Presentation on theme: "ASCO 2010 A Placebo-Controlled, Randomized Phase 2 Study of Conatumumab (C) or AMG 479 (A) or Placebo (P) + Gemcitabine (G) in Patients (pts) With Metastatic."— Presentation transcript:
ASCO 2010 A Placebo-Controlled, Randomized Phase 2 Study of Conatumumab (C) or AMG 479 (A) or Placebo (P) + Gemcitabine (G) in Patients (pts) With Metastatic Pancreatic Cancer (mPC) HL Kindler, 1 D Richards, 2 J Stephenson, 3 L Garbo, 4 C Rocha Lima, 5 H Safran, 6 J Wiezorek, 7 E Feigal, 7 SL Bray, 8 CS Fuchs 9 1 University of Chicago Medical Center, Chicago IL 2 US Oncology Research, Tyler, TX 3 Greenville Hospital System, Greenville, SC 4 New York Oncology Hematology, P.C. Albany, Albany, NY 5 University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL 6 Rhode Island Hospital, Providence, RI 7 Amgen Inc., Thousand Oaks, CA 8 Amgen Ltd, Cambridge, UK 9 Dana-Farber Cancer Institute, Boston, MA Abstract #4035
ASCO 2010 BACKGROUND The DR5/TRAIL Pathway in Pancreatic Cancer Pancreatic tumors express higher levels of death receptor 5 (DR5) than normal pancreas 1 Mutations in KRAS are found in > 90% of pancreatic cancer (PC) 2 –Transformation by RAS sensitizes cells to TRAIL-induced apoptosis 3,4 Conatumumab (AMG 655) is an investigational, fully human, monoclonal antibody agonist of DR5 –Binds DR5, activates caspases, and induces apoptosis 5 In mouse models of PC, conatumumab demonstrated single-agent activity, which was enhanced in combination with gemcitabine 5 In a phase 1b study in metastatic PC patients, conatumumab appeared safe in combination with gemcitabine 6 –Disease control rate (partial response [PR] + stable disease [SD]) = 69%; 6-month overall survival (OS) = 76%
ASCO 2010 BACKGROUND The DR5/TRAIL Pathway in Pancreatic Cancer
ASCO 2010 BACKGROUND The Type 1 Insulin-Like Growth Factor Receptor (IGF-1R) Pathway and Pancreatic Cancer IGF1-R, IGF-1, and IGF-2 are over-expressed in PC cells and tumors Risk of PC increases in patients with increased pathway activity (insulin sensitivity, Akt2 amplification, and low serum IGFBP-1) Pharmacological and genetic blockade of IGF-1R activity inhibits the growth of multiple PC xenograft models (alone and in combination with gemcitabine) Tumors driven by KRAS remain sensitive to IGF-1R inhibition 7-9 AMG 479 is an investigational, fully human, monoclonal antibody antagonist of IGF-1R –Blocks binding of IGF-1 and IGF-2 to IGF-1R 8 In mouse models of PC, AMG 479 demonstrated single-agent activity; activity was enhanced in combination with gemcitabine 8 In a phase 1b study in patients with advanced solid tumors, AMG 479 appeared safe in combination with gemcitabine 10
ASCO 2010 BACKGROUND The Type 1 Insulin-Like Growth Factor Receptor (IGF-1R) Pathway and Pancreatic Cancer
ASCO 2010 STUDY RATIONALE Current therapies for PC are inadequate: novel approaches are required Preclinical and phase I data support the evaluation of conatumumab and AMG 479 in PC patients Randomized phase II studies may be superior to single- arm trials in evaluating novel agents in PC Therefore, a 3-arm, placebo-controlled, randomized phase 2 study was conducted to evaluate conatumumab + gemcitabine and AMG gemcitabine versus placebo + gemcitabine in metastatic PC patients
ASCO 2010 PRIMARY ENDPOINT 6-month OS rate
ASCO 2010 METHODS Study Schema a The AMG gemcitabine arm was open label due to anticipated thrombocytopenia and hyperglycemia.
