1. 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 Fuchs9
1University of Chicago Medical Center, Chicago IL
2US Oncology Research, Tyler, TX
3Greenville Hospital System, Greenville, SC
4New York Oncology Hematology, P.C. Albany, Albany, NY
5University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL
6Rhode Island Hospital, Providence, RI
7Amgen Inc., Thousand Oaks, CA
8Amgen Ltd, Cambridge, UK
9Dana-Farber Cancer Institute, Boston, MA
Abstract #4035

2. BACKGROUND The DR5/TRAIL Pathway in Pancreatic Cancer
Pancreatic tumors express higher levels of death receptor 5 (DR5) than normal pancreas1
Mutations in KRAS are found in > 90% of pancreatic cancer (PC)2
Transformation by RAS sensitizes cells to TRAIL-induced apoptosis3,4
Conatumumab (AMG 655) is an investigational, fully human, monoclonal antibody agonist of DR5
Binds DR5, activates caspases, and induces apoptosis5
In mouse models of PC, conatumumab demonstrated single-agent activity, which was enhanced in combination with gemcitabine5
In a phase 1b study in metastatic PC patients, conatumumab appeared safe in combination with gemcitabine6
Disease control rate (partial response [PR] + stable disease [SD]) = 69%; 6-month overall survival (OS) = 76%

3. BACKGROUND The DR5/TRAIL Pathway in Pancreatic Cancer

4. 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 inhibition7-9
AMG 479 is an investigational, fully human, monoclonal antibody antagonist of IGF-1R
Blocks binding of IGF-1 and IGF-2 to IGF-1R8
In mouse models of PC, AMG 479 demonstrated single-agent activity; activity was enhanced in combination with gemcitabine8
In a phase 1b study in patients with advanced solid tumors, AMG 479 appeared safe in combination with gemcitabine10

5. BACKGROUND The Type 1 Insulin-Like Growth Factor Receptor (IGF-1R) Pathway and Pancreatic Cancer

6. 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

7. PRIMARY ENDPOINT
6-month OS rate

8. METHODS Study Schema
aThe AMG gemcitabine arm was open label due to anticipated thrombocytopenia and hyperglycemia.

9. 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

10. 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

11. METHODS Key Exclusion Criteria
Uncontrolled cardiac disease
Prior chemotherapy or radiation in the adjuvant or metastatic setting

12. 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%)

13. RESULTS Baseline Demographics

14. RESULTS Baseline Lesion Sites

15. RESULTS Efficacy
aPrimary 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)

16. RESULTS 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.

17. RESULTS Overall Survival
Full analysis set. aStratified hazard ratio (estimates relative to placebo + gemcitabine arm). bStratified log-rank test.

18. RESULTS Best Overall Tumor Response
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

19. RESULTS 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.

20. RESULTS Drug Exposure
aRatio of cumulative dose of drug : protocol-specified cumulative dose over the specified period. IP, investigational product.

21. 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%)

22. 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

23. 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.

24. ACKNOWLEDGMENTS
This study was sponsored by Amgen Inc. (ClinicalTrials.gov: NCT )