1. Phase 1b Study of AMG 655 in Combination With Modified FOLFOX6 (mFOLFOX6) and Bevacizumab (B) for the First-Line Treatment of Patients With Metastatic Colorectal Cancer (mCRC)
L Saltz,1 J Infante,2 L Schwartzberg,3 J Stephenson,4 C Rocha-Lima,5 A Braun,6 K Dillingham,7 M Hsu,6 J Wiezorek,6 C Fuchs8
1Memorial Sloan Kettering Cancer Center, New York, NY; 2Sarah Cannon Cancer Center, Nashville, TN; 3West Clinic, Memphis, TN; 4Cancer Center of the Carolinas, Greenville, SC; 5University of Miami, Miami, FL; 6Amgen Inc., Thousand Oaks, CA; 7Amgen Ltd, Cambridge, UK; 8Dana-Farber Cancer Institute, Boston, MA

2. INTRODUCTION
AMG 655 is an investigational, fully human agonist monoclonal antibody (IgG1) that targets human death receptor 5 (DR5)
Evidence supports the development of AMG 655 in combination with chemotherapy to treat metastatic colorectal cancer (mCRC):
CRC tumors express higher levels of DR5 compared with normal colorectal tissue1
AMG 655 demonstrated dose-dependent activity against CRC xenografts that was significantly enhanced by combining AMG 655 with 5-FU2
In the AMG 655 first in human (FIH) study, 1 patient with mCRC had a metabolic partial response (35% reduction in maximum standardized uptake value measured using FDG-PET) and a 24% decrease in tumor size (measured by RECIST); 4 patients with mCRC had stable disease > 12 weeks3
Bevacizumab plus FOLFOX is the most commonly used standard first-line regimen in the United States for patients with mCRC
We hypothesize that the addition of AMG 655 to modified (m)FOLFOX-bevacizumab may improve antitumor activity in patients with mCRC

3. INTRODUCTION: AMG 655 Mechanism of Action
The TRAIL receptor family is comprised of 2 death receptors (DR4 and DR5) and 2 decoy receptors (DcR1 and DcR2)4,5
AMG 655 mimics endogenous Apo2L/TRAIL by binding DR5 and activating caspases, thereby inducing apoptosis in sensitive cells

4. OBJECTIVES
Primary
Determine the maximum tolerated dose (up to a target dose of 10 mg/kg IV administered every 2 weeks [Q2W]) of AMG 655 that can be safely administered in combination with mFOLFOX6/bevacizumab to patients with mCRC
Secondary
Safety and tolerability of escalating doses of AMG 655 in combination with mFOLFOX6/bevacizumab
Parameters of clinical benefit (objective response rate, duration of response, time-to-response, progression-free survival, and overall survival)
Pharmacokinetics (PK) of AMG 655
Anti-AMG 655 antibody formation

5. PATIENTS AND METHODS: Study Design
Phase 1b, open-label, dose-escalation study of AMG 655 in combination with mFOLFOX6 and bevacizumab for the first-line treatment of patients with mCRC

6. PATIENTS AND METHODS: Phase 1b Study Schema

7. PATIENTS AND METHODS (continued)
Patients were enrolled in sequential dose cohorts (6 per cohort) of AMG 655 (3 or 10 mg/kg) administered IV on day 1 of each 14-day mFOLFOX6/bevacizumab cycle
Treatment regimen (Day 1 to 3):
1. Oxaliplatin (85 mg/m2) and leucovorin (400 mg/m2) administered concurrently as a 2-hour infusion
2. Then 5-FU (400 mg/m2) IV bolus for 2 to 4 minutes
3. Then bevacizumab 5 mg/kg IV for 10 to 30 minutes
4. Then AMG 655 IV for 60 minutes
5. Then 5-FU 2400 mg/m2 by continuous IV infusion over 46 to 48 hours
Patients received treatment until disease progression, drug intolerability, withdrawal of consent, or until 30 months from enrollment
Tumor assessments were performed within 21 days before enrollment, Day 1 of Cycle 5, and every 8 weeks thereafter
All patients were followed for survival

8. PATIENTS AND METHODS: Endpoints
Primary Endpoint
Incidence of dose-limiting toxicities (DLT)
Secondary Endpoints
Incidence of adverse events (AE, graded according to NCI CTCAE Version 3.0)
Incidence of anti-AMG 655 antibody formation
Pharmacokinetic parameters of AMG 655
Objective response rate (CR, PR), time-to-response, overall survival, duration of response, progression-free survival

