Paula M' Fracasso, M'D', Ph'D'

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A First Look at HRPO05-0702 An Exploratory
Study of Neoadjuvant Cetuximab Followed by
Cisplatin, Cetuximab in Women with Newly
Diagnosed Advanced Cervical Ca

• Paula M. Fracasso, M.D., Ph.D.
• Associate Professor of Medicine
• Division of Oncology
• Washington University School of Medicine
• \

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Introduction Cervical Cancer

• Incidence and Mortality in 2006
• 2nd in incidence mortality in women in the
  world
• Worldwide
• Incidence 466,000
• Mortality 232,000
• US
• Incidence 9,710
• Mortality 3,700
• Bimodal peak from ages 35-39 and 60-64
• Etiology
• HPV - 1 etiologic agent in 99 tumors
• (HPV 16-most common, 18, 35, 45 and others-less
  common)
• Smoking
• Early frequent sexual activity with multiple
  partners

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Introduction Cervical Cancer

• Staging and Treatment
• FIGO (Federation of Gynecology Obstetrics
  Staging System)
• Stage IA and IB1 Early stage
• Radical hysterectomy or radiation therapy
• 5 year survival 80-90
• Stage IB2-IVA Locally advanced disease
• Radiation or combined chemoradiation
• 5 year survival 65
• Late stage and recurrent disease
• Palliative chemotherapy novel agents
• 5 year survival lt5

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Randomized Trials of Chemoradiation in Cervical
Cancer
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Randomized Trials of Chemoradiation in Cervical
Cancer
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Randomized Trials of Chemoradiation in Cervical
Cancer
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Introduction EGFR

• EGFR one of 4 members of the ErbB (HER) family
  encoded by the ErbB1 gene
• Transmembrane glycoprotein that homo-
  
  
  or heterdimerizes with family
  members
• Extracellular ligand binding domain
• Transmembrane domain
• Intracellular tyrosine kinase domain
• Activation of EGFR triggers signal transduction
  and cell proliferation
• Ligands EGF, TGF-a, amphiregulin, betacellulin,
  epiregulin, heparin-binding EGF
• Strictly regulated in normal cells with
  controlled cell growth

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Schematic of the Signaling Pathways of the HER
Family
Yarden,Y and Sliwkowski, M.X. Nature Reviews
Molecular Cell Biology 2127-137, 2001
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Epidermal Growth Factor Receptor

• In tumor cells, EGFR signaling is inappropriately
  turned on
• EGFR mutations
• Lung cancer
• Overexpression of EGFR
• Lung cancer and GBM
• ?Binding of intracellular ligands
• ?Other receptors/crosstalk
• ?Loss of regulatory mechanisms

(Adapted from Harari and Huang, Semin Radiat
Oncol 11 281-289, 2001)
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Lack of Correlation of EGFR Expression by IHCand
Response to Cetuximab in Colorectal Cancer

• Comparison of Activity with IMC-C225/CPT-11 (in
  colorectal cancer) and Trastuzumab (in breast
  cancer) by Receptor Expression Level

Colorectal Cancer
Breast Cancer
Baselga, J. J Clin Onc 19 41s-44s, 2001
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Targeting Epidermal Growth Factor Receptor

• EGFR is a target for cancer therapy
• Coexpression of high levels of EGFR and its
  ligands lead to
  transformed phenotype
• Overexpression of EGFR is found epithelial tumors
  and tumor-derived cell lines
• EGFR is expressed in at least 60 of cervical
  cancers
• Overexpression of EGFR correlates with poor
  patient prognosis, decreased survival, and/or
  increased metastasis

EGFR Overexpression in SCC
EGFR Expression in Skin
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Cervical Cancer Trial

• Objectives
• To determine the safety of cetuximab in
  combination with concurrent chemoradiation
• To evaluate genes or gene mutations predictive of
  response to cetuximab in women with cervical
  cancer
• To correlate evidence of antitumor activity of
  cetuximab by CT-PET imaging
• Long term goal To improve the cure rate of women
  with locally advanced cervical cancer with the
  addition of cetuximab with standard
  chemoradiation

