vall d’hebron university hospital, barcelona, spain 1
DESCRIPTION
A phase I pharmacokinetic and pharmacodynamic study of weekly MK-0646, an Insulin Like Growth Factor-1 Receptor (IGF-1R) monoclonal antibody in patients with advanced solid tumors (Study P001). - PowerPoint PPT PresentationTRANSCRIPT
F. Atzori1, J. Tabernero1, A. Cervantes2, M.L. Botero1, K. Hsu3, H. Brown3, W. Hanley3, T. Macarulla1, S. Rosello2, J. Baselga1
for the study group
A phase I pharmacokinetic and pharmacodynamic study of weekly MK-0646, an Insulin Like Growth
Factor-1 Receptor (IGF-1R) monoclonal antibody in patients with advanced solid tumors (Study P001)
Vall d’Hebron University Hospital, Barcelona, Spain1
Hospital Clínico Universitario, Valencia, Spain2
Merck Research Laboratories, US3
Hospital Clínico Universitario
The IGF-1R signaling pathway
Rationale for targeting IGF-1R in cancer
1Pollak MN et al. Nat Rev Cancer 2004;4:505-18; 2Burtrum D et al. Cancer Res 2003;63:8912-21.
― IGF-1R is overexpressed/upregulated in a variety of human malignancies1.
― IGF-1R promotes cell growth, inhibits apoptosis, and regulates cell adhesion and motility1.
― Preclinical evidence of anti-cancer activity2.
IGF-1R
MK-0646
MK-0646
IGF-1R
PI3K
PTEN AKT
TSC
MK-0646*
Humanized IgG1 MAb against the IGF-1R:
― Kd ≈ 1 nM
― Blocks IGF-1 and IGF-2 mediated cellular
proliferation
― Potential to elicit ADCC activity in vivo
― Does not bind to the insulin receptor
*Licensed from Pierre Fabre Medicament
Phase I study of MK-0646 (P001)Study Objectives
• Primary:
― Determine the safety and pharmacokinetics (PK) of
MK-0646 administered I.V. weekly
• Secondary:
― Assess changes in molecular markers of the IGF-1R pathway in serial tumor and skin biopsies to determine the pharmacodynamic (PD) effects of the MK-0646
― Clinical activity (RECIST criteria)
― Assess tumor metabolism using 18FDG-PET/CT
First in human study with MK-0646
DLT assessment period
MK-0646at escalating doses
Bas
elin
e
Dose levels
MK-0646 (mg/Kg)
1 1.25
2 2.5
3 5
4 10
5 15
6 20
Skin biopsy
CT/MRI
PK
X
X
X
X X
Week 1 2 3 4 5
XX
Tumor biopsy X X
PET scan
X
0
X
X
X X
6 7 8
X
X X X
X
Phase I study of MK-0646 (P001)Study Design
Phase I study of MK-0646 (P001) Eligibility Criteria
― Histologically confirmed IGF-1R expressing tumors
( 10%) with measurable disease.
― Age 18 ECOG PS 2.
― 4 weeks since prior anti-cancer therapy or irradiation.
― No CNS primary tumors or CNS metastasis, HIV,
Hepatitis, CHF.
― Baseline fasting glucose 150 mg/dL.
― Diabetic patients with HbA1C within the past
month of <8%.
― Conserved hematological, renal and liver function.
Phase I study of MK-0646 (P001)
Demographics
ECOG PS N, (%):
0 21 (40%)
1 30 (56%)
2 2 (4%)
Prior treatments, N (%):
0-1 5 (11%)
2-3 18 (34%)
3 29 (55%)
Tumor typesN: 53
Age: median (range)
57 (22-81)
Male/Female:
26/27
11
2
2
2
2
4
6
11
13
Others
Unknown Origin
Cholangiocarcinoma
Bone Sarcoma
Melanoma
Ovarian
Ewing Sarcoma
Breast Cancer
Colorectal
Phase I study of MK-0646 (P001)Adverse Drug-related Events (ADEs) & DLTs
**DLT at a dose of 5 mg/Kg
Total patients (N=53)
All Grades Grade 3
(DLT period)
Grade 3
(Beyond DLT period)
Hyperglycemia 6 (12%) 0 3*** (6%)
Chills 2 (4%) 0 2 (4%)
Tumor pain 1 (2%) 1* (2%) 0
Purpura 1 (2%) 1** (2%) 0
Nausea 1 (2%) 0 1 (2%)
Rash 1 (2%) 0 1 (2%)
Asthenia 1 (2%) 0 1 (2%)
Pyrexia 1 (2%) 0 1 (2%)
***Treated with oral antihyperglycemic agents
*Infusion reaction at a dose of 15 mg/Kg
Time (hr), First Dose
0 24 48 72 96 120 144 168
MK
-06
46
Se
rum
Co
nc
en
tra
tio
n ( g
/mL
)
0
50
100
150
200
250
300
350
400
target vs Col 25 1.25 mg/kg 2.5 mg/kg 5.0 mg/kg 10.0 mg/kg 15.0 mg/kg
Trough Weeks
2 3 4
Trough Target
1.25 mg/kg 2.5 mg/kg 5.0 mg/kg 10.0 mg/kg
0 24 48 72 96 120 144 168
1
10
100
1000
15.0 mg/kg
*For first Dose: N=5, 1.25 mg/kg; N=3, 2.5 mg/kg; N=8, 5.0 mg/kg; N=6, 10 mg/kg; N=6, 15 mg/kg
