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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).

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Vall d’Hebron University Hospital, Barcelona, Spain 1

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  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

  2. The IGF-1R signaling pathway

  3. 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. 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.

  4. 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 AKT PTEN IGF-1R TSC *Licensed from Pierre Fabre Medicament

  5. 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

  6. Phase I study of MK-0646 (P001) Study Design DLT assessment period Baseline MK-0646 at escalating doses 0 1 2 3 4 5 6 7 8 Week Tumor biopsy X X Skin biopsy X X X X CT/MRI X X X X X PET scan X X X X X X X X PK

  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.

  8. Phase I study of MK-0646 (P001) Demographics Tumor types • N: 53 • Age: median (range) • 57 (22-81) • Male/Female: • 26/27 • ECOG PS N, (%): • 0 21 (40%) • 130 (56%) • 2 (4%) • Prior treatments, N (%): • 0-1 5 (11%) • 2-3 18 (34%) • 3 29 (55%)

  9. Phase I study of MK-0646 (P001) Adverse Drug-related Events (ADEs) & DLTs *Infusion reaction at a dose of 15 mg/Kg **DLT at a dose of 5 mg/Kg ***Treated with oral antihyperglycemic agents

  10. Phase I study of MK-0646 (P001) PK profile MK-0646 Serum Clearance (mL/min/Kg) 400 350 300 250 200 150 100 50 0 Mean MK-0646 Serum Concentration* (g/mL) Dose (mg/Kg) Anti-tumor activity in xenograft models: 25 g/mL 0 24 48 72 96 120 144 168 2 3 4 Trough Weeks Time (hr), First Dose *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

  11. 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. eIF4-E IGF-1R pAKT pMAPK 300 200 100 0 -100 300 200 100 0 -100 300 200 100 0 -100 400 300 200 100 0 -100 N=23 p<0.001 N=18 p=0.201 N=22 p=0.006 N=23 p=0.032 Pre Post Pre Post Pre Post Pre Post pS6 Ki 67% TUNEL p4EBP-1 400 300 200 100 0 -100 200 100 0 -100 80 60 40 20 0 -20 30 20 10 0 -10 N=22 p=0.036 N=23 p=0.021 N=23 p=0.034 N=20 p=0.074 Pre Post Pre Post Pre Post Pre Post Phase I study of MK-0646 (P001) Tumor PD Biomarkers Statistical Analysis: Wilcoxon signed-rank test

  14. Phase I study of MK-0646 (P001) Tumor PD Biomarkers 400 300 200 100 0 -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. 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

  16. Phase I study of MK-0646 (P001) Antitumor activity & correlation with 18FDG-PET/CT

  17. 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%

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

  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)

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