N0733_YouTubev3

N0733: Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 in Patients with HER2 Positive, Breast Cancer Previously Treated with Trastuzumab and an Anthracycline and/or a Taxane : 

N0733: Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 in Patients with HER2 Positive, Breast Cancer Previously Treated with Trastuzumab and an Anthracycline and/or a Taxane NCCTG PI: Paul Haluska MD, PhD SWOG PI: Hannah Linden MD

Rationale of N0733 : 

Camirand, A., et al Med Sci Monit, 8: BR521-526, 2002. Lu, Y., et al J Natl Cancer Inst, 93: 1852-1857, 2001. Haluska P et al. Mol Cancer Ther. 2008 Sep;7(9):2589-98 Rationale of N0733 Bidirectional ‘crosstalk’ occurs between IGF-1R and erbB receptors, including HER2 Breast Ca cells transfected with IGF-1R become resistant to trastuzumab IGF-1R expression in patients treated with lapatinib/capecitabine IGF-1R inhibition-increased HER expression and activation IGF/HER targeted combinations Synergy see with multiple agents Multiple tumor models, including breast.

Enhanced apoptosis is mechanism of synergy for combined IGF/HER inhibition : 

Enhanced apoptosis is mechanism of synergy for combined IGF/HER inhibition OV202 SKOV3.ip1 OV202 SKOV3.ip1 IGF Inhibition HER2 Inhibition Combo Vehicle IGF Blockade HER Blockade Combo Haluska P et al. Mol Cancer Ther. 2008 Sep;7(9):2589-98

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Activated erbB receptors sufficient for resistance to IGF Blockade Haluska P et al. Mol Cancer Ther. 2008 Sep;7(9):2589-98

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IGF-1 Ligand IGF-2 Ligand Basics of IGF-1R Signaling IGF-1R

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IGF-1 Ligand IGF-2 Ligand Basics of IGF-1R Signaling IGF-1R

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Proliferation/ Pro-survival IGF-1 Ligand IGF-1R HER2 Lapatinib IGF signaling can overcome HER2 blockade

Rationale for Study : 

Rationale for Study Lapatinib + an IGF-1R inhibition block major know mechanisms of resistance to trastuzumab. PI3K/Akt MAPK EGF EGFR HER2 HRG HER3 HER2 p95 IGF-1 IGF-1R Adapted Nahta and Esteva, Oncogene 2007, 26:3637. trastuzumab ECD

N0733: Study Design : 

CPxxxxxxx-9 N0733: Study Design NCCTG SWOG CTSU …the Randomized Portion was preceded by a Safety Cohort of the Three-Drug Combination

Inclusion Criteria : 

CPxxxxxxx-10 Inclusion Criteria HER2 + Breast Cancer- locally advanced or metastatic Previous trastuzumab If received in adjuvant setting, must: Received taxane, anthra or both or taxane, anthra or both for MBC Retreatment with a trastuzumab-containing regimen ok if >12 mo since adjuvant Rx If no previous adjuvant trastuzumab: A single trastuzumab containing regimen Must have taxane, anthra or both

Inclusion Criteria : 

CPxxxxxxx-11 Inclusion Criteria HER2 + as defined by IHC 3+ or HER2 gene copy number >6 Amplification HER2:D17Z1 >2.20 Measurable Disease Normal organ function, including EF≥50 Fasting glucose < 120 ECOG PS 0,1,2

Exclusion Criteria : 

CPxxxxxxx-12 Exclusion Criteria >1 regimen for MBC/advanced disease Other malignancies within 5 yrs Liver Disease Active Brain Mets (Stable OK) Previous lapatinib or other EGFR/HER2 targeted therapy beside trastuzumab Previous IGF-1R inhibitor Uncontrolled Diabetes or ICP

Correlative Studies : 

CPxxxxxxx-13 Correlative Studies InsR Isoform Analysis- FFPE IGFBP multiplex Analysis- Serum Alternative/Constitutive Signaling- CTC

More Information : 

More Information ClinicalTrials.gov Search for NCT00684983 or http://clinicaltrials.gov/ct2/show/NCT00684983?term=n0733&rank=1 Cancer Trial Support Unit (CTSU) Search for N0733 or https://www.ctsu.org/public/prot_search.aspx?browse=keyword&search=N0733 NCI Clinical Trials (PDQ®) http://www.cancer.gov/clinicaltrials/NCCTG-N0733/patient CPxxxxxxx-14

Interested in Coming to Mayo to Participate? : 

Interested in Coming to Mayo to Participate? Call (or have your doc call) 507-284-4137 Tell them you wish to see Dr. Haluska for participating in the clinical trial N0733 For Mayo Clinic- Florida in Jacksonville Call 904-953-0853 For Mayo Clinic-Arizona in Scottsdale Call 800-446-2279 Or go to http://www.mayoclinic.org/patientinfo/appointments.html CPxxxxxxx-15

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Any Questions??? : 

Any Questions??? Email me at haluska.paul@mayo.edu Or call 507-266-2123 CPxxxxxxx-75