Download An International Phase 3 Multicenter

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RILOMET-1: An International Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Rilotumumab Plus Epirubicin, Cisplatin, and
Capecitabine (ECX) as First-Line Therapy in Patients With Advanced MET-Positive Gastric or Gastroesophageal Junction (G/GEJ) Adenocarcinoma
David Cunningham, Salah-Eddin Al-Batran, Irina Davidenko, David H. Ilson, André M. Murad, Niall C. Tebbutt, Nigel Baker, Rajul Jain, Tien Hoang, on behalf of the RILOMET-1 Investigators
1
Hepatocyte Growth Factor (HGF)/MET Pathway
HGF, also known as scatter factor, is the only known ligand of MET, a receptor tyrosine kinase
The HGF/MET pathway promotes the proliferation, migration, and survival of tumor cells5
MET expression and gene amplification were noted in 26%–74% and 2%–23% of gastric cancer cases, respectively6-14
MET overexpression was correlated with tumor depth of invasion, lymph node metastasis, stage, and shortened survival in gastric cancer9,10
High MET expression was associated with developing metastases and poorer outcomes in esophageal adenocarcinomas15,16
Primary Endpoint
• OS
Key Secondary Endpoints
• Efficacy
– PFS
– Survival rate at 12 months
– TTP
– ORR
– DCR
– Duration of response
– TTR
Rilotumumab (AMG 102)
Exploratory Endpoints
• Rilotumumab is an investigational, fully human, monoclonal antibody (IgG2) against HGF
– High affinity (KD = 41 pM)
• Rilotumumab prevents the binding of HGF to the MET receptor, inhibiting HGF/MET-driven activities in cells
• In a randomized phase 2 study in patients with advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma, the addition of
rilotumumab every 3 weeks (Q3W) to epirubicin, cisplatin, and capecitabine (ECX) had manageable toxicities and showed trends toward
improved progression-free survival (PFS) and overall (OS) compared with placebo and ECX17 (figure below)
– The treatment effect of rilotumumab plus ECX was enhanced in MET-positive patients17
• RILOMET-1 is a randomized, phase 3, placebo-controlled study of rilotumumab with ECX as first-line therapy in advanced MET-positive
G/GEJ adenocarcinoma (ClinicalTrials.gov Identifier: NCT01697072)
•
•
•
•
•
•
5.7
(4.5, 7.0)
4.2
Placebo + ECX (n = 39)
(2.9, 4.9)
0.6
0.4
0.4
0.2
0.0
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
8
0
7
0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
6
0
4
0
2
0
2
0
2
0
2
0
2
0
1
0
82 81 76 71 65 60 57 53 49 45 37 36 30 28 22 20 18 16 16 14 12 10 5
39 38 36 33 32 24 20 20 19 15 15 11 9 8 7 7 6 6 5 5 3 2 2
Rilotumumab + ECX (n = 41) 6.8
(4.9, 8.5)
Placebo + ECX (n = 17) 4.4
(2.8, 5.2)
0
2
4
6
8
10
Month
12
*MET-positive: ≥ 25% membrane staining on tumor cells at any intensity.
