Download Initial Patupilone Phase I Studies

Targeting the Microtubule:
A Novel Approach to Treating
Metastatic Breast Cancer
Photo Courtesy of
National Cancer Institute
1
Challenges in Treating
Resistant/Refractory Metastatic
Breast Cancer
Harold J. Burstein, MD, PhD
Dana-Farber Cancer Institute
Harvard Medical School
Boston, Massachusetts
2
Broad Therapeutic Principles in
Breast Cancer
•  RR   PFS   OS?
• 1st-line RR/TTP >2nd-line RR/TTP >3rd-line, etc
• Combination chemotherapy may improve RR and TTP
without improving OS compared with single-agent
sequential therapy
• Chemotherapy “holiday” does not compromise OS for
patients in response or at treatment plateau
• Response does not always mean symptom relief, and not
all relief is seen among responders
– Particularly in refractory disease
• Clinical meaning of “minor response” and “stable disease”
very unclear
RR = response rate; PFS = progression-free survival; OS = overall survival; TTP = time to progression.
3
Shifting Patterns of Breast
Cancer Therapy
• Adjuvant chemotherapy
– Widespread use of anthracyclines and taxanes
• Metastatic treatment
– Many patients candidates for 3rd-, 4th-, 5th-,
6th-line chemotherapy for metastatic breast
cancer
• Biologic subsets of breast cancer
– HER2  anti-HER2 therapies
– “Basaloid” tumors seeking targeted treatment
4
Real Progress
• Novel agents and treatment schedules improve safety and
efficacy
– Weekly paclitaxel, ixabepilone
• Derivatives minimize certain side effects
– Nab paclitaxel; liposomal doxorubicin
• Novel biologic therapy
– Bevacizumab, other antiangiogenesis agents
• Orally available agents
– Capecitabine
• Better supportive care
– Bisphosphonates
– Antiemetics
– Growth factor support
5
Real Challenges in 2008
• Many patients already treated with adjuvant
anthracyclines and taxanes
• Treatment symptoms, especially neuropathy,
remain a vexing problem
• Limited data on efficacy of therapy in refractory
disease
• Integration of biologic agents on chemotherapy
backbone
• What is resistance?
6
Overcoming Resistance
to Taxanes
7
Strategies to Overcome
Taxane Resistance
•
•
•
•
Employ better schedules
Utilize novel agents
Add biologics
Focus on microtubule
8
Paclitaxel +/– Trastuzumab
Phase III CALGB 9840 Study Design
1998–2000
(n = 171; HER2 status unknown)
2000–2003
(n = 406; known HER2+)
q3wk P
q1wk P
q3wk P + T
q1wk P + T
H
E
R
2
+
H
E
R
2
-
= P = paclitaxel 80 mg/m2a q1wk vs 175 mg/m2 q3wk
= T = trastuzumab 4 mg/kg load, 2 mg/kg/wk
aFirst
116 patients at 100 mg/m2 x 6, then all patients 80 mg/m2/wk.
Seidman AD, et al. J Clin Oncol. 2004;22:Abstract 512.
Courtesy of AD Seidman, MD.
9
CALGB 9840
Tumor Response
All patients
80
HER2 normal patients
(OR = 1.61, P = .017)
(P = .34)
60
40%
28%
35%
29%
40
20
0
q1wk P q3wk P
n=
344
373
Seidman AD, et al. J Clin Oncol. 2004;22:Abstract 512.
Courtesy of AD Seidman, MD.
T
No T
112
111
10
CALGB 9840
Time to Progression
All patients
HER2 normal patients
(Adjusted HR = 1.45, P = .0008)
12
11
10
9
8
7
9 mo
5 mo
(P = .09)
7 mo
6 mo
6
5
4
3
2
1
0
q1wk P q3wk P
n (events/pts) = 221/350 324/385
Seidman AD, et al. J Clin Oncol. 2004;22:Abstract 512.
Courtesy of AD Seidman, MD.
T
74/113
No T
82/115
11
Weekly Nanoparticle Albumin-Bound (nab)
Paclitaxel in Taxane-Refractory
Metastatic Breast Cancer
• Open-label, single-arm phase II trial
• Weekly nab paclitaxel 100 mg/m2 q3wk followed by 1 wk of
rest
• Objectives
– To define the objective response rates of nab paclitaxel in patients
with taxane-refractory metastatic breast cancer
– To evaluate the safety and tolerability of nab paclitaxel at this dose
in this patient population
• Criteria for taxane-refractory disease
– Tumor growth while on taxane therapy (paclitaxel, docetaxel, or
both)
– Relapse within 12 months of adjuvant taxane therapy
Blum JL, et al. J Clin Oncol. 2004;22:Abstract 543.
12
Taxane Exposure in Patients with
Taxane-Refractory Disease
98
Prior adjuvant therapy, any
Prior adjuvant therapy, taxane
N = 105
25
Tumor growth while on taxane
therapy
88
Docetaxel alone
31
Paclitaxel alone
30
27
Both docetaxel and paclitaxel
Relapse <12 months of adjuvant
taxane therapy
12
0
Blum JL, et al. J Clin Oncol. 2004;22:Abstract 543.
