Transcript Melanoma: Nuovi approcci chemioterapici

1
Albumin-Bound Paclitaxel
for the Treatment of Melanoma
Clinical data
2
Chemotherapy in Metastatic Melanoma: Survival
Outcomes Phase II/III Trials
Author
No.
Patients
Evaluable
di Pietro1
Median
PFS or
TTP
Median
OS
Agents
Dose
36
DTIC
BEV
800 mg/m2 q 4 weeks
10 mg/kg q 2 weeks
6 mo (TTP)
16.5 mo
von Moos2
SAKK 50/07 trial
62
TMZ
BEV
150 mg/m2 days 1-7 (q 2 w)
10 mg/kg q 2 weeks
4.2 mo
9.3 mo
Perez3
NCCTG –NO47A
trial
53
Paclitaxel
Carboplatin
BEV
80 mg/m2 d. 1,8,15 (q 4 w)
AUC 6 (q 4 w)
10 mg/kg q 2 weeks
6 mo
12 mo
O’Day4
214
Paclitaxel
Carboplatin
BEV
175 mg/m2 q 3 weeks
AUC 5 q 3 weeks
15 mg/kg q 3 weeks
5.6 mo
12.3 mo
Hauschild5
270
Paclitaxel
Carboplatin
Sorafenib
225 mg/m2 q 3 weeks
AUC 6 q 3 weeks
400 mg BID d2-19 (q 3 w)
17.4 weeks
42 weeks
AUC, area under the curve; BEV, bevacizumab; BID, twice daily; DTIC,
dacarbazine; TMZ, temozolomide; TTP, time to progression.
1.Di Pietro A, et al. J Clin Oncol 2010;28:15s [abstr. 8536].
2. von Moos R, et al. Ann Oncol 2011:epub.
3. Perez D.G, et al. Cancer 2009 Jan 1;115(1):119-27.
4. O’Day K, et al. Eur J Cancer 2009; Supplement 7:13.
5. Hauschild A, et al. J Clin Oncol. 2009 ;27:2823-30.
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Rationale for NAB-Paclitaxel in Melanoma
• Dacarbazine is frequently used in the care of malignant melanoma1
• As a single agent, paclitaxel has been reported to have limited activity in
patients with malignant melanoma2-5
• In a phase I study of AB-paclitaxel in patients with advanced solid tumors, 3
of 14 patients with malignant melanoma experienced disease stabilization for
> 4 months6
• In a phase 2 study of AB-paclitaxel in patients with metastatic melanoma,
activity was seen in both previously treated (PT) and chemotherapy-naïve
(CN) populations7
– PT: Median PFS 3.5 months, median OS 12.1 months
– CN: Median PFS 4.5 months, median OS 9.6 months
– Results compare favorably with previous reports of standard dacarbazine or
temozolomide8,9
• Median PFS ≈1.6 months
• Median OS < 8 months
AB, albumin-bound; OS, overall survival; PFS,
progression-free survival.
1. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v4.2011.
2. Bedikian AY, et al. Melanoma Res. 2004;14:63-66.
3. Einzig AI, et al. Invest New Drugs. 1991;9:59-64.
4. Legha SS, et al. Cancer. 1990;65:2478-2481.
5. Walker L, et al. Melanoma Res. 2005;15:453-459.
6. Nyman DW, et al. J Clin Oncol. 2005;23:7785-7793.
7. Hersh EM, et al. Cancer. 2010;116:3.155-163.
8. Bedikian AY, et al. J Clin Oncol. 2006;24:3738-4745.
9. Middleton MR, et al. J Clin Oncol. 2000;18:158-166.
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nab-paclitaxel in Metastatic Melanoma
Trial Description
N
Dose
ORR
• Chemonaive:
ABX 100
and
10 (25.6%)
carboplatin AUC 2
administered on
• Previously
days 1, 8, and 15
treated: 3
every 28 days
(8.8%)
mg/m2
Phase II ABX + Carboplatin in
Unresectable Advanced Melanoma
A Randomized Phase II Trial of
Emosolomide (TMZ) and Avastin or
ABI-007/Carboplatin (CBDCA) and
Avastin in Patients with Unresectable
Stage IV Malignant Melanoma (N0775)
A Pilot Study of nab-paclitaxel®
(Albumin-bound Paclitaxel) and
Temodar® (Temozolomide) plus
Genasense® (Oblimersen Sodium) in
Subjects with Advanced Melanoma
(“The ATG Study”)
Phase II Study of nab-paclitaxel® and
Avastin as Therapy for Patients with
Metastatic Melanoma
76
94
Carboplatin (AUC 6;
day 1), ABX
(100mg/m2 days 1,
8 and 15), and
• 17 (33%)
Avastin (10mg/kg on
days 1 and 15)
every 28 days
32
ABX 175 mg/m2 or
260 mg/m2 d8 +d29
Temo 75 mg/m2
Obl 7 mg/kg/day
CIV or 900 mg IV
over 1 hour
50
ABX 150mg/m2 d 1,
8, 15 and
Avastin10mg/kg d 1
and 15, 28d cycle
• 12 (31%)
• 18 (36%)
PFS
• Chemonaive:
4.5 mo
OS
• Chemonaive:
11.1 mo
• Previously
• Previously
treated: 10.9
treated: 4.1 mo
mo
• 6.6 mo
• PFS at 6 mo:
54.9%
• NR
• 7.6 mo
Abstract/
Publication
• Published
Cancer 2011;
117:1704-10.
