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)
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 MeetingVenice, Italy
4 November 2006
CTOS 20062
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 malignanciesHerbst R et al. Eur J Cancer. 2005;3(Suppl):1455.
Rosen L et al. Proc ASCO. 2005. Abstract 3013.
N NH
NH
O
NH
N
CTOS 20063
AMG 706 Selectively Targets Multiple Receptor Tyrosine Kinases Involved in Angiogenesis
aStem cell factor
CTOS 20064
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
CTOS 20065
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
CTOS 20066
Study Design and Treatment Regimen
SCREENING
AMG 706 125 mg po daily7 Day
imatinibWashout
Screening /Baseline
CT
Day 1Start
AMG 70618FDG-PET
8 WkCT
FDG-PET
16 WKCT
24 WKCT
32 WKCT
Q 8 WksThereafter
CT
48 wks off studya
Responders andstable diseasemay continueAMG 706 infollow-upprotocol
aAll subjects are followed for survival for up to 2 years following last AMG 706
CTOS 20067
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
CTOS 20068
Baseline Demographics and Clinical Characteristics
All Patients
N = 138
Men, n (%) 84 (61)
Age
Median (min, max), years≥ 65 years, n (%)
61 (25, 90)54 (39)
Karnofsky performance, n (%)
100 90 80 70 60
33 (24)63 (46)22 (16)14 (10)
6 (4)
Prior chemotherapy other than imatinib, n (%)
None1 regimen≥ 2 regimens
117 (85)11 (8)10 (7)
Prior radiotherapy, n (%)
None 132 (96)
CTOS 20069
Prior Imatinib Therapy
All Patients
N = 138
Duration of first imatinib therapy, n (%)
≤ 6 months> 6 months
34 (25)104 (75)
Duration of last imatinib therapy, n (%)
≤ 6 months> 6 months
88 (64)50 (36)
Total duration of imatinib therapy, monthsmedian (min, max) 32.5 (4.1, 57.3)
Best response to most recent imatinib, n (%)
Complete responsePartial responseStable diseaseProgressive disease
4 (3)48 (35) 39 (28)47 (34)
CTOS 200610
Maximal Dose of Prestudy Imatinib
All Patients
N = 138
Highest imatinib dose administered, n (%)
800 mg 108 (78)
600 mg 21 (15)
1000 mg 4 (3)
1200 mg 3 (2)
1100 mg 1 (1)
700 mg 1 (1)
CTOS 200611
Patient Disposition
All Patients
N = 138
Completed planned AMG 706 administration (48 wks), n (%) 10 (7)
Discontinued AMG 706 administration (< 48 wks), n (%)
Disease progressionAdverse eventConsent withdrawnDeathAdministrative decisionProtocol deviationOther
128 (93)
83 (60)31 (22)
6 (4)3 (2)1 (1)1 (1)3 (2)
Weeks of AMG 706 treatment
median (min, max) 16 (0.3, 52.0)
CTOS 200612
Best Tumor Response by RECIST per Independent Review: Per-Protocol Analysis Seta
All Patients
N = 120
Confirmed RECIST response, n (%) 3 (3)
95 % CI 0.5, 7.1
Confirmed complete response (CR), n (%)Confirmed partial response (PR), n (%)
0 (0)3 (3)
Stable disease (SD ≥ 52 days), n (%) 55 (46)
Durable stable disease (SD ≥ 22 weeks), n (%) 29 (24)
Progressive disease (PD), n (%) 39 (33)
Unevaluable, n (%) 5 (4)
Not performed, n (%) 18 (15)
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.
CTOS 200613
Objective Response by 18FDG-PETa at Week 8 per Independent Review: Per-Protocol Analysis Set
Evaluableb
N = 89All Patients
N = 120
Objective response, n (%)
95% CI
27 (30)
21.0, 41.0
27 (23)
15.4, 31.0
Non-response, n (%)
95% CI
62 (70)
59.0, 79.0
93 (78)
69.0, 84.6
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.
CTOS 200614
Objective Response by 18FDG-PET
Screening: 21 June 05 Week 8: 24 August 05
CTOS 200615
Objective Response by Choi Criteriaa at Week 8 per Independent Review: Per-Protocol Analysis Set
Evaluableb
N = 97All Patients
N = 120
Objective response, n (%)
95% CI
39 (40)
30.3, 50.7
39 (33)
24.2, 41.7
Non-response, n (%)
95% CI
58 (60)
49.4, 69.6
81 (68)
58.3, 75.8
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).
