUC
Paclitaxel: 3 hr infusion
Non-linear,
less-predictable PK
Clinical PK Comparison of Total Paclitaxel
Study C008-0
[Paclitaxel], ng/ml
15000
nab-paclitaxel
(dose-adjusted to 175 mg/m2)
10000
paclitaxel (175 mg/m2)
5000
0
0
5
Hours
10
Clinical Studies
nab-paclitaxel
No. pts
Setting
Schedule
RR (%)
Med TTP
(wks)
Ibrahim1
63
No limit
300 mg/m2 Q3w
48
27
Mirtschung2
23
1st line
125 mg/m2 QW
(3 out of 4 wks)
57
NR
460
1st line
260 mg/m2 vs.
175 mg/m2 Q 3W
33 vs 19
23 vs 17
Trial
Gradishar3
nab-paclitaxel vs
paclitaxel
Significant differences in Bold; RR= response rate, TTP= time to progression; NR= not reported
1Ibrahim,
JCO 2005; 2Mirtschung Breast Ca Res Treat Suppl 2006; 3Gradishar JCO 2005
Phase II Study nab-paclitaxel vs. Docetaxel
first-line metastatic breast cancer patients randomized to 4 arms:
Comparisons (N=300)
nab-paclitaxel vs.
docetaxel
(A, B, C vs. D)
weekly vs. every-3weeks nab-paclitaxel
(B, C vs. A)
Arm A: nab-paclitaxel 300 mg/m2 q3w
R
A
N
Arm B: nab-paclitaxel 100 mg/m2
weekly 3 out of 4
D
O
M
Arm C: nab-paclitaxel 150 mg/m2
weekly 3 out of 4
I
low vs. high dose
weekly nab-paclitaxel
(B vs. C)
Z
E
Arm D: docetaxel 100 mg/m2 q3w
Arms A, C and D administered at the MTD
Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.
Phase II Study nab-paclitaxel vs. Docetaxel
ABX 300 mg/m2 every 3 wks
(N = 76)
MBC and no previous
chemotherapy for
metastatic disease
(N = 300)
ABX 100 mg/m2 wkly for 3 of 4 wks
(N = 76)
ABX 150 mg/m2 wkly for 3 of 4 wks
(N = 74)
Docetaxel 100 mg/m2 every 3 wks
(N = 74)
Gradishar W, et al. ASCO 2007. Abstract 1032.
Comparison of Investigator and Independent Radiology
Review Response Assessments
Response Rate (%)
80%
70%
Pearson Correlation Coefficient
(Investigator vs. IRR) = 0.507
60%
Investigator
70%
IRR
62%
50%
40%
30%
45%
43%
47%
38%
35%
28%
20%
10%
0%
300 mg/m2
q3w
(A: N = 76)
100 mg/m2
qw 3/4
(B: N = 76)
nab-paclitaxel
150 mg/m2
qw 3/4
(C: N = 74)
docetaxel
100 mg/m2 q3w
(D: N = 74)
Gradishar et al, San Antonio Breast
Cancer Symposium. 2006; Abstract 46.
Phase II Study Evaluating Various Doses of
nab-paclitaxel vs. Docetaxel (cont’d)
P = .002
100
90
Response Rate (%)
ABX 300 mg/m2 q3w
ABX 100 mg/m2 qw3/4
ABX 150 mg/m2 qw3/4
Docetaxel 100 mg/m2 q3w
P = .007
80
P = .003
P = .016
70
70
62
60
50
43
38
40
30
20
10
0
n=
76
76
74
74
Treatment
Gradishar W, et al. ASCO 2007. Abstract 1032.
