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Albumin-Bound PaclitaxelAlbumin-Bound Paclitaxelfor the Treatment of Melanomafor the Treatment of Melanoma
Clinical data
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Chemotherapy in Metastatic Melanoma: Survival Chemotherapy in Metastatic Melanoma: Survival Outcomes Phase II/III TrialsOutcomes Phase II/III Trials
Author
No. Patients
Evaluable Agents Dose
Median PFS or
TTPMedian
OS
di Pietro1 36 DTICBEV
800 mg/m2 q 4 weeks10 mg/kg q 2 weeks
6 mo (TTP) 16.5 mo
von Moos2
SAKK 50/07 trial 62 TMZ
BEV150 mg/m2 days 1-7 (q 2 w)
10 mg/kg q 2 weeks4.2 mo 9.3 mo
Perez3
NCCTG –NO47A trial
53 PaclitaxelCarboplatin
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 PaclitaxelCarboplatin
BEV
175 mg/m2 q 3 weeksAUC 5 q 3 weeks
15 mg/kg q 3 weeks
5.6 mo 12.3 mo
Hauschild5 270 PaclitaxelCarboplatinSorafenib
225 mg/m2 q 3 weeksAUC 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 MelanomaRationale 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 Melanomanab-paclitaxel in Metastatic Melanoma
Trial Description N Dose ORR PFS OS Abstract/ Publication
Phase II ABX + Carboplatin in Unresectable Advanced Melanoma 76
ABX 100 mg/m2 and carboplatin AUC 2 administered on days 1, 8, and 15 every 28 days
• Chemonaive: 10 (25.6%)
• Previously treated: 3 (8.8%)
• Chemonaive: 4.5 mo
• Previously treated: 4.1 mo
• Chemonaive: 11.1 mo
• Previously treated: 10.9 mo
• Published Cancer 2011;
117:1704-10.
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)
94
Carboplatin (AUC 6; day 1), ABX (100mg/m2 days 1, 8 and 15), and Avastin (10mg/kg on days 1 and 15) every 28 days
• 17 (33%)• 6.6 mo • PFS at 6 mo:
54.9%
• 13.9 mo
• ASCO 2011 [abstract #8532 Kottschade]
• Manuscript in development
A Pilot Study of nab-paclitaxel® (Albumin-bound Paclitaxel) and Temodar® (Temozolomide) plus Genasense® (Oblimersen Sodium) in Subjects with Advanced Melanoma (“The ATG Study”)
32
ABX 175 mg/m2 or 260 mg/m2 d8 +d29Temo 75 mg/m2
Obl 7 mg/kg/day CIV or 900 mg IV over 1 hour
• 12 (31%) • NR • 14.7 mo
• ASCO 2009• ASCO 2010 [abstract
#8561]• ASCO 2011 [abstract
8545 Chang]• Manuscript in
development
Phase II Study of nab-paclitaxel® and Avastin as Therapy for Patients with Metastatic Melanoma
50
ABX 150mg/m2 d 1, 8, 15 and Avastin10mg/kg d 1 and 15, 28d cycle
• 18 (36%) • 7.6 mo • 16.8 mo
• ASCO 2011 [abstract #8543 Boasberg]
• Manuscript in development
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5
A PHASE 2 CLINICAL TRIAL OF NAB-PACLITAXEL IN PREVIOUSLY TREATED A PHASE 2 CLINICAL TRIAL OF NAB-PACLITAXEL IN PREVIOUSLY TREATED
AND CHEMOTHERAPY-NAIVE PTS WITH MMAND CHEMOTHERAPY-NAIVE PTS WITH MM
HERSH ET AL, CANCER 2010HERSH ET AL, CANCER 2010
A PHASE II TRIAL OF NAB-PACLITAXEL (ABI-007) AND CARBOPLATIN IN PTS A PHASE II TRIAL OF NAB-PACLITAXEL (ABI-007) AND CARBOPLATIN IN PTS
WITH MM: A NORTH CENTRAL CANCER TREATMENT GROUP STUDY, WITH MM: A NORTH CENTRAL CANCER TREATMENT GROUP STUDY,
N057E1N057E1
KOTTSCHADE ET AL, CANCER 2011KOTTSCHADE ET AL, CANCER 2011
AN OPEN-LABEL MULTICENTRE, PHASE III TRIAL
OF ABI-007 (nab-paclitaxel) VS DACARBAZINE IN PREVIOUSLY UNTREATED
MM PTS
ON GOINGON GOING
Melanoma: new chemotherapeutical approachesMelanoma: new chemotherapeutical approaches
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A phase 2 clinical trial of nab-paclitaxel in A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive pts previously treated and chemotherapy-naive pts
with Metastatic Melanoma with Metastatic Melanoma
Hersh et al. Cancer 2010, 116 (1): 155-63
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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
nab-paclitaxel in previously treated and chemotherapy-nab-paclitaxel in previously treated and chemotherapy-naive pts with Metastatic Melanoma naive pts with Metastatic Melanoma ObjectivesObjectives
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A phase 2 clinical trial of nab-paclitaxel in previously A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive pts with MMtreated 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 37 chemonaive (CN) pts
- OR: 2.7% 21.6%- OR+SD: 37.8% 48.6% - PFS: 3.5 months 4.5 months- OS: 12.1 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 ObjectivesStudy 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
• 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.