• 13.9 mo
• ASCO 2011 [abstract
#8532 Kottschade]
• Manuscript in
development
• 14.7 mo
• ASCO 2009
• ASCO 2010 [abstract
#8561]
• ASCO 2011 [abstract
8545 Chang]
• Manuscript in
development
• 16.8 mo
• ASCO 2011 [abstract
#8543 Boasberg]
• Manuscript in
development
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Melanoma: new chemotherapeutical approaches
A PHASE 2 CLINICAL TRIAL OF NAB-PACLITAXEL IN PREVIOUSLY TREATED
AND CHEMOTHERAPY-NAIVE PTS WITH MM
HERSH ET AL, CANCER 2010
A PHASE II TRIAL OF NAB-PACLITAXEL (ABI-007) AND CARBOPLATIN IN PTS
WITH MM: A NORTH CENTRAL CANCER TREATMENT GROUP STUDY,
N057E1
KOTTSCHADE ET AL, CANCER 2011
AN OPEN-LABEL MULTICENTRE, PHASE III TRIAL
OF ABI-007 (nab-paclitaxel) VS DACARBAZINE IN PREVIOUSLY UNTREATED
MM PTS
ON GOING
6
A phase 2 clinical trial of nab-paclitaxel in
previously treated and chemotherapy-naive pts
with Metastatic Melanoma
Hersh et al. Cancer 2010, 116 (1): 155-63
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nab-paclitaxel in previously treated and chemotherapynaive pts with Metastatic Melanoma
Objectives
 Primary objectives
– to evaluate the antitumor activity and
safety/tolerability of nab-paclitaxel® on a schedule of
qw for 3 wks out of 4 (one cycle) in each cohort
• 100 mg/m2 previously treated
• 150 mg/m2 chemotherapy naïve
 Secondary objectives
– to evaluate PFS in each cohort
– to evaluate OS in each cohort
Hersh et al. Cancer 2010, 116 (1): 155-63
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A phase 2 clinical trial of nab-paclitaxel in previously
treated and chemotherapy-naive pts with MM
METHODS:
nab-Paclitaxel iv weekly for 3 of 4 weeks at a dose of 100/150 mg/m2 (in previously
treated/naive pts)
RESULTS:
37 treated (PT) pts
- OR:
- OR+SD:
- PFS:
- OS:
2.7%
37.8%
3.5 months
12.1 months
37 chemonaive (CN) pts
21.6%
48.6%
4.5 months
9.6 months
22% chemotherapy-naive patients discontinued therapy because of toxicities
(grade 3 to 4 neuropathy, alopecia, neutropenia, and fatigue)
CONCLUSIONS:
nab-Paclitaxel was found to be well tolerated and demonstrated activity in both
previously treated and chemotherapy-naive patients with MM.
Hersh et al. Cancer 2010, 116 (1): 155-63
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Study Design and Objectives
• Study design: a multi-center phase II trial of albumin-bound paclitaxel in
patients with metastatic melanoma
– N = 74
– Patients with ECOG PS 0-1, adequate organ function and histologically confirmed malignant
melanoma either previously treated with chemotherapy or chemotherapy-naïve
– Cycles of 28 days until disease progression or dose-limiting toxicity
PT Cohort
Albumin-bound paclitaxel
100 mg/m2
Days 1, 8, and 15
CN Cohort
Albumin-bound paclitaxel
150 mg/m2
Days 1,8 and 15
• Objective: to investigate safety and efficacy of this regimen in patients with
metastatic melanoma
• Primary endpoint: safety
• Secondary endpoints: PFS, OS
ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, overall response rate;
OS, overall survival; PFS, progression-free survival.
Hersh et al. Cancer 2010, 116 (1): 155-63
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Efficacy and tolerability of nab-paclitaxel in PT and CN
metastatic melanoma patients
Hersh et al. Cancer 2010, 116 (1): 155-63
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Median PFS and OS
Hersh et al. Cancer 2010, 116 (1): 155-63
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Safety
nab-paclitaxel’s patients
Main most common treatment-related
adverse eventsa, ≥ grade 3, %
PT
CN
Neutropenia
14
40
Febrile neutropenia
0
3
Sensory neuropathy
5
19
Adverse events reported to be probably, possibly, or definitely related to study treatment; only grade 3 or higher adverse events shown.
