Endometrial Cancer Commitee Agenda London November 17, Ketta Lorusso, Stefano Greggi

Transcription

1 Endometrial Cancer Commitee Agenda London November 17, 2013 Ketta Lorusso, Stefano Greggi

2 CONFLICTS OF INTEREST DISCLOSURE

3 Endometrial Cancer Commitee Agenda London November 17, 2013 GCIG STUDIES FOR BRIEF UPDATE AND FU 1. Endometrial cancer Conservative Treatment a) Conservative treatment of endometrial cancer: a multicentre registry study (ECCO trial) Dr Greggi b) femme Trial: Mirena and Metformin in Endometrial cancer Dr Quinn

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5 ENDOMETRIAL CANCER IN YOUNG WOMEN Two main questions Is it possible to preserve fertility in young EC pts? In whom? Is it possible to achieve pregnancy in pts conservatively treated for EC?

6 Age-specific Incidence of Endometrial Cancer about 25% premenopausal women almost 5% <40 years FIGO Annual Report, 2006

7 Endometrial Cancer Disease profile in young women endometrioid histotype well differentiated tumor minimal / absent myometrial invasion ER+ / PR+ Type 1 Endometrial Cancer Favorable prognosis

8 Survey papers (354 pts; <45) Study Setting Histo Grade HSC Res Hormone Therapy Retrosp 17 Prosp 11 Case rep 7 Endo 354 (100%) G1 344 (97%) G (3%) 20 (6%) MA / MPA (56%) LNG-IUD (14%) TAM (+) (9%) Greggi, et al. 2012

9 Conservative Treatment of Endometrial Ca. Limited amount of data Retrospective studies in most cases Often short follow-up Insufficient information on reprod. outcome Lack of pretreatment fertility counseling

10 Conservative Treatment of Endometrial Ca. Prospective, multicentre registry study to systematically collect data (oncological and obstet. outcomes) on consecutive pts treated according to institutionally defined protocols

11 Protocol Outline ELIGIBILITY Inclusion Criteria - age up to 45 years - histologically proven EC - strong desire to preserve fertility and complete the follow-up program - oncology and fertility counseling and informed consent Exclusion Criteria - history of previous/concomitant cancer (except for adequately treated skin basal cell or in situ cervical cancer) - patient belonging to a family with HNPCC (Lynch II syndrome) - synchronous ovarian cancer at MRI or laparoscopy - contraindications for progestin treatment or LNG-IUS insertion TREATMENT - Not one defined protocol (registry study) but treatment, however, administered according to IRB approved protocols - Pretreatment counseling and patient informed consent mandatory - Definitive surgery planned and pathological data available

12 Protocol Outline - 1 PURPOSE To learn more about the safety of conservatively treating EC and about subsequent fertility outcome STUDY TYPE Observational (Patient Registry) STUDY DESIGN Observational Model: Cohort TIME PERSPECTIVE Prospective ENDPOINT CLASSIFICATION Treatment and outcome registry study INTERVENTIONS Data collected in the registry includes patient characteristics/demographics, disease characteristics, treatment details (hormonal therapy ± surgery), disease and survival outcomes, post-intervention reproductive and obstetric outcomes

13 Protocol Outline - 2 OUTCOME MEASURES Primary Outcome Measures - Causes of patient exclusion - Proportion of complete regression - Duration of response - Frequency and pattern of relapse - Frequency of metachronous ovarian cancer - Tumor-related deaths Secondary Outcome Measures - Treatment related morbidity - Frequency of spontaneous pregnancies - Frequency of pregnancies after ART - Pattern of residual disease on definitive surgical specimens

14 Data to be collected - 1 Patients excluded Causes of exclusion (pt refusal / Stage >IA M0 / non endometrioid histotype / G>1 / PR- / P53+ / previous-concomitant ca / Lynch II syndrome / contraindications for progestins or LNG-IUS insertion / other) Patients enrolled Patient ID code Centre Date of birth Age at enrolment Weight (Kg) Height (cm) Body Mass Index (Kg/m2) Comorbidity (no / diabetes / hypertension / PCO syndrome / other) Age at menarche (yrs) Estroprogestin use (N/Y) Wish to conceive (N/Y) Gravidity (n) Spontaneous abortion (n) Voluntary abortion (n) Stillbirth (n) Sterility (N/Y) ART (N/Y)

15 Data to be collected - 2 Diagnosis Histologic diagnosis procedure (hysteroscopy / D&C / D&C + hysteroscopy) Histotype (endometrioid / serous-papillary / clear cell / other) Grade (1 / 2 / 3) FIGO stage (IA M0 / IA M<50% / > IA) PR (not available / %) ER (not available / %) P53 (not available / %) Staging transvaginal ultrasonography (not performed / performed) Staging MRI (not performed / performed) Staging laparoscopy (N/Y-negative / Y-ovary positive) Tumor pattern (not available / unifocal / multifocal) Tumor site (not available / corpus / isthmus) Tumor diameter (not available / cm) Pretreatment fertility counseling (N/Y) Pretreatment psychological counseling (N/Y)

16 Data to be collected - 3 Primary treatment Hysteroscopic resection (no / endometrium only / endometrium + myometrium) Oral progestin therapy (no / MPA / MA / others) Oral progestin dosage per day (mg) Intrauterine progestin therapy - LNG-IUS (N/Y) Planned duration (6 mos / 12 mos / > 12 mos) Real duration (mos) Cause of interruption Treatment related adverse events (no / surgical / medical / surgical + medical) Description of adverse event(s) Response Hysteroscopic controls during treatment (N/Y) Complete regression (N/Y) Time to CR (mos) Evaluation of CR (TV-USG / hysteroscopy without biopsy / hysteroscopy with biopsy)