•
•
•
•
PFS statistically superior with 150
mg/m2 (P = .002) and 300 mg/m2 nabpaclitaxel (P = .046) compared with
docetaxel in MBC
PFS statistically superior with 150
mg/m2 nab-paclitaxel compared with
100 mg/m2 nab-paclitaxel
(P = .009)
Lower incidence of neutropenia
and fatigue with all schedules of nabpaclitaxel compared with docetaxel
Randomized phase III trial comparing
weekly nab-paclitaxel 150 mg/m2 vs.
docetaxel 100 mg/m2 in MBC planned
Proportion Not Improved
Phase II Study Evaluating Various Doses of
nab-paclitaxel vs. Docetaxel (cont’d)
Progression-free Survival
Investigator Assessments
1.0
A
B
C
D
0.75
0.50
0.25
75% of patients off-study
0.0
0
3
6
9
12
Months
15
18
Gradishar W, et al. ASCO 2007. Abstract 1032.
nab-paclitaxel: Grade 3/4 Toxicity in MBC
Grade 3/4 Neutropenia 19-37%
100
80
300mg/m2 Q3w
100mg/m2 QW
150mg/m2 QW
60
40
20
N
eu
tr
op
en
i
a
0
Docetaxel 100 mg/m2 q3w 21-74%
nab-paclitaxel: Grade 3/4 Toxicity in MBC
Febrile Neutropenia 1%
100
80
300mg/m2 Q3w
100mg/m2 QW
150mg/m2 QW
60
40
20
0
ni
e
p
o
tr
u
e
N
a
FN
Docetaxel 100 mg/m2 q3w 7%
nab-paclitaxel: Grade 3/4 Toxicity in MBC
Peripheral neuropathy 7-14 %
100
80
300mg/m2 Q3w
100mg/m2 QW
150mg/m2 QW
60
40
20
N
eu
tr
PN
FN
op
en
i
a
0
100 mg/m² QW least neuropathy compared to two other nab-paclitaxel arms
Docetaxel 100 mg/m2 q3w 5%
Time to Improvement in Peripheral Neuropathy
Proportion Not Improved
1.00
nab-paclitaxel 300 mg/m2 q3w (N = 13)
nab-paclitaxel 100 mg/m2 weekly (N = 7)
nab-paclitaxel 150 mg/m2 weekly (N = 12)
Docetaxel 100 mg/m2 ( N = 8)
0.75
A) Median, 16 days, 95% CI, 12 to 24
B) Median, 22 days, 95% CI, 14 to 25
C) Median, 23 days, 95% CI, 12 to 31
D) Median, 41 days, 95% CI, 37 to 44
0.50
0.25
0.00
0
20
60
40
80
100
Days
Gradishar et al, San Antonio Breast Cancer Symposium. 2006; Abstract 46.
nab-paclitaxel: Grade 3/4 Toxicity in MBC
Fatigue 0-4 %
100
80
300mg/m2 Q3w
100mg/m2 QW
150mg/m2 QW
60
40
20
PN
FN
Fa
tig
ue
N
eu
tr
op
en
i
a
0
100 mg/m2 QW least neuropathy compared to two other nab-paclitaxel arms
Docetaxel 100 mg/m2 q3w 15%
Conclusions
• The response rates of q3w nab-paclitaxel and
docetaxel were comparable
• For each regimen of nab-paclitaxel compared to
docetaxel
– Grade 4 neutropenia, febrile neutropenia and mucositis were
less frequent
– There were no statistical differences between the rates of
peripheral neuropathy
Case: Taxane-naïve First-line
Metastatic Breast Cancer
• 54 y.o. woman diagnosed with Stage II BC in 1999
(T= 2.5 cm N = 1/15, ER/PR pos. HER2neu = 0)
• AC Q3W x 4 followed by Tamoxifen
• 2006: increased abdominal fullness
• Mild elevation of transaminases EOD: liver metastases
• Biopsy: c/w prior BC ER/PR positive and HER2-neu
non-amplified by FISH
Case: Taxane-naïve First-line
Metastatic Breast Cancer
Which treatment option would you recommend?
 nab-paclitaxel
 Docetaxel
 Capecitabine
 Vinorelbine
Case: Taxane-naïve First-line
Metastatic Breast Cancer
Which treatment option would you recommend?