14
16
18
0.46
0.013
(0.25, 0.85)
20
22
24
Parameter
Hemoglobin
Absolute neutrophil count
Platelet count
Creatinine clearance
Aspartate aminotransferase
Alanine aminotransferase
Total bilirubin
4
2
3
0
3
0
Median Months HR
P Value
(95% CI)
(95% CI)
Median Months HR
P Value
(95% CI)
(95% CI)
OS Probability
PFS Probability
MET-positive patients*
6
0
10.6
(8.0, 13.4)
Placebo + ECX (n = 17) 5.7
(4.2, 10.4)
Rilotumumab + ECX (n = 41)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
4
6
8
10 12 14
Month
8
0.46
0.016
(0.24, 0.87)
16 18 20 22 24
26
Figure adapated from Iveson T, et al. Lancet Oncol 2014.17
OBJECTIVES
Level
≥ 9 g/dL
≥ 1.5 x 109/L
≥ 100 x 109/L
≥ 60 mL/minute (calculated or measured)
≤ 2.5 x ULN (≤ 5.0 x ULN if liver metastases are present)
≤ 2.5 x ULN (≤ 5.0 x ULN if liver metastases are present)
≤ 1.5 x ULN
HER2-overexpressing locally advanced or metastatic G/GEJ adenocarcinoma
Previous systemic therapy for locally advanced or metastatic G/GEJ adenocarcinoma
Less than 6 months from completion of prior neoadjuvant or adjuvant chemotherapy or chemoradiotherapy to randomization
Previous treatment with anthracyclines exceeds total cumulative dose of epirubicin of 400 mg/m2 (or equivalent thereof, if different
anthracycline administered in the past)
• Squamous cell histology
• Left ventricular ejection fraction < 50% as determined by either multiple gated acquisition scan or echocardiogram
Primary Objective
• To determine if rilotumumab with ECX significantly improves OS as compared to placebo with ECX in patients with unresectable locally
advanced or metastatic MET-positive G/GEJ adenocarcinoma
Secondary Objectives
• To evaluate PFS, survival rate at 12 months, time to progression (TTP), objective response rate (ORR), disease control rate (DCR), duration of
response, time to response (TTR), safety, immunogenicity, rilotumumab and ECX dose exposure, dose intensity, and pharmacokinetic (PK)
parameters
• To evaluate the impact of MET expression levels on efficacy, if needed
STUDY DESIGN
Rilotumumab*
+ ECX†
(n = 300)
Rilotumumab‡
• Phase 3, multicenter, randomized, double-blind, placebo-controlled study
• Planned enrollment: approximately 600 patients
• Study medications:
– All patients are to receive open-label ECX (intravenous [IV] epirubicin 50 mg/m2 on day 1, IV cisplatin 60 mg/m2 on day 1, and oral
capecitabine 625 mg/m2 twice daily on days 1−21) Q3W for a maximum of 10 cycles
– Patients are randomized 1:1 to receive double-blind rilotumumab 15 mg/kg or placebo IV Q3W starting on day 1
• Randomization stratified by extent of disease (locally advanced vs metastatic) and ECOG score (0 vs 1)
Primary
Endpoint
Monotherapy
OS
Placebo
+ ECX†
(n = 300)
Placebo‡
Monotherapy
Rilotumumab 15 mg/kg IV Q3W on day 1
†
ECX Q3W (maximum of 10 cycles): IV epirubicin 50 mg/m2 and cisplatin 60 mg/m2 on day 1; oral capecitabine 625 mg/m2 twice daily on days 1–21
‡
Patients who complete 10 cycles of ECX or discontinue ECX for reasons other than disease progression will continue on rilotumumab or placebo monotherapy
STATISTICAL CONSIDERATIONS
• Primary analysis of OS in the full analysis set (all randomzied patients) is to occur after approximately 319 OS events
• The study is designed to have 90% power; the overall one-sided significance level of 0.025 is controlled for the analyses of the primary and
secondary endpoints
• A log-rank test stratified by the randomization factors will be used to compare OS within the full analysis set; if the result of this test is not
significant, then the analysis will be repeated in the population defined using more stringent MET selection criteria
• Independent Data Monitoring Committee (DMC) has been chartered to review safety and efficacy data
• DMC safety reviews are planned after:
