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Randomized, double-blind, placebo-controlled phase 2 study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian carcinoma Beth Y. Karlan, 1 Amit M. Oza, 2 Vincent L. Hansen, 3 Gary E. Richardson, 4 Diane Provencher, 5 Prafull Ghatage, 6 Marjan Tassoudji, 7 Daniel E. Stepan, 7 David M. Weinreich, 7 Ignace B. Vergote 8 1 Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2 Princess Margaret Hospital, Toronto, ON, Canada; 3 Northern Utah Associates, Ogden, UT, USA; 4 Cabrini Hospital, Melbourne, VIC, Australia; 5 CHUM-Hôpital Notre- Dame, Montreal, QC, Canada; 6 Tom Baker Cancer Centre, Calgary, AB, Canada; 7 Amgen Inc., Thousand Oaks, CA, USA; 8 University Hospital Leuven, European Union.

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Randomized, double-blind, placebo-controlled phase 2 study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian carcinoma. - PowerPoint PPT Presentation

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Page 1: Conflict of Interest

Randomized, double-blind, placebo-controlled phase 2 study of AMG 386

combined with weekly paclitaxel in patients with recurrent ovarian carcinoma

Beth Y. Karlan,1 Amit M. Oza,2 Vincent L. Hansen,3 Gary E. Richardson,4

Diane Provencher,5 Prafull Ghatage,6 Marjan Tassoudji,7 Daniel E. Stepan,7

David M. Weinreich,7 Ignace B. Vergote8

1Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Princess Margaret Hospital, Toronto, ON, Canada; 3Northern Utah Associates, Ogden, UT, USA;

4Cabrini Hospital, Melbourne, VIC, Australia; 5CHUM-Hôpital Notre-Dame, Montreal, QC, Canada; 6Tom Baker Cancer Centre, Calgary, AB, Canada;

7Amgen Inc., Thousand Oaks, CA, USA; 8University Hospital Leuven, European Union.

Page 2: Conflict of Interest

Conflict of Interest

• Dr. Karlan has no conflicts of interest • Conduct of the trial was funded in

part by Amgen, Inc.

Page 3: Conflict of Interest

Effective Treatments For Recurrent Ovarian Cancer Are Urgently Needed

• 80% of women diagnosed with late stage ovarian cancer will experience recurrence and eventually die from their disease

• The goals of second-line chemotherapy for recurrent disease include palliation of symptoms, preservation of quality of life, and prolongation of progression-free survival

– Median PFS in platinum-sensitive disease is 9.4-11.3 months1 and in platinum-resistant disease is 3.7-4.0 months2 in the recurrent setting

• There is a great need for new and more effective treatments for women with recurrent ovarian cancer

• Angiogenesis is an attractive therapeutic target

1.Pujade-Lauraine E. J Clin Oncol. 2009;27(18S): Abstract: LBA55092.Monk B. Ann Oncol. 2008;19(suppl 8): Abstract: LBA4

Page 4: Conflict of Interest

• Angiogenesis is a complex process that may be regulated by a number of different factors (eg, VEGF and angiopoietins)1

• Angiopoietins interact with the Tie2 receptor, which mediates vascular remodeling1,2

• Ang1 promotes vessel stabilizationby increasing endothelial junctions and pericyte coverage3,4

• Ang2 blocks Ang1’s blood vessel stabilizing action and increases angiogenesis and vascularity in tumors4,5

• Ang2 is upregulated in many ovarian cancers6

The Angiopoietin Axis

1.Papapetropoulos A, et al. J Biol Chem. 2000;275:9102-9105.2.Oliner J, et al. Cancer Cell. 2004;6:507-516.3.Machein MR, et al. Am J Pathol. 2004;165:1557-1570.4.Falcon BL, et al. Am J Pathol. 2009;175:2159-2170.5.Scharpfenecker M, et al. J Cell Sci. 2005;118:771-780.6.Zhang L, et al. Cancer Res. 2003;63:3403-3412

Page 5: Conflict of Interest

• AMG 386 (63.5 kD) is a first-in-class recombinant peptide-Fc fusion protein (peptibody)

• A peptibody is a novel proprietary platform technologythat fuses a specific peptide with the Fc region of IgG

• In preclinical studies, AMG 386 inhibited thegrowth of human xenograft tumors in mice1

• In the first-in-human (FIH) study, AMG 386was well tolerated and had a safety profilethat was distinct from that of VEGF-axis inhibitors2

– A patient with recurrent ovarian cancer had a durable partial response (PR) per RECIST which was maintained until she withdrew from the study at week 1562

AMG 386: Recombinant Peptibody That Binds and Neutralizes Ang1 and Ang2

1.Oliner J, et al. Cancer Cell. 2004;6:507-516.2.Herbst RS, et al. J Clin Oncol. 2009;27:3557-3565.