• 22% of chemo-naïve pts discontinued treatment due to toxicity
Hersh et al. Cancer 2010, 116 (1): 155-63
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Phase 2 Trial of nab-paclitaxel in previously treated or
chemotherapy naïve metastatic melanoma (CA014)
Summary
Design
• Phase 2, metastatic
melanoma, PS 0-1
• N=74
• ABX 100 mg/m2 (3 wk
on/1 wk off) in
previously treated pts
(N=37)
• Mean age 56 yrs,
70% visceral
mets, 62%
elevated LDH
• ABX 150 mg/m2 (3 wk
on/ 1 wk off) in chemonaïve pts (N=37)
• Mean age 61 yrs,
81% visceral
mets, 51%
elevated LDH
Response
Safety
Response in previously
treated and chemo-naïve
pts:
• ORR = 2.7% and 22%
• Median PFS: 3.5 and 4.5 mo
• Median OS: 12.1 and 9.6 mo
• 1 yr survival: 49% and 41%
• Response duration: 13 and
25 mo
• Stable disease for ≥16 wk:
35% and 27%
• 11% of chemo-naïve pts
were stable for ≥12 mo
Safety in previously
treated and
chemo-naïve pts:
• Gr 3/4
Neutropenia: 14%
and 40%
• Gr 3 Febrile
Neutropenia: 0
and 3%
• Gr 3/4 Sensory
Neuropathy: 5%
and 19%
• 22% of chemonaïve pts
discontinued
treatment due to
toxicity
ABX, nab-paclitaxel; DLT, dose limiting toxicity; MTD, maximum tolerated dose; ORR,
overall response rate; OS, overall survival; PC, pancreatic cancer; PS, performance
status; pts, patients; SPARC, secreted protein acidic and rich in cysteine.
Key Points
• Both ORR and
PFS compare
favorably with
dacarbazine,
single-agent
paclitaxel, and
combination
regimens
• Slow progression
or long disease
stabilization
observed in
substantial
number of pts
Hersh E.M, et al. Cancer 2010;116:155-63.
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A phase II trial of nab-paclitaxel and carboplatin in
patients with unresectable stage IV melanoma:
a North Central Cancer Treatment Group Study,
N057E(1): ABX054
Kottschade L.A, et al. Cancer 2011;117:1704-10.
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Study Design and Objectives
• Study design: a multi-center phase II trial of albumin-bound paclitaxel plus
carboplatin in patients with unresectable stage IV melanoma
– N = 76
– Patients with ECOG PS 0-2, adequate organ function and histologically confirmed stage IV melanoma
either previously treated with chemotherapy (Cohort 1, PT) or chemotherapy-naïve (Cohort 2, CN)
– Cycles of 28 days until disease progression or dose-limiting toxicity (maximum 8 cycles)
Albumin-bound paclitaxel
100 mg/m2
Days 1, 8, and 15
Carboplatin
AUC2
Days 1,8 and 15
• Objective: to investigate safety and efficacy of this combination regimen in
patients with unresectable melanoma
• Primary endpoint: ORR
• Secondary endpoints: PFS, OS, and safety
ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, overall response rate;
OS, overall survival; PFS, progression-free survival.
Kottschade L.A, et al. Cancer 2011;117:1704-10.
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Efficacy and tolerability
nab-paclitaxel’s patients
PT
(n=35)
CN
(n=41)
ORR
8.8
25.5
ORR+SD
37.8
48.6
PSF
4.1
4.5
OS
10.9
11.1
• Adverse events included neutropenia, thrombocytopenia, neurosensory
problems, fatigue, nausea, and vomiting
Kottschade L.A, et al. Cancer 2011;117:1704-10.
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A phase II trial of nab-paclitaxel and carboplatin in
patients with unresectable stage IV melanoma
a North Central Cancer Treatment Group Study, N057E(1): ABX054
METHODS:
MM pre-treated and naive pts
nab-Paclitaxel iv weekly for 3 weeks at a dose of 100 mg/m2; Carbo AUC 2
RESULTS:
35 treated (PT) pts
- ORR:
- ORR+SD:
- PFS:
- OS:
8.8%
37.8%
4.1 months
10.9 months
41 chemonaive (CN) pts
25.6%
48.6%
4.5 months
11.1 months
CONCLUSIONS:
nab-Paclitaxel + Carbo was moderately be well tolerated and demonstrated activity in
both previously treated and chemotherapy-naive patients with MM.
Kottschade L.A, et al. Cancer 2011;117:1704-10.
