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Paula M. Fracasso, M.D., Ph.D.
Associate Professor of Medicine
Division of Oncology
Washington University School of Medici...
Introduction: Cervical Cancer
• Incidence and Mortality in 2006
– 2nd
in incidence & mortality in women in the world
• Wor...
Introduction: Cervical Cancer
• Staging and Treatment
– FIGO (Federation of Gynecology & Obstetrics Staging
System)
– Stag...
Randomized Trials of Chemoradiation in Cervical Cancer
Trial Patients
Arms
(Radiation/Chemoradiation Dose)
Outcome
RTOG-90...
Randomized Trials of Chemoradiation in Cervical Cancer
Trial Patients
Arms
(Radiation/Chemoradiation Dose)
Outcome
GOG 85 ...
Randomized Trials of Chemoradiation in Cervical Cancer
Trial Patients
Arms
(Radiation/Chemoradiation Dose)
Outcome
GOG 123...
Introduction: EGFR
• EGFR – one of 4 members of the ErbB (HER) family encoded
by the ErbB1 gene
– Transmembrane glycoprote...
Schematic of the Signaling Pathways of the HER Family
Yarden,Y and Sliwkowski, M.X. Nature Reviews Molecular Cell Biology ...
Epidermal Growth Factor Receptor
• In tumor cells, EGFR signaling is inappropriately turned on
– EGFR mutations
• Lung can...
Lack of Correlation of EGFR Expression by IHC
and Response to Cetuximab in Colorectal Cancer
Comparison of Activity with I...
Targeting Epidermal Growth Factor Receptor
• EGFR is a target for cancer therapy
– Coexpression of high levels of EGFR and...
Cervical Cancer Trial
Objectives
– To determine the safety of cetuximab in combination with
concurrent chemoradiation
– To...
Inclusion Criteria
• FIGO Clinical Stage IB-IV with measurable
disease amendable to repeat biopsy
• ECOG Performance Statu...
Schema of Cervical Cancer Trial
Baseline cervical biopsy & CT-PET scan
Part A: Administer cetuximab on days 1, 8, & 15
Rep...
Patient Characteristics
Characteristics Patients (N=9)
Age, years
Mean (range) 49 (33-79)
ECOG Performance Status
0/1/2 2/...
Incidence of Hematologic Toxicity
ANC Nadir
(cells x 109
/L)
Mean Mean Mean
(Range) 1/2 3/4 (Range) 1/2 3/4 (Range) 1/2 3/...
Incidence of Non-Hematologic Toxicities - Part A
Adverse Event
Grade of Adverse Event 1 2 3 4
Constitutional Symptoms
Fati...
Incidence of Non-Hematologic Toxicities – Part B
Adverse Event
Grade of Adverse Event 1 2 3 4
Constitutional Symptoms
Fati...
Incidence of Non-Hematologic Toxicities – Part B
Adverse Event
Grade of Adverse Event 1 2 3 4
Gastrointestinal
Anorexia 1 ...
Incidence of Non-Hematologic Toxicities – Part B
Adverse Event
Grade of Adverse Event 1 2 3 4
Metabolic/Laboratory
Hypoalb...
Incidence of Non-Hematologic Toxicities – Part C
Adverse Event
Grade of Adverse Event 1 2 3 4
Constitutional Symptoms
Fati...
Incidence of Non-Hematologic Toxicities – Part C
Adverse Event
Grade of Adverse Event 1 2 3 4
Infection
Colitis 1
Infectio...
Profile of Treatment Course of Patients in Part B
Week
Patient 1 2 3 4 5 6 7 8 9 10
002 (J-P)
004 (VLH)
005 (D-M)
006 (SLK...
Chemotherapy Summary
Patient
Cetuximab
(mg/m2
)
Cisplatin
(mg/m2
)
Start Completion
Weeks
Duration
002*
J-P
500 80 8/03/06...
Radiation Summary
Patient Site
IMRT
(cGy)
HDR Implants
(cGy)
Start Completion
Days
Duration
002*
J-P
Pelvis &
PALN
1980
10...
Response by RECIST Criteria
Response
After Neoadjuvant
Cetuximab
Completion of
Therapy
Complete Response 2
Partial Respons...