9. PATIENTS AND METHODS: Key Eligibility Criteria
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum
ECOG performance status 0 or 1
≥ 18 years
Adequate hematologic, cardiac, renal, coagulation, and hepatic function
No prior adjuvant or neoadjuvant chemotherapy for the treatment of advanced or mCRC with the following exceptions:
May have received adjuvant or neo-adjuvant chemotherapy, including bevacizumab and EGFR inhibitors, if disease recurrence was documented ≥ 12 months after completion of chemotherapy
May have received prior fluoropyrimidine therapy if administered solely for the purpose of radiosensitization if completed ≥ 12 months prior to enrollment

10. PATIENTS AND METHODS: Definition of DLT
Grade 4 fatigue or grade 3 fatigue > 7 days; grade 3 or 4 nausea, diarrhea, or vomiting (despite best supportive care); grade 3 or 4 neutropenia with fever > 38.5°C; grade 4 neutropenia or thrombocytopenia > 7 days; elevated ALT or AST > 10 x ULN; and grade 4 elevation in amylase or lipase > 7 days felt to be related to AMG 655 or AMG mFOLFOX6/bevacizumab
Any other grade ≥ 3 hematologic or non-hematologic toxicity felt to be related to AMG 655 or AMG mFOLFOX6/bevacizumab

11. RESULTS
As of 25 September 2008, a total of 12 patients (6 per cohort) were enrolled and received ≥ 1 cycle of treatment

12. RESULTS: Baseline Demographics and Disease Characteristics

13. RESULTS: Patient Disposition
aPatient underwent resection.
bPatient reached maximum clinical benefit according to the investigator.

14. SAFETY: Incidence of Treatment-Emergent Adverse Eventsa
aAEs reported in ≥ 3 patients, both cohorts combined (worst grade).
bPatient incidence of either of these events.
Other grade 3 AEs: DVT (2 patients), febrile neutropenia (2 patients), hydronephrosis (1 patient), hypokalemia (1 patient), hyponatremia (1 patient).
Other grade 4 AEs: pulmonary embolism (2 patients).

15. SAFETY (continued)
There were no DLTs during the first 28 days of therapy
The following serious AEs were reported:
One patient (10-mg/kg cohort) with grade 4 abdominal pain (Day 3) and grade 4 pulmonary embolism (Day 57)
One patient (10-mg/kg cohort) with grade 4 neutropenia (Day 29) and grade 4 pulmonary embolism (Day 56)
One patient (10-mg/kg cohort) with grade 2 nausea and vomiting and grade 3 diarrhea (Day 37) and febrile neutropenia (Day 39)
Post baseline laboratory parameters grade ≥ 3
ALT or AST: none
Bilirubin: grade 3 in 1 patient (3-mg/kg cohort) on study Day 281 that resolved by the next cycle (not related to AMG 655 treatment)
Lipase: grade 3 in 3 patients (1 in the 3-mg/kg cohort; 2 in the 10-mg/kg cohort; elevations were asymptomatic)
No anti-AMG 655 antibodies have been detected to date

16. SAFETY: AMG 655 Pharmacokinetics
AMG 655 PK samples were collected before the AMG 655 infusion in Cycles 1, 2, 3, 5, and every 8 Cycles thereafter. They were also collected within 5 minutes before EOI and 48 h after the start of the AMG 655 infusion in Cycles 1 and 3.
Data shown are for both cohorts combined. EOI, end of infusion.

17. SAFETY: Oxaliplatin Pharmacokinetics
Oxaliplatin PK samples were collected on Day 1 of Cycles 1 and 3 before each infusion and within 5 minutes before the end of the oxaliplatin infusion.
Data shown are for the 3-mg/kg cohort only. EOI, end of infusion.

18. SAFETY: Bevacizumab Pharmacokinetics
Bevacizumab PK samples were collected on Day 1 of Cycles 1 and 3 before each infusion and within 5 minutes before the end of the bevacizumab infusion.
Data shown are for the 3-mg/kg cohort only. EOI, end of infusion.

19. SAFETY: Tumor Response
Median (range) time on AMG 655 treatment: 6.9 (1.6 to 11.4+) months
Time to progression in the 3 patients who progressed: 8, 42, 44 weeks
There were no deaths as of September 2008
*Unconfirmed partial response: patients underwent surgical resection prior to confirmation of response.
One patient in the 10-mg/kg cohort had no measurable disease at baseline.
A best response of stable disease required a radiologically determined response of stable disease or better no earlier than Study Day 49.
SLD, sum of longest diameter.

20. CONCLUSIONS
The addition of AMG 655 does not appear to substantially alter the safety profile of mFOLFOX6-bevacizumab
AMG 655 does not appear to affect the PK of oxaliplatin or bevacizumab
The randomized phase 2 part of the trial, mFOLFOX6-B with or without AMG 655, is in progress
Phase 2 Study Schema

21. REFERENCES Amgen data on file.
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22. ACKNOWLEDGMENT
We would like to thank Francesco Galimi for his contribution to this study and Kathryn Boorer for writing assistance.