CTOS 200616
Objective Response by Choi Criteria at Week 8
Baseline Week 8
HU = 141.4 HU = 89.8
CTOS 200617
Best Response in Tumor Measurement by CT (per RECIST) per Independent Review: Per-Protocol Analysis Set
0
20
-20
40
-40
60
-60
80
-80
100
-100
Max
imu
m P
erce
nt
Ch
ang
e in
SL
D
Change from baseline between -30% and -9%
< 2% change from baseline
RECIST
Choi criteria
Subject
Overall Best Response (RECIST)
Missing Partial ResponseStable Disease Progressive Disease
SLD = sum of longest diameters oftarget tumor lesions
CTOS 200618
Progression-Free Survival (PFS) per Independent Review: Per-Protocol Analysis Set
(N) 120 111 92 60 50 42 34 23 19 14 11 7 6 1 1 0
Kap
lan
-Mei
er P
erce
nt
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Weeks
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
K-M estimate (95% CI) of 26-week PFS: 27% (19%, 36%)K-M median time (95% CI), weeks: 16 (10, 23)Number of PFS events: 90 (75%)
95% confidence intervals of the Kaplan-Meier estimate at Week 16, Week 32 and Week 48 are presented. = Censored observation
CTOS 200619
Survival: Per-Protocol Analysis Set
(N) 120 117 114 107 102 97 93 88 80 77 70 62 60 51 40 31 23 17 11 4 3 3 0
95% confidence intervals of the Kaplan-Meier estimate at Week 16, Week 32 and Week 48 are presented. = Censored observation
Kap
lan
-Mei
er P
erce
nt
0%
10% 20%
30% 40%
50%
60% 70%
80% 90%
100%
Weeks0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88
K-M median time (95% CI), weeks: 59.3 (49.3, NE)Number of deaths: 56 (47%)
CTOS 200620
Pharmacokinetic Profiles (Day 1)
Parameter No GastrectomyPartial or Full Gastrectomy
n Mean (SD) n Mean (SD)
tmax (hr)* 180.5
(0.25, 2.0)8
0.75(0.25, 4.0)
Cmax (ng/mL) 18 572 (175) 8 581 (284)
AUC0-24 (μg•hr/mL) 12 3.03 (1.94) 7 2.81 (1.37)
AUC0- (μg•hr/mL) 12 3.28 (2.23) 7 3.08 (1.47)
t1/2, z (hr) 12 5.80 (1.61) 7 6.77 (2.33)
CL/F (L/hr) 12 54.1 (36.4) 7 59.6 (55.0)
C24 (ng/mL) 12 24.8 (27.6) 7 25.5 (13.6)
• 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).
*Median (range)Time (hr)
0 4 8 12 16 20 24A
MG
70
6 P
las
ma
Co
nc
. (n
g/m
L)
1
10
100
1000
10000
No Gastrectomy (n = 18)Partial or Full Gastrectomy (n = 8)
CTOS 200621
Treatment-Emergent Adverse Events Occurring in at Least 15% of Patients
All PatientsN = 138
Grade 3 Grade 4
Diarrhea 76 (55) 10 (7) 0
Hypertension 66 (48) 31 (22) 1 (1)a
Fatigue 62 (45) 17 (12) 0
Nausea 48 (35) 5 (4) 0
Headache 47 (34) 5 (4) 0
Abdominal Pain 44 (32) 14 (10) 0
Anorexia 42 (30) 10 (7) 0
Vomiting 41 (30) 7 (5) 0
Weight decrease 37 (27) 6 (4) 0
Constipation 33 (24) 2 (1) 0
Dysphonia 27 (20) 0 0
Asthenia 23 (17) 7 (5) 0
Dizziness 22 (16) 2 (1) 0
Insomnia 21 (15) 1 (1) 0
Data are n (%)aReversible posterior leukoencephalopathy syndrome
CTOS 200622
Adverse Events of Interest
All PatientsN = 138
Grade 3 Grade 4 Grade 5
Hemorrhage 14 (10) 5 (4) 1 (1) 0
Thromboembolic eventsa 10 (7) 2 (1) 4 (3) 1 (1)
Cardiac disordersa 5 (4) 1 (1) 2 (1) 1 (1)
Hypothyroidismb 3 (2) 1 (1) 0 0
Impaired wound healing 2 (1) 1 (1) 0 0
Cholecystitis 1 (1) 0 0 0
Pancreatitis 1 (1) 1 (1) 0 0
Data are n (%)aTwo patients experienced both a thromboembolic event and a cardiac disorderbPatients were not monitored with serial TSH levels during the study
CTOS 200623
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.
CTOS 200624
AcknowledgementsAll of the participating patients and their families
To the global network of investigators, research nurses, study coordinators, and operations staff
North America
Europe
Amgen, Inc. (Sponsor)
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)
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
Participating Investigators (Number of Patients Enrolled)
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