20
40
60
80
100
Patients (%)
13
Efficacy of Weekly nab Paclitaxel
Response by Prior Taxane Therapy
40
37
35
35
Percent
30
25
27
24
Objective Response
20
16
Disease Control
15
10
7
5
0
Docetaxel
Alone
(n = 33)
Paclitaxel
Alone
(n = 31)
Both
(n = 28)
Blum JL, et al. J Clin Oncol. 2004;22:Abstract 543.
14
Paclitaxel ± Bevacizumab
Phase III Trial (E2100), Survival Analyses
Progression-Free Survival
Overall Survival
A
B
100
100
80
Paclitaxel + bevacizumab
80
Paclitaxel + bevacizumab
Paclitaxel
60
Median: paclitaxel, 25.2 mo;
paclitaxel + bevacizumab,
26.7 mo
60
40
Median: paclitaxel, 5.9 mo;
paclitaxel + bevacizumab, 11.8 mo
20
P<.001
40
20
Paclitaxel
0
0
6
12
18
0
24
30
36
42
48
54
Month
No. at Risk
Paclitaxel +
347 323 167 100
bevacizumab
Paclitaxel
326 159 89 47
P=.16
53
20
25
12
0
6
12
18
24
30
36
42
48
54
Month
14
7
6
2
2
1
0
0
No. at Risk
Paclitaxel +
347 323 280 232 190
bevacizumab
Paclitaxel
326 284 236 199 162
147
138
88
88
46
24
7
47
23
5
Miller K, et al. N Engl J Med. 2007;357:2666. Copyright © 2007. Massachusetts Medical Society. All rights reserved.
15
Paclitaxel ± Bevacizumab
Hazard Ratios for Disease Progression
Hazard Ratio (95% CI)
Hormone-receptor status
ER-, PRER+, PRER+, PR+
Adjuvant chemotherapy
None
Nontaxane
Taxane
Anthracycline therapy
Yes
No
Age
27–49 y
50–64 y
65–85 y
Disease-free interval
0–24 mo
>24 mo
No. of sites
<3
≥3
Visceral disease
No
Yes
Bone disease only
No
Yes
Measurable disease
Yes
No
Overall
0.0
0.5
Paclitaxel + Bevacizumab Better
1.0
1.5
Paclitaxel Better
Miller K, et al. N Engl J Med. 2007;357:2666. Copyright © 2007. Massachusetts Medical Society. All rights reserved.
16
Microtubules as a Target for
Anticancer Drugs
Jordan MA, et al. Nat Rev Cancer. 2004;4:253.
Reprinted from Jordan MA, et al. Nat Rev Cancer. 2004;4:253, with permission from Nature Publishing Group.
17
Effects of Microtubule-Targeting
Drugs on Cancer Cells
DRUG-SENSITIVE CELL
DRUG-RESISTANT CELL
Drug-Resistant
Mechanisms
MDR (eg, Pgp, MRP)
Altered tubulin expression
Tubulin mutationjs
Altered MAP expression
MDR = multidrug-resistance phenotype; Pgp = P-glycoprotein; MRP = multidrug resistance-associated proteins;
MAP = microtubule-associated proteins.
Kavallaris M, et al. Drug Resist Updat. 2001;4:392.
Reprinted from Kavallaris M, et al. Drug Resist Updat. 2004;4:392, with permission from Elsevier.
18
Effect of Microtubule-Targeting Agents on Cell Cycle
Prometaphase
Early metaphase
Anaphase
Telophase
Metaphase with
paclitaxel*
Metaphase with
vinflunine*
Chromosomes
Microtubules
Kinetochores
*Some chromosomes
remain at spindle pole
Jordan MA, et al. Nat Rev Cancer. 2004;4:253.
Reprinted from Jordan MA, et al. Nat Rev Cancer. 2004;4:253, with permission from Nature Publishing Group.
19
Mechanism of Action of
Microtubule-Targeting Drugs
Vinca alkaloids
Destabilizers
Polymerization
Graphic courtesy of Harold J. Burstein, MD, PhD.
Taxanes/epothilones
Stabilizers
Polymerization
20
Potential Mechanisms of Resistance
to Tubulin-Binding Agents (TBA)
Drug efflux
Altered
interaction with
microtubule
Altered drug metabolism
Altered
apoptosis
signal
Dumontet C, et al. J Clin Oncol. 1999;17:1061.
Reprinted from Dumontet C, et al. J Clin Oncol. 1999;17:1061, with permission from the American Society of Clinical
Oncology.