17 Follow-up Last follow-up date Last follow-up status (NED / AWD / DOD / death of other cause / not available) Relapse (N/Y, first/second/.) Date Histology (complex hyperplasia without atypia / hyperplasia with atypia / EC G1 / EC G2 / EC G3) Pattern (not applicable / uterine / abdomen / distant / combined) Treatment (not applicable / conservative / definitive surgery) Fertility outcome Attempts to conceive (N/Y) ART (N/Y, date) Pregnancies (n, date) Spontaneous abortion (n, date) Voluntary abortion (n, date) Normal full term delivery (n, date) Stillbirth (n, date) Data to be collected - 4 Definitive surgery Definitive surgery (not yet planned / planned / performed) Date Pathology (not applicable / negative / complex hyperplasia without atypia / hyperplasia with atypia / endometrioid EC / non endometrioid EC) Grade (not applicable / G1 / G2 / G3) FIGO stage (not applicable / IA M0 / IA M<50% / IB / > IB)

18 Groups - Participation YES ANZGOG AGO AGO-AUSTRIA COGI GEICO GIINECO MITO NOGGO NO GICOM

19 Milestones CRF ready. January 1st, 2014 Definitive Study Protocol ready.. January 10, 2014 CRF available online... January 15th, 2014 Study Data Center Clinical Trials Unit Istituto Nazionale per lo Studio e la Cura dei Tumori di Napoli National Cancer Institute of Naples Naples, Italy

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21 Endometrial Cancer Commitee Agenda London November 17, 2013 GCIG STUDIES FOR BRIEF UPDATE AND FU 1. Endometrial cancer Conservative Treatment a) Conservative treatment of endometrial cancer: a multicentre registry study (ECCO trial) Dr Greggi b) femme Trial: Mirena and Metformin in Endometrial cancer Dr Quinn

22 femme GCIG October 2013 We research & develop the best standard of care for women experiencing gynaecological cancer

23 Insert femme Title A Phase II Randomised Clinical Trial of Mirena ± Metformin ± Weight Loss Intervention in Patients with Early Stage Cancer of the Endometrium (ANZGOG 1301) Study Chair: Andreas Obermair Lifestyle intervention: Monika Janda Biomarker: Donal Brennan Statistics: Val Gebski Central pathology review: Jane Armes Trial manager (central): Fiona Menzies ANZGOG: Julie Martyn

24 Objectives Insert and Title Endpoints Objectives Primary: To determine the efficacy of Mirena IUD ± Metformin ± Weight Loss Intervention to achieve a pathological complete response (pcr) in endometrial cancer at 6 calendar months from study treatment start. Secondary: Endometrial cancer biomarkers will be assessed at different timepoints to enhance our understanding of the molecular processes and to predict a treatment response. Endpoints Primary: Pathological Complete Response Secondary: To predict the response to treatment through blood and tissue molecular biomarkers and to increase our molecular understanding of the biological pathogenesis of early EAC.

25 Site Update Insert 04 Title Oct 2013 State Hospital HREC Site Specific Approval Pharmacy Lab Randomisation Royal Brisbane and Women's Hospital Approved Approved Yes Yes Yes Mater Public Hospital Approved Approved Yes Yes Yes Mater Private Hospital Approved Approved Yes Yes Yes Gold Coast Hospital Approved Yes QLD Brisbane Private Hospital Approved Approved Yes Yes Yes Townsville Hospital Approved Yes Lake Kawana Private Hospital Yes John Flynn Hospital Yes Pindarra Hospital Yes Greenslopes Private Hospital Approved Approved Yes Yes Yes The Wesley Hospital Approved Approved Yes Yes Yes NSW VIC SA Royal Prince Alfred Hospital John Hunter Hospital Newcastle Private Hospital Westmead Hospital Royal Hospital For Women Royal Women's Hospital Mercy Hospital for Women Box Hill Hospital Monash Medical Centre Royal Adelaide Hospital Calvary Health Care North Adelaide Queen Elizabeth Hospital Approved Approved Approved Approved TAS Royal Hobart Hospital WA St John of God Hospital King Edward Memorial Hospital Pending Pending Hollywood Private Hospital

26 Consort Statement Insert Title 04 Oct 2013 Assessed for Eligibility n = 47 Pending Randomisation n = 0 Excluded n = 41 Not meeting eligibility criteria: n = 40 Declined to participate: n = 1 Other: n = 0 Randomised n = 6 Allocated to Mirena n = 2 Allocated to Mirena+Metformin n = 2 Allocated to Mirena+Weightloss n = 2

27 Endometrial Cancer Commitee Agenda London November 17, 2013 GCIG STUDIES FOR BRIEF UPDATE AND FU 2. Endometrial staging a) KGOG 2015: Multicenter prospective observational study for the validation of preoperative low-risk criteria for lymph node metastasis in endometrial cancer. 348/514 Dr Kang

28 KGOG 2015 Prospective Validation of Preoperative Low-risk Criteria for Lymph Node Metastasis in Endometrial Cancer Korean Gynecologic Oncology Group Study PI: Dr. Sokbom Kang (National Cancer Center, Korea)

29 Background View from the NCCN 2013 guideline A subset of patients may not benefit from lymphadenectomy However, it is difficult to pre-operatively identify these patients Preoperative assessment tool KGOG-2014 (Kang et al., JCO, 2012) Preoperative risk assessment tool using MRI+CA125 4 predictors: myometrial invasion / extrauterine metastasis / lymph node enlargement / CA125 > 35U/ml False negative predictive value (NPV) :1.4% in model set / 1.7% in training set Validation Hokkaido cohort (Kang et al. Gynecol Oncol, 2013) False NPV: 1.0% in Hokkaido cancer center, 3.5% in Hokkaido university

30 KGOG-2015 & its current status KGOG-2015 Study endpoint: prospective validation of KGOG-2014 criteria (false NPV < 5%) Study design: prospective observational study Status Activated: 15 December 2011 Active sites: 20 sites from 3 countries 16 sites from KGOG 2 sites from SGOG (Shanghai-GOG, China) 2 sites from Hokkaido group (Japan) Target number: 514 patients Enrollment: 348 (as of 10 Sep 2013)

31 GOG0233/ACRIN 6671: Preoperative FDG- PET/CT to Detect Lymph Node Metastasis

32 Endometrial Cancer Commitee Agenda London November 17, 2013 GCIG STUDIES FOR BRIEF UPDATE AND FU 3. Surgery - Lymphadenectomy STATEC Trial Dr Kitchener