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A phase II trial of nab-paclitaxel and carboplatin in patients
with unresectable stage IV melanoma:
a North Central Cancer Treatment Group Study, N057E(1): ABX054
Summary
Design
• Phase 2, unresectable stage
IV melanoma, chemotherapy
naive (CN) or previously
treated (PT).
• N=76
• ABX 100 mg/m2 and
carboplatin area under the
curve (AUC2) administered
on days 1, 8, and 15 every
28 days.
• Primary endpoint: ORR
• Secondary endpoint: PFS,
OS
Response
• CN:
• 10 (25.6%) responses
(1 complete response
[CR] and 9 partial
responses [PRs]) in the
CN cohort (90% CI,
16.7%-42.3%)
• Median PFS=4.5 mos
• Median OS= 11.1 mos
• PT:
• 3 (8.8%) responses (3
PRs) in the PT cohort
(90% CI, 2.5%-21.3%).
• Median PFS =4.1 mos
• Median OS = 10.9 mos
ABX, nab-paclitaxel; DLT; ORR, overall response rate; OS, overall survival;
PFS, progression free survival.
Safety
• Adverse events
included
neutropenia,
thrombocytopenia,
neurosensory
problems, fatigue,
nausea, and
vomiting
Key Points
• The weekly
combination of
ABX and
carboplatin
appears to be
moderately well
tolerated, with
promising
clinical activity
Kottschade L.A, et al. Cancer 2011;117:1704-10.
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An Open-Label, Multicenter, Phase 3 Trial of ABPaclitaxel vs Dacarbazine in Previously Untreated
Patients With Metastatic Malignant Melanoma (CA033)
Kottschade L.A, et al.
Ongoing study
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Phase III study of Nab Paclitaxel vs dacarbazine in
previously untreated metastatic malignant melanoma
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Melanoma:
Other combinations with nab-paclitaxel
ASCO 2011 update
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Abstract #8532
A randomized phase II trial of temozolomide and
bevacizumab or albumin-bound
paclitaxel/carboplatin and bevacizumab in patients
with unresectable stage IV metastatic melanoma: A
North Central Cancer Treatment Group Study
(N0775)
L. A. Kottschade, V. Suman, D. G. Perez,
R. R. McWilliams, J. S. Kaur, T. Amatruda,
F. J. Geoffroy, H. M. Gross, P. A. Cohen,
A. J. Jaslowski, M. L. Kosel, S. Markovic
Kottschade LA et al. ASCO. 2011 [Abstract 8532].
25
Study Design and Objectives
• Study design: a randomized phase II trial of two different treatments
for stage IV melanoma patients
– N = 94
– Twenty-eight day cycles
Arm A
Arm Ba
Temozolomide
200 mg/m2
Days 1 – 5
Albumin-bound paclitaxel
80 – 100 mg/m2
Days 1, 8, and 15
Bevacizumab
10 mg/kg
Days 1 and 15
Carboplatin
AUC = 5 – 6
Day 1
Bevacizumab
10 mg/kg
Days 1 and 15
a Doses
of albumin-bound paclitaxel and carboplatin were
reduced to 80 mg/m2 and AUC = 5, respectively, due to toxicity
• Objective: to independently investigate the progression-free survival at
6 months
AUC, area under the curve.
Kottschade LA et al. ASCO. 2011 [Abstract 8532].
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Baseline Characteristics
Baseline characteristic
TMZ + Bev
(n = 42)
AB-Paclitaxel + Carbo
+ Bev
(n = 51)
Age in years, median (range)
57 (25 – 82)
57 (22 – 83)
57.1
56.9
23.8
17.6
61.9
35.7
2.4
58.8
39.2
2.0
-
ECOG PS, %
0
1
73.8
26.2
64.7
35.3
M1 sub-stage, %
M1a
M1b
M1c
23.8
31.0
45.2
23.5
25.5
51.0
Elevated LDHa, %
38.1
47.1
Male, %
Prior treatment, %
Radiation therapy
Systemic therapies
None
Immunotherapy
Vaccine therapy
Combination immuno/vaccine therapy
AB, albumin-bound; Bev, bevacizumab; Carbo, carboplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH,
lactate dehydrgonase; TMZ, temozolomide.
a Elevated LDH values exclude the 21.4% of TMZ+Bev patients and 7.8% of AB-Paclitaxel+Carbo+Bev patients of unknown baseline LDH.
Kottschade LA et al. ASCO. 2011 [Abstract 8532].
