Presentation on theme: "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."— Presentation transcript:
1A 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 Fuchs91University of Chicago Medical Center, Chicago IL2US Oncology Research, Tyler, TX3Greenville Hospital System, Greenville, SC4New York Oncology Hematology, P.C. Albany, Albany, NY5University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL6Rhode Island Hospital, Providence, RI7Amgen Inc., Thousand Oaks, CA8Amgen Ltd, Cambridge, UK9Dana-Farber Cancer Institute, Boston, MAAbstract #4035
2BACKGROUND The DR5/TRAIL Pathway in Pancreatic Cancer Pancreatic tumors express higher levels of death receptor 5 (DR5) than normal pancreas1Mutations in KRAS are found in > 90% of pancreatic cancer (PC)2Transformation by RAS sensitizes cells to TRAIL-induced apoptosis3,4Conatumumab (AMG 655) is an investigational, fully human, monoclonal antibody agonist of DR5Binds DR5, activates caspases, and induces apoptosis5In mouse models of PC, conatumumab demonstrated single-agent activity, which was enhanced in combination with gemcitabine5In a phase 1b study in metastatic PC patients, conatumumab appeared safe in combination with gemcitabine6Disease control rate (partial response [PR] + stable disease [SD]) = 69%; 6-month overall survival (OS) = 76%
3BACKGROUND The DR5/TRAIL Pathway in Pancreatic Cancer
4BACKGROUND 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 tumorsRisk 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 inhibition7-9AMG 479 is an investigational, fully human, monoclonal antibody antagonist of IGF-1RBlocks binding of IGF-1 and IGF-2 to IGF-1R8In mouse models of PC, AMG 479 demonstrated single-agent activity; activity was enhanced in combination with gemcitabine8In a phase 1b study in patients with advanced solid tumors, AMG 479 appeared safe in combination with gemcitabine10
5BACKGROUND The Type 1 Insulin-Like Growth Factor Receptor (IGF-1R) Pathway and Pancreatic Cancer
6STUDY RATIONALECurrent therapies for PC are inadequate: novel approaches are requiredPreclinical and phase I data support the evaluation of conatumumab and AMG 479 in PC patientsRandomized phase II studies may be superior to single-arm trials in evaluating novel agents in PCTherefore, 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
8METHODS Study SchemaaThe AMG gemcitabine arm was open label due to anticipated thrombocytopenia and hyperglycemia.
9METHODS Secondary Endpoints Response rate (by RECIST)Investigator defined, no central reviewProgression-free survival (PFS, investigator defined)OSIncidence of adverse events (AE) and laboratory abnormalitiesIncidence of anti-conatumumab or anti-AMG 479 antibodiesPharmacokinetics of conatumumab and AMG 479Dose intensity of gemcitabine when combined with conatumumab, AMG 479, or placebo
10METHODS Key Inclusion Criteria Histologically or cytologically documented metastatic adenocarcinoma of the pancreas≥ 18 years of ageECOG PS 0 or 1Adequate hematologic, hepatic, renal, and coagulation functionAmylase and lipase ≤ 2.0 x ULNAdequately controlled type 1 or 2 diabetes (amended during study to FBS <160 mg/dL only)Fasting blood sugar ≤ 160 mg/dLHbA1c < 8%Written informed consent
11METHODS Key Exclusion Criteria Uncontrolled cardiac diseasePrior chemotherapy or radiation in the adjuvant or metastatic setting
12METHODS 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 placebo69% for conatumumab or AMG 479 (target improvement, 10%)
15RESULTS EfficacyaPrimary endpoint. HR, hazard ratio; CI, confidence interval.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)
16RESULTS Progression-Free Survival Full analysis set. aStratified hazard ratio (estimates relative to placebo + gemcitabine arm). bStratified log-rank test. HR, hazard ratio; KM, Kaplan-Meier; CI, confidence interval.
17RESULTS Overall Survival Full analysis set. aStratified hazard ratio (estimates relative to placebo + gemcitabine arm). bStratified log-rank test.
19RESULTS Grade 3-5 Adverse Eventsa aIn ≥ 5% of patients.bOne GI perforation, 1 GI hemorrhage, 1 hepatic failure in a patient with liver metastases, 4 PD. cOne acute renal failure, 1 hemorrhage, 2 PD. dOne GI hemorrhage.
20RESULTS Drug ExposureaRatio of cumulative dose of drug : protocol-specified cumulative dose over the specified period. IP, investigational product.
21CONCLUSIONSThis randomized phase 2 study shows evidence of activity for AMG 479 with trends across several efficacy parameters in metastatic PCImproved 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%)
22CONCLUSIONS (continued) The study also shows evidence of activity for conatumumabImproved 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-toleratedThese data suggest that further study of AMG gemcitabine is warranted in advanced PC
23REFERENCES1. 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.
24ACKNOWLEDGMENTSThis study was sponsored by Amgen Inc. (ClinicalTrials.gov: NCT )