21
Cellular Changes Associated with
Multidrug and Taxane Resistance
• Overexpression of members of the ATPbinding cassette family of transporters1,2
– eg, p-glycoprotein
• Alterations in tubulin
– Total tubulin content1,2
– Tubulin isotype content2
– Isotype expression1,2
– Polymerization dynamics1,2
1. Fojo AT, et al. Semin Oncol. 2005;32:S3. 2. Dumontet C, et al. J Clin Oncol. 1999;17:1061.
22
Conclusion
• Microtubules as a neoplastic target have
been a cornerstone in early and advanced
breast cancer therapy
• Resistance is a critical limitation of taxanebased microtubule-targeting agents
• Clinical and laboratory measures of taxane
resistance are available
• Novel treatment strategies and informed
drug development may facilitate ways of
overcoming resistance
23
Role of Currently
Available Epothilones in
Resistant/Refractory Metastatic
Breast Cancer
Hope S. Rugo, MD
Clinical Professor of Medicine
Director, Breast Oncology Clinical Trials Program
UCSF Comprehensive Cancer Center
San Francisco, California
24
Limitations of Taxane Therapy
Drug Resistance
• Multidrug resistance is a key mechanism for resistance to tubulinbinding agents1,2
– Innate or acquired1
– Mediated by permeability glycoprotein3 (Pgp) or multidrug resistanceassociated protein4
• Meta-analysis of 31 breast cancer trials5
– Pgp expressed in 41% of tumors
– Chemotherapy increased Pgp tumor expression
– Pgp expression after treatment associated with 3-fold reduction in tumor
response rate
• Other mechanisms of resistance2
– Altered tubulin binding sites
– Mutations in tubulin with changes in isotype expression
1. Kavallaris M, et al. Drug Resist Updat. 2001;4:392. 2. Dumontet C, et al. J Clin Oncol. 1999;17:1061.
3. Peterson RH, et al. Cancer Res. 1983;43:222. 4. Grant CE, et al. Cancer Res. 1994;54:357.
5. Trock BJ, et al. J Natl Cancer Inst. 1997;89:917.
25
Epothilones
Discovery and Structure
• Derived from Sorangium
cellulosum along the
Zambezi River1,2
• Mycobacteria
• Secondary metabolites
(epothilones/fungicides)
• Macrolide lactones3
– Epothilone A, B, E, F
(epoxides)
– Epothilone C, D (olefins)
1. Reichenbach H, et al. Drugs R D. 2008;9:1. 2. Höfle G, et al. Chem Abstr. 1993;120:52841.
3. Kolman A. Curr Opin Investig Drugs. 2005;6:616.
Graphic courtesy of Hope S. Rugo, MD.
26
Epothilones Versus Taxanes
• Epothilones are structurally unrelated to taxanes but are
similar in function as both classes compete for tubulin
binding1
– Appear to avoid developing cross-resistance with taxanes,
perhaps due to their unique binding site on ß-tubulin2
– Cause cell cycle arrest at the G2/M transition phase, leading to
cytotoxicity and eventually cell apoptosis3
• Potent antitumor agents, overcome resistance to taxanes?
• Improved response when in combination with other
chemotherapy agents
1. Giannakakou P, et al. Proc Natl Acad Sci U S A. 2000;97:2904. 2. Nettles JH, et al. Science. 2004;305:866.
3. Wu KD, et al. Proc Natl Acad Sci U S A. 2005;102:10640.
27
Epothilones Bind Specifically and
Uniquely to ß-Tubulin
• Thiazole side-chain
occupies the region of
binding site not occupied
by taxanes1
• Only 1 polar contact point
(C7-OH) is shared with
taxanes1
Paclitaxel
Epothilone A
1. Nettles JH, et al. Science. 2004;305:866.
Graphic with permission from Nettles JH, et al. Science. 2004;305:866.
28
Tubulin Polymerization
Greater with Epothilones
Tubulin Polymerization in the Presence of Microtubule-Associated Proteins
 A350
0.4
Paclitaxel
EpoA
EpoB
0.2
20
40
60
Minutes1
Epothilone B has 2- to 10-fold tubulin polymerizing activity
compared with paclitaxel2
1. Kowalski RJ, et al. J Biol Chem. 1997;272:2534. 2. Kingston DG. Chem Biol. 2004;11:153.
Graphic with permission from Kowalski RJ, et al. J Biol Chem. 1997;272:2534.
29
Phase II Studies of Ixabepilone in
Advanced Breast Cancer
Monotherapy
• Taxane-resistant
– CA163009 (N = 49)1
– NCI-0229 (N = 37)2
Combination with
capecitabine
• Phase I/II
–CA163031 (N = 62)5
• Anthracycline-resistant
– CA163010 (N = 65)3
• Triple-resistant
– CA163081 (N = 113)4
1. Thomas E, et al. J Clin Oncol. 2007;25:3399. 2. Low JA, et al. J Clin Oncol. 2005;23:2726.
3. Roché H, et al. J Clin Oncol. 2007;25:3415. 4. Perez EA, et al. J Clin Oncol. 2007;25:3407.
5. Bunnell CA, et al. J Clin Oncol. 2006;24:Abstract 10511.
30
Ixabepilone in Taxane-Resistant
Metastatic Breast Cancer
MBC with progression
during or <4 months
after receiving taxane
therapy OR <6 months if
adjuvant only
Ixabepilone 40 mg/m2 d1, q3wk
(N = 49)
Median 10.5 treatment cycles
Results
95% CI
12
4.7–26.5
Response duration,
median (mo)
10.4
6.3–22
TTP, median (mo)
2.2
1.4–3.2
OS, median (mo)
7.9
6.1–14.5
ORR (%)
Grade 3/4 toxicities
Fatigue 27%; sensory neuropathy 12%;
myalgia 10%; nausea 6%; vomiting 6%;
neutropenia 33% (Gr3), 20% (Gr4)
MBC = metastatic breast cancer; CI = confidence interval; ORR = overall response rate; TTP = time to
progression; OS = overall survival.