– 40 patients with 1 cycle of treatment
– 120 patients with 1 cycle of treatment
– Approximately every 6 months thereafter
TOXICITY MANAGEMENT
• Treatment-withholding and dose-reduction guidelines are provided
• Key toxicities for dose modification of rilotumumab are edema, hematological toxicity, infusion reaction, and hepatotoxicity
• Key toxicities for dose modification of ECX chemotherapy follows standard guidelines and includes hematological toxicity, hepatotoxicity,
cardiac toxicity, renal toxicity, neuropathy, and capecitabine-related toxicities such as hand-foot syndrome and diarrhea
*
ASSESSMENTS
• Investigator assessment of response and progression are evaluated per RECIST v1.1
• CT or MRI scans will occur during study treatment independent of treatment cycle:
– At screening
– Week 13 (± 7 days)
– Every 12 weeks (± 7 days)
– At any time when symptoms suggestive of disease progression occur
Pharmacokinetics
• Intensive PK for rilotumumab and ECX:
– Sampling from patients at selected sites until approximately 12 evaluable patients per arm identified
• Non-intensive PK collection for rilotumumab in all patients
STUDY CENTERS
• Approximately 180 centers will participate
• Locations include but are not limited to Australia, Europe, North and South America, and Africa
PARTICIPATING COUNTRIES
•
•
•
•
2
8
• Termination:
– All study treatments are terminated if patients experience documented disease progression per RECIST v1.1
– Individual components (E, C, X, or rilotumumab) are terminated if an intolerable adverse event associated with the specific agent occurs
– Patients who complete 10 cycles of chemotherapy or discontinue chemotherapy for reasons other than disease progression will continue on
rilotumumab or placebo monotherapy
Key Exclusion Criteria
0
7
Tumor Assessments
• Pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1)
• Tumor MET-positive by immunohistochemistry (IHC; ≥ 25% tumor membrane staining at any intensity) performed by a central laboratory
– Amgen and Dako partnership was formed to develop a MET IHC companion diagnostic test
– MET IHC assay has an Investigational Device exemption from CRDH/FDA and is being utilized as a component of patient selection
• Evaluable disease by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria
• Written informed consent required
• Laboratory parameters as shown in the Table
Month
Patients at risk:
Levels of plasma or serum cytokines
Circulating tumor DNA and tumor RNA expression
Tumor genetic variation or gene copy number in pathway genes, cancer genes, drug target genes, and other biomarker genes
Inherited genetic variation in cancer genes, drug target genes, and other biomarker genes
Tumor protein levels and RNA expression
Changes in cancer-related and treatment-related symptoms and overall health-related quality of life with QLQ-C30
Key Inclusion Criteria
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Month
82 79 67 59 54 43 34 27 20 14 11 10
39 36 31 23 21 12 8 7 5 3 2 1
0.70
0.109
(0.45, 1.09)
0.6
0.2
Patients at risk:
10.6
(9.2, 12.5)
8.9
Placebo + ECX (n = 39)
(5.5, 11.2)
Rilotumumab + ECX (n = 82)
0.8
OS Probability
0.8
PFS Probability
0.60
0.016
(0.39, 0.91)
Rilotumumab + ECX (n = 82)
Median Months HR
P Value
(95% CI)
(95% CI)
1.0
• Safety
– Incidence of adverse events
– Laboratory abnormalities
– Immunogenicity
– Dose exposure and intensity
• Pharmacokinetics
– PK parameters and exposure response analysis
PATIENT ELIGIBILITY
PFS and OS in the Phase 2 Study
Median Months HR
P Value
(95% CI)
(95% CI)
6
R A N D OM I ZA TI ON
• Globally, gastric cancer is the fourth and fifth leading cancer in men and women, respectively, and the second leading cause of all
cancer-related deaths1
• Treatments for advanced disease include platinum- and fluoropyrimidine-based chemotherapy, which have shown modest improvements in
