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GCIG Cervix Committee November 14, 2008. Regimen I Paclitaxel 135 mg/m 2 IV d1 (24h) Cisplatin 50 mg/m 2 IV d2 Q21d to progression/toxicity. GOG 240 Schema. R A N D O M I Z E. Regimen II Paclitaxel 135 mg/m 2 IV d1 (24h) Cisplatin 50 mg/m 2 IV d2

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GCIG Cervix Committee November 14, 2008

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    1. GCIG Cervix CommitteeNovember 14, 2008

    2. Regimen I Paclitaxel 135 mg/m2 IV d1 (24h) Cisplatin 50 mg/m2 IV d2 Q21d to progression/toxicity GOG 240Schema R A N D O M I Z E Regimen II Paclitaxel 135 mg/m2 IV d1 (24h) Cisplatin 50 mg/m2 IV d2 Bevacizumab 15 mg/kg IV d2 Q21d to progression/toxicity Eligibility: 1. Primary stage IVB or Recurrent/persistent carcinoma of the cervix 2. Measureable disease 3. GOG PS 0-1 Regimen III Paclitaxel 175 mg/m2 IV d1 (3h) Topotecan 0.75 mg/m2 d1-3 (30m) Q21d to progression/toxicity Regimen IV Paclitaxel 175 mg/m2 IV d1 (3h) Topotecan 0.75 mg/m2 d1-3 (30m) Bevacizumab 15 mg/kg IV d1 Q21d to progression/toxicity

    3. GOG 240Primary & Secondary Endpoints • Primary Endpoints • 1. Survival time from date of randomization • 2. Frequency & severity of adverse events • CTCAE version 3.0 • Secondary endpoints • 1. PFS from date of randomization • 2. Frequency of objective tumor response

    4. GOG 240Statistical Design • Randomized, phase III trial • 2x2 factorial design (n=450) • Intent to treat principle • Random assignment to the four arms balanced for • Disease status • Performance status • Prior platinum therapy with pelvic RT • Reduction of hazard of death by 30% by addition of either bevacizumab or non-platinum doublet important to detect • Interim analysis to be conducted after 173 deaths

    5. GOG 240Toxicity monitoring

    6. GOG 240Exploratory Endpoints • Health-Related Quality of Life • FACT-Cx TOI • FACT-GOG/Ntx subscale (neuropathy symptoms) • BPI single item for pain • Prospective validation of prognostic markers • Smoking behavior • Prevalence of active smoking • Extent of nicotine dependence • Nicotine dependence with PFS & OS • Translational science

    7. GOG 240CellSearchTM Circulating Tumor Cell (CTC) Test Number of CTCs - Correlation with PFS & OS Clearance of CTCs - Correlation with response - Correlation with OS & PFS

    8. GOG 240International Collaborators Norway: Gunn Kristensen MD Germany: Falk Clemens Thiel MD South Korea: Jong-Min Lee MD PhD Spain: Ana Oaknin Benzaquen

    9. GOG 240International Collaborators NORWAY Kristensen, GunnarDepartment of Gynecologic Oncology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway Department of Medical Informatics, University of Oslo, Oslo, Norway SPAIN Dra. Ana Oaknin Benzaquen Oncología Médica. División de Ginecología Institut Català d´Oncologia. Hospital Duran i Reynals Tel :+ Fax:+ e-mail:aoaknin@iconcologia.net KOREA Jong-Min Lee, MD, PhD Associate Professor Department of Obstetrics and Gynecology East-West Neo Medical Center Kyung Hee University 149 Sangil-dong, Gangdong-gu, Seoul, 134-090, South Korea E-mail; kgo02@hanmail.net, kgo02@naver.com Office; 82-2-440-6140 Cell;82-11-738-3725 Fax; 82-2-440-7894 GERMANY Falk Clemens Thiel, MD Department of Gynecology University Hospital Erlangen Universitätsstr. 21­23 91054 Erlangen Germany Tel. +49 9131 8533553

    10. GOG 240Status This protocol has received approval by the NCI and Central IRB and we anticipate activation within the upcoming 2-3 months.

    11. John H. Farley MD Associate Professor Obstetrics and Gynecology Uniformed Services University of the Health Sciences CVM0503

    12. To determine if combining Cetuximab with cisplatin during radiation therapy increases overall survival (OS) when compared with weekly cisplatin and radiation therapy in patients with cervical cancer metastatic to high common and/or para-aortic lymph nodes. • Secondary Objective • To determine if the addition of Cetuximab to cisplatin and radiation therapy in this patient population improves progression-free survival (PFS). • To determine the relative toxicities of the addition of Cetuximab to cisplatin in this patient population. CVM0503

    13. Test the hypothesis that Cetuximab will be more effective in tumors that express low compared with high levels of the hypoxia marker Hypoxia Inducible Factor-1α (HIF-1α) and epidermal growth factor receptor (EGFR), CVM0503