ASCO 2010 METHODS Secondary Endpoints Response rate (by RECIST) –Investigator defined, no central review Progression-free survival (PFS, investigator defined) OS Incidence of adverse events (AE) and laboratory abnormalities Incidence of anti-conatumumab or anti-AMG 479 antibodies Pharmacokinetics of conatumumab and AMG 479 Dose intensity of gemcitabine when combined with conatumumab, AMG 479, or placebo
ASCO 2010 METHODS Key Inclusion Criteria Histologically or cytologically documented metastatic adenocarcinoma of the pancreas ≥ 18 years of age ECOG PS 0 or 1 Adequate hematologic, hepatic, renal, and coagulation function Amylase and lipase ≤ 2.0 x ULN Adequately controlled type 1 or 2 diabetes (amended during study to FBS <160 mg/dL only) –Fasting blood sugar ≤ 160 mg/dL –HbA1c < 8% Written informed consent
ASCO 2010 METHODS Key Exclusion Criteria Uncontrolled cardiac disease Prior chemotherapy or radiation in the adjuvant or metastatic setting
ASCO 2010 METHODS Statistics The study was designed as an estimation study –Planned sample size of 120 (40/arm) –As designed (estimation, not hypothesis-testing), the trial has 80% power to detect a difference between a 6-month OS rate of: 45% for placebo 69% for conatumumab or AMG 479 (target improvement, 10%)
ASCO 2010 RESULTS Baseline Demographics
ASCO 2010 RESULTS Baseline Lesion Sites
ASCO 2010 RESULTS Efficacy The PFS and OS results were robust after adjusting for baseline covariates (age, gender, ECOG PS status, liver metastases, and tumor sum of longest diameter) a Primary endpoint. HR, hazard ratio; CI, confidence interval.
ASCO 2010 RESULTS Progression-Free Survival Full analysis set. a Stratified hazard ratio (estimates relative to placebo + gemcitabine arm). b Stratified log-rank test. HR, hazard ratio; KM, Kaplan-Meier; CI, confidence interval.
ASCO 2010 RESULTS Overall Survival Full analysis set. a Stratified hazard ratio (estimates relative to placebo + gemcitabine arm). b Stratified log-rank test.
ASCO 2010 RESULTS Grade 3-5 Adverse Events a a In ≥ 5% of patients. b One GI perforation, 1 GI hemorrhage, 1 hepatic failure in a patient with liver metastases, 4 PD. c One acute renal failure, 1 hemorrhage, 2 PD. d One GI hemorrhage.
ASCO 2010 RESULTS Drug Exposure a Ratio of cumulative dose of drug : protocol-specified cumulative dose over the specified period. IP, investigational product.
ASCO 2010 CONCLUSIONS This randomized phase 2 study shows evidence of activity for AMG 479 with trends across several efficacy parameters in metastatic PC –Improved 6-month OS rate (primary endpoint) (57% vs 50%) –Improved 12-month OS (39% vs 23%) –Longer PFS (5.1 vs 2.1 months, HR 0.65) –Longer OS (8.7 vs 5.9 months, HR 0.67) –Higher rates of SD + PR (51% vs 41%)
ASCO 2010 CONCLUSIONS (continued) The study also shows evidence of activity for conatumumab –Improved 6-month OS rate (primary endpoint) (59% vs. 50%) –Longer PFS (4.0 vs 2.1 months, HR 0.65) –Higher rates of SD + PR (61% vs 41%) Both drug combinations were well-tolerated These data suggest that further study of AMG gemcitabine is warranted in advanced PC
ASCO 2010 REFERENCES 1. Data on file. Amgen Inc. 2. Koorstra JB, et al. Pancreatology. 2008;8: Nesterov AM, et al. Cancer Res. 2004;64: Drosopoulos KG, et al. J Biol Chem. 2005;280: Kaplan-Lefko PJ, et al. Cancer Biol Ther. 2010;9: Kindler HL, et al. J Clin Oncol. 2009;27:abstr Beltran PJ, et al. Mol Cancer Ther. 2009;8: Sell C, et al. Mol Cell Biol. 1994;14: Yeh AH, et al. Oncogene. 2006;25: Sarantopoulos J, et al. J Clin Oncol. 2008;26:abstr 3583.
ASCO 2010 ACKNOWLEDGMENTS This study was sponsored by Amgen Inc. (ClinicalTrials.gov: NCT )