1. 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)
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
Vall d’Hebron University Hospital, Barcelona, Spain1
Hospital Clínico Universitario, Valencia, Spain2
Merck Research Laboratories, US3
Hospital Clínico Universitario 1

2. The IGF-1R signaling pathway

3. Rationale for targeting IGF-1R in cancer
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.
1Pollak MN et al. Nat Rev Cancer 2004;4:505-18; 2Burtrum D et al. Cancer Res 2003;63: 3

4. Humanized IgG1 MAb against the IGF-1R: Kd ≈ 1 nM
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
MK-0646
IGF-1R
MK-0646
PI3K
PTEN
AKT
IGF-1R
TSC
*Licensed from Pierre Fabre Medicament 4

5. First in human study with MK-0646
Phase I study of MK-0646 (P001)
Study Objectives
First in human study with MK-0646
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 5

6. Phase I study of MK-0646 (P001) Study Design
DLT assessment period
Baseline
MK-0646
at escalating doses
Dose levels
MK-0646 (mg/Kg) 1
1.25 2
2.5 3 5 4 10 15 6 20
Week 1 2 3 4 5 6 7 8
Tumor biopsy X X
Skin biopsy X X X X
CT/MRI X X
PET scan X X X PK X X X X X X X X

7. 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. 7

8. Phase I study of MK-0646 (P001) Demographics
Tumor types N:
Age: median (range)
57 (22-81)
Male/Female:
26/27
ECOG PS N, (%):
(40%)
(56%)
2 (4%)
Prior treatments, N (%):
(11%)
(34%)
 (55%) 8

9. Adverse Drug-related Events (ADEs) & DLTs
Phase I study of MK-0646 (P001)
Adverse Drug-related Events (ADEs) & DLTs
Total patients (N=53)
All Grades
Grade 3
(DLT period)
(Beyond DLT period)
Hyperglycemia
6 (12%)
3*** (6%)
Chills
2 (4%)
Tumor pain
1 (2%)
1* (2%)
Purpura
1** (2%)
Nausea
Rash
Asthenia
Pyrexia
*Infusion reaction at a dose of 15 mg/Kg
**DLT at a dose of 5 mg/Kg
***Treated with oral antihyperglycemic agents 9

10. Anti-tumor activity in xenograft models: 25 g/mL
Phase I study of MK-0646 (P001)
PK profile
MK-0646 Serum Clearance (mL/min/Kg)
400
350
300
250
200
150
100 50
Mean MK-0646 Serum Concentration* (g/mL)
Dose (mg/Kg)
Anti-tumor activity in xenograft models: 25 g/mL
Time (hr), First Dose
Trough Weeks
*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 10

11. the first/multiple weekly 5.0 mg/Kg and 10 mg/Kg
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

12. Phase I study of MK-0646 (P001)
Tumor PD Biomarkers

13. Phase I study of MK-0646 (P001) Tumor PD Biomarkers
IGF-1R
p<0.001
N=23
pMAPK
pAKT
eIF4-E
N=18
p=0.201
N=22
p=0.006
p=0.032
Pre
Post
400
300
200
100
-100
p4EBP-1
pS6
Ki 67%
TUNEL
N=22
p=0.036
N=23
p=0.021
p=0.034
N=20
p=0.074
Pre
Post 80 60 40 20
-20 30 10
-10
400
300
200
100
-100
Statistical Analysis: Wilcoxon signed-rank test

14. Phase I study of MK-0646 (P001) Tumor PD Biomarkers
400
300
200
100
-100
IGF-1R
IGF-1R
5 mg/Kg
N=5
10 mg/Kg
N=3
15 mg/Kg
N=8
20 mg/Kg
N=5
Pre-treatment
Post-treatment

15. Mean IGF-1 plasma levels with MK-0646
Phase I study of MK-0646 (P001)
Mean IGF-1 plasma levels with MK-0646
Ratio: 2.5
Ratio: 3.2
Ratio: 2.28
ng/mL
Baseline
Week 2
N=3
N=4
N=9 15

16. Antitumor activity & correlation with 18FDG-PET/CT
Phase I study of MK-0646 (P001)
Antitumor activity & correlation with 18FDG-PET/CT
Tumor
Clinical response
(RECIST) and stable disease 12 weeks (wk)
Metabolic (m) response
(EORTC criteria)
At week 3
Cholangiocarcinoma
SD (24 wk)
mSD
SUV max 38.3  38.8 (ratio: 1.01)
Target SUV 10  9 (ratio: 0.9)
Adenocarcinoma of unknown origin
SD (16 wk)
mPR
SUV max 60.9  33.7 (ratio: 0.55)
Target SUV 16.5  7 (ratio: 0.42)
Ewing’s sarcoma
Mixed response
SUV max 7369.5 (ratio: 0.95)
Target SUV 16  18 (ratio: 1.12)
Melanoma
SD (13 wk)
SUV max 192177.5 (ratio: 0.92)
Target SUV 47  40 (ratio: 0.85)
Neuroendocrine tumor
Minor response (<30%)
No baseline 18FDG uptake 16

17. Metabolic activity & correlation with PD changes
Phase I study of MK-0646 (P001)
Metabolic activity & correlation with PD changes
Pre-treatment
8 weeks of treatment
PT-1044
Melanoma
(15 mg/Kg)
18FDG-PET/CT
SUV max 38 g/mL
SUV max 38 g/mL
SUV max 25 g/mL
Pre-treatment
2 weeks of treatment
IHC
Ki67
H-score 30%
H-score 5% 17

18. Phase I study of MK-0646 (P001) Clinical Activity
PT -1029
Ewing
(15 mg/Kg)
Pre-treatment
7 weeks on treatment 18

19. 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/Kg
All 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) 19