Thomas E, et al. J Clin Oncol. 2007;25:3399.
Graphic courtesy of Hope S. Rugo, MD.
31
Ixabepilone in Taxane-Pretreated
Breast Cancer
MBC or locally
advanced disease
with prior taxane as
neo/adjuvant, or
metastatic therapy
Ixabepilone
6 mg/m2/d d1–5, q3wk
(N = 37)
Median 4 cycles
Results
95% CI
22
9.8–38.2
Response duration,
median (d)
118 (3.9 mo)
––
TTP, median (d)
80 (2.7 mo)
––
ORR (%)
Grade 3/4 toxicities
Neutropenia 16% (Gr3), 19% (Gr4); febrile
neutropenia 14% (Gr3), 0% (Gr4); thrombocytopenia
3% (Gr3), 5% (Gr4); fatigue 8% (Gr3), 5% (Gr4);
diarrhea 11% (Gr3), 0% (Gr4)
MBC = metastatic breast cancer; CI = confidence interval; ORR = overall response rate; TTP = time to
progression.
Low JA, et al. J Clin Oncol. 2005;23:2726.
Graphic courtesy of Hope S. Rugo, MD.
32
Ixabepilone in
Anthracycline-Resistant MBC
Ixabepilone
40 mg/m2 d1, q3wka
(N = 65)
Median 6 cycles
MBC and prior anthracyclinebased adjuvant therapy
(17% received prior taxane)
Results
95% CI
ORR (%)
41.5
29.4–54.4
Response duration,
median (mo)
8.2
5.7–10.2
TTP, median (mo)
4.8
4.2–7.6
OS, median (mo)
22
15.6–27.0
Grade 3/4 toxicities
aReduced
Neuropathy 20% (Gr3), 0% (Gr4); myalgia 8% (Gr3),
fatigue 6% (Gr3), vomiting 5% (Gr3); stomatitis 5% (Gr3);
neutropenia 27% (Gr3), 31% (Gr4)
from 50 mg/m2 infused over 1 hour to 40 mg/m2 infused over 3 hours due to GI toxicity and neuropathy, respectively.
MBC = metastatic breast cancer; CI = confidence interval; ORR = overall response rate; TTP = time to progression;
OS = overall survival.
Roché H, et al. J Clin Oncol. 2007;25:3415.
Graphic courtesy of Hope S. Rugo, MD.
33
Ixabepilone in Heavily
Anthracycline/Taxane/Capecitabine
Pretreated MBC
MBC and
Anthracycline/taxane/
capecitabine resistant
Ixabepilone 40 mg/m2 d1, q3wk
(N = 113)
Median 4 treatment cycles
Median response
(months)
ORR: 18% (investigator), 11.5% (independent)
10
8.6
8
6
5.7
4
3.1
2
0
Duration
PFS
OS
MBC = metastatic breast cancer; ORR = overall response rate; PFS = progression-free survival; OS = overal survival.
Perez EA, et al. J Clin Oncol. 2007;25:3407.
Graphic courtesy of Hope S. Rugo, MD.
34
Summary of Phase II Trials of
Ixabepilone in Metastatic Breast Cancer
45
42
Overall Response Rate
(%)
40
35
30
30
25
22
18a
20
15
12
12b
10
5
0
aInvestigator
Roché1
After adjuvant
anthracycline
Low2
Thomas3
Taxane-pretreated Taxane-resistant
MBC
MBC
assessed; bIndependent assessed.
Perez4
Anthracycline-,
taxane-, and
capecitabineresistant
Bunnell5
Multiresistant MBC
w/capecitabine
1. Roché H, et al. J Clin Oncol. 2007;25:3415. 2. Low JA, et al. J Clin Oncol. 2005;23:2726. 3. Thomas E, et al. J Clin Oncol.
2007;25:3399. 4. Perez EA, et al. J Clin Oncol. 2007;25:3407. 5. Bunnell CA, et al. J Clin Oncol. 2006;24:Abstract 10511.
Graphic courtesy of Hope S. Rugo, MD.
35
Ixabepilone Phase II Trials
Grade 3/4 Toxicity in Metastatic Breast Cancer
100
80
Neutropenia
60
FN
PN
40
20
Myalgias
Fatigue
Diarrhea
0
FN = febrile neutropenia; PN = peripheral neuropathy.
1. Thomas E, et al. J Clin Oncol. 2007;25:3399. 2. Low JA, et al. J Clin Oncol. 2005;23:2726. 3. Roché H, et al. J Clin Oncol.
2007;25:3415. 4. Perez EA, et al. J Clin Oncol. 2007;25:3407. 5. Bunnell CA, et al. J Clin Oncol. 2006;24:Abstract 10511.
Graphic courtesy of Hope S. Rugo, MD.