PT Cohort Albumin-bound paclitaxel
100 mg/m2
Days 1, 8, and 15
CN CohortAlbumin-bound paclitaxel
150 mg/m2
Days 1,8 and 15
Hersh et al. Cancer 2010, 116 (1): 155-63
10
Efficacy and tolerability of nab-paclitaxel in PT and Efficacy and tolerability of nab-paclitaxel in PT and CN metastatic melanoma patientsCN metastatic melanoma patients
Hersh et al. Cancer 2010, 116 (1): 155-63
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SafetySafety
Main most common treatment-related adverse eventsa, ≥ grade 3, %
nab-paclitaxel’s patients
PT CN
Neutropenia 14 40
Febrile neutropenia 0 3
Sensory neuropathy 5 19Adverse 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
13
Phase 2 Trial of Phase 2 Trial of nabnab-paclitaxel in previously treated or -paclitaxel in previously treated or chemotherapy naïve metastatic melanoma (CA014chemotherapy naïve metastatic melanoma (CA014))SummarySummary
Design Response Safety Key Points
• 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 chemo-naïve pts (N=37)
• Mean age 61 yrs, 81% visceral mets, 51% elevated LDH
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 chemo-naïve pts discontinued treatment due to toxicity
• 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
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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. Hersh E.M, et al. Cancer 2010;116:155-63.
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A phase II trial of A phase II trial of nabnab-paclitaxel and carboplatin in -paclitaxel and carboplatin in patients with unresectable stage IV melanoma: patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, a North Central Cancer Treatment Group Study,
N057E(1): ABX054N057E(1): ABX054
Kottschade L.A, et al. Cancer 2011;117:1704-10.
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Study Design and ObjectivesStudy 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)
• 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.
Albumin-bound paclitaxel 100 mg/m2
Days 1, 8, and 15
CarboplatinAUC2
Days 1,8 and 15
Kottschade L.A, et al. Cancer 2011;117:1704-10.
16
Efficacy and tolerabilityEfficacy 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.
17
METHODS: MM pre-treated and naive ptsnab-Paclitaxel iv weekly for 3 weeks at a dose of 100 mg/m2; Carbo AUC 2
RESULTS: 35 treated (PT) pts 41 chemonaive (CN) pts
- ORR: 8.8% 25.6%- ORR+SD: 37.8% 48.6% - PFS: 4.1 months 4.5 months- OS: 10.9 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.
A phase II trial of A phase II trial of nabnab-paclitaxel and carboplatin in -paclitaxel and carboplatin in patients with unresectable stage IV melanoma patients with unresectable stage IV melanoma a North Central Cancer Treatment Group Study, N057E(1): ABX054a North Central Cancer Treatment Group Study, N057E(1): ABX054
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A phase II trial of A phase II trial of nabnab-paclitaxel and carboplatin in patients -paclitaxel and carboplatin in patients with unresectable stage IV melanoma: with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1): ABX054a North Central Cancer Treatment Group Study, N057E(1): ABX054
SummarySummary
Design Response Safety Key Points
• 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
• 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
• Adverse events included neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting
• The weekly combination of ABX and carboplatin appears to be moderately well tolerated, with promising clinical activity
18
ABX, nab-paclitaxel; DLT; ORR, overall response rate; OS, overall survival; PFS, progression free survival. Kottschade L.A, et al. Cancer 2011;117:1704-10.