33 Selective Targeting of Adjuvant Therapy for Endometrial Cancer- STATEC Professor Henry Kitchener The University of Manchester

34 Hypotheses Lymphadenectomy is not independently therapeutic Improvement in survival may require systemic therapy Tailoring adjuvant therapy based on node status my limit toxicity with equal survival Sentinel node biopsy may be as effective as full LND to triage patients to adjuvant therapy

35 Design All patients should be high-risk (>15-20% node positive) Adjuvant therapy should be used in node positive women and those with nodes unknown No adjuvant therapy in node negative pts Sentinel node biopsy incorporated in LND arm Primary endpoint OS; powered for non-inferiority

36 Objectives Determine OS of adjuvant therapy given to to all high-risk (unknown nodes) compared with only to node positive (staged nodes) women Secondary: compare toxicity, surgical complications, PFS, quality of life, cost effectiveness Sentinel node biopsy (with ultrastaging): evaluate accuracy compared with systematic dissection

37 STATEC Trial High-risk Endometrial Cancer Clinical stage Ib deep invasion Grade 3 endometrioid or G2 with LVSI, serous, clear cell or carcinosarcoma RANDOMISE Sentinel node sub study Lymphadenectomy (pelvic/pa) No Lymphadenectomy Lymph node negative ~ 80% Lymph node positive ~ 20% Lymph nodes unknown Vaginal Brachytherapy according to local site policy Chemotherapy and Radiation Therapy or Chemotherapy alone Follow-up, toxicity and quality of life

38 Statistics Non-inferiority trial: exclude survival difference of 5% OS for no-lnd arm 75%, non-inferiority defined as OS >70%: 2820 pts required This design would allow detection of superiority of 5% (more likely than 10%) Superiority trial with either of the arms providing 10% survival benefit: 1500 pts required (underpowered to determine noninferiority)

39 GCIG commitment Four groups committed (NCRI, GOG US; ANZGOG; DGOG), five have expressed interest (KGOG; MITO; SGOG; GICOM; ICORG; NCIC) International trial management group to be appointed (2 reps from each group)

40 Timelines Protocol outline has be submitted to CRUK August 2013 TMG to write draft protocol to follow after approval of outline (notice November/December) Full protocol submission to CRUK due March 2014 Final decision on funding April 2014 to update status re NCI

41 Endometrial Cancer Commitee Agenda London November 17, Endometrial adjuvant a) ENGOT-EN2-DGCG: A phase III trial of postoperative chemotherapy or no further treatment for patients with node negative stage I-II intermediate or high risk endometrial cancer. 31/678 Interested groups: AGO, BGOG, EORTC, MANGO Dr Mirza

42 A phase III Trial of postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer. ENGOT-EN2-DGCG / EORTC Version 2.1 Chief Investigators: Mansoor Raza Mirza (DGCG); Frederic Amant (EORTC) Supported by

43 5-year survival - FIGO Stage I G1 G2 G3 Ia Ib Ic Stage II IIa IIb mansoor@rh.regionh.dk Creasman et al., IJGO, 2007

44 ENGOT-EN2-DGCG / EORTC Endometrioid: Stage I - G3; II Non-endometrioid: Stage I-II Chemotherapy Carboplatin-Paclitaxel x 6 + Brachytherapy Observation + Brachytherapy n=678 mansoor@rh.regionh.dk Supported by

45 Stratifications 1: endometrioid versus non-endometrioid 2: stage 1a vs. 1b vs. 2 disease 3: para-aortic ( 10)and pelvic ( 20) LNE versus lesser LNE 4: Brachytherapy planned yes/no mansoor@rh.regionh.dk

46 Inclusion Criteria Patient Population FIGO 2009 Only node-negative patients are eligible Histological confirmed endometrial carcinoma with no macroscopic remaining tumour after primary surgery, with one of the following postoperative FIGO 2009 stage and grade: Stage I grade 3 endometrioid adenocarcinoma Stage II endometrioid adenocarcinoma Stage I and II type 2 histology (clear cell, serous, squamous cell carcinoma or undifferentiated carcinomas) Excluded: Carcinosarcoma, Sarcomas or small cell carcinoma with neuroendocrine differentiation mansoor@rh.regionh.dk

47 Inclusion Criteria Prior Therapy Hysterectomy (total abdominal hysterectomy, radical hysterectomy, laparoscopic or robotic hysterectomy) Bilateral salpingo-oopherectomy (BSO) pelvic lymphadenectomy (LNE): minimum 12 pelvic nodes (minimum 6 from each side) should be removed. Para-aortic LNE is optional Omentectomy recommended in clear cell, serous or undifferentiated carcinoma Surgery performed within 10 weeks of randomization. If the dates for hysterectomy and lymph node dissection are different, 10 weeks are counted from the last surgery, and in that case the gap between two surgeries should not exceed 8 weeks. mansoor@rh.regionh.dk

48 Exclusion Criteria Prohibited Treatments and/or Therapies External Beam Radiotherapy Concurrent cancer therapy Concurrent treatment with an investigational agent or participation in another clinical trial.

49 Central Pathology Review Central pathology review confirmation is not required for the patient prior to randomization. For central pathology review one H&E stained tissue slide (formalin fixedparaffin embedded, 3-4 µm) per patient are requested. Slides must be representative for the tumour diagnosed and must optimally contain at least 30% tumour. H&E slide for central pathology review must be shipped to Danish CancerBiobank. If the site participates in the Translational Research sub-study (TR substudy) H&E slide for central pathology review must be shipped to Danish CancerBiobank together with additional tissue slides for TR.

