INTRODUCTION

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ASCO-GI 2009 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 Fuchs 8 1 Memorial Sloan Kettering Cancer Center, New York, NY; 2 Sarah Cannon Cancer Center, Nashville, TN; 3 West Clinic, Memphis, TN; 4 Cancer Center of the Carolinas, Greenville, SC; 5 University of Miami, Miami, FL; 6 Amgen Inc., Thousand Oaks, CA; 7 Amgen Ltd, Cambridge, UK; 8 Dana-Farber Cancer Institute, Boston, MA

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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). - PowerPoint PPT Presentation

Transcript of INTRODUCTION

Page 1: INTRODUCTION

ASCO-GI 2009

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

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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

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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

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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

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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

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PATIENTS AND METHODS: Phase 1b Study Schema

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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 infusion2. Then 5-FU (400 mg/m2) IV bolus for 2 to 4 minutes3. Then bevacizumab 5 mg/kg IV for 10 to 30 minutes4. Then AMG 655 IV for 60 minutes5. 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

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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

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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

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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 toAMG 655 or AMG 655 + mFOLFOX6/bevacizumab

• Any other grade ≥ 3 hematologic or non-hematologic toxicity felt to be related to AMG 655 or AMG 655 + mFOLFOX6/bevacizumab

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RESULTS

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

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RESULTS: Baseline Demographics and Disease Characteristics

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RESULTS: Patient Disposition

aPatient underwent resection.bPatient reached maximum clinical benefit according to the investigator.

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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).

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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

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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.

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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.

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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.

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SAFETY: Tumor Response

*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.

• 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

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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 randomizedphase 2 part of thetrial, mFOLFOX6-Bwith or withoutAMG 655, is inprogress

Phase 2 Study Schema

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REFERENCES

1. Amgen data on file.

2. Amgen data on file.

3. LoRusso P, et al. J Clin Oncol. 2007;25(18S):abstr 3534.

4. Ghobrial IM, et al. CA Cancer J Clin. 2005;55:178-194.

5. Ashkenazi A. Nat Rev Cancer. 2002;2:420-430.

6. Gan HK, et al. Cancer Chemother Pharmacol. 2006;58:157-164.

7. Lévi F, et al. Clin Pharmacokinet. 2000;38:1-21.

8. Lu JF, et al. Cancer Chemother Pharmacol. 2008;62:779-786.

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ACKNOWLEDGMENT

• We would like to thank Francesco Galimi for his contribution to this study and Kathryn Boorer for writing assistance.


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