27
Results: Efficacy and VEGF Correlatives
TMZ + Bev
(n = 43)
AB-Paclitaxel + Carbo
+ Bev
(n = 51)
PFS at 6 months, % (95% CI)
32.0 (20.5 – 50.1)
54.9 (42.8 – 70.4)
PFS at 1 year, % (95% CI)
10.0 (3.9 – 25.0)
27.5 (17.6 – 42.9)
3.8
6.6
53.8 (40.5 – 71.4)
58.1 (45.9 – 73.6)
12.3
13.9
10 (23.3)
1 (2.3)
9 (20.9)
17 (33.3)
0
17 (33.3)
Clinical outcome
PFS in months, median
OS at 1 year, % (95% CI)
OS in months, median
ORR, n (%)
CR
PR
AB, albumin-bound; Bev, bevacizumab; Carbo, carboplatin; CI, confidence interval; CR, complete response; ORR, overall response rate; OS,
overall survival; PFS, progression-free survival; PR, partial response; TMZ, temozolomide.
TMZ + Bev
(n = 29)
AB-Paclitaxel + Carbo
+ Bev
(n = 44)
VEGF-A
58
52
VEGF-D
16
5
Reduction in VEGF staining from baselinea,
%
AB, albumin-bound; Bev, bevacizumab; Carbo, carboplatin; TMZ, temozolomide; VEGF, vascular endothelial growth factor.
a After 1 cycle of treatment.
Kottschade LA et al. ASCO. 2011 [Abstract 8532].
28
Safety
AB-Paclitaxel + Carbo + Bev
TMZ + Bev
(n = 42)
Before dose
reductions
(n = 28)
After dose
reductions
(n = 23)
Anemia
5
21
17
Leukopenia
10
29
26
Neutropenia
10
54
43
Thrombocytopenia
5
21
17
Dyspnea
2
14
0
Fatigue
10
21
9
Hypertension
2
7
0
Nausea
7
0
4
Thrombosis
5
14
9
Vomiting
12
4
0
Sensory neuropathy
0
0
0
Most common treatment-related
adverse eventsa, ≥ grade 3, %
AB, albumin-bound; Bev, bevacizumab; Carbo, carboplatin; TMZ, temozolomide.
a Adverse events reported to be probably, possibly, or definitely related to study treatment; only grade 3 or higher adverse events shown.
Kottschade LA et al. ASCO. 2011 [Abstract 8532].
29
Authors’ Conclusions
• Both treatment arms showed tolerable toxicities
• There may be a suggestion of clinical benefit for both arms over the
expected outcomes for chemotherapy alone
• The albumin-bound paclitaxel plus carboplatin plus bevacizumab arm
is under consideration for further clinical testing
Kottschade LA et al. ASCO. 2011 [Abstract 8532].
30
Phase II trial of temozolomide and bevacizumab or
nab-paclitaxel/carboplatin (CBDCA) and bevacizumab
in patients with unresectable stage IV metastatic melanoma: Study N0775 (ABX220)
Summary
Design
• Phase 2 trial ,
chemotherapy naïve
patients with unresectable
stage IV mM
• TMZ (200 mg/m2 on days
1-5) and BEV (10mg/kg IV
days 1 and 15 ) every 28
days (arm A) or CBDCA
(AUC 6; day 1), ABX
(100mg/m2 days 1, 8 and
15), and BEV (10mg/kg on
days 1 and 15) every 28
days (arm B)
• N=94
• The majority of patients had
M1c disease (46.5%-Arm A
& 51%-Arm B)
• Primary objective: PFS at 6
months
Response
Safety
Key Points
Arm A:
• PFS at 6 mo
=31.2% (95% CI:
19.9-49.0%)
• median PFS = 3.8
months
• OS =12.2 months
Arm B:
• PFS at 6 mo
=54.9% (95% CI:
42.8-70.4%)
• median PFS = 6.6
months
• OS of 15.4 months
• CBDCA and ABX
starting dose was
reduced to AUC 5
and 80mg/m2
respectively, due to
unexpected AE’s
• The most common
severe (≥ grade 3)
toxicities in both
groups (Arm A and B)
were: neutropenia
(9% & 49%);
leukopenia (9% &
27%); fatigue (9% &
16%); vomiting (12%
& 2%) and
thrombosis (5% &
12%)
• Both treatment
arms exhibited
tolerable toxicities
with a suggestion of
clinical benefit vs
expected outcomes
for chemotherapy
alone
• The regimen in Arm
B is being
considered for
phase III clinical
testing
ABX, nab-paclitaxel; AE, adverse event; BEV, bevacizumab; mM, metastatic
melanoma; PFS, progression free survival; OS, overall survival; TMZ, temozolomide.
Kottschade L.A, et al. J Clin Oncol 2011 ;29 [ abstr. 8532].
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31
Abstract #8543
Phase II trial of albumin-bound paclitaxel and
bevacizumab as first-line therapy in patients with
unresectable melanoma
P. D. Boasberg, R. W. Weber, S. Cruickshank,
O. Hamid, S. O'Day, L. E. Spitler
Boasberg PD et al. ASCO. 2011 [Abstract 8543].