36
Ixabepilone
Phase III Data
FDA approved ixabepilone in October 2007
as a single agent for triple-resistant disease,
and in combination with capecitabine
for anthracycline- and taxane-resistant disease
37
Taxane- and Anthracycline-Resistant
Advanced Breast Cancer, Phase III
MBC or locally advanced
breast cancer pretreated or
resistant to anthracyclines
and taxanes
May have received prior
chemotherapy for MBC
(N = 752)
Thomas E, et al. J Clin Oncol. 2007;25:5210.
Graphic courtesy of Hope S. Rugo, MD.
R
A
N
D
O
M
I
Z
E
D
Ixabepilone
(40 mg/m2 over 3 h d1 q3wk)
+
Capecitabine
(2000 mg/m2/d PO in 2 divided
doses d1–14 q3wk)
(n = 375)
Capecitabine
(2500 mg/m2/d PO in 2 divided
doses d1–14 q3wk)
(n = 377)
Stratification
• Visceral metastases
• Prior chemotherapy for MBC
• Anthracycline resistance
• Study site
38
Patient Characteristics
Ixabepilone + Capecitabine
n = 375
Capecitabine
n = 377
Age (year)
Median (range)
53 (25–76)
52 (25–79)
67
32
0
63
36
<1
7
48
41
5
9
49
37
6
44
54
44
53
11
87
52
9
12
85
53
9
Karnofsky performance status (%)
90–100
70–80
<70
Prior metastatic regimens (%)
0
1
2
≥3
Prior therapies (%)
Anthracycline
Resistant
Exceeded cumulative dose
Taxane
Resistant (neo/adjuvant)
Resistant (metastatic)
Hormonal
Trastuzumab (metastatic)
Thomas E, et al. J Clin Oncol. 2007;25:5210.
39
Progression-Free Survival by
Independent Review
Median 95% CI
Proportion Progression-Free
1
Ixabepilone +
capecitabine
Capecitabine
0.8
5.8 mo
5.5–7.0
4.2 mo
3.8–4.5
HR: 0.75 (0.64–0.88)
P = .0003
0.6
0.4
0.2
0
0
4
8
12
16
20
24
28
32
36
Months
Thomas E, et al. J Clin Oncol. 2007;25:5210.
Reprinted from Thomas E, et al. J Clin Oncol. 2007;25:5210, with permission from the American Society of Clinical
Oncology.
40
Capecitabine ± Ixabepilone in Anthracyclineand Taxane-Resistant, ER/PR/HER2– MBC
All Patients1,2a
ER/PR/HER2–
Patients2
Patients Without
ER/PR/HER2–
MBC2
HER2+2
I+C
C
I+C
C
I+C
C
I+C
C
(n = 375)
(n = 377)
(n = 91)
(n = 96)
(n = 284)
(n = 281)
(n = 59)
(n = 53)
ORR
35%
14%
27%
9%
37%
16%
31%
8%
PFS
5.8 mo
4.2 mo
4.1 mo
2.1 mo
7.1 mo
5.0 mo
5.3 mo
4.1 mo
HR
0.75
0.68
0.74
0.69
• Most common grade 3/4 events in combination arm were neutropenia (68%) and
reversible peripheral sensory neuropathy (21.1%)1,2
• Grade 3/4 febrile neutropenia occurred in 5% of patients on combination arm1
• Grade 3/4 peripheral neuropathy was reversible to baseline in 89% of patients within a
median of 6 weeks1
aSignificant
difference between arms for ORR (P<.001) and PFS (P =.003).
1. Thomas E, et al. J Clin Oncol. 2007;25:5210. 2. Rugo HS, et al. 30th Annual San Antonio Breast
Cancer Symposium; December 13-16, 2007. Abstract 6069.
Graphic courtesy of Hope S. Rugo, MD.
41
Grade 3/4 Hematologic Toxicities
aBy
Toxicity (%)a
Ixabepilone +
Capecitabine
N = 369
Leukopenia
57
6
Anemia
10
4.5
.005
Neutropenia
68
11
<.0001
Thrombocytopenia
8
4
.011
Febrile neutropenia
5
<1
.001
Capecitabine
N = 368
P Value
<.0001
worst CTCAE v3 grade.
Thomas E, et al. J Clin Oncol. 2007;25:5210.
42
Grade 3/4
Nonhematologic Toxicities
80
% Patients
Ixabepilone + capecitabine (n = 369)
Capecitabine (n = 368)
60
40
23
18 17
20
9
0
8
3
6
0.3
9
4
2
3
2
2
2
3
0
0
Thomas E, et al. J Clin Oncol. 2007;25:5210.
Graphic courtesy of Hope S. Rugo, MD.
43
Time to Resolution of Grade 3/4
Peripheral Neuropathy
•
•
•
1.0
Proportion Not Resolved
0.9
0.8
Primarily sensory
Cumulative
Reversible
0.7
Median time to resolutiona = 6 weeks
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
Weeks
aResolution
= return to baseline or grade 1.
Thomas E, et al. J Clin Oncol. 2007;25:5210.
Graphic courtesy of Hope S. Rugo, MD.