Page 6: Conflict of Interest

Study Objectives

Primary• To estimate the progression-free survival (PFS) in patients

with recurrent ovarian cancer receiving weekly paclitaxel combined with either AMG 386, at 3 mg/kg or 10 mg/kg, or placebo

Secondary Included• To estimate the treatment effect as measured by ORR

(RECIST and CA-125)• To evaluate the safety and tolerability of AMG 386 combined

with paclitaxel• To evaluate the incidence of AMG 386 antibodies• To evaluate AMG 386 PK when combined with paclitaxel

Page 7: Conflict of Interest

Study 20060342 Schema

PD

ArmA

AMG 386 10 mg/kg IV weekly

Paclitaxel*

ArmB

AMG 386 3 mg/kg IV weekly

Paclitaxel

ArmC

Placebo IV weekly

Paclitaxel

Open-label AMG 38610 mg/kg IV weekly

Treatment until:• Progressive Disease (PD)• Unacceptable toxicity• Consent withdrawn

RANDOMIZATION

*Paclitaxel 80 mg/m2 IV weekly, 3 weeks on/1 week off

Tumor assessments:•CT or MRI scans of the chest, abdomen, and pelvis every 8 weeks•CA-125 lab values, centrally every 8 weeks and locally as needed

This study was conducted at 38 sites in 5 countries161 patients were randomized

Page 8: Conflict of Interest

Key Eligibility Criteria• Histologically or cytologically documented epithelial

ovarian (FIGO stage II-IV), fallopian tube, or primary peritoneal cancer

• Radiographically documented progression per RECIST or CA-125 (GCIG Criteria)– Measurable or non-measurable disease

• ≤ 3 previous anticancer therapies, but at least one platinum-containing regimen

• Adequate renal and hepatic function

• GOG performance status of 0 or 1

Page 9: Conflict of Interest

Patient CharacteristicsAMG 386

Arm A10 mg/kg(N=53)

Arm B3 mg/kg(N=53)

Arm CPlacebo(N=55)

Number of randomized patients, n 53 53 55

Number of treated patients (safety pop), n 52 53 55

Median follow-up time, weeks 49.6 46.3 41.4

Median age, years (min, max) 59 (27, 80) 60 (28, 85) 62 (38, 83)

GOG performance status, n (%)0 26 (49) 32 (60) 30 (55)1 25 (47) 21 (40) 25 (45)2-3 2 (4) 0 0

Stratification factorsDisease progression on or within 6 mos

of the last chemotherapy regimen, n (%)Yes 29 (55) 29 (55) 29 (53)No 24 (45) 24 (45) 26 (47)

Prior anti-VEGF therapy, n (%)Yes 3 (6) 2 (4) 3 (5)No 50 (94) 51 (96) 52 (95)

Page 10: Conflict of Interest

AMG 386Arm A

10 mg/kg(N=53)

Arm B3 mg/kg(N=53)

Arm CPlacebo(N=55)

Primary tumor type, n (%)Ovarian cancer 46 (87) 47 (89) 44 (80)Primary peritoneal cancer 7 (13) 6 (11) 8 (15)Fallopian tube cancer 0 0 3 (5)

Histological subtype, n (%)Serous 30 (57) 23 (43) 34 (62)Endometrioid 7 (13) 6 (11) 3 (5)Clear cell 1 (2) 0 2 (4)Mucinous 0 1 (2) 1 (2)Unclassified 12 (23) 21 (40) 13 (24)Not available 3 (6) 2 (4) 2 (4)

FIGO stage, n (%)I-II 2 (4) 1 (2) 3 (5)III 22 (42) 29 (55) 25 (45)IV 13 (25) 11 (21) 17 (31)Unknown or not available 16 (30) 12 (23) 10 (18)

Measurable disease at baseline, n (%)Yes 46 (87) 47 (89) 52 (95)No 7 (13) 6 (11) 3 (5)

Baseline Disease (1)

Page 11: Conflict of Interest

AMG 386Arm A

10 mg/kg(N=53)

Arm B3 mg/kg(N=53)

Arm CPlacebo(N=55)

Number of prior anticancer therapies, n (%)1 21 (40) 23 (43) 17 (31)≥ 2 32 (60) 30 (57) 38 (69)

Number of prior platinum regimens, n (%)1 30 (57) 30 (57) 26 (47)≥ 2 23 (43) 23 (43) 29 (53)

Platinum sensitivity status, n (%)Refractory 5 (9) 3 (6) 4 (7)Resistant (PFI* < 6 mos) 20 (38) 23 (43) 20 (36)Partially sensitive (PFI 6-12 mos) 12 (23) 21 (40) 20 (36)Sensitive (PFI > 12 months) 15 (28) 6 (11) 10 (18)Not available 1 (2) 0 1 (2)

*PFI, platinum-free interval.