50 Treatment Schedule for chemotherapy Paclitaxel and Carboplatin (TC): Paclitaxel 175 mg/m 2 i.v. infusion over 3 hours on day one. Carboplatin AUC 5 i.v. infusion over minutes on day one. The treatment is to be repeated every three-weeks for six courses. Courses 2-6 can be delayed up to 3 days due to administrative reasons. mansoor@rh.regionh.dk

51 Treatment Vaginal Brachytherapy The investigator shall decide prior to informed consent and randomization, if VBT is planned for the patient. In chemotherapy arm, timing of VBT should not cause delay in chemotherapy delivery. Dose recommendation: A dose equal to 7Gy weekly x 3 times (total dose 21 Gy) at 5 mm (upper vagina) to 0 mm (mid vagina) from the applicator at the upper half of vagina (HDR/PDR). mansoor@rh.regionh.dk

52 Translational Research Methods for collection and analysis of tissue samples Formalin fixed paraffin embedded (FFPE) tissue blocks representing the tumour of the patient should be selected. The FFPE tissue for TR-substudy should be cut into 3-4 m sections. Optimally 20 unstained slides (minimum 10) on Super- Frost Plus glass plates should be shipped together with one slide stained with hema- toxylin and eosin (H&E) to evaluate and confirm tumour tissue in the selected tissue block. mansoor@rh.regionh.dk

53 Primary Endpoint Overall Survival Secondary Endpoints Disease Specific Survival (DSS) Progression-Free Survival (PFS) Toxicity Study End Points PRO: (QOL) EORTC QLQ-C30 and EORTC-QLQ-EN24 Rate of isolated pelvic relapse (central and/or pelvic wall) Rate of isolated distant relapse Rate of mix local and distant relapse

54 Statistical plan To detect an overall absolute difference in five-year survival of 10%, from 72% to 82%, at the 2.5% level with 80% power, 135 deaths corresponding to 644 patients are needed. In the endometrioid subgroup an absolute difference in five-year survival of 12%, from 74% to 86% is expected. Assuming this, 79 deaths corresponding to 438 patients are needed to yield 80% power at the 2.5% level. Assuming a dropout rate of 5%, 678 patients have to be accrued, leaving 644 patients for the overall analysis and 75% of these, or 483 patients, for the analysis in the endometrioid subgroup. mansoor@rh.regionh.dk

55 ENGOT-EN2-DGCG/ EORTC55102 Group Country No. of Institutions Authorized Patients randomized DGCG Denmark NSGO Sweden Finland BGOG Belgium EORTC Belgium Austria Germany Portugal Spain UK Netherlands Czech Republic MaNGO Italy TOTAL

56 ENGOT-EN2-DGCG/ EORTC55102 ENGOT-EN2-DGCG/EORTC Trial Specific Satellite Session Room 5 5pm-5.30pm mansoor@rh.regionh.dk

57 Endometrial: Stage I/II Adjuvant 3/23/2009 2/4/2013 Completed Endorsed by RTOG 562 accrued

58 b) PORTEC 3: Endometrial Cancer Commitee Agenda London November 17, Endometrial adjuvant Randomized phase III trail comparing Concurrent Chemoradiation and Adjuvant Chemotherapy with pelvic Radiation Alone in High Risk and Advanced Endometrial Carcinoma 662/680 Participating groups: NCRI, MaNGO, ANZGOG, NCIC-CTG. NSGO interestd. Dr Creutzberg

59 PORTEC-3 / EN7 R pelvic RT (48.6 Gy) pelvic RT plus 2x cisplatin -> 4x carboplatin/paclitaxel uniform schedule upfront pathology review QoL analysis PORTEC - 3

60 Eligibility Endometrial carcinoma FIGO 2009:» stage IA with invasion, grade 3, LVSI+» stage IB grade 3» stage II» stage IIIA or IIIC, IIIB parametrium» stage IA invasion, IB, II or III and serous or clear cell WHO PS 0-2 no residual macroscopic tumor after surgery Pathology review before randomisation PORTEC - 3 Khalifa et al, Gynecol Oncol 2003; Kwon et al, Obstet Gynecol 2007

61 Accrual 662 PORTEC - 3

62 Accrual 1 Oct 2013 Group Arm 1 Arm 2 Total Past year Netherlands Italy Australia/NZ Canada UK France Total PORTEC - 3

63 PORTEC-3 international collaboration PORTEC - 3 International Intergroup Trial

64 Endometrial Cancer Commitee Agenda London November 17, Endometrial adjuvant c) PORTEC 4: Randomized trial of vaginal brachytherapy vs observation for high-intermediate risk endometrial carcinoma. 30/250 Interested group: Mango, UK, NSGO Dr Creutzberg

65 Randomized trial of vaginal brachytherapy vs observation for high-intermediate risk endometrial carcinoma PORTEC-4 Groningen Waddenzee Friesland Noord Holland Ijsselmeer Drenthe Flevoland Overijssel Zuid Holland Utrecht Gelderland Noord Brabant Zeeland Limburg

66 Questions after PORTEC-2 More atrophy in patients who had vaginal brachytherapy Is 21 Gy in 3 fractions at 5 mm the optimal dose? Many other schedules with lower doses seem equally effective Should we treat all HIR patients or treat only for relapse? No survival difference!

67 Based on HIR competing risk Algorithms of alternative management options 100 observe 100 VBT 15 vaginal relapse CR EBRT + VBT 2-3 no CR or relapse 2 vaginal relapse NNT 12.5

68 Zeeland Zuid Holland Noord Holland Waddenzee Ijsselmeer Flevoland Utrecht Noord Brabant Friesland Limburg Gelderland Groningen Drenthe Overijssel Patient preferences PRETEC: patient preference side study VBT or watchful waiting Treatment trade off

69 Endometrial cancer, no RT or VBT First recurrence; Danish population registry Loco-regional: vaginal & pelvic recurrence Non loco-regional: abdominal & distant metastasis (if > 1 most severe recurrence registered) Recurrences 14 years Locoregional Non locoregional Low-risk 6.3 % 4.1 % 2.2 % Intermediate-risk 22 % 14.3 % 7.4 % High-risk 32 % 5.1 % 26.9 % G.Ortoft et al, Danish DEMCA group, ESGO 2013 presentation and Int J Gynecol Cancer, 2013 online

70 PORTEC-4 design HIR endometrial carcinoma 21 Gy in 3 fractions vs 15 Gy in 3 fractions Vaginal brachytherapy vs no further treatment 1 VBT 3 x 7 Gy at 5 mm R 2 1 VBT 3 x 5 Gy at 5 mm 1 No further treatment Close FU; EBRT/VBT for vaginal relapse 4

