1 albumin-bound paclitaxel for the treatment of melanoma clinical data

1

Albumin-Bound PaclitaxelAlbumin-Bound Paclitaxelfor the Treatment of Melanomafor the Treatment of Melanoma

Clinical data

2

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.

2

3

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.

4

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

4

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

6

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

Nicole Parker (AS)

During later factchecking: verify which reference is used on which slides for this section. Where unknown, both are listed.

7

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


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

8

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.


9

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


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


11

Median PFS and OS


12

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


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

13

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.

14

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.

Nicole Parker (AS)


15


• 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


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


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.


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

18

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


• 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

Nicole Parker (AS)


22

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

24

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: 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


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.


27

Results: Efficacy and VEGF CorrelativesResults: Efficacy and VEGF Correlatives

Clinical outcomeTMZ + Bev

(n = 43)


(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)


(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.


28

SafetySafety

Most common treatment-related adverse eventsa, ≥ grade 3, %

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

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.


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


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


• 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: 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.


Days 1, 8, and 15

Bevacizumab10 mg/m2

Days 1 and 15


33


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.


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).


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


36


• 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


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


• 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: 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.


IV Days 8 and 29

Cohort 1


IV Days 4 and 25 (after oblimersen)

Cohort 3


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


40


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.


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.


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.


43


• 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].

45

Back upBack up

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

48

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.

49

Comparison to cooperative group meta-analysis

Group 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

Korn, EL et al. J Clin Oncol 26:527-534 (2008) (42 trials)

1 albumin-bound paclitaxel for the treatment of melanoma clinical data

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