44
Ixabepilone Ongoing and Planned
Clinical Trials
• Completed accrual, results expected in 2009
– Phase II randomized in first-line MBC1
•
•
•
•
Ixabepilone 40 mg/m2 every 3 weeks
Ixabepilone 16 mg/m2 weekly, 3 out of every 4 weeks
Paclitaxel 90 mg/m2 weekly, 3 out of every 4 weeks
Bevacizumab given in all 3 arms either every 2 or every 3 weeks
• Planned
– Phase III randomized in first-line MBC (CALGB 40502)
1. ClinicalTrials.gov identifier = NCT00370552.
45
CALGB 40502 and
NCCTG Phase III Trial
1st-line therapy for metastatic
or locally advanced breast
cancer
Tumor biopsy on
accessible tumor
Correlative studies: tumor
block for SPARC, caveolin
mutations, tubulin isoforms
(N = 900)
R
A
N
D
O
M
I
Z
E
D
Paclitaxel 90 mg/m2 weeklya +
bevacizumab 10 mg/kg q2wk
nab paclitaxel 150 mg/m2 weeklya +
bevacizumab 10 mg/kg q2wk
Ixabepilone 16 mg/m2 weeklya +
bevacizumab 10 mg/kg q2wk
Serial serum measurement of caveolin-1
Serial measurement of CTC and CEC
aD
1, 8, 15 q28d.
CTC = circulating tumor cells; CEC = circulating endothelial cells.
Primary investigators: Rugo H and Moreno A.
Graphic courtesy of Hope S. Rugo, MD.
46
Conclusions
• Epothilones appear to avoid developing cross-resistance
with taxanes, perhaps due to their unique binding site on
ß-tubulin
• In clinical trials, epothilones have shown activity in
resistant/refractory metastatic breast cancer
• Ixabepilone (aza-epothilone B) was approved by the FDA
in October 2007
– As a single agent for triple-resistant disease, and in combination
with capecitabine for anthracycline- and taxane-resistant disease
– Primary adverse events include neutropenia and neuropathy
• Clinical development of ixabepilone and other epothilones
is ongoing
47
Emerging
Microtubule-Targeting Agents:
Strategies for Their Use in
Resistant/Refractory Metastatic
Breast Cancer
William J. Gradishar, MD
Professor of Medicine
Hematology/Oncology
Northwestern University
Chicago, Illinois
48
Emerging Microtubule-Targeting Agents
Stabilizing Agents1,2
Patupilone
BMS-310705
ZK-EPO
Epothilones
KOS-862
KOS-1584
Inhibiting Agents
Vinflunine3
Eribulin mesylate (E7389)4
1. Cortes J, et al. Oncologist. 2007;12:271. 2. Fumoleau P, et al. Ann Oncol. 2007;18:9. 3. Kruczynski
A, et al. Crit Rev Oncol Hematol. 2001;40:159. 4. Jordan MA, et al. Mol Cancer Ther. 2005;4:1086.
49
Epothilones Bind to Beta-Tubulin
• Thiazole side-chain occupies
region of binding site not
occupied by taxanes1
• Only 1 polar contact point
(C7-OH) shared with taxanes1
• Tubulin polymerizing activity
2- to 10-fold greater than
paclitaxel2
• Accumulates in G2/M phase of
cell cycle3
• Has activity in tumors with
multidrug resistance2
Paclitaxel
Epothilone A
1. Nettles JH, et al. Science. 2004;305;866. 2. Kingston DG. Chem Biol. 2004;11:153. 3. Wu KD, et
al. Proc Natl Acad Sci U S A. 2005;102:10640.
With permission from Nettles JH, et al. Science. 20104;305:866.
50
Epothilone Derivatives
S
O
S
OH
N
Epothilone B
O
OH
O
O
OH
O
S
N
O
OH
KOS-862
O
Patupilone
Epothilone D
O
N
Epothilone D
HN
OH
KOS-1584
S
N
O
O
OH
Aza-epothilone B
Ixabepilone
O
OH
O
O
OH
Graphic courtesy of William J. Gradishar, MD.
51
Epothilones in Clinical Development
Clinical Toxicities
Current
Development
Phase
Agent
Epothilone Analog
Ixabepilone1
Aza-epothilone B
Hypersensitivity reaction, neutropeniaa,
thrombocytopenia, neuropathya,
arthralgia/myalgia, fatigue, diarrhea,
stomatitis
Patupilone1
Epothilone B
Diarrheaa, fatigue, nausea, vomiting
III
I/II
(semi-synthetic)
Hypersensitivity reaction,pancytopenia,
neuropathy, arthralgia/myalgia,
asthenia, diarrheaa, ataxia, neutropeniaa,
hyponatremiaa, vomitinga
Epothilone B
Neuropathya, nausea, ataxiaa
II
Fatigue, nausea/vomiting, neuropathy,
impaired gaita, cognitive/perceptual
abnormalitiesa, chest paina
II
Approved
(natural product)
BMS-3107051
ZK-EPO2
Epothilone B
(fully synthetic)
KOS-8621
Epothilone D
(desoxyepothilone-B)
aDose-limiting
toxicity.