nab-paclitaxel
Docetaxel
Capecitabine
Vinorelbine
Recommended Approach:
•
nab-paclitaxel
Ixabepilone
Epothilones
• Derived from sorangium Cellulosum
along the Zambezi River
• Myxobacteria
• Secondary metabolites
(epothilones/fungicides)
Epothilones
• Macrolide lactones
– Epothilone A, B, E, F
(epoxides)
– Epothilone C,D (olefins)
Goodin et al JCO 2004
Epothilones: Mechanism of Action
• Induce microtubule stabilization
– Bind to b-tubulin
– Compete with same binding site as paclitaxel and neuronal tau
protein on b-tubulin
– Binding mode different from above
– Accumulate in G2/M
Effect of Epothilone B on Tumor Cells
Microtubule
bundling
Control cells displaying normal interphase microtubules .
Right: Cells treated with 10 nM epothilone B for 24 h displaying extensive microtubule bundling.
Altmann et al Biochim Biophys Acta 2000
Epothilones: Mechanism of Action
• Induces conformational changes in Bax (pro-apoptotic
protein)
• Bcl-2- dependent
• Potential for synergism with Bcl-2 inhibitors
Pharmacologic Considerations
• Epothilone A and B
– High in vitro tumor activity
– Modest in vivo activity
– Metabolic instability
– Unfavorable PK
– Narrow therapeutic window
• Analogs developed to optimize product
Class-specific Advantages
• Low susceptibility to tumor resistance mechanisms
–
MRP-1 and P-gp efflux pumps
–
b (III) tubulin overexpression
–
b-tubulin mutations
Pharmacology
ixabepilone
Ixabepilone: Pharmacology
• Excreted in the feces (75%) and urine (25%)
• Metabolized via P450 (CYP3A4)
• Linear (AUC increases with dose)
– Linear relationship between microtubule bundle formation in
PBMC and plasma concentration
• T1/2: 39 hours (range:17-50 hrs)
Data: BMS data on file
Ixabepilone: Pharmacology
Daily x 5Q21d
Daily x 3 Q21d
Weekly
Once Q21 d
1
1
0.5-1
1
Range
1.5 -8
8-10
1-30
32-65
MTD
6
8
25
50
Infusion
duration (hr)
Dose
(mg/m2/day)
DLT
Neutropenia, neuropathy
MTD: maximum tolerated dose; DLT: dose-limiting toxicity; Q: every
Goodin et al, J Clin Oncol 22:2015, 2004
Pre-clinical Data
IC50 of Various Epothilones Against
MCF-7 Cell Lines
6.9
7
6
5
4
3.26
3
2.31
2.04
2
1
0.7
0.29
0
Paclitaxel
1
1Watkins
Epo A
Epo B
1
Epo D
1
Epo F
1
1
ZK-EPO
1
2
EB et al, Current Phamaceutical Design, 2005; 2Hoffman J Breast Cancer Res Treat Abstract 1103, 2006
IC50 Values (nM) for Net Growth Inhibition of Human Carcinoma
Cell Lines by Epothilones A and B in Comparison to Paclitaxel
Altmann et al Biochim Biophys Acta 2000
Ixabepilone: Phase II Data in Breast Cancer
45
42
ORR (%)
30
22
19
15
18 pCR
12
0
Roché1
After
adjuvant
anthra
Low2
Conte3
Thomas4
Baselga5
Taxane-pretreated Taxane-resistant Multiresistant
Neoadjuvant
MBC
MBC
(anthra / tax / cape) T2-4, N0-3,
MBC
M0
1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol
2005;23:2726–34. 3. Conte P et al. J Clin Oncol 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol 2006;24(18S):abstr 660.
5. Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.