32
Study Design and Objectives
• Study design: a multi-center phase II trial of albumin-bound paclitaxel
plus bevacizumab in treatment-naïve patients with unresectable stage
III and IV melanoma
– N = 50
– Patients with ECOG PS 0-1, adequate organ function, LDH ≤ 2 Χ upper limit of normal, and no
signs of central nervous system metastases
– Cycles of 28 days until disease progression or dose-limiting toxicity
Albumin-bound paclitaxel
150 mg/m2
Days 1, 8, and 15
Bevacizumab
10 mg/m2
Days 1 and 15
• Objective: to investigate safety and efficacy of this combination
regimen in patients with unresectable melanoma
• Primary endpoint: PFS at 4 months
• Secondary endpoints: PFS, OS, ORR, and safety
ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate
dehydrogenase; ORR, overall response rate; OS, overall survival; PFS,
progression-free survival.
Boasberg PD et al. ASCO. 2011 [Abstract 8543].
33
Baseline Characteristics
Baseline characteristic (N = 50)
n (%)
Sex
Male
Female
32 (64)
18 (36)
Tumor stage
IIIC
IV: M1a
IV: M1b
IV: M1c
2 (4)
4 (8)
11 (22)
34 (66)
LDH
Normal
Elevated
30 (60)
20 (40)
LDH, lactate dehydrogenase.
Boasberg PD et al. ASCO. 2011 [Abstract 8543].
34
Results
Survival outcome (N = 50)
Overall survival in months, median (95% CI)
16.8 (11.3 – 20.7)a
Survival at 1 year, %
62
Survival at 2 years, %
30
Progression-free survival in months, median (95% CI)
Progression-free survival at 4 months, %
7.6 (5.6 – 9.9)
73
CI, confidence interval.
a Ten patients alive at the time of this analysis.
Response outcomea (N = 50)
n (%)
Complete response
2 (4)
Partial response
16 (32)
Stable disease
22 (44)
Clinical benefit (CR+PR+SD)
40 (80)
Progressive disease
10 (20)
CR, complete response; PR, partial response; SD, stable disease.
a By Response Evaluation Criteria in Solid Tumors (RECIST).
Boasberg PD et al. ASCO. 2011 [Abstract 8543].
35
Safety
Treatment-related grade 3 adverse events (N = 50)
n (%)
Neutropenia
10 (20)
Neuropathy
7 (14)
Mucositis
4 (8)
Fatigue
3 (6)
Proteinuria
1 (2)
Hand/foot syndrome
1 (2)
• Overall, 673 grade 1 – 3 adverse events occurred
• No grade 4 adverse events occurred
Boasberg PD et al. ASCO. 2011 [Abstract 8543].
36
Authors’ Conclusions
• The primary endpoint of PFS at 4 months of 73% exceeded the
predicted 15% based on historical reports
• Overall survival (median 16.8 months), 1-year survival (62%), and
clinical benefit (80%) also exceeded values from previous reports of
approved therapies
• Administration of albumin-bound paclitaxel plus bevacizumab in this
trial of patients with unresectable melanoma was well-tolerated
• Follow-up trials are warranted
Boasberg PD et al. ASCO. 2011 [Abstract 8543].
37
Phase II trial of nab-paclitaxel and bevacizumab as firstline therapy in patients with unresectable melanoma
Summary
Design
• Phase 2, chemotherapynaive patients with
unresectable melanoma, no
central nervous system
metastases, ECOG
performance status of 0-1,
and adequate organ
function
• N=50
• 66% with stage IV M1c
disease, 40% with elevated
LDH
• The treatment was given in
a 28 day cycle in which
ABX 150mg/m2 was
administered on days 1, 8,
15 and bevacizumab
10mg/kg on days 1 and 15
Response
Safety
Key Points
• Median OS= 15.6 mos
(95% CI: 11.5, 20.7)
• 1-year survival = 63%
(95% CI: 50%, 77%)
• 2-year survival =31%
(95% CI: 17%, 44%)
• Dose modifying
toxicities consisted
of proteinuria,
neutropenia,
neuropathy, and
mucositis
• ABX and
bevacizumab has
activity in patients
with metastatic
melanoma, is well
tolerated, and offers
efficacy comparable
or superior to
alternative treatment
options
• A randomized
Phase II or a Phase
III trial with this
doublet would be
required to compare
efficacy with
alternative
approaches
ABX, nab-paclitaxel; ECOG, Eastern Cooperative Oncology Group; LDH,
lactate dehydrogenase; OS, overall survival.
Boasberg P.D. et al. J Clin Oncol 2011;29: [abstr. 8543].
