GCIG Cervix Committee November 14, 2008

GOG 240 Schema R A N D O M I Z E Regimen I Paclitaxel 135 mg/m2 IV d1 (24h) Cisplatin 50 mg/m2 IV d2 Q21d to progression/toxicity 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

GOG 240 Primary & 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

GOG 240 Statistical 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

GOG 240 Toxicity monitoring Topotecan-Paclitaxel-related toxicities – DSMB evaluation (Myelosuppression and infection) Stage Cummulative Patients Min # Events 1 50 19 2 100 30 Bevacizumab-related toxicities – DSMB evaluation (Bowel perforation, hemorrhage, necrosis, fistula, PE) Stage Cummulative Patients Min # Events 1 50 12 2 100 18

GOG 240 Exploratory 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

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

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

GOG 240 International Collaborators NORWAY Kristensen, Gunnar Department 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 :+34.93.260.77.44 Fax:+34.93.260.77.41 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

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

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

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

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

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 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

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

GOG-0233/ACRIN-6671 UTILITY OF PREOPERATIVE FDG-PET/CT AND FERUMOXTRAN-10 MRI SCANNING PRIOR TO PRIMARY CHEMORADIATION THERAPY TO DETECT RETROPERITONEAL LYMPH NODE METASTASIS IN PATIENTS WITH LOCOREGIONALLY ADVANCED (IB2, IIA 4 CM, IIB-IVA) CARCINOMA OF THE CERVIX. Has accrued 22/325 patients

GOG 219 October 23, 2008

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

ENROLLMENT BY QUARTER GOG-0219

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

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

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

Korea Cancer Center Hospital 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

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

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

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

CVM 0801/KGOG 1008

CVM 0801/KGOG 1008 Cervical cancer Control Arm; Radiation therapy Randomization Cervical cancer Stage IB-IIA Radical hysterectomy+BPLND >2 of intermediate risk factors CRT Arm; Weekly CDDP 40mg/m2 concurrent to radiation

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

CVM 0801/KGOG 1008

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

CVM 0801/KGOG 1008 Radiation (GOG 92) Within 4-6 weeks postop ERT 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

CVM 0801/KGOG 1008 Chemotherapy Eligible Schedule (6 cycles) 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

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

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

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

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 Cervix GOG 109: Peters et al JCO 2000 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 Cervix GOG 109: Peters et al JCO 2000 38

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 trial Monk et al Gyn Onc 2005 39

Proposed Intergroup trial Stage 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 40

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 41

Endpoints 2.1 Primary objective: 2.2 Secondary objective(s): RTOG-0724 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 42

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

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

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

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

So where is my evidence?

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

The Study Options Maintenance chemotherapy NACT Induction CCRT Observation

Reed’s Observations I am convinced NACT is the way forward I am convinced dose dense and dose intense schedules are needed I think a taxane  is essential rather than platinum alone I think TR and  functional imaging should  be  integral

So what would I propose?? Fresh tissue for banking +/- serum Baseline  scan , preferably PET CT +/- MRI (advice from  radiologists) Explore new imaging agents (hypoxia markers) 9 weekly doses  of  carbo/paclitaxel  (AUC 2-3 and  pac 60-80 mg/m2)  Reassess clinically and  radiologically plus repeat samples for  freezing

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

Chemo-Rads CCRT Proceed to standard  concomitant chemoradiotherapy (CCRT) Try for international consensus on EBRT dose and also BT

The Other Option - Maintenance Why? Tierney IPA suggests benefit Which maintenance? How many cycles Conventional or TAT or both Candidates

The Next Steps Next phase would  be to consider adding a  biological/TAT, maybe  RCT phase 2 Next phase would  be to look at maintenance or no  maintenance

The Study Options Maintenance chemotherapy NACT Induction CCRT Observation

Where next? Discussion Manchester SOTS??

A pilot study of adjuvant chemotherapy for high-risk cervical cancer Linda Mileshkin, Danny Rischin, Kailash Narayan ANZGOG 59

Background Early-stage cervical cancer is highly curable with surgical approaches or chemoXRT Lower cure rates with more advanced disease seen in those who have not participated in screening Traditional main prognostic factor is the FIGO staging system - principally based on clinical examination Uterine and nodal involvement on imaging also prognostic ANZGOG 60

Background Prospective audit data from 238 pts treated with primary chemoXRT for cervical cancer 170 (71%) had corpus invasion on MRI 41% of these recurred cf. 19% without invasion FIGO stage and clinical diameter not prognostic in the presence of uterine invasion 108 (45%) had PET +ve nodal disease 51% PET +ve recurred cf. 22% in PET -ve Majority of recurrences distant ANZGOG Narayan K 2006 and 2007 61

Background – adjuvant chemo Chemo concurrent with XRT improves survival and is standard care Additional chemo after chemoXRT may treat distant mets and ↑ survival in high-risk pts Few small retrospective studies with older chemo in unselected patients suggest no survival advantage and some toxicity Carboplatin/paclitaxel active in cervical ca and likely more deliverable after XRT than cisplatin/topotecan ANZGOG 62

Background – adjuvant chemo GOG 109: post-op chemoXRT for those with +ve nodes/ margins or parametrium involved :2 extra cycles of cis/5FU given after chemoXRT : subset analysis suggested improved PFS and OS with more cycles of chemo ANZGOG 63

Research Plan Design: Single-arm phase II study (n=30:pragmatic) Eligibility: Stage 1b-IVa cervical cancer suitable for primary treatment with chemoradiation with curative intent in addition to one of the high-risk features of: Pelvic nodal involvement on: staging PET scan staging CT if >15mm diameter, or - frozen section during planned surgery leading to abandonment of planned hysterectomy b) Uterine involvement on MRI EBR alone; EBR plus brachytherapy; EBR plus Chemo ANZGOG

Aims and Objectives Aim: To test the feasibility of the regimen Primary objective: To determine the percentage of patients able to complete all treatment components without significant treatment interruptions or omissions due to grade 3 or 4 toxicity Secondary objectives: To determine the Acute and long-term toxicities Patterns of disease recurrence Failure-free survival ANZGOG 65

Intervention 45-50.4 Gy of external beam XRT in 25 to 28 fractions plus brachytherapy Cisplatin 40mg/m2 weekly during XRT Within 4 weeks of completion of XRT and following recovery from toxicities, 4 cycles of 3 weekly adjuvant chemotherapy using Carboplatin AUC 5 and Paclitaxel 175 mg/m2 ANZGOG 66

Future phase III study Stage Ib-IVa Cervical cancer Node positive and/or Uterine invasion 4 cycles Carboplatin + Paclitaxel Standard chemoXRT Standard chemoXRT ANZGOG 67

GCIG Consensus: Cervical Brachytherapy Produce a document that can be used as a template for upcoming GCIG trials that contains “acceptable” evidence based brachytherapy dosing. Akila Viswanathan has agreed to head the project. Plan to work via e-mail and possibly conference call(s) with goal of finalizing the manuscript by the cervical SOTS meeting in 2009.