19
An Open-Label, Multicenter, Phase 3 Trial of AB-An Open-Label, Multicenter, Phase 3 Trial of AB-Paclitaxel vs Dacarbazine in Previously Untreated Paclitaxel vs Dacarbazine in Previously Untreated
Patients With Metastatic Malignant Melanoma (CA033)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 Phase III study of Nab Paclitaxel vs dacarbazine in previously untreated metastatic malignant melanomapreviously untreated metastatic malignant melanoma
23
Melanoma:Melanoma:
Other combinations with nab-paclitaxelOther combinations with nab-paclitaxel
ASCO 2011 update ASCO 2011 update
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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
Abstract #8532Abstract #8532A randomized phase II trial of temozolomide and A randomized phase II trial of temozolomide and bevacizumab or albumin-bound bevacizumab or albumin-bound paclitaxel/carboplatin and bevacizumab in patients paclitaxel/carboplatin and bevacizumab in patients with unresectable stage IV metastatic melanoma: A with unresectable stage IV metastatic melanoma: A North Central Cancer Treatment Group Study North Central Cancer Treatment Group Study (N0775)(N0775)
Kottschade LA et al. ASCO. 2011 [Abstract 8532].
25
Study Design and ObjectivesStudy 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
• Objective: to independently investigate the progression-free survival at 6 months
AUC, area under the curve.
Albumin-bound paclitaxel 80 – 100 mg/m2
Days 1, 8, and 15
Temozolomide200 mg/m2
Days 1 – 5
Bevacizumab10 mg/kg
Days 1 and 15
CarboplatinAUC = 5 – 6
Day 1
Bevacizumab10 mg/kg
Days 1 and 15
Arm A Arm Ba
a Doses of albumin-bound paclitaxel and carboplatin were reduced to 80 mg/m2 and AUC = 5, respectively, due to toxicity
Kottschade LA et al. ASCO. 2011 [Abstract 8532].
26
Baseline CharacteristicsBaseline Characteristics
Baseline characteristicTMZ + Bev
(n = 42)
AB-Paclitaxel + Carbo + Bev
(n = 51)
Age in years, median (range) 57 (25 – 82) 57 (22 – 83)
Male, % 57.1 56.9
Prior treatment, %Radiation therapySystemic therapiesNoneImmunotherapyVaccine therapyCombination immuno/vaccine therapy
23.8
61.935.7
-2.4
17.6
58.839.22.0-
ECOG PS, %01
73.826.2
64.735.3
M1 sub-stage, %M1aM1bM1c
23.831.045.2
23.525.551.0
Elevated LDHa, % 38.1 47.1
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 CorrelativesResults: Efficacy and VEGF Correlatives
Clinical outcomeTMZ + 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)
PFS in months, median 3.8 6.6
OS at 1 year, % (95% CI) 53.8 (40.5 – 71.4) 58.1 (45.9 – 73.6)
OS in months, median 12.3 13.9
ORR, n (%)CRPR
10 (23.3)1 (2.3)
9 (20.9)
17 (33.3)0
17 (33.3)
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.
Reduction in VEGF staining from baselinea, %
TMZ + Bev
(n = 29)
AB-Paclitaxel + Carbo + Bev
(n = 44)
VEGF-A 58 52
VEGF-D 16 5
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
SafetySafety
Most common treatment-related adverse eventsa, ≥ grade 3, %
TMZ + Bev
(n = 42)
AB-Paclitaxel + Carbo + Bev
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
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’ ConclusionsAuthors’ 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 Phase II trial of temozolomide and bevacizumab or nabnab-paclitaxel/carboplatin (CBDCA) and bevacizumab -paclitaxel/carboplatin (CBDCA) and bevacizumab in patients with unresectable stage IV metastatic melanoma: Study N0775 (ABX220) in patients with unresectable stage IV metastatic melanoma: Study N0775 (ABX220)
Summary Summary
Design Response Safety Key Points
• 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
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
30ABX, 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].
31
P. D. Boasberg, R. W. Weber, S. Cruickshank,
O. Hamid, S. O'Day, L. E. Spitler
Abstract #8543Abstract #8543Phase II trial of albumin-bound paclitaxel and Phase II trial of albumin-bound paclitaxel and bevacizumab as first-line therapy in patients with bevacizumab as first-line therapy in patients with unresectable melanomaunresectable melanoma
Boasberg PD et al. ASCO. 2011 [Abstract 8543].
32
Study Design and ObjectivesStudy 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
• 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.
