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CTOS Meeting Venice, Italy 4 November 2006

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Initial Results of a Multicenter, Single-Arm Phase 2 Study of AMG 706, an Oral Multikinase Inhibitor, for the Treatment of Advanced Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST).

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Initial Results of a Multicenter, Single-Arm Phase 2 Study of AMG 706, an Oral Multikinase Inhibitor, for the Treatment of Advanced Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST)

Robert Benjamin, Patrick Schöffski, Jörg Thomas Hartmann, Binh Nguyen Bui, Justus Duyster, Scott Schuetze, Jean-Yves Blay, Peter Reichardt, Lee Rosen, Keith Skubitz, Michael Eschenberg, Daniel Stepan, and Laurence Baker

On behalf of the study investigators

CTOS Meeting

Venice, Italy

4 November 2006

amg 706 an oral multi targeted kinase inhibitor
AMG 706: An Oral Multi-targeted Kinase Inhibitor
  • A novel, orally bioavailable, small-molecule multikinase inhibitor
  • Has shown both antiangiogenic and direct antitumor activity in a phase 1 clinical trial in patients with advanced solid tumor malignancies

Herbst R et al. Eur J Cancer. 2005;3(Suppl):1455.

Rosen L et al. Proc ASCO. 2005. Abstract 3013.

amg 706 selectively targets multiple receptor tyrosine kinases involved in angiogenesis
AMG 706 Selectively Targets Multiple Receptor Tyrosine Kinases Involved in Angiogenesis

aStem cell factor

study objectives
Study Objectives

Primary

Evaluate the effect of treatment with AMG 706 on the objective response rate (by RECIST) in patients with advanced GIST who developed progressive disease or relapsed while receiving imatinib

  • Secondary
  • Assess effect of AMG 706 on duration of response, progression-free survival, time to progression, survival, and adverse events
  • Explore the utility of 18FDG-PET and target tumor size/density changes (Choi criteria) for predicting tumor response
  • Assess the pharmacokinetic profiles of AMG 706
main eligibility criteria
Main Eligibility Criteria
  • Histologically confirmed GIST expressing CD117
  • Documented failure of prior treatment with imatinib
    • At least 600 mg daily for at least 8 weeks
    • Disease progression per 2 independently assessed pre-study radiographic scans within 6 months of study day 1
  • Imatinib treatment terminated at least 7 days before study day 1
  • Presence of at least one measurable (per RECIST) and progressing tumor lesion not previously treated with radiotherapy or embolization and evaluable by CT or MRI
  • Adequate organ function
study execution
Study Execution
  • International, multicenter study at 29 sitesa
    • Participating countries (number of patients)
      • USA (64)
      • Germany (34)
      • France (20)
      • Belgium (10)
      • Canada (6)
      • Italy (2)
      • United Kingdom (2)
  • Study accrued 138 patients within 10 months
    • October 2004 to July 2005

aScreened one or more patients

best tumor response by recist per independent review per protocol analysis set a
Best Tumor Response by RECIST per Independent Review: Per-Protocol Analysis Seta

aIncludes all subjects who received at least one administration of AMG 706 and who were classified as

having pre-study disease progression (per RECIST) per independent review.

objective response by 18 fdg pet a at week 8 per independent review per protocol analysis set
Objective Response by 18FDG-PETa at Week 8 per Independent Review: Per-Protocol Analysis Set

aDefined as > 25% decrease in average standardized uptake value (SUVmax) in all RECIST target lesions compared with the average SUVmax in all RECIST target lesions at baseline as measured by the independent reviewer.

bAll patients with a baseline and week 8 18FDG-PET scan. Does not include patients who discontinue study prior to week 8, even if discontinuation is due to clinical progression.

objective response by 18 fdg pet
Objective Response by 18FDG-PET

Screening: 21 June 05

Week 8: 24 August 05

objective response by choi criteria a at week 8 per independent review per protocol analysis set
Objective Response by Choi Criteriaa at Week 8 per Independent Review: Per-Protocol Analysis Set

aDefined as ≥ 10% decrease in the sum of the longest diameter of the target lesions (identified by RECIST) and/or ≥ 15% decrease in the average target tumor density (in Hounsfield units, HU) using the RECIST target lesions compared with the average baseline density based on CT scans.

bAll patients with both baseline and week 8 measures of the sum of the longest diameters (SLD) or tumor density (in HU).

objective response by choi criteria at week 8
Objective Response by Choi Criteria at Week 8

HU = 141.4

HU = 89.8

Baseline

Week 8

slide17
Best Response in Tumor Measurement by CT (per RECIST) per Independent Review: Per-Protocol Analysis Set
pharmacokinetic profiles day 1
Pharmacokinetic Profiles (Day 1)

*Median (range)

  • Day 1 PK profiles of AMG 706 were similar in patients with partial or full gastrectomy and
  • in patients without gastrectomy.
  • PK profiles of AMG 706 were similar in patients with GIST and in patients with solid tumors (first-in-human study).
treatment emergent adverse events occurring in at least 15 of patients
Treatment-Emergent Adverse Events Occurring in at Least 15% of Patients

Data are n (%)

aReversible posterior leukoencephalopathy syndrome

adverse events of interest
Adverse Events of Interest

Data are n (%)

aTwo patients experienced both a thromboembolic event and a cardiac disorder

bPatients were not monitored with serial TSH levels during the study

conclusions
Conclusions
  • AMG 706 demonstrated an encouraging clinical benefit rate in study patients with advanced high-dose imatinib-resistant GIST:
    • Choi response rate of 33% (40% of evaluable patients)
    • PET response rate of 23% (30% of evaluable patients)
    • PR (3%) + durable SD ≥ 22 weeks (24%) of 27%
    • Median progression-free survival of 16 weeks
    • 26-week progression-free survival of 27%
    • Median survival of 59%
  • AMG 706 was reasonably well tolerated with rare incidence of grade 3/4 adverse events except hypertension.
  • Further studies of AMG 706 in GIST appear warranted.
acknowledgements all of the participating patients and their families
AcknowledgementsAll of the participating patients and their families

To the global network of investigators, research nurses, study coordinators, and operations staff

Participating Investigators (Number of Patients Enrolled)

North America

Europe

B Benjamin (14), S Schuetze and L Baker (10), L Rosen (7), K Skubitz (6), D Mahadevan (5), M Fanucchi (5), R Tozer (4), EG Chiorean (3), E Borden (3), A Staddon (2),A Evens (2), R Taub (2), M von Mehran (2), K Mulder (2), B Brockstein (1), A Elias (1), S Chawla (1)

JT Hartmann (12),P Schöffski and AT van Oosterom (10), BN Bui (10), J Duyster (10), JY Blay (7), P Reichardt (7), M Flasshove and T Ebeling (5), A Le Cesne (3), I Judson (2), P Casali (1), M Marangolo (1)

Amgen, Inc. (Sponsor)

D Stepan, D Reese, M Eschenberg, Y-N Sun, A Koutsoukos, M MacDonald, W Lovelace, K Aitchison, C Puzo, S Creamer, J Wright, T Juan

Radiology Review

RadPharm