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Inclusion Criteria

• FIGO Clinical Stage IB-IV with measurable disease
  amendable to repeat biopsy
• ECOG Performance Status 0-2
• Adequate hematologic, renal, and hepatic function
• No previous treatment for cervical carcinoma
• Patients with ureteral obstruction must be
  treated with stent or nephrostomy tube placement

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Schema of Cervical Cancer Trial
Baseline cervical biopsy CT-PET scan Part A
Administer cetuximab on days 1, 8, 15 Repeat
cervical biopsy CT-PET scan Part B Administer
chemoradiation cetuximab Part C Administer
cetuximab for 12 weeks Repeat cervical biopsy
CT-PET scan
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Patient Characteristics
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Incidence of Hematologic Toxicity
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Incidence of Non-Hematologic Toxicities - Part A
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Incidence of Non-Hematologic Toxicities Part B
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Incidence of Non-Hematologic Toxicities Part B
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Incidence of Non-Hematologic Toxicities Part B
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Incidence of Non-Hematologic Toxicities Part C
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Incidence of Non-Hematologic Toxicities Part C
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Profile of Treatment Course of Patients in Part B
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Chemotherapy Summary
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Radiation Summary
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Response by RECIST Criteria
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FDG Uptake Prior After Neoadjuvant Cetuximab
Therapy (n 7)
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Conclusions

• Part A Three weekly treatments of neoadjuvant
  cetuximab was well-tolerated and no women
  progressed by CT scan during this time.
• -Neoadjuvant cetuximab appears to have activity
  as evidenced by clinical examination and
  FDG-PET/CT scan in 7 women.
• Part B Gastrointestinal toxicities including
  diarrhea and enteritis were severe and were felt
  to be exacerbated by cetuximab given
  neoadjuvantly and concurrently with cisplatin and
  radiation therapy.
• Part C Three women completed cetuximab
  monotherapy. Two women discontinued therapy by
  choice.

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Conclusions

• Treatment Modifications
• -Part A Only one weekly treatment of
  neoadjuvant cetuximab will be given. Women will
  have a biopsy and FDG-PET/CT scan prior to and
  after this treatment.
• -Part B Concurrent therapy will begin 2 weeks
  after neoadjuvant therapy. Cisplatin will be dose
  reduced to 30 mg/m2 and cetuximab will be dose
  reduced to 200 mg/m2. If tolerated, dose
  escalation will occur in a 33 design.
• -Part C Cetuximab monotherapy will be
  discontinued as there is no proven benefit at
  this time.

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Conclusions

• Despite the gastrointestinal toxicities noted in
  our patients, we are optimistic about the
  activity of cetuximab in combination with
  chemoradiation in women with cervical cancer.
• We await microarray analyses of pre- and post-
  neoadjuvant cetuximab tumor samples in hopes that
  we will define biomarkers for response to this
  agent in cervical cancer.

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Conclusions

• Over 400 targeted agents in clinical trials
• Cell culture and animal work may not predict
  which of these therapies will be effective in
  patients with cancer
• Developing these agents is time-consuming,
  expensive, and importantly, utilizes our most
  precious resource patients
• This places an increasing priority on the need
  for directed early clinical trials

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Collaborators

• Preclinical
• Radiology Dr. Carolyn Anderson
• Biochemistry and Molecular Biophysics Dr. Linda
  Pike
• Pathology Dr. Mark Watson
• Clinical
• Medical Oncology Drs. Paula Fracasso and Tom
  Fong
• Gynecologic Oncology Drs. Janet Rader, David
  Mutch, Matthew Powell, Nicholas Taylor, and
  Israel Zighelboim
• Radiation Oncology Drs. Perry Grigsby and Imran
  Zoberi
• Pathology Dr. Mark Watson
• Radiology Drs. Farrokh Dehdashti, Barry Siegel,
  and Tom Miller
• Industry
• ImClone Systems Drs. Dan Hicklin and Eric
  Rowinsky
• BMS Dr. David Mauro