    14. Concurrent Weekly Cisplatin + Cetuximab (preferably Monday) • Cisplatin 30mg/m2/week x 6 weeks • Cetuximab 400 mg/m2 initial loading dose week 1, then 250 mg/m2 x 5 weeks • VERSUS • Cisplatin 30mg/m2/week x 6 weeks • In patients receiving extended field radiation therapy; pelvis and para-aortics. • 4500 cGy in 29 fractions to the para-aortic nodes • (150 cGy/fraction) • 4500 cGy in 25 fractions to the pelvis • (180 cGy/fraction) CVM0503

    15. Trial population • Cervical cancer patients with positive para-aortic and/or pelvic nodes : • Squamous Cell Carcinoma, Adenocarcinoma, Adenosquamous Carcinoma, • Clinical stages • IB, IIA, IIB, IIIA, IIIB, IV • Number of subjects: 328 CVM0503


    17. GOG 219October 23, 2008

    18. GOG 219 ACCRUAL TO DATE = 301 PATIENTS Enrollment primarily from U.S. sites International participation increasing, specifically NCI Canada Factors (pro) Starting dose reduced after 1st toxicity evaluation NCIC sites gaining experience with regimen Factors (con) Regulatory bodies in other countries International shipment of drug GOG-0219


    20. AMENDMENT The Data Monitoring Committee (DMC) of the Gynecologic Oncology Group convened to review the interim safety analysis as outlined in section 11.5 of the study. In reviewing toxicity data, there was a higher than 20% incidence of Grade 3 or 4 toxicity in the form of leucopenia and metabolic toxicity. Median length of radiation therapy was similar in both arms and there were no deaths related to study participation. Based on their review in assessing the clinical impact of the toxicity, the DMC recommended decreasing the starting dose on regimen II to by one dose level rather than two dose levels as originally stipulated in section 11.5. The starting dose on trial (now dose level I) is the previous dose level -1 from former versions (prior to NCI Version Date 10/03/2007). GOG-0219

    21. AMENDMENT Regimen II: Concurrent Cisplatin and TPZ and Radiation Therapy (10/23/2007) Cisplatin 60mg/m2 (max = 105 mg) administered IV over 30-60 minutes days 1, 15 and 29 with radiation therapy TPZ 220mg/m2 (max = 385 mg) IV administered over two hours prior to Cisplatin on days 1, 15 and 29 TPZ 220mg/m2 (max = 385 mg) IV over two hours days 8, 10, 12, 22, 24, 26 with radiation therapy. GOG-0219

    22. AMENDMENT A second safety analysis will be performed after treating 30 more patients on the TPZ arm (with the new starting dose). In the event Grade 3 or 4 toxicity continues to be significantly higher among patients on the TPZ arm or duration of radiotherapy is prolonged significantly in any of the arms, the trial committee may recommend further dose modification or study termination. GOG-0219

    23. CVM 0801/KGOG 1008 A Randomized Trial of Concurrent Chemoradiation for Postoperative Cervical Cancer with Intermediate Risk Factors Sang Young Ryu, M.D. Korea Cancer Center Hospital

    24. CVM 0801/KGOG 1008  Adjuvant CCRT- High Risk Factor SWOG 97-97 Peters 2000: Stage <IIB, LN, RM, PM: FP CCRT(x2) + 2 FP vs RT RR 0.50; PFS 80 vs 63%, OSR 81 vs 71%, Local rec 20 vs 7, Distant rec 13 vs 9 No brachytherapy Toxicity; 21 vs 4 Gr IV toxicity Aedno, adenosquamous CCRT; good but no statistic signif. GOG 109; FP vs RT only; FP arm is superior to RT alone arm high hematologic toxicity Standard treatment

    25. CVM 0801/KGOG 1008 Adjuvant CCRT-intermediate risk factors No Clinical Trials GOG 92 Sedlis 1999; IB intermediate, adjuvant RT vs no RT; 2 of >1/3 stromal invasion, LVSI, tumor size Rec Rate; 28 vs 15% 2YDFS; 88 vs79%, RR 0.53

    26. KCCH Retrospective Results RH with BPLND FIGO stage IB – IIA cervical cancer patients 735 cases 172 cases Any of intermediate risk factor 34 cases 49 cases 89 cases No further treatment RT only CCRT Fig. 1. Patients enrolled in this study

    27. CVM 0801/KGOG 1008

    28. CVM 0801/KGOG 1008 Control Arm; Radiation therapy Randomization Cervical cancer Stage IB-IIA Radical hysterectomy+BPLND >2 of intermediate risk factors CRT Arm; Weekly CDDP 40mg/m2concurrent to radiation

    29. CVM 0801/KGOG 1008 Primary endpoint; 3 year recurrence free survival 6.3% (87% to 93.3%) Secondary endpoint; Recurrence rate Toxicity QoL

