Phase I/ II Study of MK-0646 Phase I/ II Study of MK-0646 (Dalotuzumab), A Humanized Monoclonal (Dalotuzumab), A Humanized Monoclonal Antibody Against IGF-1R in Combination Antibody Against IGF-1R in Combination

With Gemcitabine or Gemcitabine + With Gemcitabine or Gemcitabine + Erlotinib for Advanced Pancreatic CancerErlotinib for Advanced Pancreatic Cancer

DISCUSSANTDISCUSSANT

Philip Agop PhilipPhilip Agop Philip

Karmanos Cancer InstituteKarmanos Cancer Institute

Wayne State UniversityWayne State University

Detroit, MIDetroit, MI

Javle M, Varadhachary G, Shroff R, Bhosale P, Overman M, Weatherly J, Wolff RA, Abbruzzese J

Targeted Therapies in Pancreatic Cancer

• Several agents tested in combination with gemcitabine with no improvement in clinical outcome, except for a marginal benefit with erlotinib

• Multiple genetic and epigenetic abnormalities necessitate multi-targeted approaches and biomarker driven patient selection

Ghaneh, P. et al. Gut 2007;56:1134-1152; Jones et al, Science, September, 2008

Insulin-Like Growth Factor-1 Receptor Insulin-Like Growth Factor-1 Receptor (IGF1-R) Targeting in Pancreatic Cancer(IGF1-R) Targeting in Pancreatic Cancer

• Activation of IGF-1R induces cell proliferation, survival, angiogenesis and invasion in multiple cancers

• Targeting IGF-1R in pre-clinical models leads to tumor growth inhibition and may reverse drug resistance

• Single anti-IGF-1R agent +/- gemcitabine is unlikely to succeed, especially in an unselected patient population

Gualberto and Pollak, Oncogene, 28:3009-3021, 2009; Atzori et al, Targ Oncol, 4:255-266, 2009

Cross Talk and Cooperation between Cross Talk and Cooperation between EGFR and IGF-1R Signaling PathwaysEGFR and IGF-1R Signaling Pathways

• EGFR and IGF-1R may function as alternate signaling pathways evading tyrosine kinase inhibition of either receptor

• Dual EGFR/IGF-1R blockade in multiple cancer cell lines enhances anti-tumor activity of either drug with more sustained Akt inhibition and apoptosis

Morgillo et al, Clin Cancer Res, 13:2795-2803, 2007; Kaulfub et al, 8:821-33, 2009; Huang et al, Cancer Res, 69:161-70, 2009;

G 1000 mg/m2/100 min+

MK 5 mg/kg

G 1000 mg/m2/100 min+

MK 5 mg/kg

G 1000 mg/m2/100 min+

MK 10 mg/kg

G 1000 mg/m2/100 min+

MK 10 mg/kg

G 1000 mg/m2/100 min+

Erlotinib 100 mg +

MK 5 mg/kg

G 1000 mg/m2/100 min+

Erlotinib 100 mg +

MK 5 mg/kg

G 1000 mg/m2/100 min+

Erlotinib 100 mg +

MK 10 mg/kg

G 1000 mg/m2/100 min+

Erlotinib 100 mg +

MK 10 mg/kg

Javle et al:Javle et al:Study DesignStudy Design

Gemcitabine + MK 0646 Gemcitabine + Erlotinib + MK 0646

RR

GemcitabineMK 0646Erlotinib

GemcitabineMK 0646Erlotinib

GemcitabineMK 0646

GemcitabineMK 0646

GemcitabineErlotinib

GemcitabineErlotinib

Eligibility CriteriaEligibility Criteria

• Metastatic disease• PS 0 or 1• AST/ALT < 2.5 x ULN• No prior therapy

MTD of MK 0646MTD of MK 0646

+

Gemcitabine

+

Gemcitabine

Erlotinib*

MK 0646 10 mg/kg/wk 5 mg/kg/wk

DLT x 2

Dehydration

AST/ALT

*1/3 of patients discontinued Erlotinib because of toxicity

Non-Hematological Toxicities to Non-Hematological Toxicities to MK 0646 + Gemcitabine +/- ErlotinibMK 0646 + Gemcitabine +/- Erlotinib

(Grade 3 or 4)(Grade 3 or 4)