1. Goodin et al. J Clin Oncol. 2004;22:2015. 2. Schmid et al. J Clin Oncol. 2005;23:Abstract 2051.
52
Patupilone
Epothilone B
• Naturally occurring1
• Minimal metabolism by CYP4501
• Preclinical data show anti-tumor activity in multiple cell
lines2
1. Hofstetter B, et al. Clin Cancer Res. 2005;11:1588. 2. Cortes J, et al. Oncologist. 2007;12:271
53
Patupilone in Breast Cancer
Clinical Summary
• Phase I trials in patients with advanced solid tumors
– Every 2 of 3 weeks, maximum tolerated dose 2.5 mg/m2 (N = 91)1
• Partial response 3/91; stable disease 31/91
– Every 3 weeks, maximum tolerated dose 6.0 mg/m2 (N = 42)2,3
• Partial response 1/42; stable disease 11/42; significant response 4/42
– Dose-limiting toxicity = diarrhea1,2
– Significant neuropathy uncommon; no grade 3/4 myelosuppression1,2
• Phase II trials in process
1. Rubin EH, et al. J Clin Oncol. 2005;23:9120. 2. Calvert PM, et al. Proc Am Soc Clin Oncol.
2001;20:Abstract 429. 3. Goodin S, et al. J Clin Oncol. 2004;22:2015.
54
BMS-310705 in Breast Cancer
2nd-Generation Epothilone B
• Water soluble, semisynthetic analog of epothilone B1
• Excellent preclinical activity in both taxane-sensitive
and –resistant tumor models, including those with
MDR overexpression and beta-tubulin mutation2
• Phase I clinical trials have evaluated q3wk and
weekly schedules1,3
• Clinical responses have been observed1,3
1. Mekhail T, et al. Proc Am Soc Clin Oncol. 2003;22:Abstract 515. 2. Mekhail T, et al. Proc Am Soc
Clin Oncol. 2002;21:Abstract 408. 3. Sessa C, et al. Proc Am Soc Clin Oncol. 2003;22:Abstract 519.
55
ZK-EPO in Breast Cancer
3rd-Generation Epothilone B
• ZK-EPO (sagopilone) is a fully synthetic epothilone that
exhibits activity in MDR-overexpressing and taxaneresistant tumors 1,2
• In phase I study of ZK-EPO in patients with advanced solid
tumors, dose-limiting toxicities of peripheral neuropathy and
ataxia were observed1
• Phase II trials have reported clinically relevant responses in
patients with recurrent gliomas, platinum-sensitive ovarian
cancer, and androgen-independent prostate cancer2-4
• A phase II trial of ZK-EPO in patients with advanced breast
cancer is now recruiting5
MDR = Multidrug resistance
1. Schmid P, et al. J Clin Oncol. 2005;23:Abstract 2051. 2. Silvani A, et al. J Clin Oncol. 2008;26:Abstract
2083. 3.Rustin GJ, et al. J Clin Oncol. 2007;25:Abstract 5527. 4. Graff J, et al. J Clin Oncol. 2008;26:Abstract
5141. 5. http://www.clinicaltrials.gov/ct2/show/NCT00313248.
56
KOS–862 in Breast Cancer
Epothilone D
• Phase II trial in anthracycline- and taxane-resistant
disease (N = 29)1
– 100 mg/m2 IV over 90 min weekly x 3 (days 1, 8, and
15) every 4 weeks
– H1/H2 antagonist + corticosteroid premedication
– 14% had partial response
– Grade 3 neurotoxicity 19% (including ataxia and
peripheral neuropathy)
• Metabolized by CYP3A42
1. Buzdar A, et al. Presented at: San Antonio Breast Cancer Symposium. 2005; Abstract 1087.
2. Mani S, et al. Anticancer Drugs. 2004;15:553.
57
KOS-1584 in Breast Cancer
2nd-Generation Epothilone D
• Aqueous soluble drug (no need for cremophor prophylaxis)1
• Different pharmacokinetics compared with
KOS-862
– Longer half-life1
– Decreased penetration into CNS1
– Metabolism not by CYP3A41
• 2 Phase I clinical trials in progress
– Single-dose q3wk (3-h infusion)1
– Weekly 3/4 wk(1-h infusion)2
1. Villano-Calero M, et al. J Clin Oncol. 2006;24:Abstract 2003. 2. Stopeck A, et al. J Clin Oncol.
2006;24:Abstract 2041.
58
Vinflunine
A Vinca Alkaloid
• Inhibits tubulin
polymerization
• Disrupts microtubule
dynamics
• Induces cell proliferation
arrest in mitosis
• Initiates a series of
events leading to
apoptotic cell death
2 fluorine atoms added at the 20
position of the catharanthine moiety
previously inaccessible by classic
chemistry
Kruczynski A, et al. Crit Rev Oncol Hematol. 2001;40:159.
Reprinted from Kruczynski A, et al. Crit Rev Oncol Hematol. 2001;40:159, with permission from Elsevier.
