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,2Vincent L. Hansen,3 Gary E. Richardson,4 Diane Provencher,5 Prafull Ghatage,6Marjan Tassoudji,7 Daniel E. Stepan,7David 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 • Pujade-Lauraine E. J Clin Oncol. 2009;27(18S): Abstract: LBA5509 • Monk B. Ann Oncol. 2008;19(suppl 8): Abstract: LBA4
The Angiopoietin Axis • 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 • Papapetropoulos A, et al. J Biol Chem. 2000;275:9102-9105. • Oliner J, et al. Cancer Cell. 2004;6:507-516. • Machein MR, et al. Am J Pathol. 2004;165:1557-1570. • Falcon BL, et al. Am J Pathol. 2009;175:2159-2170. • Scharpfenecker M, et al. J Cell Sci. 2005;118:771-780. • 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 • Oliner J, et al. Cancer Cell. 2004;6:507-516. • 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
Study 20060342 Schema R A N D O M I Z A T I O N Arm A AMG 386 10 mg/kg IV weekly • 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 Paclitaxel* Arm B AMG 386 3 mg/kg IV weekly Treatment until: • Progressive Disease (PD) • Unacceptable toxicity • Consent withdrawn Paclitaxel Arm C Placebo IV weekly Open-label AMG 386 10 mg/kg IV weekly PD Paclitaxel *Paclitaxel80 mg/m2 IV weekly, 3 weeks on/1 week off This study was conducted at 38 sites in 5 countries 161 patients were randomized
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
Progression-Free Survival* *PFS is defined as time from randomization to disease progression per RECIST, CA-125 (GCIG criteria), clinical progression, or death.
PFS Hazard Ratios by Subgroup* Arm A (AMG 386 10 mg/kg)vs Arm C (placebo) Arm B (AMG 386 3 mg/kg)vs Arm C (placebo) *HRs with 80% confidence intervals.
Best CA-125 Response † †One value was truncated at 300 (ie 468) ‡ ‡One value was truncated at 300 (ie 488)
AMG 386 PK and Antibodies AMG 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
Grade ≥ 3 Adverse Events Where Percent Difference* From Placebo is ≥ 5% 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.
Selected Adverse Events of Specific Interest 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
Acknowledgements All 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