FDG Uptake Prior & After Neoadjuvant Cetuximab Therapy
(n = 7)
2
4
6
8
10
12
14
16
18
SUV
Pretherapy
9.5 ± 3.9
Posttherapy...
Conclusions
• Part A: Three weekly treatments of neoadjuvant
cetuximab was well-tolerated and no women progressed
by CT sc...
Conclusions
Treatment Modifications:
-Part A: Only one weekly treatment of neoadjuvant
cetuximab will be given. Women will...
Conclusions
• Despite the gastrointestinal toxicities noted in our
patients, we are optimistic about the activity of
cetux...
Conclusions
• Over 400 targeted agents in clinical trials
– Cell culture and animal work may not
predict which of these th...
Collaborators
Preclinical
– Radiology: Dr. Carolyn Anderson
– Biochemistry and Molecular Biophysics: Dr. Linda Pike
– Path...
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  1. 1. Paula M. Fracasso, M.D., Ph.D. Associate Professor of Medicine Division of Oncology Washington University School of Medicine A First Look at HRPO#05-0702: An Exploratory Study of Neoadjuvant Cetuximab Followed by Cisplatin, & Cetuximab in Women with Newly Diagnosed Advanced Cervical Ca
  2. 2. 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
  3. 3. 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 <5%
  4. 4. Randomized Trials of Chemoradiation in Cervical Cancer Trial Patients Arms (Radiation/Chemoradiation Dose) Outcome RTOG-90-01 493, stage iiB-IVA (or IB/IIA <5cm/biopsy- proven node) • 45 Gy to pelvis & lower para-aortics, 1-2 LDR implants • 45 Gy to pelvis, 1-2 LDR implants with 5-FU 1,000 mg/m2 x 96 h + cisplatin 75 mg/m2 over 4 h on d1-5, 22-26, 2 nd implant 52% 5-yr OS 72% 5-yr OS (P <.0001) SWOG 8797 268, post-radical hysterectomy (+ margins, pelvic nodes, parametrial involvement) • 49.3 ± 45 Gy to para-aortic nodes • Same radiation with 5-FU 1,000 mg/m2 X 96 h + cisplatin 70 mg/m2 over d1-5, 22-26 + 2 additional cycles afterwards 63% 4-yr OS 80% 4-yr OS (P = .003)
  5. 5. Randomized Trials of Chemoradiation in Cervical Cancer Trial Patients Arms (Radiation/Chemoradiation Dose) Outcome GOG 85 388, stage IIB-IVA (node-negative) • Radiation to pelvis (dose varied by stage), 1-2 LDR implants with 5-FU 1,000 mg/m 2 x 96 h + cisplatin 50 mg/m2 on d1, 29 • Same radiation with hydroxyurea 80 mg/kg biweekly 55% 8.7-yr OS 43% 8.7-yr OS (P= .018) GOG 120 526, stage IIB-IVA • Radiation to pelvis (dose varied by stage) + weekly cisplatin 40 mg/m 2 x 6 cycles • Same radiation with cisplatin 50 mg/m 2 + 5-FU 1,000 mg/m 2 /d x 96 h on d1, 29 + hydroxyurea twice weekly x 6 • Same radiation with hydroxyurea 3 g/m 2 twice weekly x 6 65% 3-yr OS (both cisplatin arms) 47% 3-yr OS (P < .004)
  6. 6. Randomized Trials of Chemoradiation in Cervical Cancer Trial Patients Arms (Radiation/Chemoradiation Dose) Outcome GOG 123 368, node-negative, bulky, stage IB • 45 Gy to pelvis, 1-2 LDR implants followed by hysterectomy • Same radiation with weekly cisplatin 40 mg/m2 x 6 74% 3-yr OS 85% 3-yr OS (P = .008)
  7. 7. 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-α, amphiregulin, betacellulin, epiregulin, heparin- binding EGF – Strictly regulated in normal cells with controlled cell growth
  8. 8. Schematic of the Signaling Pathways of the HER Family Yarden,Y and Sliwkowski, M.X. Nature Reviews Molecular Cell Biology 2:127-137, 2001