71 Zeeland Zuid Holland Noord Holland Waddenzee Ijsselmeer Flevoland Utrecht Noord Brabant Friesland Limburg Gelderland Groningen Drenthe Overijssel PORTEC-4 eligibility Inclusion (FIGO 2009): Stage IA, any age, grade 3 without LVSI Stage IB, age > 60 years, grade 1 or 2 Stage IB, grade 1 or 2 with LVSI Endpoints: Vaginal recurrence / 5-year vaginal control Survival and relapse Vaginal mucosal toxicity, Quality of life

72 Zeeland Zuid Holland Noord Holland Waddenzee Ijsselmeer Flevoland Utrecht Noord Brabant Friesland Limburg Gelderland Groningen Drenthe Overijssel PORTEC-4 accrual Interested groups: MaNGO (Italy) UK NSGO N=30

73 Endometrial Cancer Commitee Agenda London November 17, Endometrial adjuvant d) GOG-0258 A randomized phase III trial of Cisplatin and Tumor Directed RT followed by Carboplatin/Paclitaxel vs Carboplatin/Paclitaxel for optimally debulked advanced endometrial cancer: 676/804. Interested group: RTOG Dr Miller

74 Endometrial: Stage III/IV 6/29/2009 Endorsed by RTOG 676/804 accrued

75 Endometrial Cancer Commitee Agenda London November 17, Endometrial follow up a) APPROPRIATENESS EVALUATION OF FOLLOW UP PROCEDURES IN GYNECOLOGY ONCOLOGY TOTEM STUDY: Multicentric randomized controlled clinical trial between two follow up regimens with different tests intensity in endometrial cancer treated patients. Dr katzaros for Zola

76 TOTEM Study: Multicentric randomized controlled clinical trial between two follow up regimens with different tests intensity in endometrial cancer treated patients Dionyssios Katsaros ClinicalTrials.gov Identifier: NCT GCIG, London 15-17th November 2013

77 Schedules of FU of endometrial cancer according to guidelines Guidelines Pap test Chest x-ray US abdomenpelvi CT scan abdomenpelvi Ca 125 NCCN 2013 Controversial NCCN Category of Evidence and Consensus: 3 Every year NCCN Category of Evidence and Consensus: 2B No No Optional ACOG 2005 reaffirmed 2009 No No No No No AGO 2009 No No 3 mos till the third year CCO 2006 No No No ESMO 2011 No No No SGO 2011 No No No No No No No No No No No

78 FU in the clinical practice

79 FU in the clinical practice

80 TOTEM trial ClinicalTrials.gov Identifier: NCT Inst: italian multicentric Randomized trial Multicentric randomized controlled clinical trial between two follow up regimens with different tests intensity in endometrial cancer treated patients Stratification Randomization Ca 125

81 Inclusion criteria -patients treated surgically for endometrial cancer, in complete clinical remission confirmed by imaging stage, FIGO I-IV - not previous or concurrent neoplasia (with the exception of carcinoma in situ of the cervix and basalioma of the skin) - other contemporaneous RCT may be allowed if there is not any restriction concerning follow up - obtaining a written informed consensus before randomization - age > 18 years -not endometrial carcinoma in the context of a hereditary syndrome A) Stratification Low risk of recurrence [stage IA (G1, G2)] High risk of recurrence [stage, IA G3] B) Randomization B) Randomization MINIMALIST FU INTENSIVE FU INTENSIVE FU MINIMALIST FU

82 LOW RISK PROCEDURES: - LOW RISK - Arm Visit X X X X X X X X X X X QoL Questionnaire X X X X X X X PROCEDURES: - LOW RISK - Arm Visit X X X X X X X X X X X X X Pap Smear X X X X X CT chest, abdomen, pelvis X X QoL Questionnaire X X X X X X X

83 PROCEDURES - HIGH RISK - Arm HIGH RISK Visit X X X X X X X X X X X X X CT chest, abdomen, pelvis X X QoL Questionnaire X X X X X X X PROCEDURES - HIGH RISK - Arm Visit X X X X X X X X X X X X X X Ca125 X X X X X X X X X X X X X Abdomen & TV US Pap Smear CT chest, abdomen, pelvis QoL Questionnaire X X X X X X X X X X X X X X X X X X X X X X X X X

84 Primary Objective Compare the effect of the two follow-up regimens on 5- years overall survival. Secondary Objectives Anticipate diagnosis of relapse (intensive vs less intensive follow-up) Evaluate the difference in terms of complications, recurrences of disease, second primary tumors or other diseases Assess accuracy of the two follow-up regimens as the ability to diagnose the relapse of disease in asymptomatic patients Describe compliance to different follow-up programs Evaluate quality of life and patients satisfaction regarding the two strategies of follow-up Evaluate the cost-effectiveness and cost-utility of the two regimens Assuming a rate of drop-out about 5% it it will be necessary to enrol in the study about 2300 patients (1150 in each arm)

85 TOTEM RCT is ongoing ClinicalTrials.gov Identifier: NCT Institutions across Italy have joined the study and are enrolling patients (MANGO, MITO and others) 963 Patients enrolled on 12th Nov 2013 If you want to join the trial: Web site of the study:

86 Thank you for your attention!

87 Endometrial Cancer Commitee Agenda London November 17, Endometrial advanced/recurrent a) GOG-0238 A randomized trial of Pelvic Irradiation with or without Concurrent Weekly Cisplatin in patients with pelvic-only recurrence of carcinoma of the uterine corpus. 72/154 Paricipating Group: RTOG Dr Miller

88 Pelvic Recurrence 2/25/2008 Endorsed by RTOG 72/154 accrued

89 Endometrial Cancer Commitee Agenda London November 17, Endometrial advanced/recurrent b) MITO BEVA END TRIAL: Randomized phase II trial on Carboplatin-Paclitaxel compared to Carboplatin-Paclitaxel-Bevacizumab in patients with advanced (stage III-IV) or recurrent endometrial cancer. 61/108 Paricipating Group: MITO-MaNGO Dr Lorusso