Phase I study of MK-0646 (P001) PK profile
Anti-tumor activity in xenograft
models: 25 g/mL
Me
an
MK
-06
46
Se
rum
Co
nc
en
tra
tio
n*
(g
/mL
)
Dose (mg/kg)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16MK
-06
46 S
eru
m C
lea
ran
ce
(m
L/m
in/k
g)
0.000
0.005
0.010
0.015
0.020MK-0646 Serum Clearance (mL/min/Kg)
Time (hr), First Dose
400
350
300
250
200
150
100
50
00 24 48 72 96 120 144 168
Trough Weeks 2 3 4
Dose (mg/Kg)
Time (hr), First Dose
0 24 48 72 96 120 144 168
MK
-06
46
Ser
um
Co
nc
en
tra
tio
n ( g
/mL
)
0
20
40
60
80
100
120
140
160
180
200
AN109AN110AN111AN112AN113AN114AN115AN151
Trough Weeks
2 3 4
0 24 48 72 96 120 144 168
10
100
Trough Target
Time (hr), First Dose
0 24 48 72 96 120 144 168
MK
-06
46
Se
rum
Co
nc
entr
ati
on
( g
/mL
)
0
50
100
150
200
250
300
AN116AN117AN118AN119AN120AN152
Trough Weeks
2 3 4
0 24 48 72 96 120 144 168
10
100
Trough Target
Phase I study of MK-0646 (P001) PK profile
Individual serum concentrations for MK-0646 following administration of the first/multiple weekly 5.0 mg/Kg and 10 mg/Kg
5.0 mg/Kg/wk 10 mg/Kg/wk
Phase I study of MK-0646 (P001) Tumor PD Biomarkers
Phase I study of MK-0646 (P001) Tumor PD Biomarkers
IGF-1Rp<0.001N=23
pMAPKpAKT eIF4-EN=18 p=0.201 N=22 p=0.006 N=23 p=0.032
Pre Pre Pre PrePost Post Post Post
400
300
200
100
0
-100
300
200
100
0
-100
300
200
100
0
-100
300
200
100
0
-100
p4EBP-1 pS6 Ki 67% TUNELN=22 p=0.036 N=23 p=0.021 N=23 p=0.034 N=20 p=0.074
Pre Pre Pre PrePost Post Post Post
80
60
40
20
0
-20
30
20
10
0
-10
400
300
200
100
0
-100
200
100
0
-100
Statistical Analysis: Wilcoxon signed-rank test
Phase I study of MK-0646 (P001) Tumor PD Biomarkers
IGF-1R
Pre-treatment Post-treatment
5 mg/Kg
N=5
10 mg/Kg
N=3
15 mg/Kg
N=8
20 mg/Kg
N=5
400
300
200
100
0
-100
IGF-1R
0
100
200
300
400
500
600
10 mg/Kg 15 mg/Kg 20 mg/Kg
Phase I study of MK-0646 (P001)Mean IGF-1 plasma levels with MK-0646
Baseline
Week 2
Ratio: 2.5
Ratio: 2.28Ratio: 3.2
ng
/mL
N=3 N=4 N=9
Phase I study of MK-0646 (P001)Antitumor activity & correlation with 18FDG-PET/CT
TumorClinical response
(RECIST) and stable disease 12 weeks (wk)
Metabolic (m) response (EORTC criteria)
At week 3
Cholangiocarcinoma SD (24 wk)mSDSUV max 38.3 38.8 (ratio: 1.01)Target SUV 10 9 (ratio: 0.9)
Adenocarcinoma of unknown origin
SD (16 wk)mPRSUV max 60.9 33.7 (ratio: 0.55)Target SUV 16.5 7 (ratio: 0.42)
Ewing’s sarcoma Mixed responsemSDSUV max 7369.5 (ratio: 0.95) Target SUV 16 18 (ratio: 1.12)
Melanoma SD (13 wk)mSDSUV max 192177.5 (ratio: 0.92)Target SUV 47 40 (ratio: 0.85)
Neuroendocrine tumor
Minor response (<30%) No baseline 18FDG uptake
Phase I study of MK-0646 (P001)
Metabolic activity & correlation with PD changes
Pre-treatment 8 weeks of treatment
Pre-treatment 2 weeks of treatment
H-score 30% H-score 5%
IHCKi67
PT-1044Melanoma (15 mg/Kg)
18FDG-PET/CT
SUV max 38 g/mLSUV max 38 g/mL SUV max 25 g/mL
Phase I study of MK-0646 (P001) Clinical Activity
Pre-treatment 7 weeks on treatment
PT -1029
Ewing
(15 mg/Kg)
Phase I study of MK-0646 (P001) Summary & Conclusions
― Single agent weekly anti IGF-1R MAb MK-0646 is well tolerated. MTD has not been reached at a dose of 20 mg/Kg/wk
― Hyperglycemia, the most common side effect, is well controlled with oral antihyperglycemic agents without interfering with MK-0646 dosing
― MK-0646 seems to exhibit a dose proportional PK behavior at dose levels >2.5 mg/KgAll patients treated at doses 10 mg/Kg/wk had trough levels above target concentration
― MK-0646 treatment resulted in inhibition of PD endpoints, in particular downregulation of IGF-1R expression in tumor
― Plasma IGF-1 increases were seen following MK-0646 treatment at doses 10 mg/Kg/wk independent of dose administered
― These results suggest 10mg/Kg as the weekly recommended dose of MK-0646 for further evaluation
― PK findings support a more extended dose interval currently under study (q2w and q3w)