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Phase I/ II Study of MK-0646 (Dalotuzumab), A Humanized Monoclonal Antibody Against IGF-1R in Combination With Gemcitabine or Gemcitabine + Erlotinib for Advanced Pancreatic Cancer. Javle M , Varadhachary G, Shroff R, Bhosale P, Overman M, Weatherly J, Wolff RA, Abbruzzese J. DISCUSSANT - PowerPoint PPT Presentation
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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