Ixabepilone: Grade 3/4 Toxicity in MBC
100
80
BMS 009
NCI 0229
BMS 010
BMS 081
BMS 031
60
40
20
0
Grade 3/4 neutropenia 35 to 58%
Ixabepilone: Grade 3/4 Toxicity in MBC
100
80
BMS 009
NCI 0229
BMS 010
BMS 081
BMS 031
60
40
20
FN
N
eu
tr
op
en
i
a
0
Febrile neutropenia 3-14% with 14 % on NCI0229
Ixabepilone: Grade 3/4 Toxicity in MBC
100
80
BMS 009
NCI 0229
BMS 010
BMS 081
BMS 031
60
40
20
0
Sensory neuropathy ranged from 3-22%
Ixabepilone: Grade 3/4 Toxicity in MBC
100
80
BMS 009
NCI 0229
BMS 010
BMS 081
BMS 031
60
40
20
0
Severe myalgias range from 3-26%
Ixabepilone: Grade 3/4 Toxicity in MBC
100
80
BMS 009
60
NCI 0229
BMS 010
40
BMS 081
20
BMS 031
0
Fatigue variable at 6 to 34%
Ixabepilone: Grade 3/4 Toxicity in MBC
100
80
BMS 009
NCI 0229
BMS 010
BMS 081
BMS 031
60
40
20
D
ia
rrh
ea
Fa
tig
ue
ya
lg
ia
s
M
PN
FN
N
eu
tro
pe
ni
a
0
Diarrhea at 1 to 11%
Case: Early Relapse After Adjuvant ACT
• 53 y.o. woman with a h/o of a stage IIIB breast cancer
– Left lumpectomy and AND T= 3.5 cm N= 6/25 ER/PR=
pos/neg and HER2-neu negative by FISH
– Received AC followed by paclitaxel Q2w
– Received chest wall RT followed by anastrozole
• Relapse in CW, lungs and liver 8 months after
completing adjuvant therapy
Case: Early Relapse After Adjuvant ACT
Which treatment option would you recommend?
 nab-paclitaxel
 Docetaxel
 Capecitabine
 Vinorelbine
 Ixabepilone
Case: Early Relapse After Adjuvant ACT
Which treatment option would you recommend?
 nab-paclitaxel
 Docetaxel
 Capecitabine
 Vinorelbine
 Ixabepilone
Recommended Approach:
•
Ixabepilone ± capecitabine
Phase III Data
A Multicenter Phase III Clinical Trial
Comparing Ixabepilone plus Capecitabine
with Capecitabine Alone in Patients with Metastatic
Breast Cancer Previously Treated with or Resistant to
Anthracycline and Resistant to Taxanes
Linda T. Vahdat, MD
Weill Cornell Medical College
New York, New York
On Behalf of the 046 Study Investigators
Study Design: International, Randomized,
Open-label, Phase III Trial
Ixabepilone
(40 mg/m2 IV over 3 hr d1 q3wk)
+
Capecitabine
Metastatic or locally
advanced breast cancer
RESISTANT
to anthracyclines
and taxanes
N = 752
Stratification
• Visceral metastases
• Prior chemotherapy for MBC
(2000 mg/m2/day PO 2 divided doses
d1-d14 q3wk)
N = 375
Capecitabine
(2500 mg/m2/day PO 2 divided doses
d1-d14 q3wk)
N = 377
•Anthracycline resistance
•Study site
Resistance to Prior Therapy
Strict definition: patients whose tumors rapidly progressed in the adjuvant or
metastatic setting after receiving both anthracyclines and taxanes
Setting
Anthracycline
Taxane
Metastatic
≤3 months of last dose
≤4 months of last dose
Neo/adjuvant
≤6 months of last dose
≤12 months of last dose
Minimum cumulative dose
Any
Doxorubicin: 240 mg/m2
Epirubicin: 360 mg/m2
Patient Eligibility Criteria
Inclusion Criteria
Exclusion Criteria
• Women ≥18 years
• Locally advanced or MBC
• >3 prior chemo regimens
(adjuvant and metastatic)
• Anthracycline-resistant or
minimum cumulative dose