90 Study N Treatment RR % PFS at 6 month (%) Prior RX GIP Aghajanian BV 15 mg/kg IV 3 wk until PD Up to 2 priors CHT lines Median: 0 PFS 4.2 mths OS 10.5 mths Wright BV 15 mg/kg IV 3 wk + CHTs Median N of previous CHT lines: 3 (1-12) Median: 0 PFS 5.4 mths OS 8.7 mths

91 STUDY DESIGN Carboplatin AUC 6 Paclitaxel 175 mg/mq RANDOM day 1 - every 21days x6-8 cycles Carboplatin AUC 5 Paclitaxel 175 mg/mq + Bevacizumab 15 mg/kg d1 q21 until PD day 1 - every 21days x6-8 cycles

92 Outcome Measures Primary Outcome Progression-free survival (PFS) of patients with advanced stage III-IV or recurrent endometrial cancer when treated with Carboplatin-Paclitaxel vs Carboplatin-Paclitaxel-Bevacizumab Secondary Outcomes Overall survival Response rate Safety and tolerability Quality of Life

93 Inclusion Criteria 1. Aged >18 years 2. ECOG performance status <2 3. Life expectancy of at least 12 weeks 4. Patients must have advanced stage III or IV, or recurrent histologically-confirmed endometrial cancer. 5. Endometrial cancer will include all carcinomas, including endometrioid carcinoma, papillary serous carcinoma, clear cell carcinoma, carcinosarcoma not included 6. One previous chemotherapy line with carboplatin is permitted if PFI >6 months 7. Measurable disease and evaluable disease 8. Adequate bone marrow, renal and hepatic function 9. Controlled hypertension, non clinically significant cardiac disease

94 Primary Endpoint & Justification of Sample Size This trial is a randomized, open-label Phase 2 multicenter study designed 108 patients will be randomized to study treatment in a 1:1 ratio. 89 events (recurrence, progression or death) will need to be observed in order to provide approximately 80% power to detect a 30% improvement based on a 0.70 hazard ratio. The hypothesis is to extend the median PFS from 12 months to 17 months. The power projection is based on a one-sided log-rank test at an alpha = 0.20 significance level.

95 c) NSGO: EN 1 A Randomized phase II trial of first line combination chemotherapy with BIBF1120/placebo in patients with advanced or recurrent endometrial cancer Endometrial Cancer Commitee Agenda London November 17, Endometrial advanced/recurrent Interested Group: MaNGO Dr Mirza

96 A randomized phase II trial of first line combination chemotherapy with BIBF 1120/placebo for patients with advanced or recurrent endometrial cancer. ENGOT EN1 Study Sponsor: NSGO PI: Mansoor Raza Mirza Supported by grant from Boehringer-Ingelheim

97 Key inclusion criteria Study population a. Primary stage 3 or 4 a. For stage 3 disease patients without evaluable disease are accepted, provided these patients have high-grade disease or carcinosarcoma b. Relapse after primary adjuvant treatment for early stage disease. a. Patients may have received adjuvant chemotherapy for stage 1 or 2. In this case the treatment-free interval shall exceed 12 months. Only post-operative adjuvant chemotherapy is allowed. A patient is ineligible if she has earlier received chemotherapy for metastatic or relapsed disease. mansoor@rh.regionh.dk

98 Key inclusion criteria Prior therapy a. Patients may have undergone primary surgery. b. Patients may have received adjuvant chemotherapy for stage 1 or 2. c. Patients may have received external beam radiotherapy and or vaginal brachytherapy d. Patients may have received hormonal treatment mansoor@rh.regionh.dk

99 Key inclusion criteria Disease status a. Patients must have evaluable (measurable or nonmeasurable) disease on Ultrasound/CT/MR scan outside irradiated field. b. For stage 3 disease patients without evaluable disease are accepted, provided these patients have high-grade disease or carcinosarcoma mansoor@rh.regionh.dk

100 Key exclusion criteria Prohibited Treatments and/or Therapies a. Concurrent cancer therapy b. Concurrent treatment with an investigational agent or participation in another clinical trial.

101 Other key exclusion criteria Relapse within six months after adjuvant chemotherapy. Previous or concurrent malignant disease except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin or other cancer for which the patient has been diseasefree for at least five years Active infection or other serious underlying medical condition Whatever reasons which interferes with an adequate follow-up No prior treatment with a VEGF targeted therapy Adequate hepatic, bone marrow and renal function No uncontrolled CNS metastasis or leptomeningeal carcinomatosis. Known uncontrolled hypersensitivity to the investigational drugs. History of myocardial infarction, cardiac angioplasty/stenting, unstable angina within the past six months. Known contraindications to VEGF directed therapy Concurrent cancer therapy mansoor@rh.regionh.dk

102 Design: 2:1 randomization Stratifications stage of disease Prior adjuvant chemotherapy Disease status (stage 3 vs. stage 4 vs. recurrent disease) (yes/no) (non-evaluable vs. evaluable) N 129 (86:43) Stage 3-4 Relapse Arm 1 Carbopltain AUC5, iv, 3wkly, 6-8courses Paclitaxel 175mg/m2, iv, 3wkly, 6-8 courses BIBF 1120, 200mg BID, po, until progression Arm 2 Carbopltain AUC5, 3wkly, 6-8courses Paclitaxel 175mg/m2, 3wkly, 6-8 courses Placebo BID, po, until progression mansoor@rh.regionh.dk

103 Primary Endpoint: Statistical Design End-points Physician Determined Progression-Free Survival (clinical or radiological) Secondary Endpoints: Overall survival Quality of life Safety Tolerability

104 Statistical Design Sample Size a. In the targeted patient population the expected median PFS on standard treatment is 10 months, b. the smallest clinically meaningful improvement should be more than 25%. c. Therefore this trial is designed to detect an improvement in physician determined PFS (PD-PFS) with a hazard ratio of This will correspond to 4 months increase in median PD-PFS provided the PD-PFS on standard arm is 10 months. d. The randomization will be 2:1 in favor of the experimental arm, which will allow us to look at exploratory endpoints in translation research. mansoor@rh.regionh.dk

