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 Beth.
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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. 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.
Conflict of Interest
• Dr. Karlan has no conflicts of interest • Conduct of the trial was funded in
part by Amgen, Inc.
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
• 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
• 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
• 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.
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
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
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
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.
Grade ≥ 3 Adverse Events Where Percent Difference* From Placebo is ≥ 5%
*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.
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.
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
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