  9. 9. 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)Adapted from Harari and Huang, Semin Radiat Oncol 11: 281-289, 2001)
  10. 10. Lack of Correlation of EGFR Expression by IHC and 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 Baselga, J. J Clin Onc 19: 41s-44s, 2001 Colorectal Cancer Breast Cancer
  11. 11. 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 Expression in Skin EGFR Overexpression in SCC
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. Patient Characteristics Characteristics Patients (N=9) Age, years Mean (range) 49 (33-79) ECOG Performance Status 0/1/2 2/6/1 Stage IB 2 IIB 1 IIIB 5 IVB 1
  16. 16. Incidence of Hematologic Toxicity ANC Nadir (cells x 109 /L) Mean Mean Mean (Range) 1/2 3/4 (Range) 1/2 3/4 (Range) 1/2 3/4 5.509 12.1 309 (3.873-6.700) (9.2-13.6) (214-547) 1.473 9.0 126 (0.448-2.369) (7.9-11.9) (28-267) 2.866 10.1 190 (1.560-6.794) (8.6-10.8) (55-384) * 1 patient each completed 2 weeks and 4 weeks, respectively. ** 2 patients completed all therapy, 1 patient with Stage IV disease at diagnosis completed 9 weeks and was removed due to PD, 1 patient each completed 5 and 3 weeks, respectively, and wished to discontinue. 1/0B* 1/0 2/1 2/4 Part Neutropenia Grade 1/0 1/1 A 0/0 0/0 1/1 C** 3/0 0/0 4/1 1/1 0/0 Hemoglobin Nadir (g/dL) Hemoglobin Grade Platelets Nadir (cells x 10 9 /L) 0/0 Platelets Grade 0/0 0/0 0/0
  17. 17. Incidence of Non-Hematologic Toxicities - Part A Adverse Event Grade of Adverse Event 1 2 3 4 Constitutional Symptoms Fatigue 1 2 Weight loss 1 Dermatology/Skin Acne/acneiform rash 3 4 Gastrointestinal Diarrhea 1 Nausea /vomiting 3 1 Metabolic/Laboratory Hypoalbuminemia 1 1 Part A(N = 7)
  18. 18. Incidence of Non-Hematologic Toxicities – Part B Adverse Event Grade of Adverse Event 1 2 3 4 Constitutional Symptoms Fatigue 3 3 1 Weight loss 3 1 Cardiac Arrhythmia Atrial fibrillation 1 Dermatology/Skin Acne/acneiform rash 2 4 1 Neurology Dizziness 1 1 * 1 patient each received 2 weeks and 4 weeks of Part B therapy, respectively Part B(N = 7*)
  19. 19. Incidence of Non-Hematologic Toxicities – Part B Adverse Event Grade of Adverse Event 1 2 3 4 Gastrointestinal Anorexia 1 2 2 Dehydration 1 2 1 Diarrhea 2 5 Enteritis 1 1 Heartburn/dyspepsia 3 Hemorrhoids 1 Mucositis/stomatitis 2 1 Nausea/vomiting 4 1 2 Obstruction, GI (small bowel) 1 Stricture/stenosis, GI (biliary) 1 Infection Infection w/neutropenia 1 Infection w/o neutropenia 2 2 * 1 patient each received 2 weeks and 4 weeks of Part B therapy, respectively Part B(N = 7*)
  20. 20. Incidence of Non-Hematologic Toxicities – Part B Adverse Event Grade of Adverse Event 1 2 3 4 Metabolic/Laboratory Hypoalbuminemia 5 2 ALT, SGPT 2 2 1 AST, SGOT 2 2 Hyperbilirubinemia 1 1 Hypocalcemia 2 3 1 Hypomagnesemia 1 2 Hypophosphatemia 2 2 Hypokalemia 2 1 2 Hyponatremia 3 1 1 * 1 patient each received 2 weeks and 4 weeks of Part B therapy, respectively Part B (N = 7*)