105 Statistical Design Sample Size a. With a one-sided alpha set at 20% and a power of 80% a total of 100 events are needed. b. If we assume an accrual period of 18 months and a follow-up period of 30 months, 114 patients need to complete the protocol. If a drop-out rate of 10% is assumed, then the total accrual is 127 patients. c. To fit the randomization ratio the target number will be 129 (86:43) patients, corresponding to 7.17 patients per month. mansoor@rh.regionh.dk

106 Translational Research Sub-Study Methods for collection and analysis of tissue samples a. Tissue samples for TR-substudy should be sent from sites once per year to NSGO. b. Formalin fixed paraffin embedded (FFPE) tissue blocks representing the tumor of the patient should be selected. a. The FFPE tissue for TR-substudy should be cut into 3-4 m sections. b. Optimally 20 unstained slides (minimum 10) on Super- Frost Plus glass plates should be shipped together with one slide stained with hematoxylin and eosin (H&E) to evaluate and confirm tumor tissue in the selected tissue block. mansoor@rh.regionh.dk

107 Trial Status Boehringer Ingelheim has accepted this trial as investigator-initiated study with complete financial support Planned first-patient-in: Q3, 2014

108 Endometrial Cancer Commitee Agenda London November 17, Endometrial cancer/rare tumors a) Endometrial Clear Cell: Randomized phase II study on BIBF 1120 compared to chemotherapy in patients with recurrent clear cell carcinoma of the ovary or endometrium Paricipating Group: SGCTG, NSGO, EORTC, GINECO Dr Glasspool

109 NiCCC Nintedanib in Clear Cell Carcinoma A Randomised Phase II Study of BIBF 1120 versus Chemotherapy in Recurrent Clear Cell Carcinoma of the Ovary or Endometrium SGCTG/NCRI/NSGO

110 NiCCC Trial Design 90 pts with progressive or relapsed CCC of ovary within 6 months of previous platinum. Plus up to 30 women with endometrial CCC R A N D O M I S E Chemotherapy Ovary: PLDH (40mg/m 2 day 1q28) Weekly Paclitaxel (80mg/m 2 day 1, 8, 15 q28) Weekly Topotecan iv (4mg/m 2 day 1, 8, 15 q28) Endometrium: Carboplatin (AUC 5) /Paclitaxel 175 mg/m 2 q21 Doxorubicin 60mg/m 2 q21 Nintedanib 200mg bd until progression Primary Endpoint: PFS Secondary Endpoints: OS, Toxicity, RR, QoL, Q-Twist

111 Trial Status Trial supported by Boehringer Ingelheim and by Cancer Research UK Sample collection grant from CTAAC Regulatory submissions made in UK

112 Endometrial Cancer Commitee Agenda London November 17, Endometrial cancer/rare tumors: uterine sarcomas b) GOG 0277 (UC1009) A Randomized Phase III trial of Gemcitabine plus Docetaxel followed by Doxorubicin vs Observation for Uterus-Limited, High Grade Uterine Leiomyosarcoma. 4/216 Interested group: EORTC Dr Miller for Dr Hensley

113 Leiomyosarcoma: Stage I 6/4/2012 4/216 accrued International Rare Cancers Initiative - Gynaecological sarcoma: EORTC

114 c) GOG 0250 A Randomized Phase III trial of Gemcitabine plus Docetaxel with or without Bevacizumab in advanced, High Grade Uterine Leiomyosarcoma. 107/130 Endometrial Cancer Commitee Agenda London November 17, Endometrial cancer/rare tumors: uterine sarcomas Dr Miller

115 Leiomyosarcoma: Measurable 11/9/2009 4/29/ /130 accrued Closed

116 Endometrial Cancer Commitee Agenda London November 17, Endometrial cancer/rare tumors: uterine sarcomas d) EORTC / GOG UC 1306 Cabozantinib maintenance in high grade, undifferentiated uterine sarcoma. 0/78 Dr Miller

117 EORTC / GOG UC1306 High Grade Undifferentiated Uterine Sarcoma International Rare Cancers Initiative

118 e) GOG 261 Endometrial Cancer Commitee Agenda London November 17, Endometrial cancer/rare tumors: UTERINE CARCINOSARCOMA Randomized phase III trial on Carboplatin-Paclitaxel vs Paclitaxel- Ifosfamide in the treatment of stage I- IV chemonaive uterine carcinosarcoma. 581/603 Dr Miller

119 Carcinosarcoma 8/17/ /603 accrued

120 f) Carcinosarcoma: new concept trial design Endometrial Cancer Commitee Agenda London November 17, Endometrial cancer/rare tumors: UTERINE CARCINOSARCOMA Dr Oza

121 Endometrial Cancer Commitee Agenda London November 17, Endometrial cancer/ Trophoblastic Neoplasia a) GOG 0275 (UC 1005): A phase III randomized trial of Pulse Actinomycin-D vs Multi-Day Methotrexate for the treatment of low risk Gestational Trophoblastic Neoplasia. 9/381 Dr Schink

122 Barriers to Activating International Phase III Randomized Trial of Low-Risk Gestational Trophoblastic Neoplasia (GTN) Julian C. Schink, MD, John Tidy, MD, MBBS, BSc, Michael Seckl, MBBS, BSc, PhD, FRCP, Ray Osborne, MD, Jeanne Carter, PhD, Virginia Filiaci, PhD, Helen Huang, MS, David S. Miller, MD, for the Gynecologic Oncology Group

123 Scoring to determine therapy FIGO 2000 Kohorn et al Int J Gynecol Cancer 2000 Low Risk (LR) 0-6, High Risk (HR) >6

124 GOG0275: A Phase III Randomized Trial of Pulse Actinomycin-D Versus Multi-Day Methotrexate for the Treatment of Low-Risk Gestational Trophoblastic Neoplasia Eligible patients: Low-risk persistent GTN FIGO Stage I, II, III FIGO Score 0-6 R A N D O M I Z E Arm Regimen 1: Patients will receive IV pulse actinomycin- D (1.25mg/m 2 ) every 14 days. (2mg max dose) Arm Regimen 2: Patients will receive their institutional preference of either: IV methotrexate (0.4 mg/kg) daily for 5 days every 14 days. (25mg max daily dose) OR IM methotrexate (50mg) on Days 1, 3, 5, 7 (4 doses per cycle) with Leucovorin (15mg) on Days 2, 4, 6, 8. Repeat every 14 days. Target Accrual: 384