survival2,3
• Biomarker-directed therapy with trastuzumab has demonstrated efficacy in HER2-overexpressing metastatic gastric and gastroesophageal cancer4
• Despite advancements in chemotherapy and targeted therapy, more effective treatments are needed
ITT Population
5
STUDY DESIGN (Continued)
ENDPOINTS
Unmet Need
1.0
4
Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, UK; 2Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany; 3Krasnodar City Oncology Center, Krasnodar, Russia; 4Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;
5
Oncology Department, Hospital das Clínicas da Universidade Federal e Minas Gerais, Horizonte, Brazil; 6Austin Health, Heidelberg, VIC, Australia; 7Amgen Limited, Cambridge, UK; 8Amgen Inc., Thousand Oaks, CA, USA
INTRODUCTION
•
•
•
•
•
3
SCREENING
1
2
AMERICAS
Brazil
Canada
Mexico
USA
AFRICA
South Africa
AUSTRALASIA
Australia
EUROPE
Austria
Belgium
Bulgaria
Czech Republic
Denmark
France
Germany
Greece
Hungary
Italy
Poland
Portugal
Romania
Russia
Spain
Slovakia
Sweden
Switzerland
Turkey
United Kingdom
Ukraine
CURRENT STATUS
• Enrollment began in November 2012
• Recruitment/accrual is ongoing and is proceeding well with the last patient expected to be enrolled on or ahead of target
ACKNOWLEDGMENTS
• We thank the patients and their families, the staff at participating sites, and the study investigators for their participation in this study
• We also thank John David Mee, Julie Gray, and Jeff Adams from Amgen Inc. for their contributions to the development or management of the
study
• Jenilyn Virrey, PhD, of Amgen Inc. provided medical writing support
• A version of this poster was initially presented at the 2013 American Society of Clinical Oncology Annual Meeting
(J Clin Oncol 31, 2013 [suppl; abstr TPS4153])
DISCLOSURES
• This study is funded by Amgen Inc.
• David Cunningham is a consultant/advisor for Roche and Amgen Inc. and received research funding from Roche, Amgen Inc., Celgene,
Sanofi Aventis, Merck Serono, and Novartis. Salah-Eddin Al-Batran is a consultant/advisor for and received research funding and honoraria
from Roche, Chugia, Novartis, and Sanofi. David H. Ilson is a consultant/advisor for Lilly and Imclone and received research funding from
Bayer. Niall C. Tebbutt is a consultant/advisor for and received research funding and honoraria from Amgen Inc. Nigel Baker, Rajul Jain, and
Tien Hoang are employees of and own stock in Amgen Inc. Irina Davidenko and André M. Murad have no conflicts of interest to declare.
REFERENCES
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17.
Jemal A, et al. CA Cancer J Clin. 2011;61:69-90.
Wagner AD, et al. J Clin Oncol. 2006;24:2903-2909.
Wagner AD, et al. Cochrane Database Syst Rev. 2010;(3):CD004064.
Herceptin® [prescribing information]. San Francisco, CA: Genentech, Inc; 2010.
Gherardi E, et al. Nat Rev Cancer. 2012;12:89-103.
Janjigian YY, et al. Cancer Epidemiol Biomarkers Prev. 2011;20:1021-1027.
Lennerz JK, et al. J Clin Oncol. 2011;29:1-8.
Drebber UTA, et al. Oncol Rep. 2008;19:1477-1483.
Nakajima M, et al. Cancer. 1999;85:1894-1902.
Taniguchi K, et al. Cancer. 1998;82:2112-2122.
Wu C, et al. Oncol Rep. 1998;5:817-822.
Amemiya H, et al. Oncology. 2002;63:286-296.
Park W, et al. APMIS. 2000;108:195-200.
Lee J, et al. Oncogene. 2000;19:4947-4953.
Herrera L, et al. Neoplasia. 2005;7:75-84.
Tuynman JB, et al. Br J Cancer. 2008;98:1102-1108.
Iveson T, et al. Lancet Oncol. Early Online Publication, 23 June 2014; doi:10.1016/S1470-2045(14)70023-3.
Corresponding author: David Cunningham (E-mail: [email protected])
Presenting author: Irina Davidenko (E-mail: [email protected])
European Society for Medical Oncology 2014 Congress; Madrid, Spain; September 26 – 30, 2014