• ≥G2 motor/sensory
neuropathy
• Taxane-resistant
• Reduced hematologic/
renal function
• KPS 70–100
• Life expectancy ≥12 wk
• ≥G2 liver function tests*
• CNS metastases
*Protocol amendment excluded patients with ≥G2 liver function tests regardless of liver metastases; 377 patients (33 with
≥G2 liver function tests) had been enrolled before amendment
Progression-free Survival
by Independent Radiologic Review
Proportion Progression Free
1.0
0.8
Median
95% CI
Ixabepilone + Capecitabine
5.8 mo
(5.5–7.0)
Capecitabine
4.2 mo
(3.8–4.5)
0.6
HR: 0.75 (0.64–0.88)
P=0.0003
0.4
0.2
0
0
4
8
12
16
20
Months
24
28
32
36
Response Rate
Investigator
% Response
ORR (CR + PR)
IRR
Ixabepilone +
Capecitabine
N=375
Capecitabine
Capecitabine
N=377
Ixabepilone +
Capecitabine
N=375
42
23
35
14
P<0.0001
N=377
P<0.0001
Stable disease
36
38
41
46
Progressive
disease
14
29
15
27
Unable to
determine
8
10
9
12
Grade 3/4 Non-hematologic Toxicities
80
Ixabepilone + Capecitabine (N = 369)
% of Patients
Capecitabine (N = 368)
60
40
23
18 17
20
9
0
0
8
3
6
0.3
9
4
2
3
2
3
2
3
0
Epothilones in Development
•
•
•
Patupilone (epothilone B):
–
Phase I trials in breast cancer in combination with other cytotoxics
–
In preliminary efficacy data, toxicity included significant gastrointestinal effects
–
New formulation appears to reduce toxicity
KOS-862 (epothilone D):
–
Phase II trial in anthracycline- and taxane-pretreated metastatic breast cancer
–
Of the 41 evaluable patients, 5 achieved a PR and 3 had SD
–
Grade 3 neurotoxicity in 43 evaluable patients: neuropathy (12%) and ataxia (9%)
–
Phase I trial combined with trastuzumab:
•
Unconfirmed response: 3/13
•
Grade 3 neurotoxicity: 2/13
ZK-EPO:
–
First fully synthetic third-generation epothilone
–
Not recognized by efflux pumps; efficacy in preclinical models in taxane-resistant
disease
Cortes et al. J Clin Oncol 2006; 24(suppl):86s (abstract 2028).
Buzdar et al. Breast Cancer Res Treat 2005; 94(suppl 1):S69 (abstract 1087).Klar et al. Breast Cancer Res Treat
2005; 94(suppl 1):S64 (abstract 1072).
Case: Refractory Triple Negative Breast Cancer
• 46 y.o. woman with a h/o stage I BC (T = 1.8 cm N = 0 ER/PR/HER
2 neu: negative diagnosed in 2000
• RLE and SLNB
• AC x 4 Q3w followed by right breast RT
• Did well until 2005 when developed soft tissue mass adjacent to
sternum
– Biopsy c/w recurrent BC ( ER/PR/HER2 neu negative)
• Capecitabine: Initial response followed by POD in bone
• Docetaxel: Initial response followed by POD in lungs and
mediastinal LNs
Case: Refractory Triple Negative Breast Cancer
Which treatment option would you recommend?
 nab-paclitaxel
 Gemcitabine
 Vinorelbine
 Ixabepilone
Case: Refractory Triple Negative Breast Cancer
Which treatment option would you recommend?
 nab-paclitaxel
 Gemcitabine
 Vinorelbine
 Ixabepilone
Recommended Approach:
•
Ixabepilone
Integration of Treatment Advances into Clinical Practice:
Novel Microtubule-Targeting Agents in
Metastatic Breast Cancer
Closing Remarks