125 GOG0275: A Phase III Randomized Trial of Pulse Actinomycin-D Versus Multi-Day Methotrexate for the Treatment of Low-Risk Gestational Trophoblastic Neoplasia Primary Objective To test whether multi-day methotrexate is inferior to treatment with pulse actinomycin-d in patients with low-risk GTD with respect to CR Secondary Objectives Describe frequency of post protocol surgical treatment for each arm. Describe frequency of post protocol multi-agent chemotherapy for each arm. Compare toxicity of multi-day methotrexate to actinomycin-d Investigate impact of treatment on overall QOL, body image, sexual functioning, patient reported side effects and disruption Exploratory Evaluate the predictive value of ultrasound measured pulsatility index for drug resistance

126 GOG0275 Activation Timeline July 2013 July 2012 January US institutions open 1 Canadian institution opens 4 Japanese institutions open Korea, Australia, UK in process GOG Activates Study

127 Advantages to International Cancer Clinical Trial Collaboration Diverse Patient Populations Diverse Population Faster Accrual of Patients with Rare Tumors Faster Accrual of Patients with Rare Cancers Faster Result s Shorter Trial Period

128 Barriers to International Clinical Trial Collaboration Regulatory Differences Institutional Review Board/Ethics Committee review processes: time and cost Sponsor approval (NCI-CTEP) Conflict of interest, disclosure policies Legal Framework Differences Contractual issues Diverse laws & regulations governing human subjects research Liability or risk coverage Regulations for shipping specimens Language Differences Translating protocol, consent & other study documents: time and cost Standardized Terminology & Clinical Care Adverse event reporting Data reporting Drug administration and nursing implications Adequate Funding Staffing/training Translations Shipping costs

129 Considerations in Developing International Clinical Trials Translate Materials Upfront Diverse National Laws & Regulations Standardize Clinical Care Protocol Expect Extended Activation Period

130 oncept for TE/TP vs EP/EMA trial in TN failing non-platinum/taxane ulti-agent chemo (EMA/CO) Michael J Seckl on behalf of ISSTD collaborative group Director of the Charing Cross GTD Centre, London, UK GCIG London meeting 17 th November 2013

131 Scoring to determine therapy FIGO 2000 Kohorn et al Int J Gynecol Cancer 2000 Low Risk (LR) 0-6, High Risk (HR) >6

132 Overall survival: EMA/CO Log-rank p< Median follow-up 4.2 years FIGO <7 (n=250) FIGO 7 (n=140) ngtt (n=6) 20% fail EMA/CO and require salvage Alifrangis et al J Clin Oncol 2013

133 EMA/CO salvage regimens? EP/EMA TE/TP CR: 75% Toxic CR: 75% Much less Toxic Newlands et al J Clin Oncol 2000 and Wang et al Annals Oncol 2008 and unpublished data

134 Endometrial Cancer Commitee Agenda London November 17, Endometrial cancer/ Trophoblastic Neoplasia b) High RisK GTD: A randomized phase II trial comparing the toxicity of Paclitaxel-Etoposide (TE) alternating two weekly with Paclitaxel-Cisplatin (TP) with Etoposide and Cisplatin (EP) alternating weekly with Etoposide, Metotrexate and Dactynomicin (EMA) in GTN patients failing non platinum-based combination agent therapies. Dr Seckl

135 TP/TE vs EP/EMA Trial Design Eligible GTN Patients Progressed or relapsed following non-platinum/taxane based multi-agent chemo such as EMA/CO Randomise 1:1 Stratified LR vs HR TE/TP EP/EMA

136 Trial Inclusion Criteria LR or HR GTN relapsed or refractory to EMA/CO, MEA or other non-platinum/taxane based multiagent chemo Up to 3 previous lines of chemo e.g. MTX, ActD, EMA/CO Histological or clinical diagnosis of GTN (excluding PSTT/ETT) PS 2 Age > 18 yrs Expected survival > 12 weeks Assessable disease (hcg) Haematological parameters at study entry: - Blood cell counts: Absolute neutrophils 1 x 10 9 /L Platelets 100 x 10 9 /L Haemoglobin 9 g/dl - Renal function: Glomerular filtration rate of >60 ml/min - Hepatic functions: Serum bilirubin within normal limits

137 Trial Endpoints Primary OS and PFS Response rates Tox and Compliance Secondary/exploratory Identification of clinical parameters ± biomarkers predictive of RR and OS (tissue/biofluid collections) Investigate the effect of compliance/tox on outcome

138 Statistical Issues Primary endpoint is traditionally either OS or RR Small numbers so standard statistical approach not possible Insufficient power to rule out clinically important difference in OS/RR Thus either: a) Accept lesser strength of evidence when making treatment decisions b) Do no research in this subgroup We choose option a)

139 Recruitment and Statistical Analysis 80 pts: 40 pts / arm over 3 years Crossover allowed for failure or toxicity Anticipate: - ~ 50% on EP/EMA will switch to TE/TP - ~ 20% on TE\TP will switch to EP\EMA Focus on estimation rather than hypothesis testing - Descriptive analysis of all endpoints - Point intervals and associated confidence intervals - Recommendations on totality of data - Only toxicity data will be definitive Kianifard F, Islam MZ. A guide to the design and analysis of small clinical studies. Pharm Stat (2011); 10(4):363-8.

140 Justification Advice on study design + analysis plan from: Design and Analysis of Trials in Rare Cancers meeting 2012 Joint with Royal Statistical Society Medical Section MRC Hubs for Trials Methodology Research European Network for Cancer Research in Children Adolescents and the International Rare Cancers Initiative Funding achieved for NCRI Children s Cancer and Leukaemia Clinical Studies Group ISSTD and GOG keen to support Application pending with CRUK/CTAAC

141 Thank you!!! See you in Chicago (June 2014)

142 GTN: Second Curettage 10/9/2007 2/25/ /66 accrued Completed