F. Atzori 1 , J. Tabernero 1 , A. Cervantes 2 , M.L. Botero 1 , K. Hsu 3 , H. Brown 3 , W. Hanley 3 , T. Macarulla 1 , S. Rosello 2 , J. Baselga 1 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, Spain 1 Hospital Clínico Universitario, Valencia, Spain 2 Merck Research Laboratories, US 3 spital Clínico Universitario
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Vall d’Hebron University Hospital, Barcelona, Spain 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). - PowerPoint PPT Presentation
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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