Albumin-bound paclitaxel 150 mg/m2
Days 1, 8, and 15
Bevacizumab10 mg/m2
Days 1 and 15
Boasberg PD et al. ASCO. 2011 [Abstract 8543].
33
Baseline CharacteristicsBaseline 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
ResultsResults
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) 7.6 (5.6 – 9.9)
Progression-free survival at 4 months, % 73CI, 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
SafetySafety
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’ ConclusionsAuthors’ 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 Phase II trial of nabnab-paclitaxel and bevacizumab as first--paclitaxel and bevacizumab as first-line therapy in patients with unresectable melanoma line therapy in patients with unresectable melanoma SummarySummary
Design Response Safety Key Points
• Phase 2, chemotherapy-naive 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
• 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
37
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].
38
J. L. Chang, P. A. Ott, C. Sorlie, C. Escano, E. Yepes, S. Mendoza, A. Gandhi, L. Liebes,
A. C. Pavlick
Abstract #8545Albumin-bound paclitaxel, temozolomide, and oblimersen (The ATG Trial): A final report of toxicity and clinical efficacy in metastatic melanoma patients with normal lactate dehydrogenase
Chang JL et al. ASCO. 2011 [Abstract 8545].
39
Study Design and ObjectivesStudy 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
• 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.
Albumin-bound paclitaxel 175 mg/m2
IV Days 8 and 29
Cohort 1
Albumin-bound paclitaxel 175 mg/m2
IV Days 4 and 25 (after oblimersen)
Cohort 3
Albumin-bound paclitaxel 260 mg/m2
IV Days 8 and 29
Cohort 2
Temozolomide 75 mg/m2
PO Days 1 – 42 Temozolomide 75 mg/m2
PO Days 1 – 42
Oblimersen 7 mg/kg/day CIVDays 1 – 7 and 22 – 28
Temozolomide 75 mg/m2
PO Days 1 – 42
Oblimersen 7 mg/kg/day CIVDays 1 – 7 and 22 – 28
Oblimersen 900 mg IV over 1 hourDays 1, 4, 8, 11, 22, 25, 29, 32
Chang JL et al. ASCO. 2011 [Abstract 8545].
40
Baseline CharacteristicsBaseline Characteristics
Baseline characteristic N = 32a
Age in years, median (range) 61 (34 – 78)
Sex, n (%)
Male
Female
17 (53)
15 (47)
Stage IV sub-stage, n (%)M1aM1bM1c
8 (25)8 (25)
16 (50)
Race, n (%)CaucasianAfrican AmericanIndian
30 (94)1 (3)1 (3)
ECOG PS, n (%)01
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: EfficacyResults: 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 months15 monthsa
18 monthsb
16 (50)12 (38)9 (28)
Subsequent brain metastases 12 (38)a One patient with ongoing response under 15 months.b Three patients with ongoing responses under 18 months.
Chang JL et al. ASCO. 2011 [Abstract 8545].
42
SafetySafety
Adverse event (N = 32)Grade 3,
n (%)
Grade 4,
n (%)
Neutropenia 3 (9) 3 (9)
Sensory neuropathy 4 (13) 0
Pleural effusion 3 (9) 0
Thrombocytopenia 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
OBL, oblimersen.
Chang JL et al. ASCO. 2011 [Abstract 8545].
43
Authors’ ConclusionsAuthors’ 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 nab-paclitaxel, temozolomide, and oblimersen (The ATG Trial): A final report of toxicity and clinical efficacy in Trial): A final report of toxicity and clinical efficacy in metastatic melanoma patients with normal lactate metastatic melanoma patients with normal lactate dehydrogenase (LDH)dehydrogenase (LDH)Summary 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
• 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
44
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 Chang J.L, et al. J Clin Oncol 2011;29: [ abstr. 8545].
46
Melanoma Disease BackgroundMelanoma 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
nab-paclitaxel particle3 (mean particle size 130 nm)
Albumin-Bound PaclitaxelAlbumin-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
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, 3. nab-paclitaxel (paclitaxel protein-bound particles) [package insert]. Bridgewater, NJ: Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation; 2010.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; 2010.5. Taxol (paclitaxel) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2010.
• 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
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Accumulation of Albumin-Bound Paclitaxel in TumorsAccumulation 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
1. Desai N, et al. Clin Cancer Res. 2006;15:1317-1324.
AB, albumin-bound; ANOVA, analysis of variance; AUC, area under the curve; CrEL, Cremophor EL; Ka, absorption rate.