37
38
Abstract #8545
Albumin-bound paclitaxel, temozolomide, and
oblimersen (The ATG Trial): A final report of
toxicity and clinical efficacy in metastatic
melanoma patients with normal lactate
dehydrogenase
J. L. Chang, P. A. Ott, C. Sorlie, C. Escano,
E. Yepes, S. Mendoza, A. Gandhi, L. Liebes,
A. C. Pavlick
Chang JL et al. ASCO. 2011 [Abstract 8545].
39
Study Design and Objectives
• Study design: a phase I trial of metastatic melanoma patients with
normal LDH receiving different dosing regimens of albumin-bound
paclitaxel plus temozolomide plus the bcl-2 inhibitor oblimersen
– Fifty-six day cycle
Cohort 1
Cohort 2
Cohort 3
Albumin-bound paclitaxel 175 mg/m2
IV Days 8 and 29
Albumin-bound paclitaxel 260 mg/m2
IV Days 8 and 29
Albumin-bound paclitaxel 175 mg/m2
IV Days 4 and 25 (after oblimersen)
Temozolomide 75 mg/m2
PO Days 1 – 42
Temozolomide 75 mg/m2
PO Days 1 – 42
Temozolomide 75 mg/m2
PO Days 1 – 42
Oblimersen 7 mg/kg/day CIV
Days 1 – 7 and 22 – 28
Oblimersen 7 mg/kg/day CIV
Days 1 – 7 and 22 – 28
Oblimersen 900 mg IV over 1 hour
Days 1, 4, 8, 11, 22, 25, 29, 32
• Objective: to evaluate safety and clinical efficacy of this combination
treatment
bcl-2, B cell lymphoma gene 2; CIV, continuous intravenous; IV, intravenous; LDH,
lactate dehydrogenase; PO, orally.
Chang JL et al. ASCO. 2011 [Abstract 8545].
40
Baseline Characteristics
Baseline characteristic
Age in years, median (range)
N = 32a
61 (34 – 78)
Sex, n (%)
Male
Female
17 (53)
15 (47)
Stage IV sub-stage, n (%)
M1a
M1b
M1c
8 (25)
8 (25)
16 (50)
Race, n (%)
Caucasian
African American
Indian
30 (94)
1 (3)
1 (3)
ECOG PS, n (%)
0
1
29 (91)
3 (9)
ECOG PS, Eastern Cooperative Oncology Group performance status.
a Combined data for all 3 cohort; Individual n per cohort: 1 – 14; 2 – 4; 3 –14.
Chang JL et al. ASCO. 2011 [Abstract 8545].
41
Results: Efficacy
Response outcome (N = 32)a
n (%)
Duration in months,
median
Complete response
2 (6)
12.6, 50.2b
Partial response
11 (34)
3.9
Stable disease
11 (34)
5.6
Disease control rate (CR+PR+SD)
24 (75)
NA
Progressive disease
8 (25)
NA
CR, complete response; NA, not applicable; PR, partial response; SD, stable disease.
a Cohort 1: n = 14; cohort 2: n = 4; cohort 3: n = 14.
b For complete response, the actual durations were given for both patients, rather than a median; the patient with a complete response at
50.2 months continues to exhibit a complete response.
Survival outcome (N = 32)
n (%)
Survival
12 months
15 monthsa
18 monthsb
16 (50)
12 (38)
9 (28)
Subsequent brain metastases
12 (38)
a
b
One patient with ongoing response under 15 months.
Three patients with ongoing responses under 18 months.
Chang JL et al. ASCO. 2011 [Abstract 8545].
42
Safety
Grade 3,
n (%)
Grade 4,
n (%)
Neutropenia
3 (9)
3 (9)
Sensory neuropathy
4 (13)
0
Pleural effusion
3 (9)
0
0
1 (3)
Port infection
1 (3)
0
OBL hypersensitivity
1 (3)
0
Fatigue
1 (3)
0
Supraventricular tachycardia
1 (3)
0
Dyspnea
1 (3)
0
Adverse event (N = 32)
Thrombocytopenia
OBL, oblimersen.
Chang JL et al. ASCO. 2011 [Abstract 8545].
43
Authors’ Conclusions
• The combination treatment of albumin-bound paclitaxel plus
oblimersen plus temozolomide is well-tolerated in metastatic
melanoma patients with normal LDH
• The disease control rate of 75% and the survival data from this study
are encouraging
• The twice-weekly fixed-dose oblimersen schedule appears to be
similar to the 7-day CIV regimen in terms of safety and efficacy
CIV, continuous intravenous; LDH, lactate dehydrogenase.
Chang JL et al. ASCO. 2011 [Abstract 8545].