59
Vinflunine
Clinical Summary
• Phase II trials anthracycline/taxane-resistant disease: 36%
partial response1
• Phase I and II trials in combination with trastuzumab
– Partial response rates in phase I (63%–74%)2 and II (58%)3
– Manageable toxicity2,3
– Ongoing phase II, 1st-line therapy in HER2+ and HER2–4
• Additional phase I/II trials in combination with other
cytotoxic agents
• Phase III trials planned
1. Fumoleau P, et al. J Clin Oncol. 2004;22:Abstract 542. 2. Paridaens R, et al. J Clin Oncol.
2007;25:Abstract 1058. 3. Peacock NW, et al. J Clin Oncol. 2007;25:Abstract 1043. 4. ClinicalTrials.gov
Identifier = NCT00284180.
60
E7389
Halichondrin B Analog
• Unique tubulin-based mechanism
– Noncompetitive binding at Vinca site
– Causes nonproductive aggregates
– Suppression of cellular microtubule assembly without the
disruption of existing tubulin structures
• Antimitotic agent (accumulates cells in G2M phase)
• Induces apoptosis
• In vivo efficacy in many xenograft models
Jordan MA, et al. Mol Cancer Ther. 2005;4:1086.
61
E7389
Clinical Summary
• Phase II trial in anthracycline/taxane-resistant disease (N = 103)1
– Overall response rate, 14.7% (all partial response)
– Median progression-free survival, 85 days
– Toxicity
• Neutropenia (grade 3/4, 61%)
• Alopecia (grade 1/2, 41%)
• Peripheral neuropathy (grade 3, 4%)
• Ongoing trials in breast cancer
– Global registration trial in anthracycline-, taxane- and capecitabine-resistant
breast cancer2
– 2 randomized trials compared with physician choice (taxane/anthracyclineresistant),3 or capecitabine4
• Ongoing analysis of biomarkers to explore tubulin isotype expression as
a response predictor5
1. Blum JL, et al. J Clin Oncol. 2007;25:Abstract 1034. 2. ClinicalTrials.gov Identifier = NCT00246090. 3.
ClinicalTrials.gov Identifier = NCT00388726. 4. ClinicalTrials.gov = NCT00337103. 5. Agoulnik S, et al. J
Clin Oncol. 2005;23:Abstract 2012.
62
Conclusion
• New microtubule-targeted agents have
shown benefit in the treatment of advanced
breast cancer
– Improved efficacy
– Reduced toxicity
– Expanded treatment options
• Ongoing and planned trials will help to
elucidate markers of resistance and
sensitivity
– Individualize choice of therapy?
63
Which Breast Cancer Patients
Can Benefit from
Microtubule-Inhibiting Agents?
Clinical Application
64
Case I
Initial Presentation and Therapy
• 45-year-old woman
– History of stage II, node-positive invasive ductal cancer
• ER/PR/HER2 negative
– Adjuvant chemotherapy with doxorubicin,
cyclophosphamide, and paclitaxel dose-dense regimen
followed by radiation
• Relapse at 18 months
– Symptoms: cough with dyspnea on exertion
– CT scan: multiple small pulmonary nodules with ground
glass appearance suggestive of lymphangitic spread
– Performance status: 1
65
Treatment Options
• What treatment would you consider?
– Bevacizumab and a weekly taxane
– Paclitaxel and gemcitabine
– Docetaxel and gemcitabine
– Taxane alone
– Capecitabine
– Other
66
Case I Continues
Second-line Treatment
• Patient receives paclitaxel and bevacizumab
– Cough resolves within 2 weeks
– Scans demonstrate significant improvement in
pulmonary disease
• 5 months into treatment, she presents with
recurrent cough
– CT scans show progression of pulmonary disease and 1
single liver lesion
– Liver function tests are normal
– Performance status remains 1
67
Treatment Options
• What treatment would you choose?
–
–
–
–
–
–
–
Capecitabine alone
Capecitabine with ixabepilone
Gemcitabine
Vinorelbine and capecitabine
Ixabepilone alone
Nab paclitaxel
Doxorubicin liposomal
68
Case II
Patient Presentation
• 40-year-old woman presents for second opinion
• History
– Stage I, high grade, ER weakly positive, PR negative,
HER2 negative invasive ductal cancer
– Treated with doxorubicin and cyclophosphamide for 4
cycles and breast radiation, followed by tamoxifen
– Relapsed in supraclavicular node 6 months after
completion of chemotherapy
– Treated with ovarian suppression and an aromatase
inhibitor
• Progression at first scans with new adenopathy, 3 liver lesions
69
Case II
Patient Presentation
• History cont’d
– Treated with capecitabine
• Initial response followed by progression at 4 months
– Treated with docetaxel at 75 mg/m2 every 3 weeks
• Response at 9 week scans
• Progression at 5 months in liver, nodes, new left-sided pleural effusion
• Performance status still good; patient active and working
part-time
– Liver function tests
• Normal bilirubin, alkaline phosphatase and transaminases mildly
elevated (grade I)
70
Treatment Options
• What treatment would you choose?
– Gemcitabine
– Gemcitabine with carboplatin
– Ixabepilone alone
– Vinorelbine
– Weekly paclitaxel
– Weekly or every 3 week nab paclitaxel
– Chemotherapy with bevacizumab
71