Baseline Disease (2)

Page 12: Conflict of Interest

Progression-Free Survival*

*PFS is defined as time from randomization to disease progression per RECIST, CA-125 (GCIG criteria), clinical progression, or death.

0

20

40

60

80

100

Months

0 5 10 15 20

535355

343021

10810

503

300

Placebo (N=55)

AMG 386 3 mg/kg (N=53)

AMG 386 10 mg/kg (N=53)

Patients at risk:

Per

centE

vent-

Fre

e

AMG 386

10 mg/kg 3 mg/kg Placebo

Median PFS, months 7.2 5.7 4.6

Cox model HR (Arm A+B vs pbo)(80% CI)P-value

0.76(0.59, 0.98)

0.17Trend test, P-value 0.037

Page 13: Conflict of Interest

PFS Hazard Ratios by Subgroup*

*HRs with 80% confidence intervals.

Arm A (AMG 386 10 mg/kg)vs Arm C (placebo)

Arm B (AMG 386 3 mg/kg)vs Arm C (placebo)

NE

Favors AMG 386Treatment Arm

No differencein hazard

FavorsPlaceboArm

0.01 0.10 1.00 10.00

All Patients

Refractory

Resistant

Partially Sensitive

Sensitive

1 Prior Therapy

≥ 2 Prior Therapies

0.01 0.10 1.00 10.00

Favors AMG 386Treatment Arm

No differencein hazard

FavorsPlaceboArm

Page 14: Conflict of Interest

Objective Response per RECISTAMG 386

Arm A10 mg/kg(N=53)

Arm B3 mg/kg(N=53)

Arm CPlacebo(N=55)

Patients with measurable disease at baseline, n (%)

46 (87) 47 (89) 52 (95)

Best response assessment, n (%)Complete response (CR) 2 (4) 1 (2) 0Partial response (PR) 15 (33) 8 (17) 14 (27)Stable disease (SD) 20 (43) 22 (47) 18 (35)Progressive disease (PD) 6 (13) 8 (17) 13 (25)Unevaluable 0 0 1 (2)Not done 3 (7) 8 (17) 6 (12)

Confirmed objective response (CR+PR), n (%)

17 (37) 9 (19) 14 (27)

Page 15: Conflict of Interest

-100

0

100

200

300

Percentage with CA-125 reduction: 63%

Placebo Arm

Per

cent

Cha

nge

fro

mB

as

eli

ne

inC

A-1

25

-100

0

100

200

300AMG 386 3 mg/kg Arm

Percentage with CA-125 reduction: 84%*

* * ** * ******

* ** * ******* ** * *******

* * ** * ******* ** * ******** * **** *

-100

0

100

200

Percentage with CA-125 reduction: 100%

AMG 386 10 mg/kg Ar

Best CA-125 ResponseAMG 386 10 mg/kg

(N=53)AMG 386 3 mg/kg

(N=53)Placebo(N=55)

Patients evaluated for CA-125 response, n (%) 39 (74) 37 (70) 32 (58)

Confirmed CA-125 response*, n (%) 29 (71) 22 (58) 11 (28)

†One value was truncated at 300 (ie 468)

‡One value was truncated at 300 (ie 488)

Page 16: Conflict of Interest

AMG 386 PK and AntibodiesAMG 386 PK• AMG 386 exhibits dose-proportional PK properties at 3 and

10 mg/kg• AMG 386 mean Cmax and Cmin values were comparable to those seen in the phase 1 first-in-human (FIH)

monotherapy study and were not impacted by the paclitaxel coadministration

AMG 386 antibodies in AMG 386-treated patients (pts)• 3.3% of evaluated pts developed anti-AMG 386 binding antibodies• 2.4% of evaluated pts had preexisting anti-AMG 386 binding antibodies• No neutralizing anti-AMG 386 antibodies were detected

Page 17: Conflict of Interest

PFS by Exposure1

1Lu JF, et al. Poster presented at ASCO 2010, June 4-8, 2010; Chicago, IL; Abstract # 5042

194521

81010

323

120

Perc

entE

vent-

Fre

e

0

20

40

60

80

100

Months

0 5 15 20

2679

Patients at risk:55

Placebo (N=55)AUC

SS< 9.6 mg*hr/mL (N=79)

AUCSS

≥ 9.6 mg*hr/mL (N=26)

AMG 386

AUCSS ≥ 9.6 AUCSS < 9.6 Placebo

Median PFS, months 8.1 5.7 4.6

Cox model HR (vs pbo)(80% CI)P-value

0.67(0.47, 0.95)

0.14

0.81(0.63, 1.05)