Toxicity %

ALT/ AST 14

Dehydration 3

Fatigue 18

Hypomagnesaemia 14

HyperglycemiaHyperglycemiaJavle et alJavle et al

MK 0646MK 0646

Philip et alPhilip et al

IMC-A12*IMC-A12*

% Grade 1 or 2 - 47

% Grade 3 or 4 18 14

% Pre-existing diabetes in grade > 2

- 37

Fasting blood glucose at entry

< 160 mg/dL

<

IULN

*Philip et al, Abstract 233, GI Symposium, 2010

Hyperglycemia in Targeting Hyperglycemia in Targeting IGF-1R in Pancreatic CancerIGF-1R in Pancreatic Cancer

• IGF-1R present on normal cells with 84% homology to insulin receptor

• Overlap between IGF-1R and insulin receptor when targeting IGF-1R

• Up to 40% of patients with pancreatic cancer have diabetes mellitus

Anti-Tumor Activity of MK Anti-Tumor Activity of MK 0646/Gemcitabine +/- Erlotinib0646/Gemcitabine +/- Erlotinib

N = 24N = 24

Objective response (%) 25

Response duration (weeks) 14 - 44+

Stable disease (%) 33

Progressive disease (%) 42

Median time to progression < 10 weeks

SWOG-0727 Study SchemaSWOG-0727 Study SchemaPhase I Phase II

IMC-A12Erlotinib

Gemcitabine

IMC-A12Erlotinib

Gemcitabine

Phase IIDose

Phase IIDose

IMC-A12Erlotinib

Gemcitabine

IMC-A12Erlotinib

Gemcitabine

ErlotinibGemcitabine

ErlotinibGemcitabine

RANDOMIZE

RANDOMIZE

Endpoint = PFSN = 45/106

Philip et al, #233, GI Symposium, January 23, 2010

N = 10

Are we ready to design a Are we ready to design a Phase III study of an anti-IGF-Phase III study of an anti-IGF-

1R in pancreatic cancer?1R in pancreatic cancer?

IRS

PI3K

Akt

mTOR

Ras

MEK

Raf1

IGF-1IGF-1

IGF-1R EGFR

IGFBPIGFBP

Biomarkers (Javle et al)Biomarkers (Javle et al)

PTEN

P P

Plasma IGF-1/IGFBP

Shc

ERK

IRS

PI3K

Akt

mTOR

Ras

MEK

Raf1

IGF-1IGF-1

IGF-1R EGFR

IGFBPIGFBP

Biomarkers (Javle et al)Biomarkers (Javle et al)

PTEN

P P

Plasma IGF-1/IGFBP

Shc

ERK

IRS

PI3K

Akt

mTOR

Ras

MEK

Raf1

IGF-1IGF-1

IGF-1R EGFR

IGFBPIGFBP

Biomarkers (Javle et al)Biomarkers (Javle et al)

PTEN

P P

Plasma IGF-1/IGFBP

SNPsIRS1SSTR5IGF1IGF2IGF1RIGF-2RIGFB3PI3KAktmTOR

SNPsIRS1SSTR5IGF1IGF2IGF1RIGF-2RIGFB3PI3KAktmTOR

Shc

ERK

IRS

PI3K

Akt

mTOR

Ras

MEK

Raf1

IGF-1IGF-1

IGF-1R EGFR

IGFBPIGFBP

Biomarkers (Javle et al)Biomarkers (Javle et al)

PTEN

P P

Plasma IGF-1/IGFBP

SNPsIRS1SSTR5IGF1IGF2IGF1RIGF-2RIGFB3PI3KAktmTOR

SNPsIRS1SSTR5IGF1IGF2IGF1RIGF-2RIGFB3PI3KAktmTOR

Shc?

EMTKRasPTENC-Met

src

?EMTKRasPTENC-Met

src

ERK

ConclusionsConclusions• Hyperglycemia may not be a dose Hyperglycemia may not be a dose

limiting toxicity to MK 0646limiting toxicity to MK 0646

• Too early to determine whether Too early to determine whether there is a signal for an anti-tumor there is a signal for an anti-tumor activityactivity

Developemnt of an Anti-IGF-1R Developemnt of an Anti-IGF-1R Strategy in Pancreatic CancerStrategy in Pancreatic Cancer

• Further preclinical Further preclinical andand clinical validation clinical validation of an IGF-1R based multi-targeted of an IGF-1R based multi-targeted strategy in pancreatic cancer must be strategy in pancreatic cancer must be undertakenundertaken

• Predictive biomarkers must be developed for patient selection and stratification

Are we ready to design a Are we ready to design a Phase III study of an anti-Phase III study of an anti-

IGF-1R in pancreas cancer?IGF-1R in pancreas cancer?

We need more data!We need more data!

JCO 27(33):5660-5669, 2009JCO 27(33):5660-5669, 2009