    30. CVM 0801/KGOG 1008

    31. CVM 0801/KGOG 1008 Pathology Review pathologic slides H&E only Tumor cell type Squamous, adenoca, adenosquamous Depth of stromal invasion in thirds of cervical thickness Tumor diameter; palpation, largest diameter on section, imaging studies Presence or absence of the LVSI

    32. CVM 0801/KGOG 1008 Radiation (GOG 92) Within 4-6 weeks postop Weekly Hg >11mg/ml, ANC > 1000/ul, Plt >100,000/ul Tranfusion of P/C or IV iron if necessary ERT Four field box technique with megavoltage beam Dose 46Gy in 23 fraction,or 50.4 Gy in 28 fraction Treatment break for clinical problems allowed to total no more than 1 week No brachytherapy

    33. CVM 0801/KGOG 1008 Chemotherapy Eligible Total WBC > 2,000/uL, ANC> 1000 /ul, Plt > 100,000/uL Schedule (6 cycles) 40mg/m2 on days 1, 8, 15, 22, 29, and 36 Dose Reduction 25% DR grade 3 stomatitis Nadir Plt < 50,000/ul, WBC <2000/uL->25% DR 50% grade 4 stomatitis Hold Caluculated Ccr < 50ml/min grade III, IV neuropathy

    34. CVM 0801/KGOG 1008 Statistics 6.3% increase of RFS Power 80% Type I error; 0.05 Sample size: 480 Total sample size: 534 Total period: 54month Expected events: 36 recurrences in control arm

    35. RTOG/GOG combined study for high-risk early stage Cervical Carcinoma Anuja Jhingran RTOG-0724

    36. Background 90% early stage cured with surgery or xrt alone 15%-20% of early stage present with positive nodes, parametrium or margins - survival drops to 50-70% with surgery alone Even with adjuvant xrt - 40% fail - 10% in field and 10% out of field Recent update of the SWOG trial – 5-yr survival with CT/RT – 2 or more positive nodes – 77% RTOG-0724

    37. Concurrent Chemotherapy and Pelvic Radiation Therapy Compared With Pelvic Radiation Therapy Alone as Adjuvant Therapy After Radical Surgery in High-Risk Early-Stage Cancer of the CervixGOG 109:Peters et al JCO 2000

    38. Concurrent Chemotherapy and Pelvic Radiation Therapy Compared With Pelvic Radiation Therapy Alone as Adjuvant Therapy After Radical Surgery in High-Risk Early-Stage Cancer of the CervixGOG 109:Peters et al JCO 2000

    39. Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical–pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trialMonk et al Gyn Onc 2005

    40. Proposed Intergroup trialStage I/IIA Cervical Cancer Radical Hyst: +LN’s, - include para-aortic nodes, and parametrium Randomize ARM 1 ARM 2 XRT 45 - 50 Gy Cisplatin 40 mg/m2 wkly XRT 45 - 50 Gy Cisplatin 40 mg/m2 wkly Carboplatin AUC 5 Paclitaxel 135mg/m2 q3weeks X4 PI’s A. Jhingran RTOG H. Gray GOG RTOG-0724 400 pts

    41. Hypothesis To determine if adjuvant systemic chemotherapy following chemoradiation therapy will improve disease-free and overall survival compared to chemoradiation therapy alone in patients with high-risk early-stage cervical carcinoma found to have positive nodes and/or positive margins and/or positive parametria after a radical hysterectomy. The expected benefit would be approximately 10%-15% – Acrrual - 400 patients. RTOG-0724

    42. Endpoints 2.1 Primary objective: Disease-free survival 2.2 Secondary objective(s): 1) Toxicity 2) Overall survival 3) Quality of life 4) To collect fixed tissue to identify tumor molecular signatures that may be associated with patient outcomes. 5) To collect blood from serum and plasma - looking factors correlated with toxicity and outcome RTOG-0724

    43. RTOG 0724 RTOG-0724 IMRT allowed. Vaginal Brachytherapy allowed.

    44. New Concepts in Locally Advanced Cervix Cancer Nick Reed Personal thoughts for debate at GCIG Nov 2008

    45. Need for Improvement Improving outcomes of bulky locally advanced cervix cancer New Approaches Induction / neoadjuvant schedules Maintenance treatments Targeted agents Functional Imaging

    46. Diagnostic Pathway CCRT Newly diagnosed Stage 1B2 – 4A Baseline Imaging NACT Induction Reassessment Imaging and CCRT

    47. So where is my evidence?

    48. Newer Approaches - Induction Meta-analysis from data with Cis +/- Carboplatin vs Cisplatin Addition of Paclitaxel - Hoskin & Glynne-Jones Mexico- Duenas -Gonzalez UCL – McCormack CX2 study Still premature but exciting interest

    49. The Study Options Maintenance chemotherapy NACT Induction CCRT Observation