0.31

Page 18: Conflict of Interest

Adverse Events Occurring in ≥ 25% of Patients

AMG 386

Arm A10 mg/kg(N=53)

Arm B3 mg/kg(N=52)

Arm CPlacebo(N=55)

Adverse Event Any grade (%)

Grade ≥3(%)

Any grade(%)

Grade ≥3 (%)

Any grade (%)

Grade ≥3 (%)

Peripheral edema 71 4 51 6 29 4Fatigue 65 2 72 6 51 5Nausea 52 2 58 2 40 2Alopecia 50 0 38 2 36 0Diarrhea 42 2 36 4 29 0Peripheral neuropathy 38 10 26 2 31 4Constipation 38 2 23 0 31 0Cough 35 0 30 0 22 2Abdominal pain 33 2 32 4 36 5Pain in extremity 29 0 28 0 18 0Headache 29 0 25 0 13 0Vomiting 27 4 26 6 20 4Dizziness 27 0 11 0 20 0Includes adverse events occurring during treatment and within 30 days of the decision to end all study treatment.

Page 19: Conflict of Interest

Grade ≥ 3 Adverse Events Where Percent Difference* From Placebo is ≥ 5%

AMG 386

Arm A10 mg/kg(N=53)

Arm B3 mg/kg(N=52)

Arm CPlacebo(N=55)

Adverse Event Any grade (%)

Grade ≥3 (%)

Any grade (%)

Grade ≥3 (%)

Any grade (%)

Grade ≥3 (%)

Hypokalemia 21 12 15 11 5 4Peripheral neuropathy 38 10 26 2 31 4Anorexia 17 2 15 6 13 0Neutropenia 15 8 19 9 13 4Dyspnea 25 2 38 9 27 4Small bowel obstruction 4 2 8 6 7 7Ovarian cancer 4 4 2 2 9 9

*Percent difference compares incidence rates of grade ≥ 3 events between either AMG 386 arm and the placebo arm. Includes adverse events occurring during treatment and within 30 days of the decision to end all study treatment.

None of these Grade ≥ 3 events had a statistically significant incident rate (P < 0.05) when comparing the AMG 386 treatment arm with the placebo arm.

Page 20: Conflict of Interest

Selected Adverse Events of Specific Interest

AMG 386

Arm A10 mg/kg(N=53)

Arm B3 mg/kg(N=52)

Arm CPlacebo(N=55)

Adverse Event (%) Any grade (%)

Grade ≥3 (%)

Any grade (%)

Grade ≥3 (%)

Any grade (%)

Grade ≥3 (%)

Bowel perforation 0 0 0 0 2 2Hypertension 8 0 8 0 5 0Venous TEa 8 6 8 6 11 9Arterial TEa 2 2 2 2 0 0Proteinuria 8 0 6 0 5 0Cardiac toxicity events 0 0 0 0 2 2Hemorrhagic events 26 2 27 4 24 0

Impaired wound healing 2 0 2 0 0 0aTE, thrombo-embolic events. Includes adverse events occurring during treatment and within 30 days of the decision to end all study treatment.

None of these events had a statistically significant incident rate (P < 0.05) when comparing the AMG 386 treatment arm with the placebo arm.

Page 21: Conflict of Interest

Conclusions• The combination of AMG 386 and paclitaxel showed

encouraging evidence of antitumor activity in patients with advanced ovarian cancer

• The primary endpoint (PFS) was met. Based on exposure-response analysis, it appears that the maximum effective dose may not have been reached at 10 mg/kg1

• Further investigation using higher doses of AMG 386 for the treatment of patients with ovarian cancer is warranted

• The adverse event profile was generally manageable and distinct from that of VEGF axis inhibitors

1Lu JF, et al. Poster presented at ASCO 2010, June 4-8, 2010; Chicago, IL; Abstract # 5042

Page 22: Conflict of Interest

AcknowledgementsAll of the participating patients and their families

To the global network of investigators, research nurses, study coordinators, and operations staff

Study 20060342 participating investigators (from 38 sites)

USA P Braly, L Brard/D Dizon, R Brito, J Brown, J Carney/C Miller, S Chambers, D Christianson, M Crispens, J Hall, V Hansen, B Karlan, P Kucera, C Leath, D Matei, D Medgyesy, S Murukutla, H Nguyen, C Pippitt Jr, B Saffari, F Swan Jr, K Tewari

Canada A Covens, P Ghatage, R Grimshaw, A Oza, C Popadiuk, D Provencher, C Tessier

European Union I Vergote

Australia M Buck, M Davy, G Goss, T Jobling, G Richardson, P Vasey

India K Lakshmaiah, S Nag, R Nagarkar

Amgen Inc. D Weinreich, D Stepan, Y-N Sun, J Lu, D Zhong, C Tran-Muchowski, (Sponsor) M Tassoudji, D Androvich