  21. 21. Incidence of Non-Hematologic Toxicities – Part C Adverse Event Grade of Adverse Event 1 2 3 4 Constitutional Symptoms Fatigue 2 2 1 Weight loss 1 3 Dermatology/Skin Acne/acneiform rash 2 1 Hyperpigmentation 3 1 Gastrointestinal Anorexia 2 1 Diarrhea 1 3 Heartburn/dyspepsia 2 Hemorrhoids 1 Nausea /vomiting 2 2 *2 patients completed all therapy, 1 patient completed 9 weeks removed due to PD, 1 patient completed 5 weeks and 1 patient completed 3 weeks and they wished to discontinue Part C (N = 5*)
  22. 22. Incidence of Non-Hematologic Toxicities – Part C Adverse Event Grade of Adverse Event 1 2 3 4 Infection Colitis 1 Infection w/o neutropenia 2 1 Metabolic/Laboratory Hypoalbuminemia 1 3 ALT, SGPT 2 Hypocalcemia 1 1 Hypomagnesemia 1 Hypokalemia 2 1 Hyponatremia 1 *2 patients completed all therapy, 1 patient completed 9 weeks removed due to PD, 1 patient completed 5 weeks and 1 patient completed 3 weeks and they wished to discontinue Part C (N = 5*)
  23. 23. Profile of Treatment Course of Patients in Part B Week Patient 1 2 3 4 5 6 7 8 9 10 002 (J-P) 004 (VLH) 005 (D-M) 006 (SLK) 007 (JMC) 008 (RET) 009 (S-T) Indicates hospitalization Indicates outpatient IVF Enteritis 8 days Enteritis/Ileus 16 days DVT 8 days 6 days 4 days DVT, Infection 4 days G-tube placement 9 days N/V, Infection 8 days Dehydration 1 day Nausea, Diarrhea, Atrial fibrillation, Neutropenic infection 35 days Intermittent outpatient IVF 1 day 1 day Intermittent outpatient IVF Ileus/SBO
  24. 24. Chemotherapy Summary Patient Cetuximab (mg/m2 ) Cisplatin (mg/m2 ) Start Completion Weeks Duration 002* J-P 500 80 8/03/06 8/24/06 Incomplete 004 VLH 1500 240 8/25/06 9/28/06 6 005 D-M 1500 240 9/07/06 11/02/06 9 006 SLK 1500 210** 9/14/06 10/26/06 7 007 JMC 1500 240 9/28/06 11/10/06 7 008* RET 1000 160 10/03/06 10/26/06 Incomplete 009 S-T 1500 240 10/20/06 12/14/06 8 * 1 patient each completed 2 weeks and 4 weeks, respectivelvely. ** Patient had cisplatin dose reduced to 30 mg/m 2 after third treatment.
  25. 25. Radiation Summary Patient Site IMRT (cGy) HDR Implants (cGy) Start Completion Days Duration 002* J-P Pelvis & PALN 1980 1080 1300 7/28/06 8/31/06 Incomplete 004 VLH Pelvis 5040 3900 8/24/06 10/12/06 50 005 D-M Pelvis 5040 3900 9/11/06 11/30/06 81 006 SLK Pelvis 5040 3900 9/14/06 11/01/06 49 007 JMC Pelvis & PALN 6000 3900 9/26/06 11/27/06 63 008* RET Pelvis 2560 3250 10/03/06 11/08/06 Incomplete 009 S-T Pelvis 5040 3900 10/20/06 12/11/06 53 * 1 patient each completed 2 weeks and 4 weeks, respectively.
  26. 26. Response by RECIST Criteria Response After Neoadjuvant Cetuximab Completion of Therapy Complete Response 2 Partial Response Stable Disease 5 Progressive Disease 1 Not Evaluable 2 2
  27. 27. FDG Uptake Prior & After Neoadjuvant Cetuximab Therapy (n = 7) 2 4 6 8 10 12 14 16 18 SUV Pretherapy 9.5 ± 3.9 Posttherapy 6.8 ± 2.7 P = 0.005 Paired t-test 2 4 6 8 10 12 14 16 18 SUV Pretherapy 9.5 ± 3.9 Posttherapy 6.8 ± 2.7 P = 0.005 Paired t-test
  28. 28. 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.
  29. 29. 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 3+3 design. -Part C: Cetuximab monotherapy will be discontinued as there is no proven benefit at this time.
  30. 30. 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.
  31. 31. 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
  32. 32. 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

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