44
nab-paclitaxel, temozolomide, and oblimersen (The ATG
Trial): A final report of toxicity and clinical efficacy in
metastatic melanoma patients with normal lactate
dehydrogenase (LDH)
Summary
Design
Response
Safety
Key Points
• Phase 1, Chemo-naïve
metastatic melanoma
• OBL, TMZ and ABX 175
mg/m2 or 260 mg/m2
• N=32
• Median age= 58 years
(range: 34-78). Stage
M1a-4; M1b-2; M1c-26.
• Correlative biomarker
analysis were performed in
pre- and post-therapy
tumor samples
• ABX and OBL PK
• Responses
• 2-CR (48+ and 14
mos)
• 10 pts PR
• 13 pts SD
• 7-pts PD
• DCR (CR+PR+SD)
78.1%
• OS =14.7 mos
• 50% survived > 1y
• Correlates: No
impact of combo on
ABX PK
•
•
•
•
•
•
•
•
•
•
ABX, nab-paclitaxel; DCR, disease control rate; mM, metastatic melanoma; OBL,
oblimersen; OS, overall survival; PD, progressive disease; PK, pharmacokinetics; PR,
partial response; pts, patients; SD, stable disease; TMZ, temozolomide
Grade 3:
leukopenia (n=1)
neutropenia(n=2)
thrombocytopenia
(n=1)
sensory neuropathy
(n=2)
OBL hypersensitivity
(n=2)
Grade 4
neutropenia (n=1)
thrombocytopenia
(n=1)
sensory neuropathy
(n=4).
• The combo of OBL,
TMZ, and ABX in
mM pts is safe
resulted in a DCR of
78.1% and
prolonged survival
• Bcl-2 antisense
therapy effectively
targets apoptotic
signaling pathways
in MM cells
• The twice-weekly,
fixed-dose OBL
schedule appears to
be similar in safety
and efficacy as the
7-day CIV regimen
Chang J.L, et al. J Clin Oncol 2011;29: [ abstr. 8545].
44
45
Back up
46
Melanoma Disease Background
• In 2011, it is estimated that
– 70,230 people will be diagnosed with melanoma of the skin1
– 8790 deaths will occur1
• 2008 prevalence of approximately 822,770 people in the United
States with melanoma2
• Least common form of skin cancer, but leading cause of skin cancer–
related deaths3
– Mortality rate: 3 per 100,000 people3
– 5-year survival rate: 91% for all stages of melanoma1
• For patients with metastatic melanoma, long-term survival rates are
less than 10%4
1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA:
American Cancer Society; 2011.
2. http://www.seer.cancer.gov/statfacts/html/melan.html.
3. Jemal A, et al. CA Cancer J Clin. 2010;60:277-300.
4. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v4.2011.
47
Albumin-Bound Paclitaxel
• Albumin is an endogenous carrier of hydrophobic molecules1
–
–
Most abundant protein in plasma with substantial ligand-binding capacity2
Important factor in the pharmacokinetic behavior of many drugs, affecting efficacy and rate of
delivery2
nab-paclitaxel particle3
(mean particle size 130 nm)
• Albumin-bound paclitaxel, produced by a proprietary nab platform, is solvent-free3
–
Provides greater tumor uptake of active paclitaxel4 and allows for dosing 49% more of active
paclitaxel compared with solvent-based paclitaxel3,5
• Indication: treatment of breast cancer after failure of combination chemotherapy for
metastatic disease or relapse within 6 months of adjuvant chemotherapy; prior
therapy should have included anthracycline unless clinically contraindicated
1. Moorthi C, et al. J Pharm Pharmaceut Sci. 2011;14:67-77.
2. Fasano M, et al. IUBMB Life. 2005; 57:787-796.
3. nab-paclitaxel (paclitaxel protein-bound particles) [package insert]. Bridgewater, NJ: Abraxis BioScience,
LLC, a wholly owned subsidiary of Celgene Corporation; 2010.
4. Desai N, et al. Clin Cancer Res. 2006; 15:1317-1324.
5. Taxol (paclitaxel) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2010.
48
Accumulation of Albumin-Bound Paclitaxel in Tumors
Accumulation of active paclitaxel in tumors was 33% higher for
albumin-bound paclitaxel compared with Cremophor® EL paclitaxel
(P < .0001)1
AB, albumin-bound; ANOVA, analysis of variance; AUC, area under
the curve; CrEL, Cremophor EL; Ka, absorption rate.
1. Desai N, et al. Clin Cancer Res. 2006;15:1317-1324.
49
Comparison to cooperative group meta-analysis
Progression-Free
Survival (months)
Overall Survival,
(months)
nab-paclitaxel®
Previously treated
3.5
12.1 *
nab-paclitaxel®
Chemo naive
4.6
9.6 *
Cooperative Group
Meta-analysis
1.7
6.2
Group
Korn, EL et al. J Clin Oncol 26:527-534 (2008) (42 trials)